Identification of Cbx6 as a potential biomarker in renal ischemia/reperfusion injury.

BACKGROUND: Renal ischemia/reperfusion injury (RIRI) is an inevitable consequence of kidney transplantation and has a negative impact on both short-term and long-term graft survival. The identification of key markers in RIRI to improve the prognosis of patients would be highly advantageous. METHODS: Gene expression profile data of GSE27274 were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were analyzed using the Limma package. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment of DEGs were performed. Support vector machine-recursive feature elimination and least absolute shrinkage and selection operator regression modeling were both performed to identify potential biomarkers. The GSE148420 dataset, quantitative reverse transcriptase-PCR, and western blotting results of kidney tissue samples were used to validate the bioinformatic analysis. Lastly, exploring differences between different groups through gene set enrichment analysis and using DsigDB database to identify potential therapeutic drugs targeting hub genes. RESULTS: A total of 160 upregulated and 180 downregulated DEGs were identified. Functional enrichment analysis identified significant enrichment in processes involving peroxisomes. As a subunit of Polycomb Repressive Complex 1(PRC1), chromobox 6(Cbx6) was identified as a potential biomarker with an area under the receiver operating characteristic curve of 0.875 (95% confidence interval 0.624-1.000) in the validation cohort, and it was highly expressed in the RIRI group (p < 0.05). In the high expression group Cbx6 was more enriched in the toll-like receptor signaling pathway. We predicted 15 potential drugs targeting hub genes of RIRI. CONCLUSIONS: We identified Cbx6 as a potential biomarker for RIRI and 15 potential drugs for the treatment of RIRI, which might shed a light on the treatment of RIRI.

High resolution acoustic sensing based on microcavity optomechanical oscillator.

In this paper, a simple sensing method based on a silicon oxide microcavity optomechanical oscillator (OMO) is proposed and demonstrated for the detection of acoustic signals. Firstly, the resonance damping was reduced by improving the optical quality factor (Qo) and increasing the sphere-to-neck ratio. After optimizing the process, a microsphere OMO was fabricated, which has an ultra-high mechanical quality factor (6.8 × 106) and greater sphere-to-neck ratio (∼11:1), based on which ultra-narrow linewidth phonon laser (∼1 Hz) is constructed. Secondly, by changing the refractive index of the coupling interval, the low-frequency acoustic pressure signal is efficiently coupled into the microcavity OMO to construct a high-resolution acoustic sensor. This sensing mechanism can not only measure the acoustic pressure, but also use the sideband signal in the modulation mechanism to measure the frequency of acoustic signals (15 Hz∼16 kHz), the sensitivity is 10.3 kHz/Pa, the minimum detectable pressure is 1.1 mPa, and noise-limited minimum detectable pressure is 28.8 µPa/Hz1/2. It is the highest detection resolution compared with the same type of low-frequency acoustic signal detection currently reported. This OMO-based acoustic sensing detection method opens up a new path for future miniaturized, ultra-high-precision, and cost-effective acoustic sensing.

Zirconium-containing nanoscale coordination polymers for positron emission tomography and fluorescence-guided cargo delivery to triple-negative breast tumors.

