Genome‐wide methylomic analyses identify prognostic epigenetic signature in lower grade glioma

Glioma is the most malignant and aggressive type of brain tumour with high heterogeneity and mortality. Although some clinicopathological factors have been identified as prognostic biomarkers, the individual variants and risk stratification in patients with lower grade glioma (LGG) have not been fully elucidated. The primary aim of this study was to identify an efficient DNA methylation combination biomarker for risk stratification and prognosis in LGG. We conducted a retrospective cohort study by analysing whole genome DNA methylation data of 646 patients with LGG from the TCGA and GEO database. Cox proportional hazard analysis was carried out to screen and construct biomarker model that predicted overall survival (OS). The Kaplan‐Meier survival curves and time‐dependent ROC were constructed to prove the efficiency of the signature. Then, another independent cohort was used to further validate the finding. A two‐CpG site DNA methylation signature was identified by multivariate Cox proportional hazard analysis. Further analysis indicated that the signature was an independent survival predictor from other clinical factors and exhibited higher predictive accuracy compared with known biomarkers. This signature was significantly correlated with immune‐checkpoint blockade, immunotherapy‐related signatures and ferroptosis regulator genes. The expression pattern and functional analysis showed that these two genes corresponding with two methylation sites contained in the model were correlated with immune infiltration level, and involved in MAPK and Rap1 signalling pathway. The signature may contribute to improve the risk stratification of patients and provide a more accurate assessment for precision medicine in the clinic.     

膝关节内干细胞/祖细胞在软骨再生中作用研究进展

关节软骨(AC)由于缺乏血管、神经和淋巴,一旦损伤无法自我修复.虽然以外源性细胞为基础的治疗策略在一定程度上能够再生关节软骨,但仍然存在手术间隔长、供体有限、细胞体外培养易去分化和病原体传播等风险.成人膝关节存在许多类型干细胞/祖细胞(SCPCs),当软骨损伤时,就会被动员,迁移到损伤部位,参与再生修复.因此,基于趋化...     

Increased Levels of Monoamine-Derived Potential Neurotoxins in Fetal Rat Brain Exposed to Ethanol

Pregnant SD rats were exposed to ethanol (25 % (v/v) ethanol at 1.0, 2.0 or 4.0 g/kg body weight from GD8 to GD20) to assess whether ethanol-derived acetaldehyde could interact with endogenous monoamine to generate tetrahydroisoquinoline or tetrahydro-beta-carboline in the fetuses. The fetal brain concentration of acetaldehyde increased remarkably after ethanol administration (2.6 times, 5.3 times and 7.8 times as compared to saline control in 1.0, 2.0 and 4.0 g/kg ethanol-treated groups, respectively) detected by HPLC with 2,4-dinitrophenylhydrazine derivatization. Compared to control, ethanol exposure induced the formation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol, Sal), N-methyl-salsolinol (NMSal) and 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (6-OH-MTHBC) in fetal rat brains. Determined by HPLC with electrochemical detector, the levels of dopamine and 5-hydroxytryptamine in whole fetal brain were not remarkably altered by ethanol treatment, while the levels of homovanillic acid and 5-hydroxyindole acetic acid in high dose (4.0 g/kg) of ethanol-treated rats were significantly decreased compared to that in the control animals. 4.0 g/kg ethanol administration inhibited the activity of mitochondrial monoamine oxidase (51.3 % as compared to control) and reduced the activity of respiratory chain complex I (61.2 % as compared to control). These results suggested that ethanol-induced alteration of monoamine metabolism and the accumulation of dopamine-derived catechol isoquinolines and 5-hydroxytryptamine-derived tetrahydro-beta-carbolines may play roles in the developmental dysfuction of monoaminergic neuronal systems.     

Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7

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Antimicrobial Characterization of Site-Directed Mutagenesis of Porcine Beta Defensin 2

Porcine β defensin 2 (pBD2) is a small, cationic and amphiphilic antimicrobial peptide. It has broad antimicrobial activities against bacteria and plays an important role in host defense. In order to enhance its antimicrobial activity and better understand the effect of positively charged residues on its activity, we substituted eight amino acid residues with arginine or lysine respectively. All mutants were cloned and expressed in BL21 (DE3) plysS and the mutant proteins were then purified. These mutant versions had higher positive charges but similar structural configurations compared to the wild-type pBD2. Moreover, these mutant proteins showed different antimicrobial activities against E. coli and S. aureus. The mutant I4R of pBD2 had the highest antimicrobial activity. In addition, all the mutants showed low hemolytic activities. Our results indicated that the positively charged residues were not the only factor that influenced antimicrobial activity, but other factors such as distribution of these residues on the surface of defensins might also contribute to their antimicrobial potency.