Exploring Safety-Stability Tradeoffs in Cooperative CAV Platoon Controls with Bidirectional Impacts.

Advanced sensing technologies and communication capabilities of Connected and Autonomous Vehicles (CAVs) empower them to capture the dynamics of surrounding vehicles, including speeds and positions of those behind, enabling judicious responsive maneuvers. The acquired dynamics information of vehicles spurred the development of various cooperative platoon controls, particularly designed to enhance platoon stability with reduced spacing for reliable roadway capacity increase. These controls leverage abundant information transmitted through various communication topologies. Despite these advancements, the impact of different vehicle dynamics information on platoon safety remains underexplored, as current research predominantly focuses on stability analysis. This knowledge gap highlights the critical need for further investigation into how diverse vehicle dynamics information influences platoon safety. To address this gap, this research introduces a novel framework based on the concept of phase shift, aiming to scrutinize the tradeoffs between the safety and stability of CAV platoons formed upon bidirectional information flow topology. Our investigation focuses on platoon controls built upon bidirectional information flow topologies using diverse dynamics information of vehicles. Our research findings emphasize that the integration of various types of information into CAV platoon controls does not universally yield benefits. Specifically, incorporating spacing information can enhance both platoon safety and string stability. In contrast, velocity difference information can improve either safety or string stability, but not both simultaneously. These findings offer valuable insights into the formulation of CAV platoon control principles built upon diverse communication topologies. This research contributes a nuanced understanding of the intricate interplay between safety and stability in CAV platoons, emphasizing the importance of information dynamics in shaping effective control strategies.

Subthalamic nucleus dynamics track microlesion effect in Parkinson's disease.

Parkinson's Disease (PD) is characterized by the temporary alleviation of motor symptoms following electrode implantation (or nucleus destruction), known as the microlesion effect (MLE). Electrophysiological studies have explored different PD stages, but understanding electrophysiological characteristics during the MLE period remains unclear. The objective was to examine the characteristics of local field potential (LFP) signals in the subthalamic nucleus (STN) during the hyperacute period following implantation (within 2 days) and 1 month post-implantation. 15 patients diagnosed with PD were enrolled in this observational study, with seven simultaneous recordings of bilateral STN-LFP signals using wireless sensing technology from an implantable pulse generator. Recordings were made in both on and off medication states over 1 month after implantation. We used a method to parameterize the neuronal power spectrum to separate periodic oscillatory and aperiodic components effectively. Our results showed that beta power exhibited a significant increase in the off medication state 1 month after implantation, compared to the postoperative hyperacute period. Notably, this elevation was effectively attenuated by levodopa administration. Furthermore, both the exponents and offsets displayed a decrease at 1 month postoperatively when compared to the hyperacute postoperative period. Remarkably, levodopa medication exerted a modulatory effect on these aperiodic parameters, restoring them back to levels observed during the hyperacute period. Our findings suggest that both periodic and aperiodic components partially capture distinct electrophysiological characteristics during the MLE. It is crucial to adequately evaluate such discrepancies when exploring the mechanisms of MLE and optimizing adaptive stimulus protocols.

Technical Issues of Vim-PSA Double-Target DBS for Essential Tremor.

BACKGROUND: Deep brain stimulation (DBS) is an effective surgical treatment for essential tremor (ET), with the ventral intermediate nucleus (Vim) and posterior subthalamic area (PSA) as the most common targets. The stimulation efficacy of ET with Vim-PSA double-target DBS has been reported. Herein, we aim to propose surgical techniques for Vim-PSA double-target DBS surgery. METHODS: This study enrolled six patients with ET who underwent Vim-PSA double-target electrode implantation from October 2019 to May 2022. The targets were located and adjusted using coordinates and multimodality MRI images. A burr hole was accurately drilled in line with the electrode trajectory under the guidance of a stereotactic frame. Novel approaches were adopted during the electrode implantation process for pneumocephalus reduction, including "arachnoid piamater welding" and "water sealing". Electrophysiological recording was used to identify the implantation sites of the electrodes. A 3D reconstruction model of electrodes and nuclei was established to facilitate programming. RESULTS: The combination of coordinates and multimodality MRI images for target location and adjustment enabled the alignment of Vim and PSA. Postoperative CT scanning showed that the electrode was precisely implanted. Stereotactic guidance facilitated accurate burr hole drilling. "Arachnoid piamater welding" and "water sealing" were efficient in reducing pneumocephalus. Intraoperative electrophysiological verified the efficacy of Vim-PSA double-target DBS surgery. CONCLUSIONS: The methods for target location and adjustment, accurate drilling of the burr hole, reduction in pneumocephalus, and intraoperative electrophysiological verification are key issues in DBS surgery targeting both the Vim and PSA. This study may provide technical support for Vim-PSA DBS, especially for surgeons with less experience in functional neurosurgery.

