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Background Neuroblastoma (NB) is the most common extracranial solid tumor in children and is characterized by marked clinical heterogeneity and poor prognosis. MYCN amplification drives NB tumorigenesis through epigenetic reprogramming and is frequently accompanied by a copy-number gain of the long arm of chromosome 17 (17q). Epigenetic dysregulation of enhancer landscapes—particularly large regulatory elements termed super‑enhancers (SEs), which are enriched for H3K27ac and bound by lineage-specific master transcription factors (TFs)—establishes distinct NB cellular identities and states. These SE domains demarcate oncogenes that function as critical regulators of cell proliferation and apoptosis. Therefore, SE-driven genes represent tumor vulnerabilities, offering selective therapeutic opportunities. Methods By integrating ATAC-seq data from 22 NB cell lines, the intratumoral heterogeneity of MYCN-amplified NB was characterized at the level of chromatin accessibility. Subsequently, based on H3K27ac ChIP-seq data from 38 NB cell lines, the ROSE algorithm was employed to identify SE-driven oncogenes. The synergistic mechanism between MYCN amplification and the 17q SE-driven gene MSI2 was investigated through genome‑wide CRISPR/Cas9 loss‑of‑function screens. At single‑cell resolution, we conducted a comprehensive analysis of the characteristics of heterogeneous tumor subpopulations and their immune microenvironment features. This analysis was performed using multiple bioinformatics workflows, including AUCell scoring, SCENIC analysis, copy‑number inference, cell differentiation‑state evaluation, neighborhood abundance tests, and separability tests. Finally, functional validation was performed using NB cell lines (MYCN‑amplified and non‑amplified) to assess gene perturbations. Results Pronounced epigenetic heterogeneity was observed within MYCN-amplified NB. MSI2 is an SE‑driven oncogene and is highly expressed in MYCN‑amplified NB. MSI2 and MYCN are co-expressed, may be mutually dependent, and are both correlated with cell cycle-related pathways. At the single-cell level, we identified and redefined an NB-MSI2 + MYCN+ subtype characterized by malignant transcriptional features, an immunosuppressive microenvironment, and poor patient prognosis. Building on this, combined targeting of MSI2 and MYCN markedly reduced proliferation and migration in MYCN‑amplified NB cells. Conclusions The NB‑MSI2 + MYCN+ subtype defines a clinically aggressive, therapy‑refractory state characterized by high proliferation, metabolic reprogramming, and immunosuppression. For patients with MYCN-amplified NB, MSI2 is both a prognostic biomarker and a candidate therapeutic target.

BackgroundPlasma exosomal microRNAs have been suggested to be potential biomarkers of disease. However, the exosomal microRNAs in Hirschsprung’s disease (HSCR) are still unclear. In this study, we analyzed the miRNA profiles of HSCR and elucidated the mechanism of the selected miR-199a-3p in the development of HSCR.MethodsPlasma exosomes were isolated, and exosomal miRNA high-throughput sequencing was performed to obtain differentially expressed miRNAs. CCK-8 and Transwell assay were used to determine the function of the most differentially expressed miRNA, which was confirmed in tissue specimen. Thereafter, target genes of the selected miRNAs were predicted by the databases. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes Genomes (KEGG) analysis, and protein–protein interaction network (PPI) construction of possible target genes were used to perform enrichment analysis and interaction. Finally, the PCR, Western blot and recovery experiment were used to confirm the function of target gene, mammalian target of rapamycin (mTOR), in vitro.ResultsThe expression of miR-199a-3p was upregulated in plasma exosomes and diseased colonic tissues of patients with HSCR. In vitro, miR-199a-3p can inhibit cell proliferation and migration. Bioinformatic analysis suggested that mTOR might be a potential target of miR-199a-3p in HSCR. mTOR was discovered to be downregulated by miR-199a-3p in vitro. The negative connection between mTOR and miR-199a-3p was confirmed in tissue samples. mTOR can partially reverse the effect of miR-199a-3p on cell proliferation and migration function in vitro.ConclusionsmiR-199a-3p suppresses cell growth and motility, partially by targeting mTOR. Plasma exosomal miR-199a-3p, a diagnostic marker, is crucial for the development of HSCR.

Copper nanowires have the potential to reach and even exceed the indium tin oxide performances as flexible transparent conductive electrodes. However, for a large-scale production, they need to be fabricated in a high-speed, low-cost way, without degrading the flexible substrate. One of the major bottlenecks resides in the post-treatment used to remove organic residues from the surface of the nanowires after forming the transparent electrode, which is necessary to obtain high optoelectronic performances. Here, we propose an ultra-violet irradiation and a subsequent acetic acid bath as an easy, scalable, fast post-treatment. After only 2 min of ultra-violet treatment, followed by 10 min of acid bath, an R s of 42 Ω sq −1 and a T 550 nm of 87% were measured. Besides, copper nanowire electrodes maintained their high transparency in the range 750–2500 nm, which makes them good candidates for applications such as infrared solar cells.

