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A key feature distinguishing high-grade glioma (HG) from low-grade glioma (LG) is the extensive neovascularization and endothelial hyperproliferation. Prior work has shown that tumor-associated vasculature from HG is molecularly and functionally distinct from normal brain vasculature and expresses higher levels of protumorigenic factors that promote glioma growth and progression. However, it remains unclear whether vessels from LG also express protumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of glioma-associated vascular cells (GVC) from IDH-mutant (mIDH) LG and IDH-wild-type (wIDH) HG and show that they exhibit significant molecular and functional differences. LG-GVC show enrichment of extracellular matrix-related gene sets and sensitivity to antiangiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and antiangiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo cotransplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, highly enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG are molecularly and functionally distinct and differentially regulate tumor growth. Implications: This study demonstrated that vascular cells from IDH-mutant LG and IDH-wild-type HG exhibit distinct molecular signatures and have differential effects on tumor growth via regulation of ASPN-TGFβ1-GPM6A signaling.

Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor-engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma.SignificanceThis study dissects the tumor-intrinsic epigenetic and transcriptional mechanisms underlying enhanced T-cell functionality targeting decitabine-induced cancer-testis antigens in glioma. Our findings demonstrate concomitant induction of tumor antigens, reactivation of human endogenous retroviruses, and stimulation of interferon signaling as a mechanistic rationale to epigenetically prime human gliomas to immunotherapeutic targeting.

IDH1mut gliomas produce high levels of D-2-hydroxyglutarate (D-2-HG), an oncometabolite capable of inhibiting α-ketoglutarate-dependent dioxygenases critical to a range of cellular functions involved in gliomagenesis. IDH1mut gliomas also exhibit slower growth rates and improved treatment sensitivity compared with their IDH1wt counterparts. This study explores the mechanism driving apparent reduced growth in IDH1mut gliomas. Specifically, we investigated the relationship between IDH1mut and the RNA N6-methyladenosine (m6A) demethylases FTO and ALKBH5, and their potential for therapeutic targeting. We investigated the role of D-2-HG and m6A in tumor proliferation/viability using glioma patient tumor samples, patient-derived gliomaspheres, and U87 cells, as well as with mouse intracranial IDH1wt gliomasphere xenografts. Methylation RNA immunoprecipitation sequencing (MeRIP-seq) RNA sequencing was used to identify m6A-enriched transcripts in IDH1mut glioma. We show that IDH1mut production of D-2-HG is capable of reducing glioma cell growth via inhibition of the m6A epitranscriptomic regulator, FTO, with resultant m6A hypermethylation of a set of mRNA transcripts. On the basis of unbiased MeRIP-seq epitranscriptomic profiling, we identify ATF5 as a hypermethylated, downregulated transcript that potentially contributes to increased apoptosis. We further demonstrate how targeting this pathway genetically and pharmacologically reduces the proliferative potential of malignant IDH1wt gliomas, both in vitro and in vivo. Our work provides evidence that selective inhibition of the m6A epitranscriptomic regulator FTO attenuates growth in IDH1wt glioma, recapitulating the clinically favorable growth phenotype seen in the IDH1mut subtype.SignificanceWe show that IDH1mut-generated D-2-HG can reduce glioma growth via inhibition of the m6A demethylase, FTO. FTO inhibition represents a potential therapeutic target for IDH1wt gliomas and possibly in conjunction with IDH1mut inhibitors for the treatment of IDH1mut glioma. Future studies are necessary to demonstrate the role of ATF5 downregulation in the indolent phenotype of IDH1mut gliomas, as well as to identify other involved gene transcripts deregulated by m6A hypermethylation.

BackgroundMalignant glioma carries a poor prognosis despite current therapeutic modalities. Standard of care therapy consists of surgical resection, fractionated radiotherapy concurrently administered with temozolomide (TMZ), a DNA-alkylating chemotherapeutic agent, followed by adjuvant TMZ. O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylated lesions from tumor DNA, thereby promoting chemoresistance. MGMT promoter methylation status predicts responsiveness to TMZ; patients harboring unmethylated MGMT (~60% of glioblastoma) have a poorer prognosis with limited treatment benefits from TMZ.MethodsVia lentiviral-mediated delivery into LN18 glioma cells, we employed deactivated Cas9-CRISPR technology to target the MGMT promoter and enhancer regions for methylation, as mediated by the catalytic domain of the methylation enzyme DNMT3A. Methylation patterns were examined at a clonal level in regions containing Differentially Methylation Regions (DMR1, DMR2) and the Methylation Specific PCR (MSP) region used for clinical assessment of MGMT methylation status. Correlative studies of genomic and transcriptomic effects of dCas9/CRISPR-based methylation were performed via Illumina 850K methylation array platform and bulk RNA-Seq analysis.ResultsWe used the dCas9/DNMT3A catalytic domain to achieve targeted MGMT methylation at specific CpG clusters in the vicinity of promoter, enhancer, DMRs and MSP regions. Consequently, we observed MGMT downregulation and enhanced glioma chemosensitivity in survival assays in vitro, with minimal off-target effects.ConclusiondCas9/CRISPR is a viable method of epigenetic editing, using the DNMT3A catalytic domain. This study provides initial proof-of-principle for CRISPR technology applications in malignant glioma, laying groundwork for subsequent translational studies, with implications for future epigenetic editing-based clinical applications.

