Search Results (144)

Corneal fibrosis, a significant source of visual impairment, can result from keratocyte-to-myofibroblast transdifferentiation during wound healing. This study investigated the antifibrotic role of 1,25-dihydroxyvitamin D₃ (1,25 Vit D) and the lesser-known vitamin D, 24,25-dihydroxyvitamin D₃ (24,25 Vit D), in human and mouse corneal stromal cells (HSCs and MSCs) and in a Vit D receptor knockout (VDR KO) mouse model. Cells were treated with TGF-β1 ± Vit D metabolites and the expression of fibrotic and antifibrotic genes and proteins was evaluated. Both metabolites significantly reduced α-smooth muscle actin levels in HSCs, MSCs and organ-cultured mouse corneas (p < 0.05). They also upregulated the mRNA expression of BMP2, BMP6, BMPR2, and TGF-β3, as well as the protein expression of BMP6 and TGF-β3. VDR KO corneas subjected to alkali injury exhibited increased fibrotic responses and reduced CD45+ immune cell infiltration compared to wild-type controls. Notably, 24,25 Vit D exerted antifibrotic effects even in VDR KO cells, and the alternative 24,25 Vit D receptor FAM57B was expressed in all corneal cell layers. These results reveal consistent antifibrotic effects of both 1,25 and 24,25 Vit D across species, support the existence of VDR-independent mechanisms in the cornea, and offer new insights into potential therapeutic strategies for preventing corneal fibrosis. Full article

Inherited retinal dystrophies (IRDs) are a diverse group of monogenic disorders associated with dysfunction of the retina. High myopia, commonly defined as a spherical equivalent ≤ −6.00 D or axial length ≥ 26.5 mm, is a recurring clinical feature across several IRDs, and could serve as an early diagnostic clue. This review provides a summary of IRDs associated with high myopia to guide the clinician in establishing a molecular diagnosis for patients. We performed a comprehensive literature review of articles in PubMed, ScienceDirect, and JAMA Network to identify associations between monogenic IRDs and high myopia. Genes associated with IRDs and high myopia clustered into functional categories that included collagen/structural integrity (COL2A1, COL9A1, COL11A1, COL18A1, P3H2), phototransduction and visual cycle (PDE6C, PDE6H, GUCY2D, ARR3, RBP3), ciliary trafficking and microtubule-associated genes (RPGR, RP2, IFT140, CFAP418, FAM161A), synaptic ribbon and bipolar cell signaling (NYX, CACNA1F, TRPM1, GRM6, LRIT3, GPR179), opsin-related genes (OPN1LW, OPN1MW), and miscellaneous categories (VPS13B, ADAMTS18, LAMA1). Associations between IRDs and high myopia spanned stationary and progressive retinal disorders and included both cone-dominant and rod-dominant diseases. High myopia accompanied by other visual symptoms and signs such as nyctalopia, photophobia, or reduced best-corrected visual acuity should heighten suspicion for an underlying IRD. Earlier diagnosis of IRDs for patients could facilitate timely genetic counseling, participation in clinical trials, and interventions for patients to preserve vision.: Full article

Background: Oncogenic fusions of MAML2 with CRTC1, CRTC3, YAP1, and NR1D1 retain the MAML2 transactivating domain (TAD) and are believed to drive aberrant gene transcription. While the oncogenic roles of these known fusions have been established, we aimed to identify novel MAML2 fusions across a range of human malignancies. Methods: DNA and RNA sequencing were performed on tumor samples submitted to Caris Life Sciences. MAML2 fusions were identified from RNA transcripts and filtered to include only known pathogenic fusions or recurrent, in-frame fusions containing a C-terminal MAML2 TAD. Fusion burden was defined as the number of unique fusion isoforms per sample. Results: Among 180,124 tumor samples, 143 specimens harbored MAML2 fusions with a MAML2 TAD: >50% of specimens harbored known fusions, but novel fusions with MTMR2 (31/143), SESN3 (11/143), CCDC82 (6/143), FAM76B (4/143), and ATXN3 (3/143) were also identified. Compared to the known fusions, the novel fusions generally had lower expressions (median: 8 vs. 13 junction reads/sample, p = 0.0064), higher fusion burdens (median: 6 vs. 2 unique fusion isoforms/sample, p < 0.0001), more frequent TP53 co-mutations (80% vs. 11.5%, p < 0.0001), and no clear association with the tissue of origin. Excluding ATXN3::MAML2, the novel fusion partners were located near MAML2 in the genome, likely arose from duplications or deletions, and occurred in samples harboring concurrent mutations. In contrast, ATXN3::MAML2 arose via interchromosomal translocation, occurred in samples with a low fusion burden, and was not associated with TP53 mutations. Conclusions: We identified novel MAML2 fusion partners, most of which likely represent passenger alterations, possibly arising from genomic instability or impaired p53 function. However, ATXN3::MAML2 fusions, previously reported in a pre-cancerous pancreatic disease case, may represent a pathogenic alteration warranting further investigation. Full article

