Novel KCNQ2 missense variant expands the genotype spectrum of DEE7.

BACKGROUND: KCNQ is a voltage-gated K + channel that controls neuronal excitability and is mutated in epilepsy and autism spectrum disorder (ASD). We focus on the KV7.2 voltage-gated potassium channel gene (KCNQ2), which is known for its association with developmental delay and various seizures (including self-limited benign familial neonatal epilepsy and epileptic encephalopathy). But the pathogenicity of many variants remains unproven, potentially leading to misinterpretation of their functional consequences. METHODS: In this study, we studied a patient who visited Nanhua Hospital. Targeted next-generation sequencing and Sanger sequencing were used to identify the pathogenic variants. Meanwhile, computational models, including hydrogen bonding and docking analyses, suggest that variants cause functional impairment. In addition, functional validation was performed in the drosophila to further evaluate the missense variant in the KCNQ2 gene as the cause of this patient. RESULTS: A new missense variant in the KCNQ2 gene was identified: NM_172107.4:c.1007C > A(p.ALa336Glu), which resulted in the change from alanine to glutamate at amino acid position 336 in the KCNQ2 gene. After computational modeling, including hydrogen bond analysis and docking analysis, it is indicated that the variants cause functional impairment. Furthermore, RNAi-mediated KCNQ knockout in flies led to the onset of epileptic behavior, lifespan and climbing capacity were affected, expression of the normal human KCNQ2 rescues the in flies RNAi-mediated KCNQ knockout behavioral abnormalities. CONCLUSION: Our findings expands the genetic profile of KCNQ2 and enhances the genotype - phenotype link.

Associations between specific dietary patterns, gut microbiome composition, and incident subthreshold depression in Chinese young adults.

INTRODUCTION: The interplay between influential factors and the incidence of subthreshold depression (SD) in young adults remains poorly understood. OBJECTIVES: This study sought to understand the dietary habits, gut microbiota composition, etc. among individuals with SD in young adults and to investigate their association with SD occurrence. METHODS: Employing a cross-sectional approach, 178 individuals with SD, aged 18-32 years, were matched with 114 healthy counterparts. SD status was evaluated using the Zung Self-rating Depression Scale (SDS), Zung Self-rating Anxiety Scale (SAS), Beck Depression Inventory 2nd version (BDI-II), the 17-item Hamilton Rating Scales of Depression (HAMD-17), and Pittsburgh Sleep Quality Index (PSQI). Metagenomic sequencing was utilized to identify fecal microbial profiles. Dietary patterns were discerned via factor analysis of a 25-item food frequency questionnaire (FFQ). Logistic regression analysis and mediation analysis were performed to explore the potential links between gut microbiota, dietary patterns, and incident SD. RESULTS: Data on dietary habits were available for 292 participants (mean [SD] age, 22.1 [2.9] years; 216 [73.9 %] female). Logistic regression analysis revealed that dietary patterns Ⅰ (odds ratio [OR], 0.34; 95 % CI, 0.15-0.75) and IV (OR, 0.39; 95 % CI, 0.17-0.86 and OR, 0.39; 95 % CI, 0.18-0.84) were associated with reduced risk of SD. Distinct microbial profiles were observed in young adults with SD, marked by increased microbial diversity and taxonomic alterations. Moreover, mediation analysis suggested Veillonella atypica as a potential mediator linking SDS or BDI-II scores with a healthy dietary pattern rich in bean products, coarse grains, nuts, fruits, mushrooms, and potatoes (ß = 0.25, 95 % CI: 0.02-0.78 and ß = 0.18, 95 % CI: 0.01-0.54). CONCLUSIONS: Our findings highlight the complex interplay between dietary patterns, gut microbiota, and the risk of developing SD in young adults, underscoring the potential for dietary interventions and microbiome modulation in mental health promotion.

