Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice.

BACKGROUND: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. METHODS: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. RESULTS: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. CONCLUSION: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.

Deep Learning Segmentation and Reconstruction for CT of Chronic Total Coronary Occlusion.

Background CT imaging of chronic total occlusion (CTO) is useful in guiding revascularization, but manual reconstruction and quantification are time consuming. Purpose To develop and validate a deep learning (DL) model for automated CTO reconstruction. Materials and Methods In this retrospective study, a DL model for automated CTO segmentation and reconstruction was developed using coronary CT angiography images from a training set of 6066 patients (582 with CTO, 5484 without CTO) and a validation set of 1962 patients (208 with CTO, 1754 without CTO). The algorithm was validated using an external test set of 211 patients with CTO. The consistency and measurement agreement of CTO quantification were compared between the DL model and the conventional manual protocol using the intraclass correlation coefficient, Cohen κ coefficient, and Bland-Altman plot. The predictive values of CT-derived Multicenter CTO Registry of Japan (J-CTO) score for revascularization success were evaluated. Results In the external test set, 211 patients (mean age, 66 years ± 11 [SD]; 164 men) with 240 CTO lesions were evaluated. Automated segmentation and reconstruction of CTOs by DL was successful in 95% of lesions (228 of 240) without manual editing and in 48% of lesions (116 of 240) with the conventional manual protocol (P < .001). The total postprocessing and measurement time was shorter for DL than for manual reconstruction (mean, 121 seconds ± 20 vs 456 seconds ± 68; P < .001). The quantitative and qualitative CTO parameters evaluated with the two methods showed excellent correlation (all correlation coefficients > 0.85, all P < .001) and minimal measurement difference. The predictive values of J-CTO score derived from DL and conventional manual quantification for procedure success showed no difference (area under the receiver operating characteristic curve, 0.76 [95% CI: 0.69, 0.82] and 0.76 [95% CI: 0.69, 0.82], respectively; P = .55). Conclusion When compared with manual reconstruction, the deep learning model considerably reduced postprocessing time for chronic total occlusion quantification and had excellent correlation and agreement in the anatomic assessment of occlusion features. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Loewe in this issue.

Assessment of automatic rib fracture detection on chest CT using a deep learning algorithm.

OBJECTIVES: To evaluate deep neural networks for automatic rib fracture detection on thoracic CT scans and to compare its performance with that of attending-level radiologists using a large amount of datasets from multiple medical institutions. METHODS: In this retrospective study, an internal dataset of 12,208 emergency room (ER) trauma patients and an external dataset of 1613 ER trauma patients taking chest CT scans were recruited. Two cascaded deep neural networks based on an extended U-Net architecture were developed to segment ribs and detect rib fractures respectively. Model performance was evaluated with a 95% confidence interval (CI) on both the internal and external dataset, and compared with attending-level radiologist readings using t test. RESULTS: On the internal dataset, the AUC of the model for detecting fractures at per-rib level was 0.970 (95% CI: 0.968, 0.972) with sensitivity of 93.3% (95% CI: 92.0%, 94.4%) at a specificity of 98.4% (95% CI: 98.3%, 98.5%). On the external dataset, the model obtained an AUC of 0.943 (95% CI: 0.941, 0.945) with sensitivity of 86.2% (95% CI: 85.0%, 87.3%) at a specificity of 98.8% (95% CI: 98.7%, 98.9%), compared to the sensitivity of 70.5% (95% CI: 69.3%, 71.8%) (p < .0001) and specificity of 98.8% (95% CI: 98.7%, 98.9%) (p = 0.175) by attending radiologists. CONCLUSIONS: The proposed DL model is a feasible approach to identify rib fractures on chest CT scans, at the very least, reaching a level on par with attending-level radiologists. KEY POINTS: • Deep learning-based algorithms automatically detected rib fractures with high sensitivity and reasonable specificity on chest CT scans. • The performance of deep learning-based algorithms reached comparable diagnostic measures with attending level radiologists for rib fracture detection on chest CT scans. • The deep learning models, similar to human readers, were susceptible to the inconspicuity and ambiguity of target lesions. More training data was required for subtle lesions to achieve comparable detection performance.