Background/Objectives: FAM72B (Family with sequence similarity 72 member B) is a gene whose function is not yet fully elucidated and which belongs to the FAM72 gene family. Recent studies have indicated that it is involved in the regulation of stem cell proliferation and DNA repair and serves as a valuable prognostic biomarker for a few types of cancer. This study aimed to systematically investigate the expression profile of FAM72B in pan-cancer, its role in the tumor immune microenvironment, and its potential as a prognostic and immunotherapeutic biomarker. Methods: Using bioinformatics tools such as SangerBox3.0, GEPIA2.0, Kaplan–Meier Plotter, and cBioPortal, we systematically analyzed the correlation of FAM72B expression levels with various cancer types, clinical pathological parameters, prognostic value, genetic mutations, genomic heterogeneity, immune checkpoint genes, immune cell infiltration levels, and single-cell-level characteristics. Results:FAM72B was found to be overexpressed in most cancers and significantly associated with poor prognosis, although it may exert a protective effect in some cancers like thymoma (THYM). Its expression level was positively correlated with tumor mutation burden (TMB), microsatellite instability (MSI), neoantigen (NEO) levels, and expression of immune checkpoint genes in most cancers, suggesting that patients with high FAM72B expression may respond better to immune checkpoint inhibitors. Moreover, FAM72B expression was significantly correlated with the infiltration levels of various immune cells in the tumor immune microenvironment across pan-cancer. Single-cell sequencing results also demonstrated a significant correlation between FAM72B and the biological functional states of multiple cancers. Conclusions:FAM72B holds promise as a potential pan-cancer prognostic biomarker and therapeutic target, providing a novel basis for the development of personalized treatment strategies. Full article

Recent multiomics advancements have improved our understanding of immune dysregulation in dilated cardiomyopathy (DCM). However, specific immune cell subsets and their regulatory genes are still ambiguous. This study aimed to explore immune cell imbalances and regulatory genes in DCM, discover diagnostic biomarkers, and identify potential therapeutic targets. Immune cell infiltration in DCM patients was quantified via deconvolution algorithms and single-cell RNA sequencing. Flow cytometry validation in 40 DCM patients and 40 healthy controls confirmed a notable increase in CD4⁺ effector memory T cells (CD4⁺ TEM cells) in DCM patients. Differential expression analysis of the GSE101585 dataset revealed 1783 genes. Weighted gene coexpression network analysis (WGCNA) identified a core immune-regulatory gene set, and protein–protein interaction (PPI) analysis highlighted 36 hub genes. Machine learning cross-validation identified four diagnostic biomarkers (LRRTM4, PTPN22, FAM175B, and PROM2) whose transcriptional changes had been validated by qPCR. Among these genes, PTPN22 was strongly correlated with CD4⁺ TEM cell abundance. Additionally, DSigDB analysis predicted 87 potential therapeutic drugs, with PTPN22 being the target of the most drugs. This study reveals a CD4⁺ T cell subset-centered immunoregulatory network in DCM, identifying novel diagnostic biomarkers and druggable targets to guide precision immunomodulatory strategies for DCM management. Full article

