A novel L-shaped ortho-quinone analog suppresses glioblastoma progression by targeting acceleration of AR degradation and regulating PI3K/AKT pathway.

Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA is a fat-soluble active ingredient obtained from Salvia miltiorrhiza, which has an inhibitory effect against various cancers. We designed and synthesized a novel L-shaped ortho-quinone analog TE5 with tanshinone IIA as the lead compound and tested its antitumor activity against GBM. The results indicated that TE5 effectively inhibited the proliferation, migration, and invasion of GBM cells, and demonstrated low toxicity in vitro. We found that TE5 may bind to androgen receptors and promote their degradation through the proteasome. Inhibition of the PI3K/AKT signaling pathway was also observed in TE5 treated GBM cells. Additionally, TE5 arrested the cell cycle at the G2/M phase and induced mitochondria-dependent apoptosis. In vivo experiments further confirmed the anti-tumor activity, safety, and effect on androgen receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.

Study on the Mechanical Properties of a Carbon-Fiber/Glass-Fiber Hybrid Foam Sandwich Structure.

Considering the different structural strength requirements of different parts of fiberglass yachts, carbon fiber/glass fiber hybrid reinforcement can be applied to the skins of sandwich panels in special areas. This paper designs and prepares 12 foam sandwich panel samples composed of pure carbon fiber, a carbon fiber/glass fiber hybrid, pure glass fiber skin, and PVC and SAN foam sandwich, with reference to the layup structure of the outer panel of a fiberglass yacht. Through a comparative analysis of low-speed impact experiments, edge compression experiments, and short beam three-point bending experiments, we seek the optimal carbon fiber/glass fiber hybrid layup design scheme for local structures to guide production. The results show that a reasonable hybrid carbon fiber layup in fiberglass skin can effectively reduce the low-speed impact damage of the sandwich structure, reduce edge compression damage, and improve the bending and compression resistance of sandwich structure. The impact resistance, compression resistance, and shear resistance of the SAN sandwich structure are stronger than the PVC sandwich structure. The carbon fiber/glass fiber hybrid SAN foam sandwich structure can be used for the local structural reinforcement of special parts such as the bow, side, and main deck of fiberglass yachts.

The TSC2 c.2742+5G>A variant causes variable splicing changes and clinical manifestations in a family with tuberous sclerosis complex.

Background: Tuberous sclerosis complex (TSC) is a genetic, variably expressed, multisystem disease characterized by benign tumors. It is caused by pathogenic variants of the TSC complex subunit 1 gene (TSC1) and the TSC complex subunit 2 gene (TSC2). Genetic testing allows for early diagnosis, genetic counseling, and improved outcomes, but it did not identify a pathogenic variant in up to 25% of all TSC patients. This study aimed to identify the disease-causing variant in a Han-Chinese family with TSC. Methods: A six-member, three-generation Han-Chinese family with TSC and three unrelated healthy women were recruited. A comprehensive medical examination, a 3-year follow-up, whole exome sequencing, Sanger sequencing, and segregation analysis were performed in the family. The splicing analysis results obtained from six in silico tools, minigene assay, and patients' lymphocyte messenger RNA were compared, and quantitative reverse transcription PCR was used to confirm the pathogenicity of the variant. Results: Two affected family members had variable clinical manifestations including a rare bilateral cerebellar ataxia symptom. The 3-year follow-up results suggest the effects of a combined treatment of anti-epilepsy drugs and sirolimus for TSC-related epilepsy and cognitive deficits. Whole exome sequencing, Sanger sequencing, segregation analysis, splicing analysis, and quantitative reverse transcription PCR identified the TSC2 gene c.2742+5G>A variant as the genetic cause. This variant inactivated the donor splice site, a cryptic non-canonical splice site was used for different splicing changes in two affected subjects, and the resulting mutant messenger RNA may be degraded by nonsense-mediated decay. The defects of in silico tools and minigene assay in predicting cryptic splice sites were suggested. Conclusions: This study identified a TSC2 c.2742+5G>A variant as the genetic cause of a Han-Chinese family with TSC and first confirmed its pathogenicity. These findings expand the phenotypic and genetic spectrum of TSC and may contribute to its diagnosis and treatment, as well as a better understanding of the splicing mechanism.

Metabolic Syndrome Prevalence among High School First-Year Students: A Cross-Sectional Study in Taiwan.

