Ten-eleven translocation protein 1 modulates medulloblastoma progression

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes. Results: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes. Conclusions: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs

Study on the turn structure of polypeptides containing glycine and L-proline

The formation of turn structure in peptide chains has direct relations with intramolecular hydrogen bonds, therefore the existence of this bond can be tested to research the turn structure. Herein, two tripeptides and three tetrapeptides are synthesized by using glycine and L-proline as raw materials, t-butoxycarbonyl and aniline as capping groups, and HBTU and HATU as condensation reagents. 1H NMR, IR and MS are adopted to characterize the structure of the products. Constant-gradient and variable-temperature 1H NMR spectra test is used to detect the intramolecular hydrogen bond of the synthesized polypeptides, and 1H-1H NOE is used for the speculation of the carbonyl group location of intramolecular hydrogen bond. The test illustrates that intramolecular hydrogen bond is found in three out of the five synthesized polypeptides, and it is not found in the other two. The polypeptides with intramolecular hydrogen bond formed all have the "-Gly-L-Pro-Gly-" segment, while the polypeptides with only "-L-Pro-Gly-" segment or "-Gly-L-Pro-" segment do not have intramolecular hydrogen bond formed. The carbonyl group forming of intramolecular hydrogen bond is attached to the amino group of the capping aniline, and amino group involved in hydrogen bond formation is linked to t-butoxycarbonyl

Clinical significance of FBXO17 gene expression in high-grade glioma

Abstract Background High-grade gliomas (HGGs) exhibit marked heterogeneity in clinical behavior. The purpose of this study was to identify a novel biomarker that predicts patient outcome, which is helpful in HGG patient management. Methods We analyzed gene expression profiles of 833 HGG cases, representing the largest patient population ever reported. Using the data set from the Cancer Genome Atlas (TCGA) and random partitioning approach, we performed Cox proportional hazards model analysis to identify novel prognostic mRNAs in HGG. The predictive capability was further assessed via multivariate analysis and validated in 4 additional data sets. The Kaplan-Meier method was used to evaluate survival difference between dichotomic groups of patients. Correlation of gene expression and DNA methylation was evaluated via Student’s t-test. Results Patients with elevated FBXO17 expression had a significantly shorter overall survival (OS) (P = 0.0011). After adjustment by IDH1 mutation, sex, and patient age, FBXO17 gene expression was significantly associated with OS (HR = 1.29, 95% CI =1.04–1.59, P = 0.018). In addition, FBXO17 expression can significantly distinguish patients by OS not only among patients who received temozolomide chemotherapy (HR 1.35, 95% CI =1.12–1.64, P = 0.002) but also among those who did not (HR = 1.48, 95% CI =1.20–1.82, P < 0.0001). The significant association of FBXO17 gene expression with OS was further validated in four external data sets. We further found that FBXO17 endogenous expression is significantly contributable from its promoter methylation. Conclusion Epigenetically modulated FBXO17 has a potential as a stratification factor for clinical decision-making in HGG

Using Real Building Energy Use Data to Explain the Energy Performance Gap of Energy-Efficient Residential Buildings: A Case Study from the Hot Summer and Cold Winter Zone in China

The International Energy Agency (IEA) emphasizes that using real building energy use data (RBEUD) to reflect the actual condition of buildings and inform policy-making is the most effective way to reduce buildings’ carbon emissions. However, based on IEA’s evaluation, regional and national building stock data are limited and lacking. Especially for China, the lack of RBEUD in buildings has limited our ability to address the energy performance gap (EPG). In this research, EPG refers to the difference between regulated energy consumption by design standards and actual energy usage. EPG makes it difficult to develop buildings that are energy-efficient. Therefore, this study aims to gather and analyze RBEUD in order to understand the role of occupants’ behavior in explaining the EPG of energy-efficient residential buildings in China. The results suggest that the actual consumption of residential buildings is less than 1/5–1/3 of the theoretical limits. The heat pump and air conditioner’s actual schedules and setpoint settings are the significant drivers that explain the EPG. In addition, the presentation of a database of 1128 households provides actual usage behavior parameters for policy-makers to improve the accuracy of building energy forecasting models.Design & Construction Managemen

Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3β Through ERK/Akt Signaling

Background: Valproic acid (VPA), an established antiepileptic drug, was assessed for antitumor activity, including its effects on glioblastoma, but its role has not been determined. Methods: In the present study, we investigated VPA-induced apoptosis effects on human U87 cells by cell viability, lactate dehydrogenase (LDH) release, TUNEL/Hoechst staining and flow cytometric in vitro, then we further explored the underlying molecular mechanisms using the selective antagonists PD98059, LY294002 and SB216763. Results: The data showed that VPA dose-dependent induction of glioma U87 cells to undergo apoptosis through the mitochondria-dependent pathway in vitro. VPA activated the ERK/Akt pathways by increasing their protein phosphorylation and in turn inhibited GKS3β activation by the induction of GKS3β phosphorylation. However, the MAPK inhibitor PD98059 and/or PI3K inhibitor LY294002 were able to antagonize the effects of VPA by abolishing ERK/Akt activations and cancelling GSK3β suppression, thus it impaired VPA apoptosis-inducing effects on glioma cells. Furthermore, the GSK3β inhibitor SB216763 caused a strong suppression of GSK3β activity, which showed similar effects of VPA on regulation of protein expression and apoptosis. Conclusion: These findings suggest that GSK3β may be the central hub for VPA-induced apoptosis and VPA can be further evaluated as a novel agent for glioma therapy

Valproic Acid Protects Primary Dopamine Neurons from MPP+-Induced Neurotoxicity: Involvement of GSK3β Phosphorylation by Akt and ERK through the Mitochondrial Intrinsic Apoptotic Pathway

Valproic acid (VPA), a drug widely used to treat manic disorder and epilepsy, has recently shown neuroprotective effects in several neurological diseases, particularly in Parkinson’s disease (PD). The goal of the present study was to confirm VPA’s dose-dependent neuroprotective propensities in the MPP+ model of PD in primary dopamine (DA) neurons and to investigate the underlying molecular mechanisms using specific mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase- (PI3K-) Akt signaling inhibitors. VPA reversed MPP+-induced mitochondrial apoptosis and counteracted MPP+-induced extracellular signal-regulated kinase (ERK) and Akt repression and inhibited glycogen synthase kinase 3β (GSK3β) activation through induction of GSK3β phosphorylation. Moreover, inhibitors of the PI3K and MAPK pathways abolished GSK3β phosphorylation and diminished the VPA-induced neuroprotective effect. These findings indicated that VPA’s neuroprotective effect in the MPP+-model of PD is associated with GSK3β phosphorylation via Akt and ERK activation in the mitochondrial intrinsic apoptotic pathway. Thus, VPA may be a promising therapeutic candidate for clinical treatment of PD

Additional file 3: of Clinical significance of FBXO17 gene expression in high-grade glioma

Table S1. The top 50 most significantly correlated genes with survival in the TCGA cohort. (DOCX 25 kb

Additional file 5: of Clinical significance of FBXO17 gene expression in high-grade glioma

Table S2. Univariate and Multivariate Models for Overall Survival in Patients with GBM in the TCGA Cohort while including MGMT methylation status as a covariate*. (DOCX 24 kb