High-mobility group box 3 (HMGB3) mediates hypoxia-induced glycolysis in various cancers and acts as an oncogene in esophageal carcinoma (EC/ESCA). However, its roles in regulating glycolysis and histone lactylation during EC progression remain unclear. In this study, quantitative polymerase chain reaction (qPCR) and western blotting were conducted to measure HMGB3 levels in EC samples and cells. 5-Ethynyl-2’-deoxyuridine (EdU) assays, colony formation assays, and flow cytometry analyses were conducted to measure cell proliferation and apoptosis. Xenograft mouse models were established to explore tumorigenesis in vivo. Lactate production and glucose uptake were measured using commercial kits. Immunofluorescence staining was used to evaluate the co-localization of c-myc with lysine lactylation (Kla) and Ki67 expression in tumor tissue. A TOP/FOP assay was employed to evaluate Wnt/β-catenin pathway activity. Results revealed upregulated HMGB3 and elevated histone lactylation in EC. HMGB3 knockdown inhibited EC glycolysis, c-myc lactylation, and cell proliferation, yet promoted apoptosis, mimicking the effect of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). HMGB3 depletion also inactivated the Wnt/β-catenin signaling and impaired xenograft tumor growth, glycolysis, and lactylation. In conclusion, HMGB3 promotes EC malignant progression and tumor growth via histone lactylation and Wnt/β-catenin-mediated c-myc transcriptional activation.

Abstract Background:Patients with hypertension commonly exhibit reduced exercise capacity. Impedance cardiography (ICG) enables continuous, non-invasive assessment of exercise-derived hemodynamic parameters; however, the relative associations of different ICG-derived parameters with exercise capacity remain unclear. Methods:In this retrospective cross-sectional study, 211 patients with hypertension who completed both ICG assessment and the six-minute walk test (6MWT) were enrolled. Exercise-derived hemodynamic parameters, including maximum heart rate (HRmax), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR), were continuously measured using the PhysioFlow® system. Univariable and multivariable linear regression analyses were performed to evaluate the associations between ICG-derived parameters and six-minute walk distance (6MWD). HRmax tertile and subgroup analyses were subsequently conducted. Results:In the final multivariable model, age (β = −2.76, 95% CI, −3.85 to −1.67, P < 0.001), male sex (β = 33.50, 95% CI, 8.40-58.60; P = 0.009), and HRmax (β = 1.26, 95% CI, 0.69-1.83; P < 0.001) were independently associated with 6MWD. 6MWD increased progressively across HRmax tertiles (P for trend < 0.001). The positive association between HRmax and 6MWD remained consistent across all prespecified and exploratory subgroups. Conclusions:Among multiple exercise-derived ICG hemodynamic parameters, HRmax demonstrated the strongest and most consistent independent association with exercise capacity in patients with hypertension. These findings suggest that HRmax may represent the most informative dynamic hemodynamic parameter during exercise and that combining ICG with the 6MWT may provide a simple and accessible complementary approach for evaluating exercise capacity.

Insufficient understanding of α-synuclein turnover mechanisms has impeded successful clinical translation for Parkinson's disease (PD). Here, we pinpointed cholesterol 25-hydroxylase (CH25H) as a pivotal regulator of α-synuclein degradation. Through bulk RNA sequencing of substantia nigra tissue from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, along with reanalysis of published datasets from induced pluripotent stem cell-derived astrocytes of patients with PD, we observed an elevated CH25H expression in PD-associated astrocytes. This finding was validated by combined fluorescence in situ hybridization for Ch25h and immunofluorescence staining for GFAP in mouse substantia nigra sections. Conditional knockout or knockdown of astrocytic Ch25h alleviated PD-like motor deficits and reduced dopaminergic neuronal loss in MPTP and α-synuclein preformed fibril (PFF) mouse models. Using 4D label-free proteomics and molecular docking approaches, we uncovered a shared binding domain on p62 where both CH25H and α-synuclein interact. Proximity ligation assays in cultured astrocytes showed that Ch25h overexpression promoted formation of p62/CH25H complex, whereas it inhibited p62/α-synuclein interaction. Conversely, Ch25h knockdown enhanced p62/α-synuclein complex formation and facilitated α-synuclein degradation. 25-Hydroxycholesterol, the enzymatic by-product of CH25H, did not affect the expression of α-synuclein in astrocytes, suggesting an activity-independent influence of CH25H on α-synuclein clearance. In addition, treatment with a p62 polypeptide (60 to 90 amino acids) effectively facilitated α-synuclein clearance by sequestering free CH25H in both cultured astrocytes and mice in the PFF model. Collectively, our study provides insights into the mechanisms underlying α-synuclein turnover and suggests promising avenues for disease-modifying interventions in synucleinopathies.