Aiming at the problem of parameter design of marine wedge gear propeller shaft clutches, the design and research of marine wedge gear propeller shaft clutches are carried out. The variation of the critical friction coefficient required for the self-locking of the marine wedge gear propeller shaft clutch with the pressure angle and wedge angle of the wedge gear is theoretically analyzed and verified by the simulation. The multi-body dynamic model of marine wedge gear propeller shaft clutches is established, and the engagement process with the tooth error is studied. The results show that the marine wedge gear propeller shaft clutch reduces the accuracy requirement of the tooth alignment process. When there is an error within 0.4° in the engagement process, the engagement can be completed under its own guidance. The formula of self-locking critical friction coefficient derived in this study can be used to guide the design of marine wedge gear propeller shaft clutches.

Current ionic artificial muscle technology necessitates a significant technological advancement to achieve increased bending strain, enhanced response rates, and prolonged stability while ensuring consistent and reliable performance across various stimuli. In this study, we aimed to develop an artificial muscle based on a novel nanocomposite composed of ionically cross-linked ZnO@Zn-CAT with poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate), showing an ultrafast rise time of less than 1.56 s in DC responses, an extremely large bending strain up to 1.22% in a very low input voltage regime (0.1 to 3 V), a long-term cycling stability of 97% up to 10 000 cycles, markedly reduced phase delay, and a very broad frequency bandwidth up to 20 Hz with good structural reliability under continuous electrical stimuli. Most importantly, the proposed ZnO@Zn-CAT-based soft actuator exhibits a remarkably enhanced strain of 2.38% and a blocking force of 66 mN under an extra 700 nm light stimulation, allowing for the realization of complex next-generation soft robotic devices, including wearable electronics and artificial muscles. [ABSTRACT FROM AUTHOR]

In this rapidly evolving era of multimodal generation, diffusion models exhibit impressive generative capabilities, significantly enhancing the realm of creative image synthesis by intricately textual prompts. Yet, their effectiveness is limited in certain niche sectors, like depicting Chinese ancient architecture. This limitation is primarily due to the insufficient data that fails to encompass the unique architectural features and corresponding text information. Hence, we build an extensive multimodal dataset capturing the essence of Chinese architectures mostly from the Tang to the Yuan Dynasties. The dataset is categorized on the types, including image&text, video, and style models. In details, images and videos are methodically categorized based on locations. All images are annotated at two levels: initial annotations and descriptive terms based on distinctive characteristics and official information. Moreover, seven artistic styles fine-tuning models are provided in our dataset for further innovations. Significantly, this is the first Chinese ancient architecture dataset and the instance of using the Pinyin system to annotate unique terms related to Chinese architectural styles. [ABSTRACT FROM AUTHOR]

Among the fascinating phenomena observed in two-dimensional (2D) magnets, the magneto-exciton effect stands out as a pivotal link between optics and magnetism. Although the excitonic effect has been revealed and exhibits a considerable correlation with the spin structures in certain 2D magnets, the underlying mechanism of the magneto-exciton effect remains underexplored, especially under high magnetic fields. Here we perform a systematic investigation of the spin-exciton coupling in 2D antiferromagnetic NiPS3 under high magnetic fields. When an in-plane magnetic field is applied, the exceptional sharp excitonic emission at ~1.4756 eV exhibits a Zeeman-like splitting with g ≈ 2.0, experimentally identifying the exciton as an excitation of dominant triplet-singlet character. By examining the polarization of excitonic emission and simulating the spin evolution, we further verify the correlation between excitonic emission and Néel vector in NiPS3. Our work elucidates the mechanism behind the spin-exciton coupling in NiPS3 and establishes a strategy for optically probing the spin evolutions in 2D magnets. NiPS3, a van der Waals antiferromagnet exhibits exciton emission with a very sharp linewidth. The exact origin of this is has been a subject of active debate. Here, Wang et al study the behavior of this sharp exciton peak under applied magnetic fields, and find a Zeeman-like splitting, indicating the exciton has triplet-singlet character. [ABSTRACT FROM AUTHOR]