Cost-effectiveness of pemigatinib as a second-line treatment for advanced intrahepatic cholangiocarcinoma with fibroblast growth factor receptor 2 fusions in Taiwan: from the evidence of the phase II trial and the perspective of Taiwan's National Health Insurance Administration.

BACKGROUND: In December 2022, the Taiwan National Health Insurance Administration (NHIA) announced the reimbursement of three dosages of pemigatinib 4.5 mg, 9 mg, and 13.5 mg for treating advanced intrahepatic cholangiocarcinoma (ICC) with fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements and set the reimbursement price for pemigatinib 4.5 mg at NT$6600. This study aims to analyze the cost-effectiveness of pemigatinib 13.5 mg as a second-line treatment compared to mFOLFOX and 5-FU chemotherapy for advanced ICC patients with FGFR2 fusions/rearrangements from the perspective of Taiwan's NHIA. METHODS: This study used a 3-state partitioned survival model to analyze the 5 year cost-effectiveness of pemigatinib as a second-line treatment for advanced ICC patients in whom first-line gemcitabine-based chemotherapy failed and to compare the results with those for the mFOLFOX and 5-FU chemotherapy regimens. Overall survival and progression-free survival were estimated from the FIGHT-202 trial (pemigatinib), ABC-06 trial (mFOLFOX), and NIFTY trial (5-FU). The price of pemigatinib 13.5 mg was set at the potentially highest listing price (NT$17,820). Other parameters of utility, disutility, and costs related to advanced ICC were obtained from the published literature. The willingness-to-pay threshold was three times the forecasted gross domestic product per capita in 2022 (NT$2,928,570). A 3% discount rate was applied to quality-adjusted life-years (QALYs) and costs. Several scenario analyses were performed, including a gradual price reduction for pemigatinib. Deterministic sensitivity analysis, probabilistic sensitivity analysis (PSA), and value of information were performed to assess uncertainty. RESULTS: Pemigatinib was not cost-effective compared to mFOLFOX or 5-FU in the base-case analysis. When the price of pemigatinib was reduced by 50% or more, pemigatinib gained a positive net monetary benefit (mFOLFOX: NT$55,374; 5-FU: NT$92,437) and a 72% (mFOLFOX) and 77.1% (5-FU) probability of being cost-effective. Most of the uncertainty came from the medication cost of pemigatinib, health state utility, and the overall survival associated with pemigatinib. CONCLUSIONS: According to the NCCN guidelines, the daily use of pemigatinib 13.5 mg at the hypothesized NHIA price of NT$17,820/13.5 mg was not cost-effective compared to mFOLFOX or 5-FU. The price reduction scenario suggested a 50% price reduction, NT$8910 per 13.5 mg, for advanced ICC patients with FGFR2 fusions/rearrangements.

This study performed a cost-effectiveness analysis on the use of targeted therapy pemigatinib 13.5 mg daily in second-line treatment for Taiwanese patients with intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusions/rearrangements. This regimen was approved by the U.S. Food and Drug Administration in 2020 and recommended by the National Comprehensive Cancer Network (NCCN). Taiwan's National Health Insurance Administration (NHIA) has announced the reimbursement of three pemigatinib dosages of 4.5 mg, 9 mg, and 13.5 mg to be listed in the NHI coverage in 2022. However, as of the middle of April 2023, only the listing price for pemigatinib 4.5 mg has been determined, while pricing for the other two dosages remains pending. Based on a hypothesized NHIA price of NT$17,820/13.5 mg, this study evaluated the cost-effectiveness of pemigatinib 13.5 mg as a second-line treatment for advanced ICC with FGFR2 fusions/rearrangements compared to mFOLFOX (a regimen recommended by NCCN) and 5-FU (a regimen fully covered by Taiwan NHIA) and recommended a listing price for NHIA as reference. Our study showed that the hypothesized price of NT$17,820/13.5 mg was not cost-effective compared to mFOLFOX or 5-FU. The price reduction scenario suggested a 50% reduction (NT$8910) in the hypothesized NHIA price for advanced ICC patients with FGFR2 fusions/rearrangements.