Salt-inducible kinase 2 (SIK2) is a serine/threonine kinase implicated in several neurological disorders; however, its role in epilepsy remains unclear. In this study, temporal lobe cortex tissues from patients with temporal lobe epilepsy and control subjects, as well as tissues from epilepsy model mice, were analyzed to investigate the expression and function of SIK2. Western blotting and immunofluorescence were used to measure SIK2 expression and cellular localization in epilepsy model mice. To assess its functional relevance, the overexpression or knockdown of SIK2 in the hippocampus was combined with a chronic PTZ kindling model to evaluate seizure susceptibility and mortality. We found that SIK2 expression was significantly increased in the cortical and hippocampal regions of epileptic mice, as well as in temporal lobe cortex of epilepsy patients, with predominant localization in neurons. Hippocampal overexpression of SIK2 decreased seizure latency, increased seizure severity, and increased mortality, whereas SIK2 knockdown had the opposite effects. These findings indicate that SIK2 contributes to seizure susceptibility and epileptogenesis and may represent a potential molecular target for epilepsy intervention.

New treatment strategies are needed for patients who relapse during or following first-line immune checkpoint inhibitor-based treatment for esophageal squamous cell carcinoma (ESCC). Second-line immune checkpoint inhibitors (ICI) rechallenge aims to reactivate the immune system’s response to tumor cells and may improve the prognosis of patients who progressed during or after completing previous treatment. The purpose of this study is to explore the effectiveness and safety of second-line ICI rechallenge therapy in the treatment of advanced ESCC. We retrospectively reviewed the records of patients with advanced ESCC at the Department of Oncology of Jiangsu Cancer Hospital (January 2021 to June 2023) who had at least one measurable lesion at progression after first-line immunotherapy, received at least two cycles of second-line treatment, and who had subsequently undergone radiographic response assessment. The primary outcomes of interest were the progression-free survival (PFS)and overall survival (OS). Treatment-related adverse events were also recorded. In the ICI rechallenge and non-ICI rechallenge groups, the objective response rate (ORR) was 15.4% and 11.8%, the disease control rate (DCR) was 67.6% and 44.1% (P = .011). Compared with the non-ICI rechallenge group, median PFS2 in the ICI rechallenge group was significantly prolonged (5.63 vs. 3.03 months, hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.28, 0.73; P = .001), while there was no statistically significant difference in median OS (12.33 vs. 7.10 months, HR: 0.80, 95% CI: 0.51, 1.27; P = .344). ICI rechallenge therapy and radiotherapy administered during second-line treatment were recognized as independent predictive factors influencing PFS2. These findings suggest that second-line ICI rechallenge is tolerable and could benefit a subset of patients with advanced ESCC.

BACKGROUND:Depression is associated with inflammation, and the uric acid to HDL-C cholesterol ratio (UHR) has emerged as a potential marker of increased inflammation; however, the association between UHR and depression is unclear. Therefore, we aimed to explore this association in a sample from the general US population. METHODS:We conducted a cross-sectional study of 11,444 participants ≥20 years of age from the 2009-2014 NHANES database. We conducted weighted multivariate logistic regression analyses and restricted cubic spline function (RCS) models exploring the association between UHR and risk of depression, as well as subgroup analyses and tests of interaction. RESULTS:UHR was positively associated with depression, especially in participants who drank alcohol (interaction P < 0.05).The prevalence of depression increased by 4 % for each 1-unit increase in UHR (OR = 1.04, 95 % CI = 1.02, 1.07, P = 0.003). After dividing the UHR into quartiles compared with the lowest reference group for UHR, participants in the fourth quartile had a significantly increased risk of depression after full adjustment (OR = 1.36, 95 % CI = 1.03, 1.80, P = 0.033).There was a linear dose-response relationship between the UHR and the risk of depression (P for nonlinear = 0.744). LIMITATIONS:As this was a cross-sectional study, we could not determine a causal relationship between UHR and depression. CONCLUSION:The UHR is positively associated with an increased prevalence of depression among adults in the U.S.

