The discovery of a novel IκB kinase ß inhibitor based on pharmacophore modeling, virtual screening and biological evaluation.

Background: IκB kinase ß (IKKß) plays a pivotal role in the NF-κB signaling pathway and is considered a promising therapeutic target for various diseases. Materials & methods: The authors developed and validated a 3D pharmacophore model of IKKß inhibitors via the HypoGen algorithm in Discovery Studio 2019, then performed virtual screening, molecular docking and kinase assays to identify hit compounds from the ChemDiv database. The compound with the highest inhibitory activity was further evaluated in adjuvant-induced arthritis rat models. Results: Among the four hit compounds, Hit 4 had the highest IKKß inhibitory activity (IC50 = 30.4 ± 3.8), and it could significantly ameliorate joint inflammation and damage in vivo. Conclusion: The identified compound, Hit 4, can be optimized as a therapeutic agent for inflammatory diseases.

This research paper focuses on the development and validation of IκB kinase ß (IKKß) inhibitors. IKKß is a crucial enzyme that plays an important role in the NF-κB signaling pathway, which is involved in many diseases such as inflammatory diseases and cancers. The researchers used computer-aided drug design strategies to identify potential IKKß inhibitors. First, they used a model to screen a large database of chemical compounds. Then, they conducted further tests to pinpoint the ones that could effectively inhibit IKKß. Out of all the tested compounds, one referred to as 'Hit 4' showed the highest inhibitory activity. It was even able to significantly reduce joint inflammation and damage in rat models. Although many drugs targeting IKKß have been developed, none are commercially available yet due to issues with efficacy or safety. Therefore, the findings of this study are significant and could lead to the development of new effective therapeutic agents for inflammatory diseases.

Negative regulation of angiogenesis and the MAPK pathway may be a shared biological pathway between IS and epilepsy.

Ischemia stroke and epilepsy are two neurological diseases that have significant patient and societal burden, with similar symptoms of neurological deficits. However, the underlying mechanism of their co-morbidity are still unclear. In this study, we performed a combined analysis of six gene expression profiles (GSE58294, GSE22255, GSE143272, GSE88723, GSE163654, and GSE174574) to reveal the common mechanisms of IS and epilepsy. In the mouse datasets, 74 genes were co-upregulated and 7 genes were co-downregulated in the stroke and epilepsy groups. Further analysis revealed that the co-expressed differentially expressed genes (DEGs) were involved in negative regulation of angiogenesis and the MAPK signaling pathway, and this was verified by Gene Set Enrichment Analysis of human datasets and single cell RNA sequence of middle cerebral artery occlusion mice. In addition, combining DEGs of human and mouse, PTGS2, TMCC3, KCNJ2, and GADD45B were identified as cross species conserved hub genes. Meanwhile, molecular docking results revealed that trichostatin A and valproic acid may be potential therapeutic drugs. In conclusion, to our best knowledge, this study conducted the first comorbidity analysis of epilepsy and ischemic stroke to identify the potential common pathogenic mechanisms and drugs. The findings may provide an important reference for the further studies on post-stroke epilepsy.

Effectiveness of vagus nerve stimulation for drug-resistant generalized epilepsy in children aged six and younger.

BACKGROUND: To explore a novel scoring system to evaluate the efficacy of vagus nerve stimulation (VNS) in children with drug-resistant generalized epilepsy (DRGE) aged six and younger. BASIC PROCEDURES: The data of twelve children with DRGE under the age of 6 years who accepted VNS and have been followed up for at least 3 years were retrospectively reviewed. The outcome was evaluated with the McHugh Classification System and a novel scoring system we proposed. MAIN FINDINGS: Based on the McHugh Classification System, the total response rate was 91.67% (11/12) and the rate of Grade I was 41.67% (5/12). A novel scoring system involving seizure frequency, seizure duration and quality of life (QOL) was proposed, by which the outcome was scored from -3 to 11 and graded from IV to I. Based on the novel scoring system, the total response rate was 91.67% (11/12) and the rate of Grade I was 33.33% (4/12). The incidence of complication was 16.67% (2/12). The efficacy of VNS appeared a gradually improving trend with plateau or fluctuation over time. Shorter course of epilepsy prior to VNS may be related to better outcome. PRINCIPAL CONCLUSIONS: VNS could effectively reduce the seizure frequency and improve the QOL of children with DRGE aged six and younger. The novel scoring system was comprehensive and feasible to evaluate the efficacy of VNS. The time pattern of the long-term efficacy of VNS requires further investigation.

