DNA Methylation Analysis Identifies Novel Epigenetic Loci in Dilated Murine Heart upon Exposure to Volume Overload.

Left ventricular (LV) dilatation, a prominent risk factor for heart failure (HF), precedes functional deterioration and is used to stratify patients at risk for arrhythmias and cardiac mortality. Aberrant DNA methylation contributes to maladaptive cardiac remodeling and HF progression following pressure overload and ischemic cardiac insults. However, no study has examined cardiac DNA methylation upon exposure to volume overload (VO) despite being relatively common among HF patients. We carried out global methylome analysis of LV harvested at a decompensated HF stage following exposure to VO induced by aortocaval shunt. VO resulted in pathological cardiac remodeling, characterized by massive LV dilatation and contractile dysfunction at 16 weeks after shunt. Although methylated DNA was not markedly altered globally, 25 differentially methylated promoter regions (DMRs) were identified in shunt vs. sham hearts (20 hypermethylated and 5 hypomethylated regions). The validated hypermethylated loci in Junctophilin-2 (Jph2), Signal peptidase complex subunit 3 (Spcs3), Vesicle-associated membrane protein-associated protein B (Vapb), and Inositol polyphosphate multikinase (Ipmk) were associated with the respective downregulated expression and were consistently observed in dilated LV early after shunt at 1 week after shunt, before functional deterioration starts to manifest. These hypermethylated loci were also detected peripherally in the blood of the shunt mice. Altogether, we have identified conserved DMRs that could be novel epigenetic biomarkers in dilated LV upon VO exposure.

Improving the thermal structure predictions in the Yellow Sea by conducting targeted observations in the CNOP-identified sensitive areas.

Targeted observation is an appealing procedure for improving model predictions. However, studies on oceanic targeted observations have been largely based on modeling efforts, and there is a need for field validating operations. Here, we report the results of a field targeted observation that is designed based on the sensitive areas identified by the Conditional Nonlinear Optimal Perturbation approach to improve the 7th day thermal structure prediction in the Yellow Sea. By introducing the technique of cycle data assimilation and the new concept of time-varying sensitive areas, an observing strategy is designed and validated by a set of Observing System Simulation Experiments. Then, the impact of targeted observations was investigated by a choreographed field campaign in the summer of 2019. The results of the in-field Observing System Experiments show that, compared to conventional local data assimilation, conducting targeted observations in the sensitive areas can yield more benefit at the verification time. Furthermore, dynamic analysis demonstrates that the refinement of vertical thermal structures is mainly caused by the changes in the upstream horizontal temperature advection driven by the Yellow Sea Cold Water Mass circulation. This study highlights the effectiveness of targeted observations on reducing the forecast uncertainty in the ocean.

Modulating poststroke inflammatory mechanisms: Novel aspects of mesenchymal stem cells, extracellular vesicles and microglia.

Inflammation plays an important role in the pathological process of ischemic stroke, and systemic inflammation affects patient prognosis. As resident immune cells in the brain, microglia are significantly involved in immune defense and tissue repair under various pathological conditions, including cerebral ischemia. Although the differentiation of M1 and M2 microglia is certainly oversimplified, changing the activation state of microglia appears to be an intriguing therapeutic strategy for cerebral ischemia. Recent evidence indicates that both mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) regulate inflammation and modify tissue repair under preclinical stroke conditions. However, the precise mechanisms of these signaling pathways, especially in the context of the mutual interaction between MSCs or MSC-derived EVs and resident microglia, have not been sufficiently unveiled. Hence, this review summarizes the state-of-the-art knowledge on MSC- and MSC-EV-mediated regulation of microglial activity under ischemic stroke conditions with respect to various signaling pathways, including cytokines, neurotrophic factors, transcription factors, and microRNAs.

The necessity or not of the addition of fusion to decompression for lumbar degenerative spondylolisthesis patients: A PRISMA compliant meta-analysis.