Facial nerve in skullbase tumors: imaging and clinical relevance.

Facial nerve, the 7th cranial nerve, is a mixed nerve composed of sensory and motor fibers, and its main branch is situated in the cerebellopontine angle. Facial nerve dysfunction is a debilitating phenomenon that can occur in skullbase tumors and Bell's pals. Recovery of the facial nerve dysfunction after surgery for skullbase tumors can be disappointing, but is usually favorable in Bell's palsy. Advances in magnetic resonance imaging (MRI) allow to visualize the facial nerve and its course in the cerebellopontine angle, also when a large tumor is present and compresses the nerve. Here, we describe the anatomical, neurochemical and clinical aspects of the facial nerve and highlight the recent progress in visualizing the facial nerve with MRI.

Delivery of Fc-fusion Protein by a Recombinant Newcastle Disease Virus Vector.

Fc-fusion proteins (FCPs), a new generation biological medicine, have revolutionized the practice of medicines that treat diseases. However, complex manufacturing techniques are required for FCP production, casting the affordability and accessibility issues in low- and middle-income economies (LMIEs). Virus-vectored system may serve as a simple and cost-effective platform for FCP delivery. As a proof-of-concept study, Newcastle disease virus (NDV), a widely-used vector for vaccine generation, was used as a vector to express and deliver a model FCP composed of the hemagglutinin (HA) and IgG Fc. A recombinant NDV expressing the HA-Fc fusion protein was generated using reverse genetics, which had comparable replication and virulence to the parental virus. High levels of expression of soluble HA-Fc were detected in cell culture and embryonated chicken eggs inoculated with the recombinant NDV. In addition, the recombinant NDV replicated in the lung of mouse, delivering the HA-Fc protein to this organ. The HA-Fc expressed by NDV specifically bound to murine FcγRI, which was dependent on the presence of the Fc tag. The recombinant NDV induced high vector-specific antibody response, whereas it failed to elicit H7N9-specific antibody immunity in mice. The absence of HA-specific antibodies may be attributed to deficient incorporation of the HA-Fc protein into NDV virion particles. Our results indicated that NDV may be potentially used as a vector for FCP expression and delivery. This strategy may help to enhance the affordability and equal accessibility of FCP biological medicines, especially in LIMEs.

Current situation and future direction of Newcastle disease vaccines.

Newcastle disease (ND) is one of the most economically devastating infectious diseases affecting the poultry industry. Virulent Newcastle disease virus (NDV) can cause high mortality and severe tissue lesions in the respiratory, gastrointestinal, neurological, reproductive and immune systems of poultry. Tremendous progress has been made in preventing morbidity and mortality caused by ND based on strict biosecurity and wide vaccine application. In recent decades, the continual evolution of NDV has resulted in a total of twenty genotypes, and genetic variation may be associated with disease outbreaks in vaccinated chickens. In some countries, the administration of genotype-matched novel vaccines in poultry successfully suppresses the circulation of virulent NDV strains in the field. However, virulent NDV is still endemic in many regions of the world, especially in low- and middle-income countries, impacting the livelihood of millions of people dependent on poultry for food. In ND-endemic countries, although vaccination is implemented for disease control, the lack of genotype-matched vaccines that can reduce virus infection and transmission as well as the inadequate administration of vaccines in the field undermines the effectiveness of vaccination. Dissection of the profiles of existing ND vaccines is fundamental for establishing proper vaccination regimes and developing next-generation vaccines. Therefore, in this article, we provide a broad review of commercial and experimental ND vaccines and promising new platforms for the development of next-generation vaccines.

Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.

The mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) has shown oncogenic roles in various cancers and may have non-metabolic functions. This study investigated the role of MTHFD2 in glioblastoma pathogenesis. We find that MTHFD2 expression is enriched in gliomas by analysing public databases and clinical specimens. RNA interference (RNAi) and inhibitor of MTHFD2 hamper the proliferation of glioblastoma and induce apoptosis in cell lines, glioma stem-like cells (GSCs) and patient-derived xenografts (PDX). Metabolomic analyses show that MTHFD2 depletion suppresses the central carbon metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle. GSEA reveals a novel non-metabolic function of MTHFD2 in association with the unfolded protein response (UPR). MTHFD2 depletion activates the PERK/eIF2α axis which contributes to translation inhibition and apoptosis; these effects are attenuated by a PERK inhibitor. Mechanistically, MTHFD2 may be linked to UPR via the post-transcriptionally regulation of chaperone protein GRP78. In conclusion, MTHFD2 could be a promising therapeutic target for glioblastoma. Besides its canonical role, MTHFD2 may contribute to glioblastoma pathogenesis via UPR, highlighting a newly identified functional link between one-carbon metabolism and cell stress response.

Correlation between cerebrospinal fluid abnormalities before ventriculoperitoneal shunt and postoperative intracranial infection in adult patients with hydrocephalus: A clinical study.

Objective: To identify the relationship between preoperative cerebrospinal fluid (CSF) leukocyte, chloride, glucose, aspartate aminotransferase, lactate dehydrogenase, adenosine deaminase, lactic acid and protein levels and ventriculoperitoneal shunt infection. Methods: Records of 671 consecutive adult patients who underwent ventriculoperitoneal shunt surgery for the treatment of hydrocephalus at Zhujiang Hospital affiliated with Southern Medical University from January 2011 to March 2022 were reviewed. The patients were divided into infection and non-infection groups based on the presence of postoperative infection. For all patients, we analyzed age; sex; primary disease; preoperative CSF leukocyte, chloride, glucose, aspartate aminotransferase, lactate dehydrogenase, adenosine deaminase, lactic acid and protein levels; postoperative temperature; and postoperative infection. Results: A total of 397 patients were included, 28 (7.05%) of whom had an infection within 6 months of the operation and the remaining had no infection. There was no significant difference in age, sex, primary disease, leukocyte, chloride ion, aspartate aminotransferase, lactate dehydrogenase, adenosine deaminase and protein levels in CSF between infection group and non-infection group (p > 0.05). The postoperative infection rate of patients with CSF glucose < 2.8 mmol/L (x 2 = 11.650, p = 0.001) and CSF lactic acid >2.8 mmol/L (x 2 = 12.455, p < 0.001) was higher than that of patients with CSF glucose level ≥2.8 mmol/L and CSF lactic acid level in the range of (1-2.8) mmol/L, respectively, with statistical difference. Compared with the non-infection group, the level of CSF glucose (t = 4.113, p < 0.001) was significantly lower, and the level of CSF lactic acid (t = 6.651, p < 0.001) was significantly higher in the infection group. Multivariate logistic regression analysis showed that preoperative cerebrospinal fluid glucose < 2.8 mmol/L (OR = 3.911, 95% CI: 1.653~9.253, p = 0.002) and cerebrospinal fluid lactate >2.8 mmol/L (OR = 4.712, 95% CI: 1.892~11.734, p = 0.001) are risk factors for infection after ventriculoperitoneal shunt. ROC analysis revealed that the area under the curve (AUC) for CSF glucose and lactic acid level were 0.602 (95% CI: 0.492-0.713) and 0.818 (95% CI: 0.738-0.898), respectively. The infection group had higher rates of fever and body temperature on postoperative day 3-7 (p < 0.05). Conclusions: For adult hydrocephalus patients without clinical manifestations of intracranial infection but only with simple abnormality of cerebrospinal fluid, when the content of glucose in cerebrospinal fluid is < 2.8 mmol/L, and the content of lactic acid is >2.8 mmol/L, it is recommended to perform ventriculoperitoneal shunt after further improvement of cerebrospinal fluid indicators, otherwise, hasty operation will increase the postoperative infection rate. The postoperative fever rate of ventriculoperitoneal shunt surgery is high and the body temperature drops rapidly. If there is still fever after day 3 after surgery, whether there is intracranial infection should be considered.

Hydroxyethyl Starch Curcumin Enhances Antiproliferative Effect of Curcumin Against HepG2 Cells via Apoptosis and Autophagy Induction.