Integrative analysis of single-cell and bulk RNA sequencing unveils the senescence landscape in ischemic stroke.

Ischemic stroke (IS) is a fatal neurological disease that occurs when the blood flow to the brain is disrupted, leading to brain tissue damage and functional impairment. Cellular senescence, a vital characteristic of aging, is associated with a poor prognosis for IS. This study explores the potential role of cellular senescence in the pathological process following IS by analyzing transcriptome data from multiple datasets (GSE163654, GSE16561, GSE119121, and GSE174574). By using bioinformatics methods, we identified hub-senescence-related genes such as ANGPTL4, CCL3, CCL7, CXCL16, and TNF and verified them using quantitative reverse transcription polymerase chain reaction. Further analysis of single-cell RNA sequencing data suggests that MG4 microglial is highly correlated with cellular senescence in MCAO, and might play a crucial role in the pathological process after IS. Additionally, we identified retinoic acid as a potential drug for improving the prognosis of IS. This comprehensive investigation of cellular senescence in various brain tissues and peripheral blood cell types provides valuable insights into the underlying mechanisms of the pathology of IS and identifies potential therapeutic targets for improving patient outcomes.

Exploration of the potential common pathogenic mechanisms in COVID-19 and silicosis by using bioinformatics and system biology.

Silicosis is an occupational lung disease that is common worldwide. In recent years, coronavirus disease 2019 (COVID-19) has provided daunting challenges to public healthcare systems globally. Although multiple studies have shown a close link between COVID-19 and other respiratory diseases, the inter-relational mechanisms between COVID-19 and silicosis remain unclear. This study aimed to explore the shared molecular mechanisms and drug targets of COVID-19 and silicosis. Gene expression profiling identified four modules that were most closely associated with both diseases. Furthermore, we performed functional analysis and constructed a protein-protein interaction network. Seven hub genes (budding uninhibited by benzimidazoles 1 [BUB1], protein regulator of cytokinesis 1 [PRC1], kinesin family member C1 [KIFC1], ribonucleotide reductase regulatory subunit M2 [RRM2], cyclin-dependent kinase inhibitor 3 [CDKN3], Cyclin B2 [CCNB2], and minichromosome maintenance complex component 6 [MCM6]) were involved in the interaction between COVID-19 and silicosis. We investigated how diverse microRNAs and transcription factors regulate these seven genes. Subsequently, the correlation between the hub genes and infiltrating immune cells was explored. Further in-depth analyses were performed based on single-cell transcriptomic data from COVID-19, and the expression of hub-shared genes was characterized and located in multiple cell clusters. Finally, molecular docking results reveal small molecular compounds that may improve COVID-19 and silicosis. The current study reveals the common pathogenesis of COVID-19 and silicosis, which may provide a novel reference for further research.

Clinical Features and Blood Indicators for Severity and Prognosis in COVID-19 Patients.

BACKGROUND: This study aimed to analyze the clinical manifestations and blood indicators to deepen the understanding of Coronavirus disease 2019 (COVID-19). METHODS: COVID-19 patients admitted to C10 West Ward, Tongji Hospital in Wuhan City ("West Ward") between January 31 and March 28, 2020, were retrospectively analyzed. RESULTS: A total of 61 COVID-19 patients were hospitalized, wherein the non-critical Group had 30 cases, while the critical group had 31 (including 14 survivors and 17 deaths). Age, the proportion of fever cases, white blood cell (WBC), basophils, red blood cell (RBC), hemoglobin, lactate dehydrogenase (LDH), C-reactive protein (CRP), high-sensitivity troponin, pro-BNP (brain natriuretic peptide), prothrombin time (PT), and D-dimer were higher in the critical group while lymphocytes, eosinophils, albumin were lower compared with those of the non-critical group (all p < 0.05). WBC (p = 0.008), basophils (p = 0.034), and LDH (p = 0.005) of the death subgroup climbed remarkably in comparison with those of the survival subgroup. CONCLUSIONS: Advanced age, high fever, increases in indicators such as WBC, basophils, CRP, LDH, high-sensitivity troponin, pro-BNP, and D-dimer, and decreases in indicators, including lymphocytes, eosinophils, and albumin, might forebode a critical condition.