Unveiling the role of HP1α-HDAC1-STAT1 axis as a therapeutic target for HP1α-positive intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α (HP1α) is one of the most important nonhistone chromosomal proteins involved in transcriptional silencing via heterochromatin formation and structural maintenance. The effect of HP1α on the progression of ICCA remained unclear. METHODS: The effect on the proliferation of ICCA was detected by experiments in two cell lines and two ICCA mouse models. The interaction between HP1α and Histone Deacetylase 1 (HDAC1) was determined using Electrospray Ionization Mass Spectrometry (ESI-MS) and the binding mechanism was studied using immunoprecipitation assays (co-IP). The target gene was screened out by RNA sequencing (RNA-seq). The occupation of DNA binding proteins and histone modifications were predicted by bioinformatic methods and evaluated by Cleavage Under Targets and Tagmentation (CUT & Tag) and Chromatin immunoprecipitation (ChIP). RESULTS: HP1α was upregulated in intrahepatic cholangiocarcinoma (ICCA) tissues and regulated the proliferation of ICCA cells by inhibiting the interferon pathway in a Signal Transducer and Activator of Transcription 1 (STAT1)-dependent manner. Mechanistically, STAT1 is transcriptionally regulated by the HP1α-HDAC1 complex directly and epigenetically via promoter binding and changes in different histone modifications, as validated by high-throughput sequencing. Broad-spectrum HDAC inhibitor (HDACi) activates the interferon pathway and inhibits the proliferation of ICCA cells by downregulating HP1α and targeting the heterodimer. Broad-spectrum HDACi plus interferon preparation regimen was found to improve the antiproliferative effects and delay ICCA development in vivo and in vitro, which took advantage of basal activation as well as direct activation of the interferon pathway. HP1α participates in mediating the cellular resistance to both agents. CONCLUSIONS: HP1α-HDAC1 complex influences interferon pathway activation by directly and epigenetically regulating STAT1 in transcriptional level. The broad-spectrum HDACi plus interferon preparation regimen inhibits ICCA development, providing feasible strategies for ICCA treatment. Targeting the HP1α-HDAC1-STAT1 axis is a possible strategy for treating ICCA, especially HP1α-positive cases.

The pattern of tumor progression on first-line immune checkpoint inhibitor-based systemic therapy for Chinese advanced hepatocellular carcinoma -CLEAP 004 study.

Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Association between the blood urea nitrogen-to-creatinine ratio and 3-month outcomes in patients with acute ischemic stroke: a secondary analysis based on a prospective cohort study.

Introduction: This study aimed to assess the correlation between the blood urea nitrogen (BUN)-to-creatinine (BUN/Cr) ratio and adverse outcomes (AOs) at 3 months in patients with acute ischemic stroke (AIS) in the Korean population. Methods: This cohort study encompassed 1906 cases of AIS at a South Korean hospital from January 2010 to December 2016. To determine the linear correlation between the BUN/Cr ratio and AOs in AIS, a binary logistic regression model (BLRM) was employed. Additionally, generalized additive models and techniques for smooth curve fitting were utilized to reveal the nonlinear dynamics between the BUN/Cr ratio and AOs in patients with AIS. Results: The prevalence of AOs was 28.65%, with a median BUN/Cr ratio of 18.96. Following adjustments for covariates, the BLRM disclosed that the association between the BUN/Cr ratio and the risk of AOs in patients with AIS did not attain statistical significance. Nevertheless, a nonlinear relationship surfaced, pinpointing an inflection point at 21.591. To the left of this inflection point, a 31.42% reduction in the risk of AOs was noted for every 1-unit surge in the Z score of the BUN/Cr ratio [odds ratio (OR) = 0.686, 95% confidence interval (CI): 0.519, 0.906, p = 0.008]. On the right side of the inflection point, the effect size (OR = 1.405, 95% CI: 1.018, 1.902, p = 0.039) was determined. Conclusion: The findings of this study underscore the intricate nature of the relationship between the BUN/Cr ratio and 3-month outcomes in patients with AIS, establishing a robust groundwork for future investigations.

Excessive level of dietary insect protein negatively changed growth metabolomic and transcriptomic profiles of largemouth bass (Micropterus salmoides).

Hermetia illucens (HI) meal is a promising substitute for fish meal (FM) in the feeds of farmed fish. However, the impacts of dietary HI meal on largemouth bass (LMB) remain unknown. In this study, we formulated three isonitrogenous and isolipid diets with 0% (HI0, control), 20% (HI20) and 40% (HI40) of FM substituted by HI meal. A total of 270 juvenile largemouth bass with an initial body weight of 10.02 ± 0.03 g were used (30 fish per tank). After an 80-day feeding trial, the fish fed with the HI40 diet demonstrated decreased growth performance and protein efficiency ratio (PER), and increased liver oxidative indices and lipid accumulation compared to the control (P < 0.05). Transcriptomic analysis revealed the effects of high dietary HI meal on liver gene expression. Consistent with the reduced growth and disturbed liver oxidative status, the upregulated genes were enriched in the biological processes associated with protein catabolism and endoplasmic reticulum (ER) stress; while the downregulated genes were enriched in cellular proliferation, growth, metabolism, immunity and maintenance of tissue homeostasis. Differential metabolites in the liver samples were also identified by untargeted metabolomic assay. The results of joint transcriptomic-metabolomic analyses revealed that the pathways such as one carbon pool by folate, propanoate metabolism and alpha-linolenic acid metabolism were disturbed by high dietary HI meal. In summary, our data revealed the candidate genes, metabolites and biological pathways that account for the adverse effects of high HI meal diet on the growth and health of LMB.