Nanoscale coordination polymer (NCP) is a class of hybrid materials formed by self-assembly of metal ions and organic ligands through coordination. The applications of NCP in biomedicine are quite extensive due to the diversity choice of metal ions and organic ligands. Here we designed Zr-P1 NCP based on Zr4+ selected as metal ion nodes and tetrakis(4-carboxyphenyl) ethylene as bridging ligands. Zr-P1 NCP was modified with functionalized pyrene derived polyethylene glycol (Py-PAA-PEG-Mal) on the surface and further conjugated with cRGD for active targeting of integrin αvß3 overexpressed in triple-negative breast cancer. Doxorubicin was loaded on Zr-P1 NCP with encapsulation efficiency up to 22 % for the treatment of triple negative breast cancer. 89Zr-P1 NCP can be used for in vivo tumor imaging due to the fluorescence properties resulting from the enhanced aggregation-induced Emission (AIE) behavior of P1 ligands and its positron emission tomography (PET) capability. Cellular evaluation indicated that the functionalized Zr-P1@PEG-RGD presented a good function for tumor cell targeting imaging and doxorubicin could be targeted to triple negative breast cancer when it was loaded onto Zr-P1@PEG-RGD, which corroborated with the in vivo results. In summary, 89Zr-P1@PEG-RGD can serve as a biocompatible nanoplatform for fluorescence and PET image-guided cargo delivery. STATEMENT OF SIGNIFICANCE: Nanoscale coordination polymer (NCP) is a class of hybrid materials formed by self-assembly of metal ions and organic ligands through coordination. The diversity of available metals and ligand structures upon NCP synthesis plays an advantage in establishing multimodal imaging platforms. Here we designed 89Zr-P1@PEG-RGD NCP based on Zr4+ selected as metal ion nodes and tetrakis(4-carboxyphenyl) ethylene as bridging ligands. 89Zr-P1@PEG-RGD nanomaterials have positron emission tomography (PET) capability due to the incorporation of zirconium-89, which can be used for in vivo tumor imaging with high sensitivity. The chemotherapeutic drug DOX was loaded on Zr-P1 NCP for the treatment of triple-negative breast cancer, and dual modality imaging can provide visual guidance for drug delivery.

Copy number gain of FAM131B-AS2 promotes the progression of glioblastoma by mitigating replication stress.

BACKGROUND: Glioblastoma (GBM) is characterized by chromosome 7 copy number gains, notably 7q34, potentially contributing to therapeutic resistance, yet the underlying oncogenes have not been fully characterized. Pertinently, the significance of long noncoding RNAs (lncRNAs) in this context has gained attention, necessitating further exploration. METHODS: FAM131B-AS2 was quantified in GBM samples and cells using qPCR. Overexpression and knockdown of FAM131B-AS2 in GBM cells were used to study its functions in vivo and in vitro. The mechanisms of FAM131B-AS2 were studied using RNA-seq, qPCR, Western blotting, RNA pull-down, coimmunoprecipitation assays, and mass spectrometry analysis. The phenotypic changes that resulted from FAM131B-AS2 variation were evaluated through CCK8 assay, EdU assay, comet assay, and immunofluorescence. RESULTS: Our analysis of 149 primary GBM patients identified FAM131B-AS2, a lncRNA located in the 7q34 region, whose upregulation predicts poor survival. Mechanistically, FAM131B-AS2 is a crucial regulator of the replication stress response, stabilizing RPA1 through recruitment of USP7 and activating the ATR pathway to protect single-stranded DNA from breakage. Furthermore, FAM131B-AS2 overexpression inhibited CD8+ T-cell infiltration, while FAM131B-AS2 inhibition activated the cGAS-STING pathway, increasing lymphocyte infiltration and improving the response to immune checkpoint inhibitors. CONCLUSION: FAM131B-AS2 emerges as a promising indicator for adjuvant therapy response and could also be a viable candidate for combined immunotherapies against GBMs.

Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells.

Neuronal activity can drive progression of high-grade glioma by mediating mitogen production and neuron-glioma synaptic communications. Glioma stem cells (GSC) also play a significant role in progression, therapy resistance, and recurrence in glioma, which implicates potential cross-talk between neuronal activity and GSC biology. Here, we manipulated neuronal activity using chemogenetics in vitro and in vivo to study how it influences GSCs. Neuronal activity supported glioblastoma (GBM) progression and radioresistance through exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. Molecularly, neuronal activation led to elevated miR-184-3p in neuron-derived exosomes that were taken up by GSCs and reduced the mRNA N6-methyladenosine (m6A) levels by inhibiting RBM15 expression. RBM15 deficiency decreased m6A modification of DLG3 mRNA and subsequently induced GSC PMT by activating the STAT3 pathway. Loss of miR-184-3p in cortical neurons reduced GSC xenograft growth, even when neurons were activated. Levetiracetam, an antiepileptic drug, reduced the neuronal production of miR-184-3p-enriched exosomes, inhibited GSC PMT, and increased radiosensitivity of tumors to prolong survival in xenograft mouse models. Together, these findings indicate that exosomes derived from active neurons promote GBM progression and radioresistance by inducing PMT of GSCs. SIGNIFICANCE: Active neurons secrete exosomes enriched with miR-184-3p that promote glioblastoma progression and radioresistance by driving the proneural-to-mesenchymal transition in glioma stem cells, which can be reversed by antiseizure medication levetiracetam.

