Epigenetic regulatory mechanism of ADAMTS12 expression in osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease with lacking effective prevention targets. A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is a member of the ADAMTS family and is upregulated in OA pathologic tissues with no fully understood molecular mechanisms. METHODS: The anterior cruciate ligament transection (ACL-T) method was used to establish rat OA models, and interleukin-1 beta (IL-1ß) was administered to induce rat chondrocyte inflammation. Cartilage damage was analyzed via hematoxylin-eosin, Periodic Acid-Schiff, safranin O-fast green, Osteoarthritis Research Society International score, and micro-computed tomography assays. Chondrocyte apoptosis was detected by flow cytometry and TdT dUTP nick-end labeling. Signal transducer and activator of transcription 1 (STAT1), ADAMTS12, and methyltransferase-like 3 (METTL3) levels were detected by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blot, or immunofluorescence assay. The binding ability was confirmed by chromatin immunoprecipitation-qPCR, electromobility shift assay, dual-luciferase reporter, or RNA immunoprecipitation (RIP) assay. The methylation level of STAT1 was analyzed by MeRIP-qPCR assay. STAT1 stability was investigated by actinomycin D assay. RESULTS: The STAT1 and ADAMTS12 expressions were significantly increased in the human and rat samples of cartilage injury, as well as in IL-1ß-treated rat chondrocytes. STAT1 is bound to the promoter region of ADAMTS12 to activate its transcription. METTL3/ Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) mediated N6-methyladenosine modification of STAT1 promoted STAT1 mRNA stability, resulting in increased expression. ADAMTS12 expression was reduced and the IL-1ß-induced inflammatory chondrocyte injury was attenuated by silencing METTL3. Additionally, knocking down METTL3 in ACL-T-produced OA rats reduced ADAMTS12 expression in their cartilage tissues, thereby alleviating cartilage damage. CONCLUSION: METTL3/IGF2BP2 axis increases STAT1 stability and expression to promote OA progression by up-regulating ADAMTS12 expression.

Association Between Pre-operative BUN and Post-operative 30-Day Mortality in Patients Undergoing Craniotomy for Tumors: Data From the ACS NSQIP Database.

Objective: There is limited evidence to clarify the specific relationship between pre-operative blood urea nitrogen (BUN) and post-operative 30-day mortality in patients undergoing craniotomy for tumors. Therefore, we aimed to investigate this relationship in detail. Methods: Electronic medical records of 18,642 patients undergoing craniotomy for tumors in the ACS NSQIP from 2012 to 2015 were subjected to secondary retrospective analysis. The principal exposure was pre-operative BUN. Outcome measures were post-operative 30-day mortality. We used binary logistic regression modeling to evaluate the association between them and conducted a generalized additive model and smooth curve fitting (penalized spline method) to explore the potential relationship and its explicit curve shape. We also conducted sensitivity analyses to ensure the robustness of the results and performed subgroup analyses. Results: A total of 16,876 patients were included in this analysis. Of these, 47.48% of patients were men. The post-operative 30-day mortality of the included cases was 2.49% (420/16,876), and the mean BUN was 16.874 ± 6.648 mg/dl. After adjusting covariates, the results showed that pre-operative BUN was positively associated with post-operative 30-day mortality (OR = 1.020, 95% CI: 1.004, 1.036). There was also a non-linear relationship between BUN and post-operative 30-day mortality, and the inflection point of the BUN was 9.804. For patients with BUN < 9.804 mg/dl, a 1 unit decrease in BUN was related to a 16.8% increase in the risk of post-operative 30-day mortality (OR = 0.832, 95% CI: 0.737, 0.941); for patients with BUN > 9.804 mg/dl, a 1 unit increase in BUN was related to a 2.8% increase in the risk of post-operative 30-day mortality (OR = 1.028, 95% CI: 1.011, 1.045). The sensitivity analysis proved that the results were robust. The subgroup analysis revealed that all listed subgroups did not affect the relationship between pre-operative BUN and post-operative 30-day mortality (P > 0.05). Conclusion: Our study demonstrated that pre-operative BUN (mg/dl) has specific linear and non-linear relationships with post-operative 30-day mortality in patients over 18 years of age who underwent craniotomy for tumors. Proper pre-operative management of BUN and maintenance of BUN near the inflection point (9.804 mg/dl) could reduce the risk of post-operative 30-day mortality in these cases.

The changing features of serum adropin, copeptin, neprilysin and chitotriosidase which are associated with vascular endothelial function in type 2 diabetic retinopathy patients.