INTRODUCTION:Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and confers a high risk of stroke recurrence, despite aggressive medical therapy. Asymptomatic ICAS (aICAS) is a frequent finding on neuroimaging, and it's an independent risk factor for future stroke. Alirocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and effectively lower low-density lipoprotein cholesterol levels. We hypothesize that extra alirocumab in addition to statin therapy (EAST) could stabilize intracranial plaques in patients with aICAS. METHODS AND ANALYSIS:In this prospective, randomized, open-label, blinded end-point study, we will use high-resolution vessel-wall magnetic resonance imaging (HR-vwMRI) to evaluate the efficacy and safety of alirocumab in patients with asymptomatic ICAS. Eighty patients with aICAS (50 %-99 %) caused by unstable plaques will be assigned to the arm of alirocumab plus statin therapy, or the arm of statin therapy in a 1:1 ratio. Patients will undergo HR-vwMRI at recruitment and after 6 months. The primary outcome is changes in plaque features evaluated by HR-vwMRI after 6 months' treatment. This trial is being conducted at the first affiliated hospital of Nanjing medical university, China. ETHICS AND DISSEMINATION:The study has been approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University. Written informed consents will be obtained from all participants. Study results will be published as peer-reviewed articles. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov, Identifier: NCT06080256.

The nervous system is the dominant regulatory system in the human body. The traditional theory is that tumors lack innervation. However, an increasing number of studies have shown complex bidirectional interactions between tumors and the nervous system. Globally, colorectal cancer (CRC) is the third most common cancer. With the rise of tumor neuroscience, the role of nervous system imbalances in the occurrence and development of CRC has attracted increasing amounts of attention. However, there are still many gaps in the research on the interactions and mechanisms involved in the nervous system in CRC. This article systematically reviews emerging research on the bidirectional relationships between the nervous system and CRC, focusing on the following areas: (1) Effects of the nervous system on colon cancer. (2) Effects of CRC on the nervous system. (3) Treatment of CRC associated with the nervous system.

Parkinson's disease (PD) poses a significant challenge in neurodegenerative disorders, characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The intricate mechanisms orchestrating DA neurodegeneration in PD are not fully understood, necessitating the exploration of innovative therapeutic approaches. Recent studies have implicated ferroptosis as a major contributor to the loss of DA neurons, revealing a complex interplay between iron accumulation and neurodegeneration. However, the sophisticated nature of this process challenges the conventional belief that mere iron removal could effectively prevent DA neuronal ferroptosis. Here, we report JWA, alternatively referred to as ARL6IP5, as a negative regulator of ferroptosis, capable of ameliorating DA neuronal loss in the context of PD. In this study, synchronized expression patterns of JWA and tyrosine hydroxylase (TH) in PD patients and mice were observed, underscoring the importance of JWA for DA neuronal survival. Screening of ferroptosis-related genes unraveled the engagement of iron metabolism in the JWA-dependent inhibition of DA neuronal ferroptosis. Genetic manipulation of JWA provided compelling evidence linking its neuroprotective effects to the attenuation of NCOA4-mediated ferritinophagy. Molecular docking, co-immunoprecipitation, and immunofluorescence studies confirmed that JWA mitigated DA neuronal ferroptosis by occupying the ferritin binding site of NCOA4. Moreover, the JWA-activating compound, JAC4, demonstrated promising neuroprotective effects in cellular and animal PD models by elevating JWA expression, offering a potential avenue for neuroprotection in PD. Collectively, our work establishes JWA as a novel regulator of ferritinophagy, presenting a promising therapeutic target for addressing DA neuronal ferroptosis in PD.

