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Abstract Previous studies have found that the peripheral immune environment is closely related to the occurrence and development of intracranial aneurysms. However, it remains unclear how the metabolism of peripheral blood mononuclear cells (PBMCs) and the composition of polymorphonuclear leukocytes (PMNs) changes in the process of intracranial aneurysm rupture. This study utilized cytometry by time of flight technology to conduct single‐cell profiling analysis of PBMCs and PMNs from 72 patients with IAs. By comparing the expression differences of key metabolic enzymes in PBMCs between patients with ruptured intracranial aneurysms (RIAs) and unruptured intracranial aneurysms, we found that most PBMCs subsets from RIA group showed upregulation of rate‐limiting enzymes related to the glycolytic pathway. By comparing the composition of PMNs, it was found that the proinflammatory CD101+HLA DR+ subsets were increased in the RIA group, accompanied by a decrease in the anti‐inflammatory polymorphonuclear myeloid‐derived suppressor cells. In conclusion, this study showed the changes in the peripheral immune profile of RIAs, which is helpful for our understanding of the mechanisms underlying peripheral changes and provides a direction for future related research.

Abstract At present, there is limited research on the mechanisms underlying moyamoya disease (MMD). Herein, we aimed to determine the role of glutamine in MMD pathogenesis, and 360 adult patients were prospectively enrolled. Human brain microvascular endothelial cells (HBMECs) were subjected to Integrin Subunit Beta 4 (ITGB4) overexpression or knockdown and atorvastatin. We assessed factors associated with various signaling pathways in the context of the endothelial‐to‐mesenchymal transition (EndMT), and the expression level of related proteins was validated in the superficial temporal arteries of patients. We found glutamine levels were positively associated with a greater risk of stroke (OR = 1.599, p = 0.022). After treatment with glutamine, HBMECs exhibited enhanced proliferation, migration, and EndMT, all reversed by ITGB4 knockdown. In ITGB4‐transfected HBMECs, the MAPK–ERK–TGF–β/BMP pathway was activated, with Smad4 knockdown reversing the EndMT. Furthermore, atorvastatin suppressed the EndMT by inhibiting Smad1/5 phosphorylation and promoting Smad4 ubiquitination in ITGB4‐transfected HBMECs. We also found the protein level of ITGB4 was upregulated in the superficial temporal arteries of patients with MMD. In conclusion, our study suggests that glutamine may be an independent risk factor for hemorrhage or infarction in patients with MMD and targeting ITGB4 could potentially be therapeutic approaches for MMD.

Abstract Background Moyamoya disease (MMD) stands as a prominent cause of stroke among children and adolescents in East Asian populations. Although a growing body of evidence suggests that dysregulated inflammation and autoimmune responses might contribute to the development of MMD, a comprehensive and detailed understanding of the alterations in circulating immune cells associated with MMD remains elusive. Methods In this study, we employed a combination of single‐cell RNA sequencing (scRNA‐seq), mass cytometry and RNA‐sequencing techniques to compare immune cell profiles in peripheral blood samples obtained from patients with MMD and age‐matched healthy controls. Results Our investigation unveiled immune dysfunction in MMD patients, primarily characterized by perturbations in T‐cell (TC) subpopulations, including a reduction in effector TCs and an increase in regulatory TCs (Tregs). Additionally, we observed diminished natural killer cells and dendritic cells alongside heightened B cells and monocytes in MMD patients. Notably, within the MMD group, there was an augmented proportion of fragile Tregs, whereas the stable Treg fraction decreased. MMD was also linked to heightened immune activation, as evidenced by elevated expression levels of HLA‐DR and p‐STAT3. Conclusions Our findings offer a comprehensive view of the circulating immune cell landscape in MMD patients. Immune dysregulation in patients with MMD was characterized by alterations in T‐cell populations, including a decrease in effector T‐cells and an increase in regulatory T‐cells (Tregs), suggest a potential role for disrupted circulating immunity in the aetiology of MMD.

Abstract Background Intracranial aneurysms (IAs) represent a severe cerebrovascular disease that can potentially lead to subarachnoid haemorrhage. Previous studies have demonstrated the involvement of peripheral immune cells in the formation and progression of IAs. Nevertheless, the impact of metabolic alterations in peripheral immune cells and changes in neutrophil heterogeneity on the occurrence and progression of IAs remains uncertain. Methods Single‐cell Cytometry by Time‐of‐Flight (CyTOF) technology was employed to profile the single‐cell atlas of peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) in 72 patients with IAs. In a matched cohort, metabolic shifts in PBMC subsets of IA patients were investigated by contrasting the expression levels of key metabolic enzymes with their respective counterparts in the healthy control group. Simultaneously, compositional differences in peripheral blood PMNs subsets between the two groups were analysed to explore the impact of altered heterogeneity in neutrophils on the initiation and progression of IAs. Furthermore, integrating immune features based on CyTOF analysis and clinical characteristics, we constructed an aneurysm occurrence model and an aneurysm growth model using the random forest method in conjunction with LASSO regression. Results Different subsets exhibited distinct metabolic characteristics. Overall, PBMCs from patients elevated CD98 expression and increased proliferation. Conversely, CD36 was up‐regulated in T cells, B cells and monocytes from the controls but down‐regulated in NK and NKT cells. The comparison also revealed differences in the metabolism and function of specific subsets between the two groups. In terms of PMNs, the neutrophil landscape within patients group revealed a pronounced shift towards heightened complexity. Various neutrophil subsets from the IA group generally exhibited lower expression levels of anti‐inflammatory functional molecules (IL‐4 and IL‐10). By integrating clinical and immune features, the constructed aneurysm occurrence model could precisely identify patients with IAs with high prediction accuracy (AUC = 0.987). Furthermore, the aneurysm growth model also exhibited superiority over ELAPSS scores in predicting aneurysm growth (lower prediction errors and out‐of‐bag errors). Conclusion These findings enhanced our understanding of peripheral immune cell participation in aneurysm formation and growth from the perspectives of immune metabolism and neutrophil heterogeneity. Moreover, the predictive model based on CyTOF features holds the potential to aid in diagnosing and monitoring the progression of human IAs.