Clinical features and outcomes of pediatric intracranial gliomas: results from single center's 226 cases and corroborated with SEER database.

BACKGROUND: Pediatric gliomas are the most common central nervous system (CNS) tumors in children and adolescents and show different clinical and histopathological characteristics from the adult. The prognostic factors were poorly defined in pediatric intracranial gliomas. METHODS: We collected pediatric intracranial glioma cases in our institution between February 2011 and June 2022. The patient clinical data, tumor growth characteristics, treatments, and follow-up data were analyzed by Cox regression analysis to identify impact factors on the prognosis of pediatric intracranial glioma patients. To corroborate our data, an independent cohort of pediatric intracranial glioma from the Surveillance, Epidemiology, and End Results Program (SEER) database was analyzed. RESULTS: A total of 181 cases of pediatric low-grade glioma (PLGG) and 45 cases of pediatric high-grade glioma (PHGG) were included. In multivariate Cox regression analysis, tumor size > 59.5 mm (p = 0.006) and non-gross total resection (non-GTR; subtotal resection, STR, p = 0.042; biopsy, p = 0.012) were associated with decreased overall survival (OS) in PLGG patients. In PHGG patients, only chemotherapy (p = 0.023) was associated with OS while tumor size was marginally prognostic for OS (p = 0.051). Additional independent analysis of 2734 PLGG and 741 PHGG from the SEER database corroborated that larger tumor size was associated with decreased OS in LGG (p = 0.001) and HGG (p < 0.001) patients, separately. CONCLUSION: In this study, we found that tumor size was a significant prognostic factor for the OS of PLGG patients in our series. Besides the tumor size, the extent of resection also independently impacted the prognosis of PLGG patients. While in PHGG patients, only chemotherapy was associated with improved OS and tumor size was marginally prognostic.

Growing and symptomatic intracranial arachnoid cyst in an elderly patient: a case report and literature review.

We report an elderly patient with a symptomatic and growing arachnoid cyst. Physician should be cautious in counseling asymptomatic arachnoid cyst patients, regardless of their age, and inform them of the possibility, although rare, of growth and symptom development even in their late life.

Gustatory event-related potential alterations in olfactory dysfunction patients.

The phenomenon that longstanding impaired olfactory function is associated with the decreased gustatory function was described in present studies, which was seems attributed to mutual chemosensory interactions. And the interaction between olfaction and gustation still needs more research to figure out. The objective of the study was to investigate how the taste was influenced by olfactory impairment in the central pathway. We tested 33 subjects with normal (n = 19) or impaired (n = 14) olfactory function for their gustatory event-related potentials (gERPs). Validated tests were used for olfactory and gustatory testing (Sniffin' Sticks, gERPs, and three-drop test). This study reported an objective gustatory function decline in olfactory dysfunction participants. However, it also reported the increased gustatory event-related potentials of olfactory dysfunction participants, especially at the frontal electrode (FZ) and electrode 16 (E16), and the reduced latency of P2 peak of them at electrode 21 (E21), while no obvious difference was observed at the centro-parietal electrode (PZ). Inferior insula might be the main response area for the increase in gERPs, and this increase averaged amplitude of the P2 component may attribute to compensation of the secondary gustatory response that occurred in the gustatory processing of olfactory-impaired patients.

Clinical significance of the cognition-related pathogenic proteins in plasma neuronal-derived exosomes among normal cognitive adults over 45 years old with olfactory dysfunction.