AIMS: Adropin (AD), copeptin (CP), neprilysin (NEP) and chitotriosidase (CHIT1) have been associated with the regulation of vascular endothelial function. In this work, we analyzed the plasma concentrations of cytokines (AD, CP, NEP and CHIT1) in type 2 diabetic patients with or without retinopathy (DR) to predict the risk of DR for diabetic patients. METHOD: A total of 392 patients diagnosed as type 2 diabetes mellitus (T2DM) and 120 healthy volunteers as a control group were enrolled in this study. T2DM patients were divided into three groups: diabetes without retinopathy (NDR, n = 174) group, non-proliferative diabetic retinopathy (NPDR, n = 118) group and proliferative diabetic retinopathy (PDR, n = 100) group. The serum AD, CP, NEP and CHIT1 levels of subjects were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: We reported a significant decrease in AD and a significant increase in CP, NEP and CHIT1 in NDR as well as DR patients when compared with controls (p < 0.05), the lower level of AD and significantly higher levels of CP, NEP and CHIT1 were seen in DR patients compared to NDR group (p < 0.05), at the same time, we observed the lowest level of AD and the highest levels of CP, NEP and CHIT1 in the PDR group. Logistic regression analysis showed that AD was a protective factor for DR, conversely, CP, NEP and CHIT1 were the independent risk factors (p < 0.05). Moreover, receiver operating characteristic curve analyses indicated that CP had greater diagnosis capacity with an AUC (the areas under the ROC curve) of 0.901 than AD, NEP, CHIT1 for DR patients. CONCLUSION: The decreased AD level and the elevated CP, NEP and CHIT1 levels involved in vascular endothelial function may be evidence facilitating the presence of DR. Thereby they can be explored to use as promising non-invasive biomarkers for prediction of DR severity, distinguishing DR from diabetic patients.

Pentraxin-3 and adropin as inflammatory markers of early renal damage in type 2 diabetes patients.

PURPOSE: Renal inflammatory response is involved in the development and progression of diabetic kidney disease (DKD). We sought to evaluate pentraxin-3 (PTX3) and adropin variability as inflammatory markers among type 2 diabetes mellitus (T2DM) patients with different urinary albumin, and to examine if these factors assist in the early diagnosis of diabetic kidney disease. METHODS: We enrolled 447 T2DM patients and 100 healthy non-diabetic control subjects in this study. The patients with T2DM were divided into three groups based on their urinary albumin/creatinine ratio (UACR): the normoalbuminuric group (DM group, UACR < 30 mg/g); the microalbuminuric group (DKD1 group, 30 ≤ UACR ≤ 300 mg/g); the macroalbuminuric group (DKD2 group, UACR > 300 mg/g). The levels of PTX3 and adropin were determined by enzyme-linked immunosorbent assay (ELISA). Spearman correlation and multiple linear regression analysis were performed to determine the correlations among these inflammatory markers and other clinical parameters. Receiver operating characteristic (ROC) curves analysis was used to assess the diagnostic potential of PTX3 and adropin for DKD. RESULTS: Compared to non-diabetes, serum levels of PTX3 were distinctly elevated, whereas the adropin were significantly declined in diabetic patients (p < 0.05). Significantly higher levels of PTX3 and lower levels of adropin were seen in the macroalbuminuric patients compared with the microalbuminuric patients (p < 0.05). Multiple stepwise linear regression analysis showed that the control of hemoglobin A1c (HbA1c) and UACR were independent factors associated with PTX3 and adropin. In addition, ROC curves analysis showed PTX3 and adropin could be used to evaluate the early detect of DKD, further adropin might be a better marker than PTX3 in compliance with their veracity. CONCLUSION: As inflammatory markers, the diverse changes of pentraxin-3 and adropin showed that they may forecast the renal damage in diabetic patients in varying degrees and link with the pathogenesis of diabetic kidney disease.

Election forensics: Using machine learning and synthetic data for possible election anomaly detection.

Assuring election integrity is essential for the legitimacy of elected representative democratic government. Until recently, other than in-person election observation, there have been few quantitative methods for determining the integrity of a democratic election. Here we present a machine learning methodology for identifying polling places at risk of election fraud and estimating the extent of potential electoral manipulation, using synthetic training data. We apply this methodology to mesa-level data from Argentina's 2015 national elections.

Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia.

Dystonia is a neurological movement disorder that is clinically and genetically heterogeneous. Herein, we report the identification a novel homozygous missense mutation, c.156 C > A in VPS16, co-segregating with disease status in a Chinese consanguineous family with adolescent-onset primary dystonia by whole exome sequencing and homozygosity mapping. To assess the biological role of c.156 C > A homozygous mutation of VPS16, we generated mice with targeted mutation site of Vps16 through CRISPR-Cas9 genome-editing approach. Vps16 c.156 C > A homozygous mutant mice exhibited significantly impaired motor function, suggesting that VPS16 is a new causative gene for adolescent-onset primary dystonia.