Hypoxia-Induced Neuronal Activity in Glioma Patients Polarizes Microglia by Potentiating RNA m6A Demethylation.

PURPOSE: Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear. EXPERIMENTAL DESIGN: By applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression. RESULTS: We demonstrate that hypoxia drove glioma stem cells (GSC) to produce higher levels of glutamate, which activated local neurons. Neuronal activity promoted GBM progression by facilitating microglial M2 polarization through enriching miR-200c-3p in neuron-derived exosomes, which decreased the expression of the m6A writer zinc finger CCCH-type containing 13 (ZC3H13) in microglia, impairing methylation of dual specificity phosphatase 9 (DUSP9) mRNA. Downregulation of DUSP9 promoted ERK pathway activation, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted microglial M2 polarization whereas cortical neuronal inhibition decreased microglial M2 polarization in GBM xenografts. miR-200c-3p knockdown in cortical neurons impaired microglial M2 polarization and GBM xenograft growth, even when cortical neurons were activated. Treatment with the anti-seizure medication levetiracetam impaired neuronal activation and subsequently reduced neuron-mediated microglial M2 polarization. CONCLUSIONS: These findings indicated that hypoxic GSC-induced neuron activation promotes GBM progression by polarizing microglia via the exosomal miR-200c-3p/ZC3H13/DUSP9/p-ERK pathway. Levetiracetam, an antiepileptic drug, blocks the abnormal activation of neurons in GBM and impairs activity-dependent GBM progression. See related commentary by Cui et al., p. 1073.

Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop.

BACKGROUND: The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear. RESULTS: We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb). CONCLUSIONS: Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

SPI1-mediated MIR222HG transcription promotes proneural-to-mesenchymal transition of glioma stem cells and immunosuppressive polarization of macrophages.

Background: Glioma stem cells (GSCs) are a key factor in glioblastoma (GBM) development and treatment resistance. GSCs can be divided into the mesenchymal (MES) and proneural (PN) subtypes, and these two subtypes of GSCs can undergo interconversion under certain conditions. MES GSCs have higher malignancy and radioresistance and are closely associated with an immunosuppressive microenvironment. Long noncoding RNAs (lncRNAs) play a broad role in GBM, while the role of GSCs subtype remains unknown. Methods: We performed RNA sequencing to explore the lncRNA expression profile in MES- and PN-subtype GBM tissues. The biological function of a host gene-MIR222HG-in GBM development was confirmed in vitro and in vivo. Specifically, RNA sequencing, RNA pulldown, mass spectrometry, RIP, ChIP, luciferase reporter assays and Co-IP were performed. Results: MIR222HG, the expression of which can be induced by SPI1, has high levels in MES GBM tissues. Functionally, we demonstrated that MIR222HG promotes the MES transition and radioresistance in GSCs in vivo and in vitro. Mechanistically, MIR222HG can bind to the YWHAE/HDAC5 complex to promote the MES transition of GSCs through H4 deacetylation. Moreover, cotranscribed miR221 and miR222 can be delivered to macrophages via exosomes to target SOCS3, causing immunosuppressive polarization. Finally, PLX-4720 sensitivity is associated with SPI1 expression and acts on MES GSCs to enhance radiosensitivity. Conclusions: This study demonstrates that targeting SPI1 to block transcription of the MIR222HG cluster helps to reduce radioresistance and combat the immunosuppressive microenvironment in GBM. PLX-4720 is a potential GBM drug and radiosensitizer.