It is well documented that curcumin (CUR), as a polyphenol molecule originated from turmeric, has many advantages such as antioxidative, anti-inflammatory, neuroprotective, and antitumor effects. However, because of its poor water solubility and low bioavailability, the biomedical applications of CUR are limited. So, in this study, we modified CUR with conjugation to a food-derived hydrophilic hydroxyethyl starch (HES) via an ester linkage to fabricate the amphiphilic conjugate HES-CUR prior to self-assembling into uniform nanoparticles (HES-CUR NPs). And, the results of the 1H NMR spectra and FT-IR spectrum showed successful synthesis of HES-CUR NPs; moreover, the solubility and the drug loading efficiency of CUR were significantly increased. Next, we further explored the differences on the antitumor effects between HES-CUR NPs and CUR in HepG2 cells, and the results of the CCK8-assay and cell counting experiment showed that HES-CUR NPs exhibited a more significant antiproliferative effect than that of CUR in HepG2 cells. And HepG2 cells were more sensitive to apoptosis induced by HES-CUR NPs as evidenced by flow cytometry, increased cytochrome c level, and decreased full length caspase-3 and Bcl-2 protein expressions. Additionally, we found that the efficacy of HES-CUR NPs against HepG2 cells might be related to the enhanced degree of mitochondrial damage (decrease of the mitochondrial membrane potential and ATP) and autophagy (increased levels of Beclin-1 and LC3-II proteins). So, the findings in this study suggest that HES-CUR NPs have a great application potential in antitumor efficacy and play an important role in multiple signal pathways.

α and θ oscillations in the subthalamic nucleus are potential biomarkers for Parkinson's disease with depressive symptoms.

INTRODUCTION: Abnormal α oscillations in the bed nucleus of stria terminalis and subgenual cingulate of patients with depression correlate with symptom severity. Some Parkinson's disease (PD) patients also have abnormal θ-α oscillations in the subthalamic nucleus (STN). However, the relationship between abnormal θ-α oscillations and depressive symptoms in PD patients has not been determined. This study explored the correlation between α and θ oscillations of the STN and depressive symptoms in PD patients. METHODS: We conducted a retrospective case-control study on 36 PD patients with (dPD group) or without depressive symptoms (nPD group), analyzing the difference in the average power spectral density (PSD) of α and θ oscillations of the local field potential (LFP) recorded in the STN during deep brain stimulation (DBS), and their correlation with the Hamilton depression rating scale (HAMD) of PD patients during the same period. RESULTS: The dPD group had a higher PSD of α oscillations and a lower PSD of θ oscillations in the left ventral STN. The PSD of α oscillations of the left ventral STN were positively correlated with the severity of depressive symptoms, whereas the PSD of θ oscillations of this location was negatively correlated with severity of depressive symptoms. The PSD of α and θ oscillations did not correlate with motor symptoms, sleep quality, or quality of life score. CONCLUSION: Abnormal α and θ oscillations of the left ventral STN could be used as biomarkers of PD with depressive symptoms, which might guide STN-DBS treatment.

TERT Mutation Is Accompanied by Neutrophil Infiltration and Contributes to Poor Survival in Isocitrate Dehydrogenase Wild-Type Glioma.

Mutation of the telomerase reverse transcriptase (TERT) promoter has been demonstrated as an unfavorable prognostic marker in patients with isocitrate dehydrogenase wild-type (IDHwt) glioma. This study aimed to investigate the immune role of TERT promoter mutation status which could improve prognostic prediction in IDHwt. TERT mutation status, IDH mutation, and 1p-19q codeletion status data were obtained from 614 glioma cases from the Cancer Genome Atlas, and 325 cases from the Chinese Glioma Genome Atlas. The same information was obtained from 49 clinical glioma tissues. TERT mutation is preferentially present in glioblastoma and IDH-wt gliomas and is associated with poor prognosis. Moreover, TERT mutation was associated with infiltration of neutrophils and expression of neutrophil chemokines. which might partially contribute to the poor outcome in IDH-wt glioma. Furthermore, patients with IDH-wt glioma did not harbor increased peripheral neutrophils, implying that the infiltrated neutrophil in the tumor environment might due to cytokine chemotaxis. In this study, we hereby propose that TERT mutation might be a molecular driver of the dysfunctional immune microenvironment in IDH-wt glioma. TERT mutation may be a potential immune therapeutic target for optimizing treatment combinations and patient selection for glioma immunotherapy.

Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease.