Effects of miRNA-Modified Exosomes Alleviate Cerebral Ischemic Reperfusion Injury in Preclinical Studies: A Meta-Analysis.

BACKGROUND: Cell-derived exosomes bearing microRNAs (miRNAs) have emerged as a potential therapeutic option for cerebral ischemia-reperfusion injury (CIRI). However, their mechanism of action and clinical translation value remain unclear. The present meta-analysis investigated the therapeutic effects of miRNA-modified exosomes used in preclinical animal models of CIRI. METHODS: The PubMed, Embase, and Web of Science databases were searched on April 20, 2022, to retrieve studies involving middle cerebral artery occlusion model animals treated with exosomes bearing miRNAs. The primary outcome was infarct volume, and the secondary outcome was neurobehavioral performance. FunRich software was used for bioinformatic analysis of exosomal miRNAs, and statistical analysis was performed using R version 4.1.1 (R Foundation for Statistical Computing). RESULTS: Eleven relevant studies were included in the meta-analysis. miRNA-modified exosomes significantly reduced infarct volume (standardized mean difference [SMD], 4.50 [95% confidence interval, 3.02-5.99]; P < 0.01) and improved neurological score (SMD, 2.80 [95% confidence interval, 1.37-4.23]; P < 0.01). Subgroup analysis revealed that a higher injection frequency of exosomes could better reduce infarct volume. The top 6 biological pathways, expression sites, and transcription factors of related exosomal miRNAs were identified through bioinformatics analysis. An asymmetrical funnel plot and Egger's test (P = 0.10) revealed publication bias. Trim-and-fill analysis identified 5 unpublished studies addressing the primary outcome. CONCLUSIONS: miRNA-modified exosomal therapy demonstrated the potential to improve infarct volume and neurobehavioral performance in preclinical animal models of CIRI. Despite the heterogeneity among studies, the results may provide some direction for future clinical research.

A novel risk score model based on fourteen chromatin regulators-based genes for predicting overall survival of patients with lower-grade gliomas.

Background: Low grade gliomas(LGGs) present vexatious management issues for neurosurgeons. Chromatin regulators (CRs) are emerging as a focus of tumor research due to their pivotal role in tumorigenesis and progression. Hence, the goal of the current work was to unveil the function and value of CRs in patients with LGGs. Methods: RNA-Sequencing and corresponding clinical data were extracted from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) database. A single-cell RNA-seq dataset was sourced from the Gene Expression Omnibus (GEO) database. Altogether 870 CRs were retrieved from the published articles in top academic journals. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis were applied to construct the prognostic risk model. Patients were then assigned into high- and low-risk groups based on the median risk score. The Kaplan-Meier (K-M) survival curve and receiver operating characteristic curve (ROC) were performed to assess the prognostic value. Sequentially, functional enrichment, tumor immune microenvironment, tumor mutation burden, drug prediction, single cell analysis and so on were analyzed to further explore the value of CR-based signature. Finally, the expression of signature genes were validated by immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR). Results: We successfully constructed and validated a 14 CRs-based model for predicting the prognosis of patients with LGGs. Moreover, we also found 14 CRs-based model was an independent prognostic factor. Functional analysis revealed that the differentially expressed genes were mainly enriched in tumor and immune related pathways. Subsequently, our research uncovered that LGGs patients with higher risk scores exhibited a higher TMB and were less likely to be responsive to immunotherapy. Meanwhile, the results of drug analysis offered several potential drug candidates. Furthermore, tSNE plots highlighting the magnitude of expression of the genes of interest in the cells from the scRNA-seq assay. Ultimately, transcription expression of six representative signature genes at the mRNA level was consistent with their protein expression changes. Conclusion: Our findings provided a reliable biomarker for predicting the prognosis, which is expected to offer new insight into LGGs management and would hopefully become a promising target for future research.

Experimental verification and validation of immune biomarkers based on chromatin regulators in ischemic stroke.