Surgical treatment improves overall survival of hepatocellular carcinoma with extrahepatic metastases after conversion therapy: a multicenter retrospective study.

Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases.

Prediction of the Ki-67 expression level in head and neck squamous cell carcinoma with machine learning-based multiparametric MRI radiomics: a multicenter study.

BACKGROUND: This study aimed to develop and validate a machine learning (ML)-based fusion model to preoperatively predict Ki-67 expression levels in patients with head and neck squamous cell carcinoma (HNSCC) using multiparametric magnetic resonance imaging (MRI). METHODS: A total of 351 patients with pathologically proven HNSCC from two medical centers were retrospectively enrolled in the study and divided into training (n = 196), internal validation (n = 84), and external validation (n = 71) cohorts. Radiomics features were extracted from T2-weighted images and contrast-enhanced T1-weighted images and screened. Seven ML classifiers, including k-nearest neighbors (KNN), support vector machine (SVM), logistic regression (LR), random forest (RF), linear discriminant analysis (LDA), naive Bayes (NB), and eXtreme Gradient Boosting (XGBoost) were trained. The best classifier was used to calculate radiomics (Rad)-scores and combine clinical factors to construct a fusion model. Performance was evaluated based on calibration, discrimination, reclassification, and clinical utility. RESULTS: Thirteen features combining multiparametric MRI were finally selected. The SVM classifier showed the best performance, with the highest average area under the curve (AUC) of 0.851 in the validation cohorts. The fusion model incorporating SVM-based Rad-scores with clinical T stage and MR-reported lymph node status achieved encouraging predictive performance in the training (AUC = 0.916), internal validation (AUC = 0.903), and external validation (AUC = 0.885) cohorts. Furthermore, the fusion model showed better clinical benefit and higher classification accuracy than the clinical model. CONCLUSIONS: The ML-based fusion model based on multiparametric MRI exhibited promise for predicting Ki-67 expression levels in HNSCC patients, which might be helpful for prognosis evaluation and clinical decision-making.

In-situ construction of cation vacancies in amphoteric-metallic element-doped NiFe-LDH as ultrastable and efficient alkaline hydrogen evolution electrocatalysts at 1000 mA cm-2.

Developing efficient and stable electrocatalysts at affordable costs is very important for large-scale production of green hydrogen. In this study, unique amphoteric metallic element-doped NiFe-LDH nanosheet arrays (NiFeCd-LDH, NiFeZn-LDH and NiFeAl-LDH) using as high-performance bifunctional electrocatalysts for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) were reported, by tuning electronic structure and vacancy engineering. It was found that NiFeCd-LDH possesses the lowest overpotentials of 85 mV and 240 mV (at 10 mA cm-2) for HER and OER, respectively. Density functional theory (DFT) calculations reveal the synergistic effect of Cd vacancies and Cd doping on improving alkaline HER performance, which promote the achievement of excellent catalytic activity and ultrastable hydrogen production at a large current density of 1000 mA cm-2 within 250 h. Besides, the overall water splitting performance of the as-prepared NiFeCd-LDH requires only 1.580 V to achieve a current density of 10 mA cm-2 in alkaline seawater media, underscoring the importance of modifying the electronic properties of LDH for efficient overall water splitting in both alkaline water/seawater environments.

1D Pb halide perovskite-like materials for high performance X-ray detection.

The strategy of bandgap regulation is important for X-ray detection, but has not been reported for 1D Pb halide perovskite materials. In this work, three such materials, 1, 2 and 3, with a tunable bandgap, were fabricated for application in X-ray detection. 3 shows high sensitivity, far superior to commercial X-ray detectors.

Reprint of: Recessive APC2 missense variants associated with epilepsies without neurodevelopmental disorders.

OBJECTIVES: The APC2 gene, encoding adenomatous polyposis coli protein-2, is involved in cytoskeletal regulation in neurons responding to endogenous extracellular signals and plays an important role in brain development. Previously, the APC2 variants have been reported to be associated with cortical dysplasia and intellectual disability. This study aims to explore the association between APC2 variants and epilepsy. METHODS: Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations. RESULTS: Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation. SIGNIFICANCE: This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity.