OBJECTIVES: Exosomal Phospho-Tau-181(P-T181-tau), Total tau (T-tau), and amyloid-ß peptide 42 (Aß42) have been proved the capacity for the amnestic mild cognitive impairment (MCI) and the diagnosis of Alzheimer's disease (AD). This study aimed to explore the cognitive function and the levels of P-T181-tau, T-tau, and Aß42 in neuronal-derived exosomes (NDEs) extracted from plasma in normal cognitive adults over 45 years old with olfactory dysfunction. METHODS: A cross-sectional survey of 29 participants aged over 45 was conducted. Plasma exosomes were isolated, precipitated, and enriched by immuno-absorption with anti- L1 cell adhesion molecule (L1CAM) antibody. NDEs were characterized by CD81, and extracted NDE protein (P-T181-tau, T-tau, and Aß42) biomarkers were quantified by enzyme-linked immunosorbent assay (ELISAs). Olfactory performance was assessed by Sniffin' Sticks and cognitive performance was assessed by Montreal Cognitive Assessment (MoCA). RESULTS: There was no significant difference between adults with olfactory dysfunction and without olfactory dysfunction regarding the cognitive function as measured by MoCA and all the participants showed normal cognition. Adults with olfactory dysfunction showed a higher concentration of P-T181-tau in plasma NDEs than did adults without olfactory dysfunction (P = 0.034). Both the levels of P-T181-tau (r = - 0.553, P = 0.003) and T-tau (r = - 0.417, P = 0.034) negatively correlated with the odor identification scores. In addition, the level of T-tau negatively correlated with MoCA scores (r = - 0.597, P = 0.002). The levels of P-T181-tau (r = - 0.464, P = 0.022) and T-tau (r = - 0.438, P = 0.032) negatively correlated with the delayed recall scores. CONCLUSIONS: This study demonstrated that cognition-related pathogenic proteins including P-T181-tau in plasma NDEs were significantly increased in adults over 45 years old with olfactory dysfunction before the occurrence of cognitive impairment. The impaired odor identification and the delayed recall function were highly associated with the increased levels of P-T181-tau and T-tau in plasma NDEs.

Septin 7 is a centrosomal protein that ensures S phase entry and microtubule nucleation by maintaining the abundance of p150glued.

Septins play important roles in regulating development and differentiation. Septin 7 (SEPT7) is a crucial component in orchestrating the septin core complex into highly ordered filamentous structures. Here, we showed that genetic depletion of SEPT7 or treatment with forchlorfenuron (FCF; a compound known to affect septin filament assembly) led to reduced the S phase entry in cell models and zebrafish embryos. In addition to colocalizing with actin filaments, SEPT7 resided in the centrosome, and SEPT7 depletion led to aberrant mitotic spindle pole formation. This mitotic defect was rescued in SEPT7-deficient cells by wild-type SEPT7, suggesting that SEPT7 maintained mitotic spindle poles. In addition, we observed disorganized microtubule nucleation and reduced cell migration with SEPT7 depletion. Furthermore, SEPT7 formed a complex with and maintained the abundance of p150glued , the component of centriole subdistal appendages. Depletion of p150glued resulted in a phenotype reminiscent of SEPT7-deficient cells, and overexpression of p150glued reversed the defective phenotypes. Thus, SEPT7 is a centrosomal protein that maintains proper cell proliferation and microtubule array formation via maintaining the abundance of p150glued .

Surgical fenestration might not be the best option for very young patients with middle fossa arachnoid cysts.

PURPOSE: Surgical fenestration is widely accepted as a primary treatment for middle fossa arachnoid cysts (MFACs) in pediatric patients. However, postoperative subdural effusion and/or hydrocephalus always affect treatment outcomes. In this study, we presented our experience of treating MFACs with surgical fenestration in pediatric patients and analyzed the cases complicated by postoperative subdural effusion and/or hydrocephalus, to give insight into the clinical characteristics predisposing the complications. METHODS: We retrospectively analyzed 21 pediatric cases with MFACs treated by surgical fenestration suffering postoperative subdural effusion and/or hydrocephalus in our department from November 2011 to April 2019. We reviewed the clinical characteristics and treatment outcomes. RESULTS: A total of 21 patients, among a total of 53 pediatric patients with MFACs treated by surgical fenestration, developed subdural effusion and/or hydrocephalus postoperatively. The mean age at the time of the initial surgery was 49 months. A total of 75% (6/8) of the patients under 2 years old and 13.3% (6/45) of the older patient group sustaining postoperative subdural effusion and/or hydrocephalus required further surgeries, respectively (Fisher's exact test, p = 0.001). Notably, among the 21 cases with postoperative subdural effusion and/or hydrocephalus, all the 6 patients under 2 years old needed additional surgeries, while of the other 15 older patients, only 40% (6/15) needed further surgical interventions (Fisher's exact test, p = 0.019). CONCLUSION: The immature CSF absorption in MFAC patients younger than 2 years old might predispose them to the relatively serious postoperative subdural effusion and/or hydrocephalus. For very young patients with giant MFACs, surgical fenestration might not be the best option.