For maritime cognitive radio networks (MCRN), spectrum sensing (SS) is challenging due to the movement of the sea, channel interference, and unstable link quality. Besides the basic sensing capabilities that are required, SS in MCRN also requires the ability to adapt to complex and dynamic environments. By transforming spectrum sensing into a classification problem and leveraging cyclostationary features and Convolutional Neural Networks (CNN), This paper proposes a classification-guided TC2NND (Transfer Cyclostationary- feature and Convolutional Neural Networks Detection) spectrum sensing algorithm, which regards the maritime spectrum sensing as a classification problem. The TC2NND algorithm first classifies the received signal features by extracting cycle power spectrum (CPS) features using the FFT (Fast Fourier Transform) Accumulation Method (FAM), and then makes a judgment using a variety of C2NND decision models. The experimental results demonstrate that the proposed TC2NND algorithm could achieve a detection probability of 91.5% with a false-alarm probability of 5% at SNR = −10 dB, which significantly outperforms the conventional methods. Full article

Background: Personalized anti-tumor therapy that activates the immune response has demonstrated clinical benefits in various cancers. However, its efficacy against testicular cancer (TC) remains uncertain. This study aims to identify suitable patients for anti-tumor immunotherapy and to uncover potential therapeutic targets in TC for the development of tailored anti-tumor immunotherapy. Methods: Consensus clustering analysis was conducted to delineate immune subtypes, while weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) regression, and support vector machine (SVM) algorithms were employed to evaluate the potential efficacy of anti-tumor immunotherapy. Candidate immunotherapy targets were systematically identified through multi-gene panel analyses and subsequently validated using molecular biology assays. A prioritized target emerging from cellular screening was further evaluated for its capacity to potentiate anti-tumor immunity. The therapeutic efficacy of this candidate was rigorously confirmed through a comprehensive suite of immunological experiments. Results: Following systematic screening of five candidate genes (WNT11, FAM181B, GRK5, FSCN1, and ECHS1), GRK5 emerged as a promising therapeutic target for immunotherapy based on its distinct functional and molecular associations with immune evasion mechanisms. Cellular functional assays revealed that GRK5 knockdown significantly attenuated the malignant phenotype of testicular cancer cells, as evidenced by reduced proliferative capacity and invasive potential. Complementary immunological validation established that specific targeting of GRK5 with the selective antagonist GRK5-IN-2 disrupts immune evasion pathways in testicular cancer, as quantified by T-cell-mediated cytotoxicity. Conclusions: These findings position GRK5 as a critical modulator of tumor-immune escape, warranting further preclinical exploration of GRK5-IN-2 as a candidate immunotherapeutic agent. Full article

Transcriptomic profiling has shown that exposure to PM_2.5, a common air pollutant, can modulate gene expression, which has been linked to negative health effects and diseases. However, there are few population-based cohort studies on the association between PM_2.5 exposure and specific gene set expression. In this study, we used an unbiased transcriptomic profiling approach to examine gene expression in a mouse model exposed to PM_2.5 and to identify PM_2.5-responsive genes. The gene expressions were further validated in both the human cell lines and a population-based cohort study. Two cohorts of healthy older adults (aged ≥ 65 years) were recruited from regions characterized by differing levels of PM_2.5. Logistic regression and decision tree algorithms were then utilized to construct predictive models for PM_2.5 exposure based on these gene expression profiles. Our results indicated that the expression of five genes (FAM102B, PPP2R1B, OXR1, ITGAM, and PRP38B) increased with PM_2.5 exposure in both cell-based assay and population-based cohort studies. Furthermore, the predictive models demonstrated high accuracy in classifying high-and-low PM_2.5 exposure, potentially supporting the integration of gene biomarkers into public health practices. Full article

A ratiometric fluorescent film with high gas sensitivity and stability was developed using electrospinning technology for monitoring food spoilage. 5(6)-Carboxyfluorescein (5(6)-FAM) was used as the indicator, combined with the internal reference Rhodamine B (RHB), to establish a composite ratiometric fluorescent probe (FAM@RHB). The hydrophobic fluorescent films were fabricated by incorporating FAM@RHB probes into polyvinylidene fluoride (PVDF) at varying molar ratios through electrospinning. The FR-2 film with a 2:8 ratio of 5(6)-FAM to RHB exhibited the best performance, demonstrating excellent hydrophobicity with a water contact angle (WCA) of 113.45° and good color stability, with a ΔE value of 2.05 after 14 days of storage at 4 °C. Gas sensitivity tests indicated that FR-2 exhibited a limit of detection (LOD) of 0.54 μM for trimethylamine (TMA). In the application of monitoring the freshness of pork and beef at 4 °C, the fluorescence color of the FR-2 film significantly changed from orange–yellow to green, enabling the visual monitoring of meat freshness. Hence, this study provides a new approach for intelligent food packaging. Full article