Epilepsy, one of the most common neurological disorders, is characterized by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE) is one of the most common medically intractable seizure disorders. Traf2-and NcK-interacting kinase (TNIK) has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders, but its role in epilepsy remains unclear. In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy. Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) was used to identify the potential mechanism. Through Co-IP, we detected and confirmed the main potential TNIK interactors. Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density (PSD) fractions. We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls. NCB-0846 delayed kindling progression and decreased seizure severity. Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi, notably CaMKII. Co-IP showed that TNIK might correlate with endogenous GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

BACKGROUND:Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuron degeneration and diverse motor and nonmotor symptoms. Early diagnosis and intervention are crucial but challenging due to reliance on clinical presentation. Recent research suggests potential biomarkers for early detection, including plasma netrin-1 (NTN-1), a protein implicated in neuronal survival. METHODS:This cross-sectional study recruited 105 PD patients and 65 healthy controls, assessing plasma NTN-1 levels and correlating them with clinical characteristics. Statistical analyses explored associations between NTN-1 levels and PD symptoms, considering demographic factors. RESULTS:PD patients exhibited significantly lower plasma NTN-1 levels compared to controls. NTN-1 demonstrated moderate potential as a PD biomarker. Positive correlations were found between NTN-1 levels and motor, depression, and cognitive symptoms. Multiple regression analysis revealed disease duration and NTN-1 levels as key factors influencing symptom severity. Gender also impacted symptom scores. CONCLUSION:Reduced plasma NTN-1 levels correlate with PD severity, suggesting its potential as a biomarker. However, further research is needed to elucidate the roles of NTN-1 in PD pathophysiology and validate its diagnostic and therapeutic implications. Understanding the involvement of NTN-1 may lead to personalized management strategies for PD.

Abstract Purpose To explore the predictive potential of intratumoral and multiregion peritumoral radiomics features extracted from multiparametric MRI for predicting pathological differentiation in hepatocellular carcinoma (HCC) patients. Methods A total of 265 patients with 277 HCCs (training cohort n = 193, validation cohort n = 84) who underwent preoperative MRI were retrospectively analyzed. The risk factors identified through stepwise regression analysis were utilized to construct a clinical model. Radiomics models based on MRI (arterial phase, portal venous phase, delayed phase) across various regions (entire tumor, Peri_5mm, Peri_10mm, Peri_20mm) were developed using the LASSO approach. The features obtained from the intratumoral region and the optimal peritumoral region were combined to design the IntraPeri fusion model. Model performance was assessed using the area under the curve (AUC). Results Larger size, non-smooth margins, and mosaic architecture were risk factors for poorly differentiated HCC (pHCC). The clinical model achieved AUCs of 0.77 and 0.73 in the training and validation cohorts, respectively, while the intratumoral model achieved corresponding AUC values of 0.92 and 0.82. The Peri_10mm model demonstrated superior performance to the Peri_5mm and Peri_20mm models, with AUC values of 0.87 vs. 0.84 vs. 0.73 in the training cohort and 0.80 vs. 0.77 vs. 0.68 in the validation cohort, respectively. The IntraPeri model exhibited remarkable AUC values of 0.95 and 0.86 in predicting pHCC in the training and validation cohorts, respectively. Conclusions Our study highlights the potential of a multiparametric MRI-based radiomic model that integrates intratumoral and peritumoral features as a tool for predicting HCC differentiation. Critical relevance statement Both clinical and multiparametric MRI-based radiomic models, particularly the intratumoral radiomic model, are non-invasive tools for predicting HCC differentiation. Importantly, the IntraPeri fusion model exhibited remarkable predictiveness for individualized HCC differentiation. Key points • Both the intratumoral radiomics model and clinical features were useful for predicting HCC differentiation. • The Peri_10mm radiomics model demonstrated better diagnostic ability than other peritumoral region-based models. • The IntraPeri radiomics fusion model outperformed the other models for predicting HCC differentiation. Graphical Abstract