The relationship between major depressive disorder and dementia: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Major depressive disorder (MDD) and dementia psychiatric and neurological diseases that are clinically widespread, but whether there is a causal link between them is still unclear. In this study, bidirectional two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between MDD and dementia via a genome-wide association study (GWAS) database, containing samples from the European population. METHOD: We collected data on MDD and common clinical dementia subtypes from GWAS, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and vascular dementia (VaD). A series of bidirectional two-sample MR studies and correlation sensitivity analysis were carried out. RESULTS: In the study of the effect of MDD on dementia subtypes, no causal relationship was found between MDD and dementia subtypes other than VaD, inverse variance weighted (IVW) method: odds ratio (OR), 2.131; 95 % confidence interval (CI), 1.249-3.639, P = 0.006; MDD-AD: OR, 1.000; 95 % CI, 0.999-1.001, P = 0.537; MDD-FTD: OR, 1.476; 95 % CI, 0.471-4.627, P = 0.505; MDD-PDD: OR, 0.592; 95 % CI, 0.204-1.718, P = 0.335; MR-Egger method: MDD-DLB: OR, 0.582; 95 % CI, 0.021-15.962, P = 0.751. In reverse MR analyses, no dementia subtype was found to be a risk factor for MDD. LIMITATIONS: The results of this study may not be generalizable to non-European populations. CONCLUSION: MDD was identified as a potential risk factor for VaD, but no dementia subtype was found to be a risk factor for MDD. These results suggest a new avenue for the prevention of VaD.

Metabotropic Glutamate Receptor 8 Suppresses M1 Polarization in Microglia by Alleviating Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

BACKGROUND: Microglia-mediated neuroinflammation is a hallmark of neurodegeneration. Metabotropic glutamate receptor 8 (GRM8) has been reported to promote neuronal survival in neurodegenerative diseases, yet the effect of GRM8 on neuroinflammation is still unclear. Calcium overload-induced endoplasmic reticulum (ER)-mitochondrial miscommunication has been reported to trigger neuroinflammation in the brain. The aim of this study was to investigate putative anti-inflammatory effects of GRM8 in microglia, specifically focusing on its role in calcium overload-induced ER stress and mitochondrial dysfunction. METHODS: BV2 microglial cells were pretreated with GRM8 agonist prior to lipopolysaccharide administration. Pro-inflammatory cytokine levels and the microglial polarization state in BV2 cells were then quantified. Cellular apoptosis and the viability of neuron-like PC12 cells co-cultured with BV2 cells were examined using flow cytometry and a Cell Counting Kit-8, respectively. The concentration of cAMP, inositol-1,4,5-triphosphate receptor (IP3R)-dependent calcium release, ER Ca2+ concentration, mitochondrial function as reflected by reactive oxygen species levels, ATP production, mitochondrial membrane potential, expression of ER stress-sensing protein, and phosphorylation of the nuclear factor kappa B (NF-κB) p65 subunit were also quantified in BV2 cells. RESULTS: GRM8 activation inhibited pro-inflammatory cytokine release and shifted microglia polarization towards an anti-inflammatory-like phenotype in BV2 cells, as well as promoting neuron-like PC12 cell survival when co-cultured with BV2 cells. Mechanistically, microglial GRM8 activation significantly inhibited cAMP production, thereby desensitizing the IP3R located within the ER. This process markedly limited IP3R-dependent calcium release, thus restoring mitochondrial function while inhibiting ER stress and subsequently deactivating NF-κB signaling. CONCLUSIONS: Our results indicate that GRM8 activation can protect against microglia-mediated neuroinflammation by attenuating ER stress and mitochondrial dysfunction, and that IP3R-mediated calcium signaling may play a vital role in this process. GRM8 may thus be a potential target for limiting neuroinflammation.

nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus.