Persistent thallium contamination in river sediments, source apportionment and environmental implications.

The adverse impacts of detrimental thallium (Tl) contamination are of increasing concerns to sustainable development. Herein, the contents, distributions and sources of Tl and potential toxic elements (PTEs) (Pb, As, Cr, Cu, Ni, Co, Sb, Cd and U) were investigated in sediments collected in Gaofeng River, which has been contaminated by long-term mining activities, located in Yunfu City, Southern China. Results indicated that excessive Tl levels were found in sediments (1.80-16.70 mg/kg). Sequential extraction procedure indicated that despite a large amount of Tl entrapped in residual fraction, a significant level of Tl (0.28-2.34 mg/kg) still exhibited in geochemically labile fractions, which was easy for Tl mobilization and availability. Pb isotope tracing method further confirmed that the pyrite exploitations may be the prime contaminated contributor (47-76%) to these sediments. These findings highlight that it is essential to establish more effective measures for Tl contamination control and call for engineered remediation countermeasures towards polluted river sediments.

Shunt Dependency Syndrome after Cyst-Peritoneal Shunt Resolved by Keyhole Microsurgical Cyst Resection: Two Case Reports and Literature Review.

OBJECTIVE: Shunt dependency syndrome after cyst-peritoneal (CP) shunt is a rare but serious complication which leads to increased intracranial pressure and neurological deficit. The possible mechanism still remains in controversy. We present our experience on the treatment of the complication and attempt to find a better therapy strategy for the complication. METHODS: Two children with middle fossa arachnoid cysts underwent CP shunt with fixed pressure catheters at an opening pressure of 7 cmH2O and then developed dependency syndrome. Both patients were effectively treated by mini-invasive cyst wall excision with the shunts reserved. The clinical manifestation, radiological findings, treatment methods, and therapeutic outcomes were reviewed retrospectively. RESULTS: The time from shunt surgery to shunt dependency syndrome occurrence was 4 and 2 years, respectively. Computed tomography/magnetic resonance findings of the brain showed remarkably collapsed cysts with normal or small ventricles. Both patients underwent secondary mini-invasive cyst wall excision and shunt catheters were reserved. After the operations, their symptoms were resolved except one case with marginally improved visual impairment. CONCLUSION: Shunt dependency syndrome is a rare but dangerous complication of CP shunt and should be treated in time. Collapsed and thickened cyst wall intermittent covering the catheter head end, decreased brain compliance due to chronic fibrosis, as well as regression of cerebrospinal fluid absorption could be the pathogenesis. We suggest keyhole resection of the residual cyst wall as an effective and mini-invasive treatment option.

Gene expression profiling analysis of CRTC1-MAML2 fusion oncogene-induced transcriptional program in human mucoepidermoid carcinoma cells.