Different types of high schools in Taiwan have the same physical education curriculum. In this cross-sectional study, we investigated the difference in the prevalence of metabolic syndrome between senior and vocational high school students. We retrospectively collected health check-up data from 81,076 first-year senior and 68,863 vocational high school students in Taipei City from 2011 to 2014, including their blood pressure, height, weight, waist circumference, fasting blood glucose, total cholesterol, triglyceride, and HDL-c levels. The prevalence of metabolic syndrome was determined using definitions from the Taiwan Pediatric Association (TPA), International Diabetes Federation (IDF), and de Ferranti et al. The prevalence of metabolic syndrome was 1.73% (senior and vocational high school students: 1.22% and 2.33%, respectively) using TPA criteria, 1.02% (0.69% and 1.40%, respectively) using IDF criteria, and 5.11% (3.92% and 6.51%, respectively) using de Ferranti et al. criteria. The most prevalent risk factors overall were increased blood pressure and central obesity. Given the significantly higher prevalence of metabolic syndrome in vocational school students regardless of the criteria, and that metabolic syndrome causes future adult health risks, the physical education curriculum and health education program in vocational schools should be strengthened to decrease the risk and prevalence of metabolic syndrome.

Research on multi-objective optimal scheduling considering the balance of labor workload distribution.

In order to solve the problem of unbalanced workload of employees in parallel flow shop scheduling, a method of job standard balance is proposed to describe the work balance of employees. The minimum delay time of completion and the imbalance of employee work are taken as the two goals of the model. A bi-objective nonlinear integer programming model is proposed. NSGA-II-EDSP, NSGA-II-KES, and NSGA-II-QKES heuristic rule algorithms are designed to solve the problem. A number of computational experiments of different sizes are conducted, and compared with solutions generated by NSGA-II. The experimental results show the advantages of the proposed model and method, which error is reduced 14.56%, 15.16% and 15.67%.

Novel Compound Heterozygous PRKN Variants in a Han-Chinese Family with Early-Onset Parkinson's Disease.

Genetic factors are thought to play an important role in the pathogenesis of Parkinson's disease (PD), particularly early-onset PD. The PRKN gene is the primary disease-causing gene for early-onset PD. The details of its functions remain unclear. This study identified novel compound heterozygous variants (p.T240K and p.L272R) of the PRKN gene in a Han-Chinese family with early-onset PD. This finding is helpful in the genetic diagnosis of PD and also the functional research of the PRKN gene.

The identification of a transthyretin variant p.D38G in a Chinese family with early-onset leptomeningeal amyloidosis.

Familial amyloid polyneuropathies (FAPs) are life-threatening, autosomal dominant diseases resulting, in most instances, from transthyretin gene (TTR) variants. A small number of TTR variants lead to leptomeningeal amyloidosis (LA), which is a rare FAP subtype with late-onset central nervous system (CNS) impairment symptoms. Previous studies suggest that LA's CNS selectivity was due to complete endoplasmic reticulum-associated degradation of highly destabilized mutants in peripheral tissues. LA's later age at onset (AAO) was due to lower choroid plexus secretory efficacy. This study reports on a family with LA, including six symptomatic and three presymptomatic members. The LA diagnosis was confirmed by leptomeningeal enhancement on contrast MRI, elevated cerebrospinal fluid protein levels, and positive Congo red staining. The predominant symptoms included headaches, dizziness, vomiting, hallucinations, and cognitive impairments which associated with obstructive hydrocephalus. The TTR p.D38G variant with the lowest secretory efficacy was identified as the genetic cause by whole exome sequencing. The family had a statistically significantly earlier mean AAO of 31.3 ± 7.4 (p = 0.001). These uncommon phenotypes indicate unknown factors influencing the progress of CNS impairment via TTR mutants. Medical imaging examinations suggest the potential early diagnosis value of contrast MRI and the importance of ependyma involvement in LA. LA genetic and clinical data were reviewed and summarized. These findings expand the FAPs' phenotypic spectrum and are valuable in FAP diagnosis, treatment, and further research.

The Role of TMEM230 Gene in Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease whose pathogenesis remains unknown. TMEM230 gene, encoding a transmembrane protein in secretory and recycling vesicle, has been recently identified as a novel disease-causing gene of autosomal dominant PD with Lewy pathology and typical clinical symptoms. Although its mutation and variants seem to be rare in PD patients, functional studies have indicated that TMEM230 protein probably plays an important role in secretory and recycling pathway and may be involved in Lewy pathological mechanism. Here we summarize current genetic and functional reports about TMEM230 and focus on its relation with PD.

Alzheimer's disease susceptibility genes modify the risk of Parkinson disease and Parkinson's disease-associated cognitive impairment.

The pathogenic mechanism underlying Parkinson's disease (PD) and PD- Cognitive impairment (CI) remains elusive. Its potential link to the risk factors in Alzheimer's disease (AD) is unclear. In this study, we analyzed 16 CE-associated single nucleotide polymorphisms (SNPs) in twelve genes in a Chinese cohort of 450 PD cases and 449 controls. Among our 298 cases clinically evaluated for CI, 113 cases did not show CI signs (PD-NC), 86 cases had mildly cognitive impairment (PD-MCI) and 99 cases had dementia (PD-D). We found that the APOE ε4 allele is associated with a higher risk for PD-D. Gene-gene interaction analysis revealed that three significant gene-gene interactions, including BDNF and CLU, APOE and CR1, and DYRK1A and CD2AP increase the risk for PD. Because these SNPs are known genetic risk factors for AD, their contribution to PD and PD-D shown in this study suggests that PD/PD-D and AD may share convergent pathways in their pathogenesis through gene-gene interactions.