BACKGROUND: The new emerging application of decompression combined with fusion comes with a concern of cost performance, however, it is a lack of big data support. We aimed to evaluate the necessity or not of the addition of fusion for decompression in patients with lumbar degenerative spondylolisthesis. METHODS: Potential studies were selected from PubMed, Web of Science, and Cochrane Library, and gray relevant studies were manually searched. We set the searching time spanning from the creating date of electronic engines to August 2020. STATA version 11.0 was exerted to process the pooled data. RESULTS: Six RCTs were included in this study. A total of 650 patients were divided into 275 in the decompression group and 375 in the fusion group. No statistic differences were found in the visual analog scales (VAS) score for low back pain (weighted mean difference [WMD], -0.045; 95% confidence interval [CI], -1.259-1.169; P = .942) and leg pain (WMD, 0.075; 95% CI, -1.201-1.35; P = .908), Oswestry Disability Index (ODI) score (WMD, 1.489; 95% CI, -7.232-10.211; P = .738), European Quality of Life-5 Dimensions (EQ-5D) score (WMD, 0.03; 95% CI, -0.05-0.12; P = .43), Odom classification (OR, 0.353; 95% CI 0.113-1.099; P = .072), postoperative complications (OR, 0.437; 95% CI, 0.065-2.949; P = .395), secondary operation (OR, 2.541; 95% CI 0.897-7.198; P = .079), and postoperative degenerative spondylolisthesis (OR = 8.59, P = .27). Subgroup analysis of VAS score on low back pain (OR = 0.77, 95% CI, 0.36-1.65; P = .50) was demonstrated as no significant difference as well. CONCLUSION: The overall efficacy of the decompression combined with fusion is not revealed to be superior to decompression alone. At the same time, more evidence-based performance is needed to supplement this opinion.

NEK1 mutations and the risk of amyotrophic lateral sclerosis (ALS): a meta-analysis.

Recently, NEK1 (NIMA-related kinase 1) mutations were identified as a cause of amyotrophic lateral sclerosis (ALS), but the relationship between them remains unclear owing to the small sample size and low mutation rate. We made a meta-analysis to make clear the relationship. Eight case-control studies involving 8603 cases and 18,695 controls were enrolled. Results demonstrated that the frequency of NEK1 mutations was 3.1% (95% CI 2.5-3.8%) in ALS patients, including the frequencies of loss of function (LoF) and missense mutations, which were 0.9% (95% CI 0.6-1.1%) and 2.3% (95% CI 1.7-2.8%) in ALS patients, respectively. NEK1 mutations (OR 2.14; 95% CI 1.81-2.52; p < 0.001), including LoF mutations (OR 6.93; 95% CI 4.38-10.96; p < 0.001) and missense mutations (OR 1.65; 95% CI 1.37-1.99; p < 0.001) were associated with a significantly increased risk for ALS. And the risk of NEK1 LoF mutations (OR 6.93) is more than four times of that of NEK1 missense mutations (OR 1.65). Subgroup analysis suggested that the frequency of LoF mutations was higher in European patients (1%) than that in Asian patients (0.7%). In conclusion, NEK1 LoF and missense mutations are low frequencies in ALS patients, but both of them are associated with the increased risk for ALS. Altogether, NEK1 mutations including LoF mutations and missense mutations are more associated with Asian patients than European patients.

Risk factors involved in the formation of multiple intracranial aneurysms.

BACKGROUND: Although several risk factors of the multiple intracranial aneurysms (MIAs) formation has been reported, the results are controversial. We aimed to find out the risk factors of MIAs formation by analyzing our clinic data combined with a meta-analysis. MATERIAL AND METHODS: A retrospective review work of medical records for the patients with aneurysms was undertaken. Univariate analysis was used to examine all mentioned variables. Binary logistic regression analysis was used to identify the risk factors of MIAs formation. RESULTS: In the retrospective review work, a total of 565 patients with aneurysm were included in this study. Of these 565 participants, 449 patients suffered SIAs and 116 patients suffered MIAs. Univariate analysis showed a significant difference in terms of female, cigarette smoking, family history of hypertension, and primary hypertension between the SIAs and MIAs group. The binary logistic regression analysis showed that the female (OR = 1.624), primary hypertension (OR = 1.563), and family history of hypertension (OR = 2.496) were independent risk factors of the formation of MIAs (for each P < 0.05). With regard to the meta-analysis results, it revealed that there was significant difference in the rates of female (P < 0.001), cigarette smoking (P < 0.001), primary hypertension (P = 0.001), and higher age (P = 0.011) among the MIAs patients. CONCLUSIONS: A higher rate of the formation of MIAs is closely associated with the elder and female. Patients with hypertension history, cigarette smoking, and family primary hypertension history also affected the formation of MIAs, these risk factors should be a guard against.