Background This study aimed to explore the molecular mechanism through which circular RNA of ataxin 7 (circATXN7) regulates the proliferation and invasion of esophageal cancer (EC) cells via microRNA (miR)-4319/NLR family CARD domain containing 5 (NLRC5). Methods The localization of circATXN7 in EC cells was determined by RNA fluorescent in situ hybridization (RNA-FISH). The mRNA levels of circATXN7, miR-4319, and NLRC5 were quantified by reverse transcription-polymerase chain reactions. The binding activity of circATXN7 to miR-4319 was assessed using RNA-binding protein immunoprecipitation. Whether circATXN7 regulates the proliferation of EC cells via miR-4319 was explored using dual-luciferase reporter gene colony formation assays. Protein levels were quantified by western blot. The effect of NLRC5 on the proliferation and invasion of EC cells was examined using colony formation and Transwell assays. A subcutaneous transplanted tumor nude mouse model was established to observe the effect of circATXN7 on the proliferation of EC cells in vivo. Results circATXN7 localized mainly to the cytoplasm. Overexpression or inhibition of miR-4319 significantly regulated the proliferation of EC cells, while circATXN7 competitively inhibited miR-4319 expression. Overexpression of miR-4319 significantly inhibited NLRC5 expression, indicating NLRC5 is a downstream regulatory target of miR-4319. circATXN7 influenced NLRC5 expression via miR-4319. In vivo tumor formation experiments in nude mice revealed that knocking down circATXN7 regulated NLRC5 expression via miR-4319 and significantly inhibited the proliferation of EC cells. Conclusions In vitro cell and in vivo animal experiments showed that circATXN7 regulates the proliferation, invasion, and migration of EC cells through the miR-4319/NLRC5 signaling pathway.

Objective:The study intended to analyze the effects of a group nursing intervention on quality of life (QoL) of patients with epilepsy (EP) after treatment with sodium valproate combined with lamotrigine.Design:The research team performed a randomized controlled trial.Setting:The study took place in the Department of Neurology at the Affiliated Brain Hospital of Nanjing Medical University in Nanjing, Jiangsu, China.Participants:Participants were 170 EP patients at the hospital between January 2019 and August 2022.Intervention:The research team randomly assigned participants to one of two groups: (1) 85 to the intervention group, and they took part in a group nursing intervention; and (2) 85 to the control group (n = 85) and they received conventional care.Outcome Measures:To evaluate participants' risk of suicide, psychological state, and QOL, participants completed at baseline and postintervention: (1) the Mini-International Neuropsychiatric Interview (MINI), (2) the Self-Rating Scale for Psychiatric Symptoms 90 (SCL-90), and (3) the Short Form Health Survey (SF-36) To assess participants' management ability, self-efficacy, and social functioning, they also completed at those time points: (1) the EP Self-Management Behavior Scale (ESMS), (2) the General Self-Efficacy Scale (GSES), and (3) the Social Functioning Deficit Screening Scale (SDSS). Finally, the research also investigated participants' satisfaction with the nursing care.Results:The intervention group's risk of suicide decreased between baseline and postintervention, and its SCL-90 scores were significantly lower and SF-36 scores were significantly higher than those of the control group (both P < .05). In addition, the intervention group's ESMS and GSES scores were also significantly higher than those of the control group, while its SDSS score was significantly lower than that of the control group (all P < .05). Finally, the intervention group's nursing satisfaction was also significantly higher than that of the control group (P < .05).Conclusions:The group nursing intervention can effectively improve the psychological states of EP patients, reduce their pain, improve their self-management skills and QoL, provide them with better and more detailed nursing care, and facilitate the treatment and recovery of EP patients, which can have a significant value in clinical practice.