BACKGROUND: Mucoepidermoid carcinoma (MEC) arises from multiple organs and accounts for the most common types of salivary gland malignancies. Currently, patients with unresectable and metastatic MEC have poor long-term clinical outcomes and no targeted therapies are available. The majority of MEC tumors contain a t(11;19) chromosomal translocation that fuses two genes, CRTC1 and MAML2, to generate the chimeric protein CRTC1-MAML2. CRTC1-MAML2 displays transforming activity in vitro and is required for human MEC cell growth and survival, partially due to its ability to constitutively activate CREB-mediated transcription. Consequently, CRTC1-MAML2 is implicated as a major etiologic molecular event and a therapeutic target for MEC. However, the molecular mechanisms underlying CRTC1-MAML2 oncogenic action in MEC have not yet been systematically analyzed. Elucidation of the CRTC1-MAML2-regulated transcriptional program and its underlying mechanisms will provide important insights into MEC pathogenesis that are essential for the development of targeted therapeutics. METHODS: Transcriptional profiling was performed on human MEC cells with the depletion of endogenous CRTC1-MAML2 fusion or its interacting partner CREB via shRNA-mediated gene knockdown. A subset of target genes was validated via real-time RT-PCR assays. CRTC1-MAML2-perturbed molecular pathways in MEC were identified through pathway analyses. Finally, comparative analysis of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles was carried out to assess the contribution of CREB in mediating CRTC1-MAML2-induced transcription. RESULTS: A total of 808 differentially expressed genes were identified in human MEC cells after CRTC1-MAML2 knockdown and a subset of known and novel fusion target genes was confirmed by real-time RT-PCR. Pathway Analysis revealed that CRTC1-MAML2-regulated genes were associated with network functions that are important for cell growth, proliferation, survival, migration, and metabolism. Comparison of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles revealed common and distinct genes regulated by CRTC1-MAML2 and CREB, respectively. CONCLUSION: This study identified a specific CRTC1-MAML2-induced transcriptional program in human MEC cells and demonstrated that CRTC1-MAML2 regulates gene expression in CREB-dependent and independent manners. Our data provide the molecular basis underlying CRTC1-MAML2 oncogenic functions and lay a foundation for further functional investigation of CRTC1-MAML2-induced signaling in MEC initiation and maintenance.

Temporal lobe epilepsy: decreased thalamic resting-state functional connectivity and their relationships with alertness performance.

OBJECTIVES: Studies have provided evidence regarding the pathology of the thalamus in patients with temporal lobe epilepsy (TLE). The thalamus, particularly the right thalamus, is one of the subcortical structures that are most uniformly accepted as being significantly involved in alertness. Moreover, alertness impairment in epilepsy has been reported. This study aimed to investigate alterations in thalamic resting-state functional connectivity (FC) and their relationships with alertness performance in patients with TLE; an issue that has not yet been addressed. METHODS: A total of 15 patients with right TLE (rTLE) and 16 healthy controls were recruited for the present study. All of the participants underwent a resting-state functional magnetic resonance imaging (fMRI) scan and the attention network test (ANT). Whole-brain voxel-wise FC analyses were applied to extract the thalamic resting-state functional networks in the patients with rTLE and healthy controls, and the differences between the two groups were evaluated. Correlation analyses were employed to examine the relationships between alterations in thalamic FC and alertness performance in patients with rTLE. RESULTS: Compared to the healthy controls, the FC within and between the bilateral thalamus was decreased in the patients with rTLE. Moreover, in the patient group, the bilateral anterior cingulate cortex (ACC) and subcortical regions, including the bilateral brainstem, cerebellum, putamen, right caudate nucleus, and amygdala, exhibited decreased FC with the ipsilateral thalamus (p<0.05, AlphaSim corrected, cluster size>44) but not with the contralateral thalamus (p<0.05, AlphaSim corrected, cluster size>43). The intrinsic and phasic alertness performances of the patients were impaired (p=0.001 and p<0.001, respectively) but not correlated with decreased thalamic FC. Meanwhile, the alertness performance was not altered in right TLE but was negatively correlated with decreased thalamic FC with ACC (p<0.05). CONCLUSIONS: Our findings highlight the functional importance of the thalamus in TLE pathology and suggest that damage to the thalamic resting-state functional networks, particularly ipsilateral to the epileptogenic focus, is present in patients with TLE.

Proteomic and functional analyses reveal the role of chromatin reader SFMBT1 in regulating epigenetic silencing and the myogenic gene program.