Tristetraprolin (TTP), an RNA-binding protein encoded by the ZFP36 gene, is vital for neural differentiation; however, its involvement in neurodegenerative diseases such as Parkinson's disease (PD) remains unclear. To explore the role of TTP in PD, an in vitro 1-methyl-4-phenylpyridinium (MPP+ ) cell model and an in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of PD were used. Transfection of small interfering (si)-TTP RNA upregulated pro-oxidative NOX2 expression and ROS formation, downregulated anti-oxidative GSH and SOD activity；si-TTP upregulated pro-apoptotic cleaved-caspase-3 expression, and downregulated antiapoptotic Bcl-2 expression; while overexpression (OE)-TTP lentivirus caused opposite effects. Through database prediction, luciferase experiment, RNA immunoprecipitation (RIP), and mRNA stability analysis, we evaluated the potential binding sites of TTP to 3'-untranslated regions (3'-UTR) of NOX2 mRNA. TTP affected the NOX2 luciferase activity by binding to two sites in the NOX2 3'-UTR. RIP-qPCR confirmed TTP binding to both sites, with a higher affinity for site-2. In addition, TTP reduced the NOX2 mRNA stability. si-NOX2 and antioxidant N-acetyl cysteine (NAC) reversed si-TTP-induced cell apoptosis. In MPTP-treated mice, TTP expression increased and was co-located with dopaminergic neurons. TTP also inhibited NOX2 and decreased the oxidative stress in vivo. In conclusion, TTP protects against dopaminergic oxidative injury by promoting NOX2 mRNA degradation in the MPP+ /MPTP model of PD, suggesting that TTP could be a potential therapeutic target for regulating the oxidative stress in PD.

Downregulated lncRNA-SNHG1 enhances autophagy and prevents cell death through the miR-221/222 /p27/mTOR pathway in Parkinson's disease.

Autophagy has been shown to be critically associated with the central mechanisms underlying Parkinson's disease (PD), while the mechanisms contributing to the imbalance of autophagy remain unclear. Small nucleolar RNA host gene 1 (SNHG1), a well-studied long noncoding RNA, has been reported to be significantly increased in PD. The potential biological functions of SNHG1 in the regulation of neuronal autophagy and cell death in PD, however, have not yet been completely elucidated. In this study, we examined the existence of regulatory networks involving SNHG1, the miR-221/222 cluster and the cyclin-dependent kinase inhibitor 1B (CDKN1B/p27)/mammalian target of rapamycin (mTOR) signaling pathway in PD. We observed that SNHG1 expression was gradually upregulated in PD cellular and animal models. Furthermore, silencing SNHG1 promoted autophagy and prevented MPP+-induced cell death, similar to the overexpression of the miR-221/222 cluster. Mechanistically, SNHG1 competitively binds to the miR-221/222 cluster and indirectly regulates the expression of p27/mTOR. In conclusion, these results demonstrated that downregulation of SNHG1 attenuated MPP+-induced decreases in LC3-II (an autophagic marker) levels and cytotoxicity through the miR-221/222/p27/mTOR pathway, suggesting that SNHG1 may be a therapeutic target for neuroprotection and disease treatment in PD.

Characteristics of acidogenic fermentation for volatile fatty acid production from food waste at high concentrations of NaCl.

This study explored the effects of NaCl on volatile fatty acid (VFA) production from food waste by acidogenic fermentation. The production and composition of VFAs, and the microbial community in acidogenic fermentation were investigated at four different NaCl concentrations: 10, 30, 50, and 70 g/L, and at 0 g/L (control). The highest VFA production was 0.542 g/g dry weight of food waste at 10 g/L NaCl, and about 23% lower but still high at 70 g/L NaCl. Interestingly, as NaCl concentration increased, the residence time of lactic acid in the reactor increased, and the maximum production also increased. The type of acidogenic fermentation also changed from butyric acid to propionic acid as the NaCl concentration increased. Microbial community analysis showed that a large number of propionibacteria were present at the end of fermentation, indicating their high tolerance to NaCl.

miR-497/Wnt3a/c-jun feedback loop regulates growth and epithelial-to-mesenchymal transition phenotype in glioma cells.