FPGA-based burst-error performance analysis and optimization of regular and irregular SD-LDPC codes for 50G-PON and beyond.

We evaluate the burst-error performance of the regular low-density parity-check (LDPC) code and the irregular LDPC code that has been considered for ITU-T's 50G-PON standard via experimental measurements in FPGA. By using intra codeword interleaving and parity-check matrix rearrangement, we demonstrate that the BER performance can be improved under ∼44-ns-duration burst errors for 50-Gb/s upstream signals.

Unpacking Chinese EFL Students' Academic Engagement and Psychological Well-Being: The Roles of Language Teachers' Affective Scaffolding.

Over the past decade, there has appeared a surge of research interest in language learners' academic engagement and psychological well-being as important factors in improving the quality of education. However, research on the roles of English as a foreign language (EFL) teachers' affective scaffolding in enhancing the academic engagement and psychological well-being of their students is relatively scant. Inspired by this gap, the current study aimed to investigate the impact of Chinese EFL teachers' affective scaffolding on their learners' academic engagement and psychological well-being. To this end, a total number of 1968 Chinese EFL learners participated in this questionnaire survey. The results of the study showed that EFL teachers' affective scaffolding positively and significantly predicted students' academic engagement and psychological well-being. More specifically, it was found that teachers' affective scaffolding explained about 73% and 65% of variances in EFL students' academic engagement and psychological well-being. Moreover, it was found that psychological well-being and academic engagement were positively correlated and predicted 56% of each other's variances. In accordance with these findings, educators are recommended to build up a harmonious teacher-student relationship to foster students' psych-emotional development.

The moderating effect of participation in online learning activities and perceived importance of online learning on EFL teachers' teaching ability.

With the sudden outbreak of COVID-19, many educational contexts shifted from traditional face-to-face instruction to online and remote modes of delivery. This inspired a surge of scholarly attention in various countries to disclose the status and perceptions of stakeholders regarding online education. However, most of the existing studies in second/foreign language contexts are limited to students' and teachers' perceived emotions and experiences in e-instruction. Moreover, the extent to which online participation and the perceived importance of e-education influence teachers' teaching ability has been widely overlooked. To fill this gap, this study explored the moderating influence of EFL teachers' participation in online learning activities and the perceived importance of online learning on their teaching ability. In doing so, a questionnaire was spread and filled in by 453 Chinese EFL teachers with different backgrounds. The results of Structural Equation Modeling (SEM) obtained by Amos (v. 24) indicated that individual/demographic factors do not affect teachers' perceived importance of online learning. It was also demonstrated that the perceived importance of online learning and learning time does not predict EFL teachers' teaching ability. Furthermore, the results reveal that EFL teachers' teaching ability does not predict their perceived importance of online learning. However, teachers' participation in online learning activities predicted and explained 66% of the variance in their perceived importance of online learning. The study has implications for EFL teachers and teacher trainers in that it improves their awareness of the value of technologies in L2 education and practice.

Identification and Verification of Potential Biomarkers in Renal Ischemia-Reperfusion Injury by Integrated Bioinformatic Analysis.

Background: Renal ischemia-reperfusion injury (RIRI) plays an important role in the poor prognosis of patients with renal transplants. However, the potential targets and mechanism of IRI are still unclear. Method: Differential gene expression (DEG) analysis and weighted correlation network analysis (WGCNA) were performed on the GSE27274 dataset. Pathway enrichment analysis on the DEGs was performed. To identify the hub DEGs, we constructed a protein-protein interaction (PPI) network. Finally, the hub genes were verified, and candidate drugs were screened from the DsigDB database. Results: A hundred DEGs and four hub genes (Atf3, Psmb6, Psmb8, and Psmb10) were screened out. Pathway enrichment analysis revealed that 100 DEGs were mainly enriched in apoptosis and the TNF signaling pathway. The four hub genes were verified in animal models and another dataset (GSE148420). Thereafter, a PPI network was used to identify the four hub genes (Atf3, Psmb6, Psmb8, and Psmb10). Finally, eight candidate drugs were identified as potential drugs. Conclusion: Three hub genes (Psmb6, Psmb8, and Psmb10) were associated with RIRI and could be potential novel biomarkers for RIRI.

