Recovery of glymphatic system function in patients with temporal lobe epilepsy after surgery.

OBJECTIVES: To investigate the recovery of human glymphatic system (GS) function in patients with temporal lobe epilepsy (TLE) after successful anterior temporal lobectomy (ATL) using diffusion tensor image analysis along the perivascular space (DTI-ALPS). METHODS: We retrospectively analysed DTI-ALPS index in 13 patients with unilateral TLE before and after ATL, and compared the index with 20 healthy controls (HCs). Two-sample t tests and paired t tests were performed to analyse differences in the DTI-ALPS index between patients and HCs. The Pearson correlation analysis was used to observe the relationship between the disease duration and GS function. RESULTS: The DTI-ALPS index before ATL was significantly lower in the hemisphere ipsilateral to the epileptogenic foci than in the contralateral hemisphere of the patients (p < 0.001, t = - 4.81) and in the ipsilateral hemisphere of the HCs (p = 0.007, t = - 2.90). A significant increase in the DTI-ALPS index was found in the hemisphere ipsilateral to the epileptogenic foci after successful ATL (p = 0.01, t = - 3.01). In addition, the DTI-ALPS index of the lesion side before ATL was significantly correlated with disease duration (p = 0.04, r = - 0.59). CONCLUSIONS: DTI-ALPS may be used as a quantitative biomarker evaluating surgical outcomes and TLE disease duration. DTI-ALPS index may also help localise epileptogenic foci in unilateral TLE. Overall, our study suggests that GS may potentially serve as a new method for the management of TLE and a new direction for investigating the mechanism of epilepsy. KEY POINTS: • DTI-ALPS index may contribute to epileptogenic foci lateralisation in TLE. • DTI-ALPS index is a potential quantitative feature evaluating surgical outcomes and TLE disease duration. • The GS provides a new perspective for the study of TLE.

Topological patterns of motor networks in Parkinson's disease with different sides of onset: A resting-state-informed structural connectome study.

Parkinson's disease (PD) has a characteristically unilateral pattern of symptoms at onset and in the early stages; this lateralization is considered a diagnostically important diagnosis feature. We aimed to compare the graph-theoretical properties of whole-brain networks generated by using resting-state functional MRI (rs-fMRI), diffusion tensor imaging (DTI), and the resting-state-informed structural connectome (rsSC) in patients with left-onset PD (LPD), right-onset PD (RPD), and healthy controls (HCs). We recruited 26 patients with PD (13 with LPD and 13 with RPD) as well as 13 age- and sex-matched HCs. Rs-fMRI and DTI were performed in all subjects. Graph-theoretical analysis was used to calculate the local and global efficiency of a whole-brain network generated by rs-fMRI, DTI, and rsSC. Two-sample t-tests and Pearson correlation analysis were conducted. Significantly decreased global and local efficiency were revealed specifically in LPD patients compared with HCs when the rsSC network was used; no significant intergroup difference was found by using rs-fMRI or DTI alone. For rsSC network analysis, multiple network metrics were found to be abnormal in LPD. The degree centrality of the left precuneus was significantly correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) score and disease duration (p = 0.030, r = 0.599; p = 0.037, r = 0.582). The topological properties of motor-related brain networks can differentiate LPD and RPD. Nodal metrics may serve as important structural features for PD diagnosis and monitoring of disease progression. Collectively, these findings may provide neurobiological insights into the lateralization of PD onset.

Evaluation of the Glymphatic System Using the DTI-ALPS Index in Patients with Spontaneous Intracerebral Haemorrhage.

