BackgroundPrevious studies have shown that patients with systemic lupus erythematosus (SLE) tend to have a higher risk of cardiovascular disease (CVD), but the potential causal relationship between genetic susceptibility to SLE and CVD risk is not clear. This study systematically investigated the potential association between genetically determined SLE and the risk of CVD.MethodsThe genetic tools were obtained from genome-wide association studies of SLE and CVD, with no overlap between their participating populations. Mendelian randomization (MR) analysis was performed using inverse variance weighting as the primary method. Simultaneously, a series of repeated analyses, sensitivity analyses, and instrumental variable strength evaluations were performed to verify the reliability of our results.ResultsMR analysis showed that genetic susceptibility to SLE was associated with a higher risk of heart failure (OR=1.025, 95% CI [1.009-1.041], P=0.002), ischemic stroke (OR=1.020, 95% CI [1.005-1.034], P=0.009), and venous thromboembolism (OR=1.001, 95% CI [1.000-1.002], P=0.014). However, genetic susceptibility to SLE was negatively correlated with the risk of type 2 diabetes (OR=0.968, 95% CI [0.947-0.990], P=0.004). Sensitivity analysis found no evidence of horizontal pleiotropy or heterogeneity.ConclusionOur MR study explored the causal role of SLE in the etiology of CVD, which would help improve our understanding of the basic disease mechanisms of SLE and provide comprehensive CVD assessment and treatment for SLE patients.

To reveal overwintering dormancy (diapause) mechanisms of Culex pipiens pallens (L.), global protein expression differences at three separate time points represent nondiapause, diapause preparation and overwintering diapause phases of Cx . pipiens pallens were compared using iTRAQ. Cx . pipiens pallens females accumulate more lipid droplets during diapause preparation and overwintering diapause maintenance than during the nondiapause phase. A total of 1030 proteins were identified, among which 1020 were quantified and compared. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Domain and Clusters of Orthologous Groups (COG) analyses revealed key groups of proteins, pathways and domains differentially regulated during diapause preparation and overwintering diapause maintenance phases in this mosquito, including major shifts in energy production and conversion, fatty acid metabolism, the citrate (TCA) cycle, and the cytoskeletal reorganization pathway. Our results provide novel insight into the molecular bases of diapause in mosquitoes and corroborate previously reported diapause-associated features in invertebrates. More interestingly, the phototransduction pathway exists in Cx . pipiens pallens , in particular, actin, rather than other proteins, appears to have substantial role in diapause regulation. In addition, the differential changes in calmodulin protein expression in each stage implicate its important regulatory role of the Cx . pipiens pallens biological clock. Finally, 24 proteins were selected for verification of differential expression using a parallel reaction monitoring strategy. The findings of this study provide a unique opportunity to explore the molecular modifications underlying diapause in mosquitoes and might therefore enable the future design and development of novel genetic tools for improving management strategies in mosquitoes.

Background The prognostic significance of diabetic retinopathy (DR) for cardiovascular diseases (CVD) remained unclear. Therefore, we performed this meta-analysis to assess whether DR predicted CVD mortality in diabetic patients. Methods We searched PubMed, Embase, Web of Science and Cochrane Library for cohort studies reporting the association of DR and CVD mortality. Then we pooled the data for analysis. Results After screening the literature, 10 eligible studies with 11,239 diabetic subjects were finally included in quantitative synthesis. The pooled risk ratio (RR) of DR, mild DR, and severe DR for CVD mortality was 1.83 (95% confidence interval (CI): 1.42, 2.36; p < 0.001), 1.13 (95% CI 0.81, 1.59; p = 0.46), and 2.26 (1.31, 3.91; p = 0.003), respectively, compared to those without DR. In type 2 DM, the patients with DR had a significantly higher CVD mortality (RR: 1.69; 95% CI 1.27, 2.24; p < 0.001). Subgroup analysis also showed a significantly higher CVD mortality in DR according to various regions, study design, data source, and follow-up period (all RR > 1; all P values < 0.05). Data from 2 studies showed no significant correlation of DR and CVD mortality in diabetic patients receiving cardiovascular surgery (RR: 2.40; 95% CI 0.63, 9.18; P = 0.200). Conclusions DR is a risk marker of cardiovascular death, and severe DR predicts a doubled mortality of CVD in diabetes. These findings indicate the importance of early identification and management of diabetic patients with DR to reduce the risk of death.

Resistance to chemotherapy is a long-standing problem in the management of cancer, and cancer stem cells are regarded as the main source of this resistance. This study aimed to investigate metallothionein (MT)-1G involvement in the regulation of cancer stemness and provide a strategy to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Methods: MT1G was identified as a critical factor related with gemcitabine resistance in PDAC cells by mRNA microarray. Its effects on PDAC stemness were evaluated through sphere formation and tumorigenicity. LC-MS/MS analysis of conditional medium revealed that activin A, a NF-κB target, was a major protein secreted from gemcitabine resistant PDAC cells. Both loss-of-function and gain-of-function approaches were used to validate that MT1G inhibited NF-κB-activin A pathway. Orthotopic pancreatic tumor model was employed to explore the effects on gemcitabine resistance with recombinant follistatin to block activin A. Results: Downregulation of MT1G due to hypermethylation of its promoter is related with pancreatic cancer stemness. Secretome analysis revealed that activin A, a NF-κB target, was highly secreted by drug resistant cells. It promotes pancreatic cancer stemness in Smad4-dependent or independent manners. Mechanistically, MT1G negatively regulates NF-κB signaling and promotes the degradation of NF-κB p65 subunit by enhancing the expression of E3 ligase TRAF7. Blockade of activin A signaling with follistatin could overcome gemcitabine resistance. Conclusions: MT1G suppresses PDAC stemness by limiting activin A secretion via NF-κB inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC.

BackgroundA large number of observational studies showed that patients with psoriasis have a higher risk of cardiovascular disease (CVD), but most studies did not fully adjust for confounding factors, so it is not clear whether the risk of CVD is directly attributed to psoriasis. We used Mendelian randomization (MR) to evaluate the potential causal relationship between psoriasis and CVD.MethodsWe used genetic instruments from the genome-wide association study (GWAS) of European descent for psoriasis to investigate its relationship with CVD. Inverse variance-weighted (IVW) MR analyses were used for the primary analysis. In addition, a variety of other methods were used to replicate the analysis.ResultsThe fixed-effects IVW method indicated that genetic susceptibility to psoriasis was associated with a higher risk of heart failure (HF) [odds ratio (OR) = 1.04; 95% CI, 1.01–1.06, P = 2.72E-03], atrial fibrillation (AF) (OR = 1.04; 95% CI, 1.02–1.07, P = 3.27E-04), myocardial infarction (MI) (OR = 1.07; 95% CI, 1.01–1.12, P = 0.01), valvular heart disease (VHD) (OR = 1.001; 95% CI, 1.000–1.002, P = 1.85E-03), and large artery stroke (LAS) (OR = 1.11; 95% CI, 1.05–1.18, P = 5.37E-04) but not with the other two subtypes of ischemic stroke (IS) [cardioembolic stroke (CES) (OR = 1.03; 95% CI, 0.98–1.07, P = 0.27) and small vessel stroke (SVS) (OR = 1.00; 95% CI, 0.95–1.07), P = 0.88)]. Sensitivity analysis found weak evidence of horizontal diversity and heterogeneity to ensure the stability of the results.ConclusionOur study provided evidence for a potential causal link between psoriasis and CVD. These findings partly suggest that early monitoring of cardiovascular risk in patients with psoriasis is intentional.