Ischemic stroke (IS) is a disease characterized by rapid progression and high mortality and disability rates. Its pathophysiological process is inseparable from immune dysfunction. Recently, chromatin regulators (CRs) have been described as a class of enzymes that can recognize, form, and maintain the epigenetic state of an organism, and are closely associated with immune regulation. Nevertheless, the role of CR-related genes in IS has not been fully elucidated. In this study, seven CR-related immune biomarkers in the GSE58294 and GSE22255 datasets were identified by combining differential gene expression analysis, weighted correlation network analysis, and single sample gene set enrichment analysis. After experimental validation using quantitative polymerase chain reaction, four genes (DPF2, LMNB1, MLLT3, and JAK2) were screened as candidate immune biomarkers. These four biomarkers demonstrated good predictive power in the clinical risk model (area under the curve, 0.775). Molecular docking simulations revealed that mevastatin, WP1066, cladribine, trichostatin A, mequitazine, and zuclomiphene may be potential immunomodulatory drugs for IS. Overall, the results of this study contribute to the identification of CR-related immune therapeutics target in IS and provide an important reference for further research.

Inhibition of FAM83D displays antitumor effects in glioblastoma via down-regulation of the AKT/Wnt/ß-catenin pathway.

Up-regulation of family with sequence similarity 83 member D (FAM83D) has been acknowledged as a vital contributor for the carcinogenesis of numerous cancers. The relevance of FAM83D in glioblastoma (GBM), however, is not well understood. This current work aimed to determine the possible roles and mechanisms of FAM83D in GBM. By analyzing The Cancer Genome Atlas (TCGA) data, we found dramatic increases in FAM83D expression in GBM tissue. We also observed elevated levels of FAM83D in the clinical specimens of GBM. In vitro data showed that silencing FAM83D resulted in remarkable antitumor effects via inhibiting the proliferation, invasion and epithelial-mesenchymal transition of GBM cells. Moreover, the knockdown of FAM83D improved sensitivity to the chemotherapy drug temozolomide. In-depth mechanism research revealed that the silencing of FAM83D strikingly decreased the phosphorylation levels of AKT and glycogen synthase kinase-3ß, and prohibited activation of the Wnt/ß-catenin pathway. The suppression of AKT abolished FAM83D-mediated activation of the Wnt/ß-catenin pathway. The re-expression of ß-catenin reversed FAM83D-silencing-induced antitumor effects in GBM cells. In addition, GBM cells with FAM83D silencing exhibited reduced tumorigenic potential in vivo. Overall, the data from this work show that the inhibition of FAM83D displays antitumor effects in GBM via down-regulation of the AKT/Wnt/ß-catenin pathway and propose FAM83D as a new therapeutic target for GBM.

Experimental verification and comprehensive analysis of m7G methylation regulators in the subcluster classification of ischemic stroke.

Background: Ischemic stroke (IS) is a fatal cerebrovascular disease involving several pathological mechanisms. Modification of 7-methylguanosine (m7G) has multiple regulatory functions. However, the expression pattern and mechanism of m7G in IS remain unknown. Herein, we aimed to explore the effect of m7G modification on IS. Methods: We screened significantly different m7G-regulated genes in Gene Expression Omnibus datasets, GSE58294 and GSE22255. The random forest (RF) algorithm was selected to identify key m7G-regulated genes that were subsequently validated using the middle cerebral artery occlusion (MCAO) model and quantitative polymerase chain reaction (qPCR). A risk model was subsequently generated using key m7G-regulated genes. Then, "ConsensusClusterPlus" package was used to distinguish different m7G clusters of patients with IS. Simultaneously, between two m7G clusters, differentially expressed genes (DEGs) and immune infiltration differences were also explored. Finally, we investigated functional enrichment and the mRNA-miRNA-transcription factor network of DEGs. Results: RF and qPCR confirmed that EIF3D, CYFIP2, NCBP2, DCPS, and NUDT1 were key m7G-related genes in IS that could accurately predict clinical risk (area under the curve = 0.967). NCBP2 was the most significantly associated gene with immune infiltration. Based on the expression profiles of these key m7G-related genes, the IS group could be divided into two clusters. According to the single-sample gene set enrichment analysis algorithm, four types of immune cells (immature dendritic cells, macrophages, natural killer T cells, and TH1 cells) were significantly different in the two m7G clusters. The functional enrichment of 282 DEGs between the two clusters was mainly concentrated in the "regulation of apoptotic signaling pathway," "cellular response to DNA damage stimulus," "adaptive immune system," and "pyroptosis." The miR-214-LTF-FOXJ1 axis may be a key regulatory pathway for IS. Conclusion: Our findings suggest that EIF3D, CYFIP2, NCBP2, DCPS, and NUDT1 may serve as potential diagnostic biomarkers for IS and that the m7G clusters developed by these genes provide more evidence for the regulation of m7G in IS.