Abstract Owing to their superior capabilities and advanced achievements, Transformers have gradually attracted attention with regard to understanding complex brain processing mechanisms. This study aims to comprehensively review and discuss the applications of Transformers in brain sciences. First, we present a brief introduction of the critical architecture of Transformers. Then, we overview and analyze their most relevant applications in brain sciences, including brain disease diagnosis, brain age prediction, brain anomaly detection, semantic segmentation, multi‐modal registration, functional Magnetic Resonance Imaging (fMRI) modeling, Electroencephalogram (EEG) processing, and multi‐task collaboration. We organize the model details and open sources for reference and replication. In addition, we discuss the quantitative assessments, model complexity, and optimization of Transformers, which are topics of great concern in the field. Finally, we explore possible future challenges and opportunities, exploiting some concrete and recent cases to provoke discussion and innovation. We hope that this review will stimulate interest in further research on Transformers in the context of brain sciences.

Abstract Due to the extremely intrinsic heterogeneity among glioma patients, the outcomes of these patients are tremendously different. Therefore, the exploitation of novel biomarker classification of glioma is vitally important for deep insight into the essence and predicting the prognosis of glioma. We aim to analyze the correlation between TP73 mRNA expression, DNA methylated alteration and the prognosis of WHO grade II/III glioma, utilizing bioinformatics to evaluate its significance as a risk‐factor in predicting the prognosis of these glioma patients. The analysis found that TP73 expression was positively correlated with the grade of glioma, and showed a strong correlation with glioma molecular classification, which revealed significantly higher TP73 expression in IDH‐wildtype than in IDH‐mutant subtype of WHO grade II/III glioma. Cox regression analysis indicated that high expression of TP73 shared an independent high‐risk factor impacting the prognosis of WHO grade II/III glioma. We discovered 8 DNA promoter methylation sites with prognostic significance, which were negatively associated with TP73 expression, and positively associated with beneficial overall survival (OS) and progression‐free survival (PFS). Integrating with four independent glioma datasets, subsequent Meta‐analysis verified that low expression of TP73 was closely related to favorable OS, especially in IDH‐mutant subtype. Moreover, we found that 1p/19qCodel/TP73low subgroup shared the most favorable OS, 1p/19qNon−codel/TP73high subgroup suffered the worst OS. Meanwhile, the enrichment analysis of TP73‐related differential mRNAs demonstrated that TP73 aberration in WHO grade II/III glioma might be closely related to cell cycle and P53 signaling pathways. Finally, TP73 expression of 53 glioma specimens was measured by qRT‐PCR, which was consistent with the previous analytical result, and TP73 high‐expression subgroup suffered worse PFS than TP73 low‐expression subgroup. In summary, our funding supports that TP73 gene can perform as a reliable biomarker to evaluate the survival outcome of patients diagnosed with WHO grade II/III glioma.

Abstract Glioma is the most common intracranial malignant tumors, accounting for about 40% of intracranial tumors. Primary or secondary drug resistance is one of the main reasons for the failure of treatment. The oncogenic or tumor‐suppressive roles of miR‐634 have been revealed in different types of cancer. However, the role of miR‐634 in glioma remains unknown and whether miR‐634 could sensitize glioma cells to temozolomide also is unclear. Here, we aim to investigate the biological function of miR‐634 and the possible mechanisms in glioma. In this study, we found that miR‐634 was downregulated in glioma tissues compared with normal brain tissues, and its expression was associated with tumor size and WHO grade. Importantly, glioma patients with low miR‐634 expression showed a shorter survival time than patients which had high expression of miR‐634. This study also showed that miR‐634 was decreased in temozolomide‐resistant glioma cells, and restoration of miR‐634 could sensitize the resistant cells to temozolomide by targeting CYR61 through Raf‐ERK signaling. Our study provides a potential target for overcome drug resistance in glioma.

Background The blood flow rate of brain arteriovenous malformations (bAVMs) is an important clinical characteristic closely associated with the hemorrhage risk and radiosurgery obliteration rate of bAVMs. However, the underlying molecular properties remain unclear. To identify potential key molecules, signaling pathways, and vascular cell types involved, we compared gene expression profiles between bAVMs with high flow rates and low flow rates (LFR) and validated the functions of selected key molecules in vitro. Methods and Results We performed RNA‐sequencing analysis on 51 samples, including 14 high flow rate bAVMs and 37 LFR bAVMs. Functional pathway analysis was performed to identify potential signals influencing the flow rate phenotype of bAVMs. Candidate genes were investigated in bAVM specimens by immunohistochemical staining. Migration, tube formation, and proliferation assays were used to test the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells and human brain vascular smooth muscle cells. We identified 250 upregulated and 118 downregulated genes in LFR bAVMs compared with high flow rate bAVMs. Wnt signaling was activated in the LFR group via upregulation of FZD10 and MYOC. Immunohistochemical staining showed that vascular endothelial and smooth muscle cells of LFR bAVMs exhibited increased FZD10 and MYOC expression. Experimentally elevating these genes promoted human umbilical vein endothelial cells and migration and tube formation by activating canonical Wnt signaling in vitro. Conclusions Our results suggest that canonical Wnt signaling mediated by FZD10 and MYOC is activated in vascular endothelial and smooth muscle cells in LFR bAVMs.