Neuronal nitric oxide synthase (nNOS, gene name Nos1) orchestrates the synthesis of nitric oxide (NO) within neurons, pivotal for diverse neural processes encompassing synaptic transmission, plasticity, neuronal excitability, learning, memory, and neurogenesis. Despite its significance, the precise regulation of nNOS activity across distinct neuronal types remains incompletely understood. Erb-b2 receptor tyrosine kinase 4 (ErbB4), selectively expressed in GABAergic interneurons and activated by its ligand neuregulin 1 (NRG1), modulates GABA release in the brain. Our investigation reveals the presence of nNOS in a subset of GABAergic interneurons expressing ErbB4. Notably, NRG1 activates nNOS via ErbB4 and its downstream phosphatidylinositol 3-kinase (PI3K), critical for NRG1-induced GABA release. Genetic removal of nNos from Erbb4-positive neurons impairs GABAergic transmission, partially rescued by the NO donor sodium nitroprusside (SNP). Intriguingly, the genetic deletion of nNos from Erbb4-positive neurons induces schizophrenia-relevant behavioral deficits, including hyperactivity, impaired sensorimotor gating, and deficient working memory and social interaction. These deficits are ameliorated by the atypical antipsychotic clozapine. This study underscores the role and regulation of nNOS within a specific subset of GABAergic interneurons, offering insights into the pathophysiological mechanisms of schizophrenia, given the association of Nrg1, Erbb4, Pi3k, and Nos1 genes with this mental disorder.

Alternative splicing-related long noncoding RNA ANRIL facilitates hepatocellular carcinoma by targeting the miR-199a-5p/SRSF1 axis and impacting Anillin.

Hepatocellular carcinoma (HCC) is characterized by aberrant alternative splicing (AS), which plays an important part in the pathological process of this disease. However, available reports about genes and mechanisms involved in AS process are limited. Our previous research has identified ANRIL as a long noncoding RNA related to the AS process of HCC. Here, we investigated the exact effect and the mechanism of ANRIL on HCC progress. The ANRIL expression profile was validated using the real-time quantitative polymerase chain reaction assay. The western blot analysis and IHC assay were conducted on candidate targets, including SRSF1 and Anillin. The clinicopathological features of 97 patients were collected and analyzed. Loss-of and gain-of-function experiments were conducted. The dual-luciferase reporter assay was applied to verify the interaction between ANRIL, miR-199a-5p, and SRSF1. Anomalous upregulation of ANRIL in HCC was observed, correlating with worse clinicopathological features of HCC. HCC cell proliferation, mobility, tumorigenesis, and metastasis were impaired by depleting ANRIL. We found that ANRIL acts as a sponger of miRNA-199a-5p, resulting in an elevated level of its target protein SRSF1. The phenotypes induced by ANRIL/miR-199a-5p/SRSF1 alteration are associated with Anillin, a validated HCC promoter. ANRIL is an AS-related lncRNA promoting HCC progress by modulating the miR-199a-5p/SRSF1 axis. The downstream effector of this axis in the development of HCC is Anillin.

Research progress on the relationship between epilepsy and circRNA.

OBJECTIVE: This review aims to provide a comprehensive summary of the latest research progress regarding the relationship between epilepsy and circular RNA (circRNA). METHODS: Relevant literature from the PubMed database was meticulously searched and reviewed. The selected articles focused on investigating the association between epilepsy and circRNA, including studies on expression patterns, diagnostic markers, therapeutic targets, and functional mechanisms. RESULTS: Epilepsy, characterized by recurrent seizures, is a neurological disorder. Numerous studies have demonstrated significant alterations in the expression profiles of circRNA in epileptic brain tissues, animal models, and peripheral blood samples. These differential expressions of circRNA are believed to be closely linked with the occurrence and development of epilepsy. Moreover, circRNA has shown promising potential as diagnostic markers for epilepsy, as well as prognostic indicators for predicting disease outcomes. Furthermore, circRNA has emerged as a potential therapeutic target for epilepsy treatment, offering prospects for gene therapy interventions. CONCLUSION: The dysregulation of circRNA expression in epilepsy suggests its potential involvement in the pathogenesis and progression of this disorder. Identifying specific circRNA molecules associated with epilepsy may pave the way for novel diagnostic approaches and therapeutic strategies. However, further investigations are imperative to elucidate the precise functional mechanisms of circRNA in epilepsy and validate its clinical utility.

Three-Dimensional Multifrequency MR Elastography for Microvascular Invasion and Prognosis Assessment in Hepatocellular Carcinoma.