SFMBT1 belongs to the malignant brain tumor domain-containing chromatin reader family that recognizes repressive histone marks and represses transcription. The biological functions and molecular basis underlying SFMBT1-mediated transcriptional repression are poorly elucidated. Here, our proteomic analysis revealed that SFMBT1 is associated with multiple transcriptional corepressor complexes, including CtBP/LSD1/HDAC complexes, polycomb repressive complexes, and malignant brain tumor family proteins, that collectively contribute to SFMBT1 repressor activity. During myogenesis, Sfmbt1 represses myogenic differentiation of cultured and primary myoblasts. Mechanistically, Sfmbt1 interacts with MyoD and mediates epigenetic silencing of MyoD target genes via recruitment of its associated corepressors and subsequent induction of epigenetic modifications and chromatin compaction. Therefore, our study identified novel mechanisms accounting for SFMBT1-mediated transcription repression and revealed an essential role of Sfmbt1 in regulating MyoD-mediated transcriptional silencing that is required for the maintenance of undifferentiated states of myogenic progenitor cells.

Brief report: Blockade of Notch signaling in muscle stem cells causes muscular dystrophic phenotype and impaired muscle regeneration.

Muscular dystrophies are a group of devastating diseases characterized by progressive muscle weakness and degeneration, with etiologies including muscle gene mutations and regenerative defects of muscle stem cells. Notch signaling is critical for skeletal myogenesis and has important roles in maintaining the muscle stem cell pool and preventing premature muscle differentiation. To investigate the functional impact of Notch signaling blockade in muscle stem cells, we developed a conditional knock-in mouse model in which endogenous Notch signaling is specifically blocked in muscle stem cell compartment. Mice with Notch signaling inhibition in muscle stem cells showed several muscular dystrophic features and impaired muscle regeneration. Analyses of satellite cells and isolated primary myoblasts revealed that Notch signaling blockade in muscle stem cells caused reduced activation and proliferation of satellite cells but enhanced differentiation of myoblasts. Our data thus indicate that Notch signaling controls processes that are critical to regeneration in muscular dystrophy, suggesting that Notch inhibitor therapies could have potential side effects on muscle functions.

Alteration of functional connectivity within visuospatial working memory-related brain network in patients with right temporal lobe epilepsy: a resting-state fMRI study.

PURPOSE: This study aimed to investigate the resting-state brain network related to visuospatial working memory (VSWM) in patients with right temporal lobe epilepsy (rTLE). The functional mechanism underlying the cognitive impairment in VSWM was also determined. METHOD: Fifteen patients with rTLE and 16 healthy controls matched for age, gender, and handedness underwent a 6-min resting-state functional MRI session and a neuropsychological test using VSWM_Nback. The VSWM-related brain network at rest was extracted using multiple independent component analysis; the spatial distribution and the functional connectivity (FC) parameters of the cerebral network were compared between groups. Behavioral data were subsequently correlated with the mean Z-value in voxels showing significant FC difference during intergroup comparison. RESULTS: The distribution of the VSWM-related resting-state network (RSN) in the group with rTLE was virtually consistent with that in the healthy controls. The distribution involved the dorsolateral prefrontal lobe and parietal lobe in the right hemisphere and the partial inferior parietal lobe and posterior lobe of the cerebellum in the left hemisphere (p<0.05, AlphaSim corrected). Between-group differences suggest that the group with rTLE had a decreased FC within the right superior frontal lobe (BA8), right middle frontal lobe, and right ventromedial prefrontal lobe compared with the controls (p<0.05, AlphaSim corrected). The regions of increased FC in rTLE were localized within the right superior frontal lobe (BA11), right superior parietal lobe, and left posterior lobe of the cerebellum (p<0.05, AlphaSim corrected). Moreover, patients with rTLE performed worse than controls in the VSWM_Nback test, and there were negative correlations between ACCmeanRT (2-back) and the mean Z-value in the voxels showing decreased or increased FC in rTLE (p<0.05). CONCLUSION: The results suggest that the alteration of the VSWM-related RSN might underpin the VSWM impairment in patients with rTLE and possibly implies a functional compensation by enlarging the FC within the ipsilateral cerebral network.