Glioma is one of the most frequent intracranial malignant tumors. Abnormal expression of microRNAs usually contributes to the development and progression of glioma. In the current study, we explored the role and underlying mechanism of miR-497 in glioma. We revealed that miR-497 expression was significantly down-regulated in glioma tissues and cell lines. Reduced expression of miR-497 was associated with poor disease-free and over-all survival rate. Restoration of miR-497 decreased glioma cell growth and invasion both in vitro and in vivo. The oncogene Wnt3a was identified as a downstream target of miR-497 by using luciferase and western blot assays. Knockdown of Wnt3a mimicked the effect of miR-497 in glioma cells. In summary, our study demonstrated that miR-497 may function as a tumor suppressor in glioma and suggested that miR-497 is a potential therapeutic target for glioma patients.

A lincRNA-p21/miR-181 family feedback loop regulates microglial activation during systemic LPS- and MPTP- induced neuroinflammation.

The role of microglial-mediated sustained neuroinflammation in the onset and progression of Parkinson's disease (PD) is well established, but the mechanisms contributing to microglial activation remain unclear. LincRNA-p21, a well studied long intergenic noncoding RNA (lincRNA), plays pivotal roles in diverse biological processes and diseases. Its role in microglial activation and inflammation-induced neurotoxicity, however, has not yet been fully elucidated. Here, we report that lincRNA-p21 promotes microglial activation through a p53-dependent transcriptional pathway. We further demonstrate that lincRNA-p21 competitively binds to the miR-181 family and induces microglial activation through the miR-181/PKC-δ pathway. Moreover, PKC-δ induction further increases the expression of p53/lincRNA-p21 and thus forms a circuit. Taken together, our results suggest that p53/lincRNA-p21, together with miR-181/PKC-δ, form a double-negative feedback loop that facilitates sustained microglial activation and the deterioration of neurodegeneration.

MicroRNA-124 regulates the expression of MEKK3 in the inflammatory pathogenesis of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the most prevalent neurodegenerative disorder that is characterised by selective loss of midbrain dopaminergic (DA) neurons. Chronic inflammation of the central nervous system is mediated by microglial cells and plays a critical role in the pathological progression of PD. Brain-specific microRNA-124 (miR-124) expression is significantly downregulated in lipopolysaccharide (LPS)-treated BV2 cells and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. However, whether abnormal miR-124 expression could regulate the activation of microglia remains poorly understood. METHODS: BV2 cells were activated by exposure to LPS, and the expression levels of miR-124, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and the nuclear factor of kappaB (NF-κB) p-p65 were analysed. Over-expression and knockdown studies of miR-124 were performed to observe the effects on MEKK3/NF-κB signalling pathways, and the induction of pro-inflammatory and neurotoxic factors was assessed. In addition, a luciferase reporter assay was conducted to confirm whether MEKK3 is a direct target of miR-124. Meanwhile, production of miR-124, MEKK3, and p-p65; midbrain DA neuronal death; or activation of microglia were analysed when treated with or without miR-124 in the MPTP-induced model of PD. RESULTS: We found that the knockdown of MEKK3 could inhibit the activation of microglia by regulating NF-κB expression. Over-expression of miR-124 could effectively attenuate the LPS-induced expression of pro-inflammatory cytokines and promote the secretion of neuroprotective factors. We also first identified a unique role of miR-124 in mediating the microglial inflammatory response by targeting MEKK3/NF-κB signalling pathways. In the microglial culture supernatant (MCS) transfer model, over-expression of the miR-124 or knockdown of MEKK3 in BV2 cells prevented SH-SY5Y from apoptosis and death. Moreover, MEKK3 and p-p65 were abundantly expressed in the midbrain. Furthermore, their expression levels increased and microglial activation was observed in the MPTP-induced model of PD. In addition, exogenous delivery of miR-124 could suppress MEKK3 and p-p65 expression and attenuate the activation of microglia in the substantia nigra pars compacta of MPTP-treated mice. miR-124 also could prevent MPTP-dependent apoptotic midbrain DA cell death in a MPTP-induced PD model. CONCLUSIONS: Taken together, our data suggest that miR-124 can inhibit neuroinflammation in the development of PD by regulating the MEKK3/NF-κB signalling pathways and implicate miR-124 as a potential therapeutic target for regulating the inflammatory response in PD.

Prognostic value of ion channel genes in Chinese patients with gliomas based on mRNA expression profiling.