Increased levels of ferritin on admission predicts intensive care unit mortality in patients with COVID-19.

BACKGROUND: The aim of this study was to evaluate hyperferritinemia could be a predicting factor of mortality in hospitalized patients with coronavirus disease-2019 (COVID-19). METHODS: A total of 100 hospitalized patients with COVID-19 in intensive care unit (ICU) were enrolled and classified into moderate (n = 17), severe (n = 40) and critical groups (n = 43). Clinical information and laboratory results were collected and the concentrations of ferritin were compared among different groups. The association between ferritin and mortality was evaluated by logistic regression analysis. Moreover, the efficiency of the predicting value was assessed using receiver operating characteristic (ROC) curve. RESULTS: The amount of ferritin was significantly higher in critical group compared with moderate and severe groups. The median of ferritin concentration was about three times higher in death group than survival group (1722.25 µg/L vs. 501.90 µg/L, p < 0.01). The concentration of ferritin was positively correlated with other inflammatory cytokines, such as interleukin (IL)-8, IL-10, C-reactive protein (CRP) and tumor necrosis factor (TNF)-α. Logistic regression analysis demonstrated that ferritin was an independent predictor of in-hospital mortality. Especially, high-ferritin group was associated with higher incidence of mortality, with adjusted odds ratio of 104.97 [95% confidence interval (CI) 2.63-4185.89; p = 0.013]. Moreover, ferritin had an advantage of discriminative capacity with the area under ROC (AUC) of 0.822 (95% CI 0.737-0.907) higher than procalcitonin and CRP. CONCLUSION: The ferritin measured at admission may serve as an independent factor for predicting in-hospital mortality in patients with COVID-19 in ICU.

ANTECEDENTES: El objetivo de este estudio fue evaluar si la hiperferritinemia podría ser un factor predictivo de la mortalidad en pacientes hospitalizados con enfermedad por coronavirus de 2019 (COVID-19). MÉTODOS: Se incluyó un total de 100 pacientes hospitalizados con COVID-19 en la unidad de cuidados intensivos (UCI), clasificándose como grupos moderado (n = 17), grave (n = 40) y crítico (n = 43). Se recopiló la información clínica y de laboratorio, comparándose los niveles de ferritina entre los diferentes grupos. Se evaluó la asociación entre ferritina y mortalidad mediante un análisis de regresión logística. Además, se evaluó la eficacia del valor predictivo utilizando la curva ROC (receiver operating characteristic). RESULTADOS: La cantidad de ferritina fue significativamente superior en el grupo de pacientes críticos en comparación con el grupo de pacientes graves. La media de concentración de ferritina fue cerca de 3 veces superior en el grupo de muerte que en el grupo de supervivientes (1.722,25 µg/L vs. 501,90 µg/L, p < 0,01). La concentración de ferritina guardó una correlación positiva con otras citoquinas inflamatorias tales como interleucina (IL)-8, IL-10, proteína C reactiva (PRC) y factor de necrosis tumoral (TNF)-α. El análisis de regresión logística demostró que la ferritina era un factor predictivo independiente de la mortalidad intrahospitalaria. En especial, el grupo de ferritina alta estuvo asociado a una mayor incidencia de la mortalidad, con un valor de odds ratio ajustado de 104,97 [intervalo de confianza (IC) del 95% 2,63-4.185,89; p = 0,013]. Además, el valor de ferritina tuvo una ventaja de capacidad discriminativa en el área bajo la curva ROC (AUC) de 0,822 (IC 95% 0,737-0,907] superior al de procalcitonina y PRC. CONCLUSIÓN: El valor de ferritina medido durante el ingreso puede servir de factor independiente para prevenir la mortalidad intrahospitalaria en los pacientes de COVID-19 en la UCI.