Connectome-based prediction of cognitive performance in patients with temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) patients often exhibit varying degrees of cognitive impairments. This study aims to predict cognitive performance in TLE patients by applying a connectome-based predictive model (CPM) to whole-brain resting-state functional connectivity (RSFC) data. METHODS: A CPM was established and leave-one-out cross-validation was employed to decode the cognitive performance of patients with TLE based on the whole-brain RSFC. RESULTS: Our findings indicate that cognitive performance in TLE can be predicted through the internal and network connections of the parietal lobe, limbic lobe, and cerebellum systems. These systems play crucial roles in cognitive control, emotion processing, and social perception and communication, respectively. In the subgroup analysis, CPM successfully predicted TLE patients with and without focal to bilateral tonic-clonic seizures (FBCTS). Additionally, significant differences were noted between the two TLE patient groups and the normal control group. CONCLUSION: This data-driven approach provides evidence for the potential of predicting brain features based on the inherent resting-state brain network organization. Our study offers an initial step towards an individualized prediction of cognitive performance in TLE patients, which may be beneficial for diagnosis, prognosis, and treatment planning.

Acute resistance exercise combined with whole body vibration and blood flow restriction: Molecular and neurocognitive effects in late-middle-aged and older adults.

Limited research exists regarding the effects of resistance exercise (RE) combined with whole body vibration (WBV), blood flow restriction (BFR), or both on the neuropsychological performance of working memory (WM) in late-middle-aged and older adults and regarding the physiological mechanisms underlying this effect. This study thus explored the acute molecular and neurophysiological mechanisms underlying WM performance following RE combined with WBV, BFR, or both. Sixty-six participants were randomly assigned into a WBV, BFR, or WBV + BFR group. Before and after the participants engaged in a single bout of isometric RE combined with WBV, BFR, or both, this study gathered data on several neurocognitive measures of WM performance, namely, accuracy rate (AR), reaction time (RT), and brain event-related potential (specifically P3 latency and amplitude), and data on biochemical indices, such as the levels of insulin-like growth factor-1 (IGF-1), norepinephrine (NE), and brain-derived neurotrophic factor (BDNF). Although none of the RE modalities significantly affected RTs and P3 latencies, ARs and P3 amplitudes significantly improved in the WBV and WBV + BFR groups. The WBV + BFR group exhibited greater improvements than the WBV group did. Following acute RE combined with WBV, BFR, or both, IGF-1 and NE levels significantly increased in all groups, whereas BDNF levels did not change. Crucially, only the changes in NE levels were significantly correlated with improvements in ARs in the WBV + BFR and WBV groups. The findings suggest that combining acute RE with WBV, BFR, or both could distinctively mitigate neurocognitive decline in late-middle-aged and older adults.

Hypoxia-induced TREM1 promotes mesenchymal-like states of glioma stem cells via alternatively activating tumor-associated macrophages.

The mesenchymal subtype of glioblastoma (GBM) cells characterized by aggressive invasion and therapeutic resistance is thought to be dependent on cell-intrinsic alteration and extrinsic cellular crosstalk. Tumor-associated macrophages (TAMs) are pivotal in tumor progression, chemo-resistance, angiogenesis, and stemness maintenance. However, the impact of TAMs on the shifts in glioma stem cells (GSCs) states remains largely uncovered. Herein, we showed that the triggering receptor expressed on myeloid cells-1 (TREM1) preferentially expressed by M2-like TAMs and induced GSCs into mesenchymal-like states by modulating the secretion of TGFß2, which activated the TGFßR/SMAD2/3 signaling in GSCs. Furthermore, we demonstrated that TREM1 was transcriptionally regulated by HIF1a under the hypoxic environment and thus promoted an immunosuppressive type of TAMs via activating the TLR2/AKT/mTOR/c-MYC axis. Collectively, this study reveals that cellular communication between TAMs and GSCs through the TREM1-mediated TGFß2/TGFßR axis is involved in the mesenchymal-like transitions of GSCs. Our study provides valuable insights into the regulatory mechanisms between the tumor immune microenvironment and the malignant characteristics of GBM, which can lead to potential novel strategies targeting TAMs for tumor control.