BACKGROUND: Pretreatment identification of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is important when selecting treatment strategies. PURPOSE: To improve models for predicting MVI and recurrence-free survival (RFS) by developing nomograms containing three-dimensional (3D) MR elastography (MRE). STUDY TYPE: Prospective. POPULATION: 188 patients with HCC, divided into a training cohort (n = 150) and a validation cohort (n = 38). In the training cohort, 106/150 patients completed a 2-year follow-up. FIELD STRENGTH/SEQUENCE: 1.5T 3D multifrequency MRE with a single-shot spin-echo echo planar imaging sequence, and 3.0T multiparametric MRI (mp-MRI), consisting of diffusion-weighted echo planar imaging, T2-weighted fast spin echo, in-phase out-of-phase T1-weighted fast spoiled gradient-recalled dual-echo and dynamic contrast-enhanced gradient echo sequences. ASSESSMENT: Multivariable analysis was used to identify the independent predictors for MVI and RFS. Nomograms were constructed for visualization. Models for predicting MVI and RFS were built using mp-MRI parameters and a combination of mp-MRI and 3D MRE predictors. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, chi-squared or Fisher's exact tests, multivariable analysis, area under the receiver operating characteristic curve (AUC), DeLong test, Kaplan-Meier analysis and log rank tests. P < 0.05 was considered significant. RESULTS: Tumor c and liver c were independent predictors of MVI and RFS, respectively. Adding tumor c significantly improved the diagnostic performance of mp-MRI (AUC increased from 0.70 to 0.87) for MVI detection. Of the 106 patients in the training cohort who completed the 2-year follow up, 34 experienced recurrence. RFS was shorter for patients with MVI-positive histology than MVI-negative histology (27.1 months vs. >40 months). The MVI predicted by the 3D MRE model yielded similar results (26.9 months vs. >40 months). The MVI and RFS nomograms of the histologic-MVI and model-predicted MVI-positive showed good predictive performance. DATA CONCLUSION: Biomechanical properties of 3D MRE were biomarkers for MVI and RFS. MVI and RFS nomograms were established. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Current research status and reflection on acupuncture treatment for brain disorders. / é’ˆç¸æ²»ç–—è„‘ç— çš„ç ”ç©¶çŽ°çŠ¶ä¸Žæ€è€ƒ.

Acupuncture has demonstrated positive efficacy in the treatment of brain disorders. However, significant challenges lie in integrating acupuncture with modern technologies, promoting its clinical application in treating brain disorders, elucidating the mechanisms underlying acupuncture's preventive and therapeutic effects on brain disorders, and accelerating the pace of translational development in acupuncture medicine. This paper briefly outlines the current research status, challenges, and potential future directions in acupuncture treatment for brain disorders, aiming to provide essential insights for the modernization and development of acupuncture in the treatment of brain disorders.

Calcitriol restrains microglial M1 polarization and alleviates dopaminergic degeneration in hemiparkinsonian mice by boosting regulatory T-cell expansion.

OBJECTIVE: Vitamin D deficiency is a risk factor for Parkinson's disease (PD) and vitamin D supplementation robustly alleviates neurodegeneration in PD models. However, the mechanisms underlying this effect require further clarification. Current evidence suggests that harnessing regulatory T cells (Treg) may mitigate neuronal degeneration. In this study, we investigated the therapeutic effects of vitamin D receptor activation by calcitriol on PD, specifically focusing on its role in Treg. METHODS: Hemiparkinsonian mice model was established through the injection of 6-OHDA into the striatum. Mice were pretreated with calcitriol before 6-OHDA injection. The motor performance, dopaminergic neuronal survival, contents of dopamine, and dopamine metabolites were evaluated. The pro-inflammatory cytokines levels, T-cell infiltration, mRNA expression of indicated microglial M1/M2 phenotypic markers, and microglial marker in the midbrain were detected. Populations of Treg in the splenic tissues were assessed using a flow cytometry assay. PC61 monoclonal antibody was applied to deplete Treg in vivo. RESULTS: We show that calcitriol supplementation notably improved motor performance and reduced dopaminergic degeneration in the 6-OHDA-induced PD model. Mechanistically, calcitriol promoted anti-inflammatory/neuroprotective Treg and inhibited pro-inflammatory/neurodestructive effector T-cell generation in this model. This process significantly inhibited T-cell infiltration in the midbrain, restrained microglial activation, microglial M1 polarization, and decreased pro-inflammatory cytokines release. This more favorable inflammatory microenvironment rescued dopaminergic degeneration. To further verify that the anti-inflammatory effects of calcitriol are associated with Treg expansion, we applied an antibody-mediated Treg depletion assay. As predicted, the anti-inflammatory effects of calcitriol in the PD model were diminished following Treg depletion. CONCLUSION: These findings suggest that calcitriol's anti-inflammatory and neuroprotective effects in PD are associated with its potential to boost Treg expansion.