Glioblastoma upregulates SUMOylation of hnRNP A2/B1 to eliminate the tumor suppressor miR-204-3p, accelerating angiogenesis under hypoxia.

Glioma is the most common malignant tumor of the central nervous system in adults. The tumor microenvironment (TME) is related to poor prognosis in glioma patients. Glioma cells could sort miRNA into exosomes to modify TME. And hypoxia played an important role in this sorting process, but the mechanism is not clear yet. Our study was to find miRNAs sorted into glioma exosomes and reveal the sorting process. Sequencing analysis of glioma patients cerebrospinal fluid (CSF) and tissue showed that miR-204-3p tends to be sorted into exosomes. miR-204-3p suppressed glioma proliferation through the CACNA1C/MAPK pathway. hnRNP A2/B1 can accelerate exosome sorting of miR-204-3p by binding a specific sequence. Hypoxia plays an important role in exosome sorting of miR-204-3p. Hypoxia can upregulate miR-204-3p by upregulating the translation factor SOX9. Hypoxia promotes the transfer of hnRNP A2/B1 to the cytoplasm by upregulating SUMOylation of hnRNP A2/B1 to eliminate miR-204-3p. Exosomal miR-204-3p promoted tube formation of vascular endothelial cells through the ATXN1/STAT3 pathway. The SUMOylation inhibitor TAK-981 can inhibit the exosome-sorting process of miR-204-3p to inhibit tumor growth and angiogenesis. This study revealed that glioma cells can eliminate the suppressor miR-204-3p to accelerate angiogenesis under hypoxia by upregulating SUMOylation. The SUMOylation inhibitor TAK-981 could be a potential drug for glioma. This study revealed that glioma cells can eliminate the suppressor miR-204-3p to accelerate angiogenesis under hypoxia by upregulating SUMOylation. The SUMOylation inhibitor TAK-981 could be a potential drug for glioma.

Hypoxia-induced circADAMTS6 in a TDP43-dependent manner accelerates glioblastoma progression via ANXA2/ NF-κB pathway.

Circular RNAs (circRNAs) play important roles in the malignant progression of tumours. Herein, we identified an unreported circRNA (hsa-circ-0072688, also named circADAMTS6) that is specifically upregulated in the hypoxic microenvironment of glioblastoma and closely correlated with poor prognosis of gliblastoma patients. We found that circADAMTS6 promotes the malignant progression of glioblastoma by promoting cell proliferation and inhibiting apoptosis. Mechanistically, the hypoxic tumour microenvironment upregulates circADAMTS6 expression through transcription factor activator protein 1 (AP-1) and RNA-binding protein TAR DNA-binding protein 43 (TDP43). Moreover, circADAMTS6 accelerates glioblastoma progression by recruiting and stabilising annexin A2 (ANXA2) in a proteasomes-dependent manner. Furthermore, we found T-5224 (AP-1 inhibitor) treatment induces downregulation of circADAMTS6 and then inhibits tumour growth. In conclusion, our findings highlight the important role of the circADAMTS6/ANXA2 axis based on hypoxic microenvironment in glioblastoma progression, as well as its regulation in NF-κB pathway. Targeting circADAMTS6 is thus expected to become a novel therapeutic strategy for glioblastoma.

Bioinformatics analysis of immune-related prognostic genes and immunotherapy in renal clear cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor, and investigating the immunorelated genes is essential. To investigate the immunoprognostic genes of ccRCC, we analyzed the data assimilated from a public database (The Cancer Genome Atlas (TCGA) database and the gene expression omnibus (GEO) database) using bioinformatics. Then, an immunoprognosis model was constructed to identify four hub genes with moderate predictive values for the prognosis of ccRCC patients. These four genes were associated with the prognosis of ccRCC patients based on Oncomine and Gena Expression Profiling Interactive Analysis (GEPIA) databases. The correlation analysis between the immune infiltrate, immune checkpoints, and immunotherapy and this immunoprognosis model showed that immune infiltration could predict the immunotherapy effects. We also conducted a quantitative real-time polymerase chain reaction analysis and found that the expressions of three hub genes were associated with tumor progression (P<0.1). In conclusion, four genes that may serve as potential biomarkers in ccRCC were identified with respect to prognosis.

Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression.

Exosomes can selectively secrete harmful metabolic substances from cells to maintain cellular homeostasis, and complex crosstalk occurs between exosomes and tumor-associated macrophages (TAMs) in the glioma immune microenvironment. However, the precise mechanisms by which these exosome-encapsulated cargos create an immunosuppressive microenvironment remain unclear. Herein, we investigated the effect of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We performed sequencing analysis of cerebrospinal fluid (CSF) and tumor tissues from glioma patients to identify functional microRNAs (miRNAs). High levels of miR-3591-3p were found in CSF and GDEs but not in normal brain tissue or glial cells. Functionally, GDEs and miR-3591-3p significantly induced M2 macrophage polarization and increased the secretion of IL10 and TGFß1, which in turn promoted glioma invasion and migration. Moreover, miR-3591-3p overexpression in glioma cell lines resulted in G2/M arrest and markedly increased apoptosis. Mechanistically, miR-3591-3p can directly target CBLB and MAPK1 in macrophages and glioma cells, respectively, and further activate the JAK2/PI3K/AKT/mTOR, JAK2/STAT3, and MAPK signaling pathways. In vivo experiments confirmed that macrophages lentivirally transduced with miR-3591-3p can significantly promote glioma progression. Thus, our study demonstrates that tumor-suppressive miR-3591-3p in glioma cells can be secreted via exosomes and target TAMs to induce the formation of an immunosuppressive microenvironment. Collectively, these findings provide new insights into the role of glioma exosomal miRNAs in mediating the establishment of an immunosuppressive tumor microenvironment and show that miR-3591-3p may be a valuable biomarker and that blocking the encapsulation of miR-3591-3p into exosomes may become a novel immunotherapeutic strategy for glioma.

The N6-methyladenosine-mediated lncRNA WEE2-AS1 promotes glioblastoma progression by stabilizing RPN2.

Background: Glioblastoma (GBM) is the most common primary brain malignancy and has high aggressiveness and a poor prognosis. N6-methyladenosine (m6A) represents the most prevalent methylation modification of lncRNAs and has been shown to play important roles in the pathophysiological processes of tumors. However, the distribution and function of m6A modifications in lncRNAs in GBM tissues have not been fully revealed. Methods: The global depiction of m6A-modified lncRNA expression patterns in GBM tumor tissues was screened via m6A high-throughput sequencing. Gain- and loss-of-function assays were performed to investigate the role of WEE2-AS1 in GBM. Mass spectrometry and RNA-pulldown, RNA immunoprecipitation (RIP), luciferase reporter and coimmunoprecipitation assays were performed to explore the mechanism of m6A-mediated upregulation of WEE2-AS1 expression and the downstream mechanism promoting the malignant progression of GBM. Results: Herein, we report the differential expression profile of m6A-modified lncRNAs in human GBM tissues for the first time. WEE2-AS1 was identified as a novel m6A-modified lncRNA that promotes GBM progression and was post-transcriptionally stabilized by IGF2BP3, an m6A reader. Moreover, we confirmed that WEE2-AS1 promoted RPN2 protein stabilization by preventing CUL2-mediated RPN2 K322 ubiquitination, thereby contributing to GBM malignant progression by activating the PI3K-Akt signaling pathway. In translational medicine, we found that blocking WEE2-AS1 expression improved the therapeutic sensitivity of dasatinib, a central nervous system penetrant that is FDA-approved in GBM. Conclusions: Overall, this work highlights that WEE2-AS1 may serve as a potential prognostic biomarker and therapeutic target in GBM, the knockdown of which significantly improves the efficacy of dasatinib, providing a promising strategy for improving targeted combination therapy for GBM patients.