Objective: To investigate the function of the human glymphatic system (GS) in patients with spontaneous intracerebral haemorrhage (sICH) using diffusion tensor imaging analysis along with the perivascular space (DTI-ALPS). Methods: Twenty patients with sICH and 31 healthy controls (HCs) were recruited for DTI and susceptibility-weighted imaging scanning. The diffusivity along the perivascular spaces, as well as the projection fibres and association fibres, was evaluated separately. The DTI-ALPS index of each subject was also calculated. Two-sample t-tests and paired t-tests were performed to analyse the difference in ALPS scores between patients and HCs, as well as that between the lesion side and contralateral side. Pearson correlation analysis was used to observe the relationship between disease duration and GS function. Results: The DTI-ALPS index on the lesion side was significantly lower than that of the contralateral side in patients with sICH (p < 0.01, t = -5.77), and it was also significantly lower than that of the ipsilateral side of HCs (p < 0.01, t = -9.50). No significant differences were found in the DTI-ALPS index on the nonlesion side between patients and HCs (p = 0.96, t = 0.05) or between the left and right cerebral hemispheres of HCs (p = 0.41, t = -0.83). The DTI-ALPS index of the lesion side in patients with sICH was significantly correlated with disease duration (p = 0.018, r = 0.537). Conclusions: The present study confirmed that GS dysfunction on the ipsilateral side of the lesion is impaired in patients with haemorrhagic stroke, indicating that the GS may be a separate system in the left and right cerebral hemispheres. The DTI-ALPS index can reflect disease duration. These findings have significant implications for understanding sICH from a new perspective.

Transcription factor GATA4 drives RNA polymerase III-directed transcription and transformed cell proliferation through a filamin A/GATA4/SP1 pathway.

RNA polymerase III (pol III) products play fundamental roles in a variety of cellular processes, including protein synthesis and cancer cell proliferation. In addition, dysregulation of pol III-directed transcription closely correlates with tumorigenesis. It is therefore of interest to identify novel pathways or factors governing pol III-directed transcription. Here, we show that transcription factor (TF) GATA binding protein 4 (GATA4) expression in SaOS2 cells was stimulated by the silencing of filamin A (FLNA), a repressor of pol III-directed transcription, suggesting that GATA4 is potentially associated with the regulation of pol III-directed transcription. Indeed, we show that GATA4 expression positively correlates with pol III-mediated transcription and tumor cell proliferation. Mechanistically, we found that GATA4 depletion inhibits the occupancies of the pol III transcription machinery factors at the loci of pol III target genes by reducing expression of both TFIIIB subunit TFIIB-related factor 1 and TFIIIC subunit general transcription factor 3C subunit 2 (GTF3C2). GATA4 has been shown to activate specificity factor 1 (Sp1) gene transcription by binding to the Sp1 gene promoter, and Sp1 has been confirmed to activate pol III gene transcription by directly binding to both Brf1 and Gtf3c2 gene promoters. Thus, the findings from this study suggest that GATA4 links FLNA and Sp1 signaling to form an FLNA/GATA4/Sp1 axis to modulate pol III-directed transcription and transformed cell proliferation. Taken together, these results provide novel insights into the regulatory mechanism of pol III-directed transcription.

A novel method to investigate the effects of gene mutations at the cellular level using a dual expression lentiviral vector.

One of the conventional methods to study the effects of gene mutations is that gene mutants are transfected into mammalian cells, and the dominant effects of gene mutants in the cells are examined. However, the result obtained using this method is not always satisfactory due to the interference of endogenous expression. Whether there is a better method to investigate the effects of gene mutations in cells remains to be examined. In the present study, a novel dual expression lentiviral vector was constructed using a shRNA-expressing lentiviral vector and combined techniques. Using this dual expression system, the vectors expressing both transcription factor IIA γ (TFIIAγ) shRNA and HA-TFIIAγ or its mutants were generated, and the effects of TFIIAγ gene mutations on transcription and protein-DNA interaction were investigated. We show that the transfection of the vector expressing TFIIAγ shRNA and HA-TFIIAγ fusion gene was able to silence the expression of endogenous TFIIAγ gene but not affect that of exogenous HA-TFIIAγ fusion gene in either transiently transfected cells or stable cell lines. Mutations in the conservative domain between AA62 and AA69 in TFIIAγ inhibit the activities of promoters and endogenous gene expression, and reduce TFIIAγ binding to AdML core promoter compared with wild-type (WT) TFIIAγ. ChIP-qPCR data suggest that the TFIIAγ N63A mutant inhibits insulin-like growth factor 2 (IGF2) transcription by reducing the recruitments of TFIIAγ, polymerase II (Pol II), TATA box-binding protein (TBP), and TBP associated factor 1 (250 kDa) (TAF1) at its promoter. Our study provides a novel method that is used to investigate the effects of gene mutations at the cellular level.