The efficiency and safety of high-dose vitamin C in patients with COVID-19: a retrospective cohort study.

BACKGROUND: The inflammatory reaction is the main cause of acute respiratory distress syndrome and multiple organ failure in patients with Coronavirus disease 2019, especially those with severe and critical illness. Several studies suggested that high-dose vitamin C reduced inflammatory reaction associated with sepsis and acute respiratory distress syndrome. This study aimed to determine the efficacy and safety of high-dose vitamin C in Coronavirus disease 2019. METHODS: We included 76 patients with Coronavirus disease 2019, classified into the high-dose vitamin C group (loading dose of 6g intravenous infusion per 12 hr on the first day, and 6g once for the following 4 days, n=46) and the standard therapy group (standard therapy alone, n=30). RESULTS: The risk of 28-day mortality was reduced for the high-dose vitamin C versus the standard therapy group (HR=0.14, 95% CI, 0.03-0.72). Oxygen support status was improved more with high-dose vitamin C than standard therapy (63.9% vs 36.1%). No safety events were associated with high-dose vitamin C therapy. CONCLUSION: High-dose vitamin C may reduce the mortality and improve oxygen support status in patients with Coronavirus disease 2019 without adverse events.

[Increased levels of ferritin on admission predicts intensive care unit mortality in patients with COVID-19]. / El incremento de ferritina sérica durante el ingreso predice la mortalidad de los pacientes de COVID-19 en Cuidados Intensivos.

BACKGROUND: The aim of this study was to evaluate hyperferritinemia could be a predicting factor of mortality in hospitalized patients with coronavirus disease-2019 (COVID-19). METHODS: A total of 100 hospitalized patients with COVID-19 in intensive care unit (ICU) were enrolled and classified into moderate (n=17), severe (n=40) and critical groups (n=43). Clinical information and laboratory results were collected and the concentrations of ferritin were compared among different groups. The association between ferritin and mortality was evaluated by logistic regression analysis. Moreover, the efficiency of the predicting value was assessed using receiver operating characteristic (ROC) curve. RESULTS: The amount of ferritin was significantly higher in critical group compared with moderate and severe groups. The median of ferritin concentration was about three times higher in death group than survival group (1722.25µg/L vs. 501.90µg/L, p<0.01). The concentration of ferritin was positively correlated with other inflammatory cytokines, such as interleukin (IL)-8, IL-10, C-reactive protein (CRP) and tumor necrosis factor (TNF)-α. Logistic regression analysis demonstrated that ferritin was an independent predictor of in-hospital mortality. Especially, high-ferritin group was associated with higher incidence of mortality, with adjusted odds ratio of 104.97 [95% confidence interval (CI) 2.63-4185.89; p=0.013]. Moreover, ferritin had an advantage of discriminative capacity with the area under ROC (AUC) of 0.822 (95% CI 0.737-0.907) higher than procalcitonin and CRP. CONCLUSION: The ferritin measured at admission may serve as an independent factor for predicting in-hospital mortality in patients with COVID-19 in ICU.

The head fixation based on skull cap: An improved protocol used in single unit recording in the vestibular system.

Single unit recording has an important application in neuroscience, especially in the vestibular system such as visual stabilization, posture maintenance, spatial orientation and cognition. However, single unit recording conducted in living animals is a demanding technique and non-ideal mechanical stability between the recording location of nerve tissues and the tip of microelectrode always results in failure to obtain successful recordings in the vestibular system. In order to improve the mechanical stability during single unit recording, we constructed a novel head fixation method based on skull cap. This article describes in detail how to construct this novel head fixation. Following the step-by-step procedure mentioned in this article will provide a high-quality mechanical stability for single unit recording in the vestibular system, allowing us to successfully record the nonlinear neural dynamic response over a big magnitude motion stimulation. This improvement of head fixation contributes to the in-depth understanding of the vestibular system.

LncRNA IDH1-AS1 suppresses cell proliferation and tumor growth in glioma.