Increasing evidence suggests that ion channels not only regulate electric signaling in excitable cells but also play important roles in the development of human cancer. However, the roles of ion channels in glioma remain controversial. We systematically analyzed the expression patterns of ion channel genes in a cohort of Chinese patients with glioma using whole-genome mRNA expression profiling. First, a molecular signature comprising 47 ion channel genes (IC47) was identified using Spearman's rank correlation test conducted between tumor grade and gene expression. We assigned a risk score based on IC47 to each glioma patient. We demonstrated that the risk score effectively predicted overall survival in glioma patients. Next, we screened IC47 in different molecular glioma subtypes. IC47 showed a Mesenchymal subtype and wild-type IDH1 preference. Gene ontology (GO) analysis and gene set variation analysis (GSVA) for the functional annotation of IC47 showed that patients with high-risk scores tended to exhibit the decreased expression of proteins associated with the apoptosis and cell adhesion, and higher expression of proteins associated with the cell cycle and cell proliferation. These results suggest that ion channel gene expression could improve the subtype classification in gliomas at the molecular level. The findings in the present study have been validated in two independent cohorts.

The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in low-grade gliomas and secondary glioblastomas (sGBM). Because they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent and pooled. The objective of this study was to provide insight into the differences between IDH1 and IDH2 mutant gliomas. METHODS: To investigate the different clinical and molecular characterization between IDH1 mutant and IDH2 mutant gliomas, we studied 811 patients with IDH1 mutations, IDH2 mutations and IDH1/2 wild-type. In addition, whole-transcriptome sequencing and DNA methylation data were used to assess the distribution of genetic changes in IDH1 and IDH2 mutant gliomas in a Chinese population-based cohort. RESULTS: Among 811 gliomas in our cohort, 448 cases (55.2%) harbored an IDH1 mutation, 18 cases (2.2%) harbored an IDH2 mutation and 345 cases (42.6%) harbored an IDH1/2 wild-type. We found that IDH1 and IDH2 are mutually exclusive in gliomas, and IDH2 mutations are mutually exclusive with PTEN, P53 and ATRX mutations. Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion (p < 0.05) than IDH1 mutant patients. In addition, a Gene Set Enrichment Analysis (GSEA) showed that IDH2 mutant gliomas were associated with the oxidative phosphorylation gene set, and the four most representative biological processes for genes commonly altered by hypermethylation in IDH2 mutant gliomas were the regulation of cell proliferation, cell motion, cell migration and response to hypoxia. Patients with IDH2 mutant gliomas exhibited longer Overall survival (OS) (p < 0.05) and longer Progression-free survival (PFS) (p < 0.05) than patients with IDH1/2 wild-type gliomas. However, their OS and PFS did not differ from that of IDH1 mutant patients. CONCLUSIONS: Our study revealed an intrinsic distinction between IDH1 and IDH2 mutant gliomas, and these mutations should be considered separately because their differences could have implications for the diagnosis and treatment of IDH1/2 mutant gliomas.

miR-124 regulates cell apoptosis and autophagy in dopaminergic neurons and protects them by regulating AMPK/mTOR pathway in Parkinson's disease.

The important roles of miR-124 in the development and progression of various diseases are being increasing recognized. This study was aimed to investigate the potential roles of miR-124 in dopaminergic (DA) neuronal apoptosis and autophagy in Parkinson's disease (PD) and to explore their mechanisms. Human SH-SY5Y cells that are treated with MPTP were transfected with mature miR-124 vector and control empty vector. The effect of MPTP on miR-124 mRNA level was analyzed using RT-PCR analysis. Furthermore, the effects of miR-124 expression on neuronal apoptosis and autophagy, as well as the expression of proteins in the AMPK/mTOR pathway, were analyzed using RT-PCR and western blotting. This study found that miR-124 was down-regulated in the MPTP-treated (100 µM) neurons, and miR-124 suppression significantly increased cell apoptosis and induced autophagy-associated protein expression, including that of Beclin 1 and increased the ratio of LC3 II/LC3 I compared with that in controls. In addition, in vitro rescue of miR-124 significantly decreased the percentage of apoptotic cells and the ratio of LC3 II/LC3 I, findings that were approximately equal to the controls. Moreover, miR-124 suppression increased p-AMPK but decreased p-mTOR levels in neurons. Our study suggested that miR-124 functions as a protector of DA neurons during PD through the involvement of cell apoptosis and autophagy by regulating the AMPK/mTOR pathway.