Abstract Purposes In present study, we aimed to identify mRNA expression signature which can predict biochemical recurrence-free (BCR-free) survival of prostate cancer (PCa) patients. Methods A total of 415 patients with pathologic confirmed PRAD in TCGA dataset were recruited and included. With the specific risk score formula, patients were further classified into high-risk and low-risk group. Kaplan–Meier survival analyses and Cox regression analyses were performed to determine the association between mRNA signature and survival outcomes. KEGG was carried out to identify the potentially associated biological processes and signaling pathway. CCK8 assay and transwell assay were used to explore the changes of cell proliferation and invasion ability after gene knockdown. Results Overall, 83 differentially expressed mRNAs were found with more than logFC(4) and p value <0.05 after making a pair between biochemical recurrence. Among which, eight mRNAs were identified to be significantly associated with BCR-free survival. Then, using a risk score based on the signature of these mRNAs, we divided the patients into low-risk and high-risk groups with significantly different BCR-free survival and disease-free survival. KEGG suggested that this signature was involved in Oxytocin signaling pathway. Cell experiments also proved that the genes in the signature can affect the proliferation and invasion functions of Pca cells. Conclusions In present study, a novel eight-mRNAs signature that is useful in survival prediction in PCa patients was developed. The clinical implications and the mechanism of these eight-mRNAs deserve further investigation in future studies.

Despite growing evidence that has declared the importance of circRNAs in neurodegenerative diseases, the clinical significance of circRNAs in dopaminergic (DA) neuronal degeneration in the pathogenesis of Parkinson disease (PD) remains unclear. Here, we performed rRNA-depleted RNA sequencing and detected more than 10,000 circRNAs in the plasma samples of PD patients. In consideration of ROC and the correlation between Hohen-Yahr stage (H-Y stage) and Unified Parkinson Disease Rating Scale-motor score (UPDRS) of 40 PD patients, circEPS15 was selected for further research. Low expression of circEPS15 was found in PD patients and there was a negative positive correlation between the circEPS15 level and severity of PD motor symptoms, while overexpression of circEPS15 protected DA neurons against neurotoxin-induced PD-like neurodegeneration in vitro and in vivo. Mechanistically, circEPS15 acted as a MIR24-3p sponge to promote the stable expression of target gene PINK1, thus enhancing PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and maintain mitochondrial homeostasis. Thus, circEPS15 rescued DA neuronal degeneration through the MIR24-3p-PINK1 axis-mediated improvement of mitochondrial function. This study reveals that circEPS15 exerts a critical role in participating in PD pathogenesis, and may give us an insight into the novel avenue to develop potential biomarkers and therapeutic targets for PD.

AIMS:The aim of this study was to clarify the dynamic neural activity of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD).METHODS:Using dynamic functional network connectivity (dFNC) analysis, we evaluated 41 PD patients with LID (LID group) and 34 PD patients without LID (No-LID group). Group spatial independent component analysis and sliding-window approach were employed. Moreover, we applied a k-means clustering algorithm on windowed functional connectivity (FC) matrices to identify reoccurring FC patterns (i.e., states).RESULTS:The optimal number of states was determined to be five, the so-called State 1, 2, 3, 4, and 5. In ON phase, compared with No-LID group, LID group occurred more frequently and dwelled longer in strongly connected State 1, characterized by strong positive connections between visual network (VIS) and sensorimotor network (SMN). When switching from OFF to ON phase, LID group occurred less frequently in State 3 and State 4. Meanwhile, LID group dwelled longer in State 2 and shorter in State 3. No-LID group occurred more frequently in State 5 and less frequently in State 3. Additionally, correlation analysis demonstrated that dyskinesia's severity was associated with frequency of occurrence and dwell time in State 2, dominated by inferior frontal cortex in cognitive executive network (CEN).CONCLUSION:Using dFNC analysis, we found that dyskinesia may be related to the dysfunctional inhibition of CEN on motor loops and excessive excitation of VIS and SMN, which provided evidence of the changes in brain dynamics associated with the occurrence of dyskinesia.