Glioma is a type of brain tumor that is common globally, and is associated with a variety of genetic changes. It has been reported that isocitrate dehydrogenase 1 (IDH1) is overexpressed in glioma and in HeLa cells. The lncRNA IDH1-AS1 is believed to interact with IDH1, and when IDH1-AS1 is overexpressed, HeLa cell proliferation is inhibited. However, the effects of IDH1-AS1 on glioma were relatively unknown. The results from this work show that IDH1-AS1 is downregulated in the glioma tissues. We used primary glioblastoma cell lines U251 and U87-MG to study the effects of IDH1-AS1 on glioma cell growth, in vitro and in vivo. We found that when IDH1-AS1 is overexpressed cell proliferation is inhibited, cell cycle is arrested at the G1 phase, and the protein expression levels of cyclinD1, cyclinA, cyclinE, CDK2, and CDK4 are decreased. We found that cell apoptosis was increased when IDH1-AS1 was overexpressed, as evidenced by increases in the levels of cleaved caspase-9 and -3. Conversely, knockdown of IDH1-AS1 promoted cell proliferation. Moreover, we proved that overexpression of IDH1-AS1 inhibits the tumorigenesis of U251 cells, in vivo. Furthermore, IDH1-AS1 did not affect IDH1 protein expression, but altered its enzymatic activities in glioma cells. Silencing of IDH1 reversed the effects of IDH1-AS1 upregulation on cell viability. Hence, our study provides first-hand evidence for the effects of lncRNA IDH1-AS1 on gliomas. Because overexpressing IDH1-AS1 inhibited cell growth, IDH1-AS1 could also be considered as a potential target for glioma treatment.

The real identity and sensory overlap mechanism of special vestibular afferent neurons that sense both rotation and linear force.

AIMS: Although the vestibular system has been widely investigated over the past 50 years, there is still an unsolved mystery. Some special vestibular afferent (SVA) neurons responding to both rotation and linear force were found through neurophysiological techniques, however, the sensory overlap mechanism of SVA neurons is still unclear, which may be closely related to vestibular-related diseases. MATERIALS AND METHODS: To address the above-mentioned problem, a cupula buoyancy theory was established in the present study, where SVA neurons were considered semicircular canal afferent (SCCA) neurons. Then labyrinth anatomy and neural response dynamics of vestibular afferent neurons in chinchilla were investigated through vestibular labyrinth reconstruction and single unit recording technique, respectively. KEY FINDINGS: We analyzed the deflections of cupulae under multiple conditions with the help of Amira Software and predicted the neural response law of SCCA neurons to linear force based on the cupula buoyancy theory. Data analysis confirmed that the basic response characteristic of SVA neurons had no significant difference to those of SCCA neurons, but were significantly different from those of otolith afferent neurons. Further, the actual responses of SVA neurons to linear force are completely consistent with our predictions. These results strongly suggest that SVA neurons actually are SCCA neurons, and the cupula buoyancy theory is the key to the sensory overlap mechanism of SCCA neurons. SIGNIFICANCE: Our study revealed the real identity of SVA neurons and provided a reasonable mechanism for sensory overlap of rotation and linear force, which improved our understanding about the vestibular system.

[Optimal design of neural modulation strategy of vestibular prosthesis].

Objective:To reveal the response characteristics of semicircular canal neurons（SCN） in the nonlinear perceptual interval, and to establish and screen out the precise SCN information coding model and function expression, which lays a foundation for the optimization and improvement of neuromodulation strategy of multichannel vestibular prosthesis. Method:The perceptual electrophysiological information data of the SCNs during the rotational stimulation was recorded in the nonlinear perceptual interval. The nonlinear least-squares algorithm was used to fit the electrophysiological information data to establish the linear-nonlinear models. The Akaike information criterion was used to calculate the goodness of fit of each model to determine the optimal expression function. Result:In the frequency experiment, the accurate information coding model of more than 85% of SCNs is a quadratic polynomial, and the frequency has no significant effect on the linear-nonlinear selection of the SCNs information coding model（P>0.05）. In the amplitude experiment, the accurate information coding model of more than 83.33% of SCNs is quadratic polynomial when the maximum angular velocity is>80 deg/s, and the amplitude has a significant effect on the linear-nonlinear selection of the SCNs information coding model（P=0.038）. Conclusion:The information coding models of SCN population in the nonlinear perceptual interval have two expressions, linear and nonlinear function, which is closely related to angular velocity. The quadratic polynomial function is more accurate and more advantageous and it can be used to design the precise neuromodulation strategy of multichannel vestibular prosthesis.