Background: Ovarian cancer (OC) is characterized by high incidence and mortality rates; however, due to its immunologically “cold” phenotype, the effectiveness of immunotherapy as a strategy for OC remains inadequate. Although the FAM111B gene promotes the progression of various solid tumors, its specific function within the tumor immune microenvironment (TIME) of OC remains unclear. Methods: This study used multiplex immunofluorescence techniques and bioinformatics analysis to examine the role of FAM111B within the TIME of OC. Through multiplex immunofluorescence, we assessed the protein expression levels of FAM111B alongside key immune cell markers, including FOXP3, CD4, CD8, CD68, CD163, CD66b, and CD11c. Furthermore, we employed bioinformatics methods using The Cancer Genome Atlas database to validate FAM111B function at the mRNA level in OC. Results: We observed a positive correlation between FAM111B expression and immune cell infiltration, including T cells, macrophages, and dendritic cells. FAM111B, M2 macrophages, and regulatory T cells were associated with poorer overall survival in OC patients. Additionally, specific T cell subsets and dendritic cells were correlated positively with programmed death-ligand 1 expression, while FAM111B levels were linked to multiple immune checkpoint molecules. Conclusions: This study reveals a positive correlation between FAM111B overexpression and the infiltration levels of immune cells in OC. In OC patients characterized by elevated FAM111B expression, the potential augmentation of immune cell infiltration within the TIME may consequently enhance the efficacy of immunotherapy. Full article

Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PGs) are essential regulators of many biological processes including cell differentiation, signalization, and proliferation. PGs interact mainly via their glycosaminoglycan (GAG) chains, with a large number of ligands including growth factors, enzymes, and extracellular matrix components, thereby modulating their biological activities. HSPGs and CSPGs share a common tetrasaccharide linker region, which undergoes modifications, particularly the phosphorylation of the xylose residue by the kinase FAM20B. Here, we demonstrated that FAM20B gain-of-function decreased, in a dose dependent manner, the synthesis of both CS- and HS-attached PGs. In addition, we showed that blockage of GAG chain synthesis by FAM20B was suppressed by the mutation of aspartic acid residues D289 and D309 of the catalytic domain. Interestingly, we bring evidence that, in contrast to FAM20B, expression of the 2-phosphoxylose phosphatase XYLP increases, in a dose dependent manner, GAG chain synthesis and rescues the blockage of GAG chains synthesis induced by FAM20B. In line with previous reports, we found that FAM20B loss-of-function reduced GAG chain synthesis. Finally, we found that FAM20B inhibited proliferation and migration of glioblastoma cells, thus revealing the critical role of GAG chains of PGs in glioblastoma cell tumorigenesis. This study revealed that both gain- and loss-of-function of FAM20B led to decreased GAG chain synthesis, therefore suggesting that a balance between phosphorylation and dephosphorylation of the xylose by FAM20B and XYLP, respectively, is probably an essential factor for the regulation of the rate of PG synthesis. Full article

The author reviewed and classified maintenance reports that cited smoke, odor, or fumes (SOFs) that US airlines sent to the FAA over four years between 2018 and 2023. The US fleet composition was also calculated to put the number of SOF reports on each aircraft type in perspective. “Fume events” (engine oil or hydraulic fluid) were the most common type of onboard SOFs reported by US airlines (43%), followed by electrical (20%), and fans (6.1%). During these years, A320fam aircraft made up 20% of the US fleet but 80% of the reported fume events. Conversely, B737fam aircraft made up 27% of the US fleet but only 3.0% of the reported fume events. Aircraft design features, airline reporting practices, and maintenance procedures that may contribute to these differences were reviewed. Pilots were most likely to document a fume event during descent (47%) and takeoff/climb (19%). The A320fam, MD80fam, A330, and ERJ140-145 aircraft were over-represented in other types of SOFs reports. Airline narratives show that the APU can be the primary source of oil/hydraulic fumes, even when it is not operating. Additionally, failure to find the source of fumes, rectify it, and clean any secondary sources of fumes can cause repeat events. Full article