Pancancer landscape analysis of the thymosin family identified TMSB10 as a potential prognostic biomarker and immunotherapy target in glioma.

BACKGROUND: Thymosin family genes (TMSs), biologically important peptides with diverse intracellular and extracellular functions, have been shown to promote the progression of multiple cancers. However, multiomics characterization of TMSs and their role in human cancer prognosis has not been systematically performed. METHODS: We performed a comprehensive analysis of TMSs and thymosin ß10 (TMSB10) using multiomics data from more than 10,000 tumor samples of 33 cancer types from The Cancer Genome Atlas (TCGA). We used single-sample gene set enrichment analysis (ssGSEA) and the gene set variation analysis (GSVA) algorithm to investigate the differences in tumor microenvironment (TME) cell infiltration and functional annotation for individual tumor samples, respectively. The role of TMSB10 in the malignant progression of glioma, the promotion of macrophage infiltration,and immunosuppressive polarization, and the combination drug efficacy were assessed via biological function assays. RESULTS: We comprehensively assessed genomic mutations, expression dysregulation, prognosis and immunotherapeutic response across 33 human cancer samples and showed that TMSB10 is specifically overexpressed in almost all types of cancer tissues. Further pan-cancer analysis showed that TMSB10 is closely related to the biological function, immune regulation and prognosis of glioma. Similar results were also found in several public glioma cohorts and our Qilu local cohort. Further integration with other biological experiments revealed the key roles of TMSB10 in the malignant progression of glioma, the promotion of macrophage infiltration and immunosuppressive polarization. We also identified multiple drugs targeting cells with high TMSB10 expression and validated that knockdown of TMSB10 improved the efficacy of selumetinib (a MEK1/2 inhibitor approved by the FDA for the treatment of neurofibromatosis-associated tumors) and anti-PD1 treatment in glioma. CONCLUSION: These results indicate that TMSB10 holds promise as a novel prognostic marker and therapeutic target, providing a theoretical basis for the development of more effective and targeted clinical treatment strategies for glioma patients.

Positioning an Agenda on a Loving Pedagogy in Second Language Acquisition: Conceptualization, Practice, and Research.

Second/foreign language teaching has been found as one of the most emotional professions worldwide. To generate optimal academic outcomes and run an effective education, teachers and students' emotions and feelings must be positively cared for. Given the significance of emotions in L2 education, many studies have followed positive psychology (PP) and examined various positive constructs. Nevertheless, love, as a PP variable, has been ignored in education due to its cultural/religious sensitivities. Trying to dispel the myths, recently, a new trend called a "loving pedagogy" has started to find itself a place in second language acquisition (SLA) research and practice. Yet, proposing a model of its application and an agenda for its research has been overlooked by scholars in this domain. Motivated by this lacuna, this research article provided the conceptualization, definitions, research bases, practical models, and implications of a loving pedagogy for SLA practitioners and future researchers.

Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.

Glioblastoma (GBM) is one of the most fatal central nervous system tumors and lacks effective or sufficient therapies. Ferroptosis is a newly discovered method of programmed cell death and opens a new direction for GBM treatment. However, poor blood-brain barrier (BBB) penetration, reduced tumor targeting ability, and potential compensatory mechanisms hinder the effectiveness of ferroptosis agents during GBM treatment. Here, a novel composite therapeutic platform combining the magnetic targeting features and drug delivery properties of magnetic nanoparticles with the BBB penetration abilities and siRNA encapsulation properties of engineered exosomes for GBM therapy is presented. This platform can be enriched in the brain under local magnetic localization and angiopep-2 peptide-modified engineered exosomes can trigger transcytosis, allowing the particles to cross the BBB and target GBM cells by recognizing the LRP-1 receptor. Synergistic ferroptosis therapy of GBM is achieved by the combined triple actions of the disintegration of dihydroorotate dehydrogenase and the glutathione peroxidase 4 ferroptosis defense axis with Fe3 O4 nanoparticle-mediated Fe2+ release. Thus, the present findings show that this system can serve as a promising platform for the treatment of glioblastoma.