The GBA, DYRK1A and MS4A6A polymorphisms influence the age at onset of Chinese Parkinson patients.

Parkinson's disease (PD) is known as the most common neurodegenerative disease after Alzheimer's disease (AD). The precise pathogenic mechanism of PD remains unclear, but genetic and environmental factors are widely recognized to be associated with it. Although many associated genes have been discovered, they account for only a few PD patients. Recently, there are growing evidences indicating that patients with PD and AD share similarities in clinical features, pathology and genetic risks. However, no study has been conducted on the relations between AD associated genes and age at onset (AAO) of PD. In this study, we have detected 14 single nucleotide polymorphisms (SNPs) in 9 AD genome wide association studies top hit genes and 4 SNPs in 4 PD-cognitive impairment related genes among 297 Chinese PD patients. Through the linear regression analysis, we identified the significant associations of the GBA L444P mutation and DYRK1A rs8126696 T allele with the earlier AAO in PD patients, and the A allele at MS4A6A rs610932 with the delayed AAO of PD. This is the first report of significant associations of DYRK1A and MS4A6A SNPs and the AAO of PD. On account of their effects both in AD and PD, it is indicated that AD and PD possibly share some common pathways.

Association of CYBA rs7195830 polymorphism with estimated glomerular filtration rate in an adult Han sample from Jiangsu province, China.

BACKGROUND: Reactive oxygen species are thought to contribute to the development of renal damage. The P22phox subunit of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase, encoded by the cytochrome b245a polypeptide gene, CYBA, plays a key role in superoxide anion production. We investigated the association of CYBA rs7195830 polymorphism with estimated glomerular filtration rate (eGFR) and the role it plays in the pathogenesis of chronic kidney disease (CKD) in a Han Chinese sample. METHODS: The Gaoyou study enrolled 4473 participants. Serum levels of creatinine were measured and eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equations. The CYBA polymorphisms were genotyped. Then we investigated the association between eGFR and the rs7195830 polymorphism in the recessive model. RESULTS: The AA genotype of rs7195830 was associated with significantly lower values of eGFR compared with the GG and AG genotypes ((102.76 ± 17.07) ml×min(-1)×1.73 m(-2) vs. (105.08 ± 16.30) ml×min(-1)± 1.73 m(-2)). The association remained significant in the recessive model after adjusting for age, gender, body mass index, smoking, hypertension, diabetes mellitus, uric acid, triglyceride, low density lipoprotein cholesterol and high density lipoprotein cholesterol (ß=1.666, P=0.031). The rs7195832 AA genotype was an independent risk factor for CKD: eGFR <60 ml×min(-1)×1.73 m(-2) (odds ratio=3.32; 95% CI=1.21-9.13). CONCLUSION: The AA genotype of rs7195830 is independently associated with lower estimated glomerular filtration rate and is significantly associated with CKD.

Circulating microRNAs levels in Chinese heart failure patients caused by dilated cardiomyopathy.

BACKGROUND: Previous studies demonstrated dysregulated expression of microRNAs (miRNAs) in the myocardium of patients with dilated cardiomyopathy (DCM). This study investigated levels of miRNAs in the circulation of DCM patients, and the value of miRNAs as biomarkers for DCM. METHODS AND MATERIALS: In 45 DCM patients and 39 age- and sex-matched controls, circulating miR-423-5p, miR-126, miR-361-5p, miR-155, and miR-146a concentrations were measured and correlated to cardiac functional parameters, including left ventricular ejection fraction (LVEF) and N-terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS: Plasma levels of miR-126 and miR-361-5P did not differ between the DCM and control groups (p = 0.331 and p = 0.784, respectively). Plasma levels of the immunity-associated miRNAs, miR-146a and miR-155, did not differ between the DCM and control groups (p = 0.437 and p = 0.702, respectively). Levels of circulating miR-423-5p were significantly greater in the DCM group (p = 0.003). Further, there was a positive correlation between plasma levels of miR-423-5p and NT-proBNP (r = 0.430, p = 0.003). MiR-423-5p distinguished DCM cases from controls with an area under the curve (AUC) receiver operating characteristic (ROC) curve of 0.674 (95% CI, 0.555-0.793). CONCLUSIONS: Patients with DCM have elevated plasma miR-423-5p levels. The plasma concentration of miR-423-5p was positively correlated with the level of NT-proBNP. Circulating levels of miR-423-5p could be served as a diagnostic biomarker for heart failure caused by DCM. Plasma levels of immunity-associated miR-146a, -155, and -126 were not significantly different between DCM and control groups.