Although the roles of proteoglycans (PGs) have been well documented in the development and homeostasis of the temporomandibular joint (TMJ), how the glycosaminoglycan (GAG) chains of PGs contribute to TMJ chondrogenesis and osteogenesis still requires explication. In this study, we found that FAM20B, a hexokinase essential for attaching GAG chains to the core proteins of PGs, was robustly activated in the condylar mesenchyme during TMJ development. The inactivation of Fam20b in craniofacial neural crest cells (CNCCs) dramatically reduced the synthesis and accumulation of GAG chains rather than core proteins in the condylar cartilage, which resulted in a hypoplastic condylar cartilage by severely promoting chondrocyte hypertrophy and perichondral ossification. In the condyles of Wnt1-Cre;Fam20b^f/f mouse embryos, enlarged Ihh- and COL10-expressing domains indicated premature hypertrophy resulting from an attenuated IHH-PTHRP negative feedback in condylar chondrocytes, while increased osteogenic markers, canonical Wnt activity, and type-H angiogenesis verified the enhanced osteogenesis in the perichondrium. Further ex vivo investigations revealed that the loss of Fam20b decreased the domain area but increased the activity of HH signaling in the embryonic condylar mesenchyme. Moreover, the abrogation of GAG chains in heparan sulfate and chondroitin sulfate proteoglycans led to a rapid up- and then downregulation of HH signaling in condylar chondrocytes, implicating a “slow-release” manner of growth factors controlled by GAG chains. Overall, this study revealed a comprehensive role of the FAM20B-catalyzed GAG chain synthesis in the chondrogenic and osteogenic differentiation of the embryonic TMJ condyle. Full article

Recent evidence indicates that FAM111B is significantly involved in the progression of various cancers. Nonetheless, the potential pan-cancer implications of FAM111B have not been systematically investigated. In this study, FAM111B’s expression and oncogenic potential were studied using TCGA and GTEx data via GEPIA2, TIMER2.0, and STRING tools. Pathway enrichment analyses with the GO, KEGG, Reactome, and WikiPathways databases were conducted to explore its role in cancer development. The results were validated via multiplex immunofluorescence assays of pancreatic cancer tissues, microarray assays of ovarian cancer tissues, and protein transcriptomics of ovarian cancer cells. The expression levels of FAM111B were elevated in most cancer types and were associated with poor prognostic outcomes. Mechanistically, FAM111B expression was positively correlated with the expression of genes involved in DNA homologous recombination repair and with the infiltration of Th2 CD4+ T cells. These observations were further substantiated in ovarian cancer cell lines and tissue specimens from pancreatic and ovarian cancers. FAM111B functions as a biomarker for the DNA repair pathway and Th2 CD4+ T-cell infiltration in human malignancies. Full article

Crohn’s disease (CD) is a chronic inflammatory disorder with potential progression to stricturing (B2) or penetrating (B3) phenotypes, leading to significant complications. Early identification of patients at risk for these complications is critical for personalized management. This study aimed to develop a predictive model using clinical data and a Korean-specific transcriptome-wide association study (TWAS) to forecast early progression in CD patients. A retrospective analysis of 430 Korean CD patients from 15 hospitals was conducted. Genotyping was performed using the Korea Biobank Array, and gene expression predictions were derived from a TWAS model based on terminal ileum data. Logistic regression models incorporating clinical and gene expression data predicted progression to B2 or B3 within 24 months of diagnosis. Among the cohort, 13.9% (60 patients) progressed to B2 and 16.9% (73 patients) to B3. The combined model achieved mean area under the curve (AUC) values of 0.788 for B2 and 0.785 for B3 progression. Key predictive genes for B2 included CCDC154, FAM189A2, and TAS2R19, while PUS7, CCDC146, and MLXIP were linked to B3 progression. This integrative model provides a robust approach for identifying high-risk CD patients, potentially enabling early, targeted interventions to reduce disease progression and associated complications. Full article