Atmospheric pressure plasma (APP) etching has been developed recently into a manufacturing technique for silicon-based materials used for large optical lenses. However, there are few reports published regarding APP etching of non-silicon-based materials. We report here the development of an APP process using SF6 for the etching of Ti-6Al-4 V metal alloy. Ti-6Al-4V is extensively used in aerospace and biomedical fields for its excellent properties; however, these properties also make it difficult to machine. Current techniques such as precision grinding and laser polishing can be slow, energy intensive, and cause damages and defects which reduce the lifetime of vital components. The results in this paper demonstrate effective material removal and little surface damage by APP etching of Ti-6Al-4V. Material removal rates between 0.5 and 2 mm3 min−1 were obtained, and the proposed material removal mechanism is through the formation of volatile VFx and TiF4. These results show that APP etching is a promising technique for surface finishing of Ti-6Al-4V, particularly for large- and complex-shaped components.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with limited therapeutic options. Although targeted therapies like pemigatinib provide partial clinical benefits, acquired resistance remains a significant challenge. Through integrative bioinformatics analysis of public datasets and immunohistochemical validation, we identified the retinoid-related orphan receptor gamma (RORγ) as markedly upregulated in iCCA. Genetic silencing and pharmacological inhibition of RORγ (GSK805/XY101) suppressed proliferation, induced apoptosis in vitro, and significantly reduced xenograft tumor growth in vivo. Mechanistically, RORγ promoted fibroblast growth factor receptor 2 (FGFR2) signaling via two complementary mechanisms: direct transcriptional activation of FGFR2 and induction of fibroblast growth factor 1 (FGF1) expression and secretion, which in turn activated FGFR2. Inhibition of RORγ markedly decreased FGF1 levels in conditioned media, whereas exogenous FGF1 restored tumor growth. Notably, RORγ antagonists synergized with pemigatinib to overcome resistance in pemigatinib-refractory models. Collectively, these findings identify the RORγ-FGF1-FGFR2 axis as a critical oncogenic driver in iCCA and highlight RORγ inhibition as a promising therapeutic strategy to suppress tumor progression and enhance sensitivity to FGFR inhibitors.

Background METTL3, an mRNA m 6 A methyltransferase, has been implicated in various steps of mRNA metabolism, such as stabilization, splicing, nuclear transportation, translation, and degradation. However, whether METTL3 dysregulation is involved in Hirschsprung disease (HSCR) development remains unclear. In this study, we preliminarily elucidated the role of METTL3 in HSCR and sought to identify the associated molecular mechanism. Methods The gene expression levels of YAP and several methyltransferases, demethylases, and effectors were evaluated by RT-qPCR. Protein levels were evaluated by western blot and immunohistochemistry. Cell proliferation and migration were detected by CCK-8 and Transwell assays, respectively. The overall levels of m 6 A modification were determined by colorimetry. Results We found that m 6 A levels were reduced in the stenotic intestinal tissue of patients with HSCR. When METTL3 was knocked down in SH-SY5Y and HEK-293T cells, the proliferative and migratory abilities of the cells were inhibited, m 6 A modification levels were reduced, and YAP expression was increased. Importantly, YAP and METTL3 expression displayed a negative correlation in both cell lines as well as in HSCR tissue. Conclusions Our results provide evidence for an interaction between METTL3 and YAP in HSCR, and further suggest that METTL3 is involved in the pathogenesis of HSCR by regulating neural crest cell proliferation and migration upstream of YAP.

METTL3, an mRNA m A methyltransferase, has been implicated in various steps of mRNA metabolism, such as stabilization, splicing, nuclear transportation, translation, and degradation. However, whether METTL3 dysregulation is involved in Hirschsprung disease (HSCR) development remains unclear. In this study, we preliminarily elucidated the role of METTL3 in HSCR and sought to identify the associated molecular mechanism. The gene expression levels of YAP and several methyltransferases, demethylases, and effectors were evaluated by RT-qPCR. Protein levels were evaluated by western blot and immunohistochemistry. Cell proliferation and migration were detected by CCK-8 and Transwell assays, respectively. The overall levels of m A modification were determined by colorimetry. We found that m A levels were reduced in the stenotic intestinal tissue of patients with HSCR. When METTL3 was knocked down in SH-SY5Y and HEK-293T cells, the proliferative and migratory abilities of the cells were inhibited, m A modification levels were reduced, and YAP expression was increased. Importantly, YAP and METTL3 expression displayed a negative correlation in both cell lines as well as in HSCR tissue. Our results provide evidence for an interaction between METTL3 and YAP in HSCR, and further suggest that METTL3 is involved in the pathogenesis of HSCR by regulating neural crest cell proliferation and migration upstream of YAP.

Protein function annotation has been one of the longstanding issues in biological sciences, and various computational methods have been developed. However, the existing methods suffer from a serious long-tail problem, with a large number of GO families containing few annotated proteins. Herein, an innovative strategy named AnnoPRO was therefore constructed by enabling sequence-based multi-scale protein representation, dual-path protein encoding using pre-training, and function annotation by long short-term memory-based decoding. A variety of case studies based on different benchmarks were conducted, which confirmed the superior performance of AnnoPRO among available methods. Source code and models have been made freely available at: https://github.com/idrblab/AnnoPRO and https://zenodo.org/records/10012272

Background Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). Methods The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.