Background:The goal of the current research was to investigate circATXN7 expression in esophageal cancer (EC) and its impact on the proliferation, migration, and invasion of EC cells.Methods:Determination of circATXN7 expression in esophageal cancer tissues and adjacent tissueswas carried out using quantitative reverse transcription polymerase chain reaction (qRT-PCR), and we further analyzed the correlation between patients' clinical characteristics and circATXN7 expression. EC cell lines (EC-9706, Eca-109, TE-1, KYSE-30, and KYSE-150) and normal esophageal cell line (HET-1A) were cultured, and circATXN7 expression was detected by qRT-PCR. The lowest circATXN7-containing Eca-109 cells were selected to be transfected with an overexpressing lentiviral vector (circATXN7). EC-9706 cells with the highest expression of circATXN7 were selected for transfection with knockdown vectors [short hairpin RNA (shRNA)#1 and shRNA#2] of the circATXN7 sequence. Cell proliferation was determined via MTT assay. The formation of cell clones was investigated via colony formation assay. Transwell migration assay was utilized to determine cell migration and invasion ability.Results:Significantly higher levels of circATXN7 were observed in EC tissues compared with paracancerous tissues (P<0.01), and circATXN7 expression level showed a significant correlation with the tumor/lymph nodes/metastasis (TNM) stage and metastasis of lymph nodes (P<0.05). Among all esophageal cell lines, EC-9706 had the highest expression level and Eca-109 had the lowest expression level. The MTT assay revealed that circATXN7 overexpression could significantly promote the proliferation of Eca-109 cells, while circATXN7 knockdown was capable of significantly inhibiting EC cell proliferation. The colony formation experiments revealed a significant increase in the number of clones in the circATXN7 overexpression model and a significant decrease in the circATXN7 knockdown model. The results of transwell migration experiments suggested that circATXN7 overexpression could promote EC cell invasion and migration, while knockdown of circATXN7 expression was associated with significant inhibition of the invasion and migration of these cells.Conclusions:CircATXN7 exerted a critical role in the incidence and progression of EC. This study identified a novel molecular target and established a theoretical basis for the early detection and treatment of EC.

Aberrantly synchronized neuronal discharges in the brain lead to epilepsy, a devastating neurological disease whose pathogenesis and mechanism are unclear. SAPAP3, a cytoskeletal protein expressed at high levels in the postsynaptic density (PSD) of excitatory synapses, has been well studied in the striatum, but the role of SAPAP3 in epilepsy remains elusive. In this study, we sought to investigate the molecular, cellular, electrophysiological and behavioral consequences of SAPAP3 perturbations in the mouse hippocampus. We identified a significant increase in the SAPAP3 levels in patients with temporal lobe epilepsy (TLE) and in mouse models of epilepsy. In addition, behavioral studies showed that the downregulation of SAPAP3 by shRNA decreased the seizure severity and that the overexpression of SAPAP3 by recombinant SAPAP3 yielded the opposite effect. Moreover, SAPAP3 affected action potentials (APs), miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents in the CA1 region, which indicated that SAPAP3 plays an important role in excitatory synaptic transmission. Additionally, the levels of the GluN2A protein, which is involved in synaptic function, were perturbed in the hippocampal PSD, and this perturbation was accompanied by ultrastructural morphological changes. These results revealed a previously unknown function of SAPAP3 in epileptogenesis and showed that SAPAP3 may represent a novel target for the treatment of epilepsy.

Alanine-serine-cysteine transporter 2 (ASCT2) is reported to participate in the progression of tumors and metabolic diseases. It is also considered to play a crucial role in the glutamate-glutamine shuttle of neuroglial network. However, it remains unclear the involvement of ASCT2 in neurological diseases such as Parkinson's disease (PD). In this study, we demonstrated that high expression of ASCT2 in the plasma samples of PD patients and the midbrain of MPTP mouse models is positively correlated with dyskinesia. We further illustrated that ASCT2 expressed in astrocytes rather than neurons significantly upregulated in response to either MPP+ or LPS/ATP challenge. Genetic ablation of astrocytic ASCT2 alleviated the neuroinflammation and rescued dopaminergic (DA) neuron damage in PD models in vitro and in vivo. Notably, the binding of ASCT2 to NLRP3 aggravates astrocytic inflammasome-triggered neuroinflammation. Then a panel of 2513 FDA-approved drugs were performed via virtual molecular screening based on the target ASCT2 and we succeed in getting the drug talniflumate. It is validated talniflumate impedes astrocytic inflammation and prevents degeneration of DA neurons in PD models. Collectively, these findings reveal the role of astrocytic ASCT2 in the pathogenesis of PD, broaden the therapeutic strategy and provide a promising candidate drug for PD treatment.