Comprehensive Analysis of Differential m6A RNA Methylomes in the Hippocampus of Cocaine-Conditioned Mice.

N6-methyladenosine (m6A) is the most prevalent internal modification found in mRNAs and lncRNA and plays a vital role in posttranscriptional regulation in mammals. m6A is abundant in the nervous system, where it modulates neuronal development and hippocampus-dependent learning and memory. However, the roles of RNAs m6A modification and its related enzymes in cocaine reward are still not fully understood. In this study, we found that the fat mass and obesity-associated gene (FTO) demethylase, but not methyltransferase-like 3 (METTL3) and 14 (METTL14), was downregulated in the hippocampus following cocaine-induced conditioned place preference (CPP), and the level of m6A is notably higher in the hippocampus of cocaine CPP training mice. Using methylated m6A RNA immunoprecipitation sequencing (MeRIP-m6A-seq), we identified a total of 6516 m6A peaks within 4460 mRNAs, and 3083 m6A peaks within 850 lncRNAs were significantly dysregulated. Intriguingly, the altered m6A peaks within mRNAs and lncRNAs were enriched in synapse maturation and localization processes. Our study uncovers a critical role for an m6A epitranscriptomic dysregulation and downregulation of FTO expression in the hippocampus following cocaine-induced CPP.

Combined transcriptomic and lipidomic analysis reveals aberrant lipid metabolism in central nervous system hemangioblastomas.

Peritumoral cysts are commonly detected in the central nervous system tumors, especially hemangioblastomas (HBs). However, the molecular mechanisms driving their formation and propagation are still unknown. We conducted an integrated lipidomics and transcriptomics analysis on solid and cystic HB samples in order to elucidate the changes in the lipid profile and expression of lipid metabolism-related genes during cyst formation. Transcriptomic analysis revealed differential expression of several genes between the solid and cystic HBs, and those associated with lipid metabolism, such as ADCY4, MGLL, ACOT2, DGKG, SHC1 and LPAR2, were markedly dysregulated in the cystic HBs. The lipidomic analysis further showed a significant reduction in the abundance of triacylglycerol, ceramide, lysophosphatidylcholine and lysophosphatidylethanolamine, and an increase in phosphatidylcholine and phosphatidylethanolamine levels in the cystic HBs. Furthermore, bioinformatics analysis revealed altered lipid biosynthesis, glycerophospholipid metabolism and phospholipase activity in the cystic HBs. Taken together, our findings indicate that cyst formation in HBs is related with aberrant lipid metabolism.

NMR-based metabonomic study of the sub-acute toxicity of titanium dioxide nanoparticles in rats after oral administration.

As titanium dioxide nanoparticles (TiO(2) NPs) are widely used commercially, their potential toxicity on human health has attracted particular attention. In the present study, the oral toxicological effects of TiO(2) NPs (dosed at 0.16, 0.4 and 1 g kg( - 1), respectively) were investigated using conventional approaches and metabonomic analysis in Wistar rats. Serum chemistry, hematology and histopathology examinations were performed. The urine and serum were investigated by (1)H nuclear magnetic resonance (NMR) using principal components and partial least squares discriminant analysis. The metabolic signature of urinalysis in TiO(2) NP-treated rats showed increases in the levels of taurine, citrate, hippurate, histidine, trimethylamine-N-oxide (TMAO), citrulline, alpha-ketoglutarate, phenylacetylglycine (PAG) and acetate; moreover, decreases in the levels of lactate, betaine, methionine, threonine, pyruvate, 3-D-hydroxybutyrate (3-D-HB), choline and leucine were observed. The metabonomics analysis of serum showed increases in TMAO, choline, creatine, phosphocholine and 3-D-HB as well as decreases in glutamine, pyruvate, glutamate, acetoacetate, glutathione and methionine after TiO(2) NP treatment. Aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) were elevated and mitochondrial swelling in heart tissue was observed in TiO(2) NP-treated rats. These findings indicate that disturbances in energy and amino acid metabolism and the gut microflora environment may be attributable to the slight injury to the liver and heart caused by TiO(2) NPs. Moreover, the NMR-based metabolomic approach is a reliable and sensitive method to study the biochemical effects of nanomaterials.

Generation of an NANS homozygous knockout human induced pluripotent stem cell line by the insertion of GFP-P2A-Puro via CRISPR/Cas9 editing.

N-acetylneuraminic acid synthase (NANS), the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), is closely associated with infantile-onset severe developmental delay and skeletal dysplasia. However, the role and the involved mechanisms of NANS functioning have not been fully understood to date. Here, we generated a homozygous NANS-knockout human induced pluripotent stem cell (iPSC) line, NCCSEDi001-A-1, via the CRISPR/Cas9-based gene editing method. The NCCSEDi001-A-1 cell line does not express NANS protein, but maintains a normal karyotype, pluripotency, and trilineage differentiation potential.

Acrylamide exposure represses neuronal differentiation, induces cell apoptosis and promotes tau hyperphosphorylation in hESC-derived 3D cerebral organoids.

Acrylamide (ACR) is a common food contaminant with neurotoxic effects that are formed in the Maillard browning reaction during the heat processing of food. Importantly, pregnant women are also exposed to ACR in food during pregnancy and thus, the fetus is likely affected. However, the mechanisms of ACR-caused neurotoxicity on human brain development are still unclear. Many recent studies employed cerebral organoids based on human embryonic stem cells (hESC) for investigating human neurodevelopmental disorders and toxicity. Here, we generated hESC-derived cerebral organoids to evaluate the neurodevelopmental toxicity of ACR. The results indicated that exposure to ACR significantly altered the transcriptional profile, increased nuclear factor erythroid 2-related factor 2 (NRF2)-mediated gene expression, induced cell apoptosis, repressed neuronal differentiation, and promoted tau hyperphosphorylation in cerebral organoids, which may contribute to ACR-induced neurodevelopmental toxicity. These results indicate that the risk of transplacental exposure of the fetus to ACR should be evaluated and pregnant mothers should limit their exposure to ACR.

A randomized trial of remifentanil for analgesia in external cephalic version for breech presentation.

BACKGROUND: Although external cephalic version (ECV) can be effective for correcting the fetus in a cephalic presentation, it may be painful for the mother. This study aimed to evaluate the efficacy and safety of remifentanil for pain relief during ECV in China. METHODS: In all, 152 Chinese parturients with singleton breech presentation were randomly divided into 2 groups, each with 76 patients. All 152 patients were assigned to receive either remifentanil (infused at 0.1 µg/kg/min and demand boluses of 0.1 µg/kg) or saline placebo. The study was performed between January 2012 and December 2015. Outcome measurements included the Numerical Rating Pain Scale score (0-10) after ECV, success rate for ECV, and maternal satisfaction after ECV. Adverse events were also evaluated. RESULTS: The study was completed by 146 patients. Remifentanil showed greater efficacy than placebo in decreasing the pain score immediately after ECV (remifentanil 4.6 ±â€Š2.6 vs placebo 6.5 ±â€Š2.7; P < 0.001). The success rate for ECV showed a significant difference between the 2 groups (remifentanil 56.5% vs placebo 39.5%; P = 0.04). Maternal satisfaction also showed a significant difference between the 2 groups (remifentanil 9.6 ±â€Š1.4 vs placebo 6.4 ±â€Š3.7; P < 0.001). However, the adverse events profiles were similar between both groups. CONCLUSION: The results of this study demonstrate that remifentanil is an effective intervention for reducing pain, achieving successful ECV, and increasing maternal satisfaction during ECV, and is generally well-tolerated without additional adverse effects.