Abstract Alzheimer’s disease (AD) pathogenesis features progressive neurodegeneration, amyloid-β plaque formation and neurofibrillary tangles. Ample evidence has indicated the involvement of epigenetic pathways in AD pathogenesis. Here, we show that the expression of microRNA 650 (miR-650) is altered in brains from AD patients. Furthermore, we found that the processing of primary miR-650 to mature miR-650 is misregulated. Bioinformatic analysis predicted that miR-650 targets the expression of three AD-associated components: Apolipoprotein E (APOE), Presenilin 1 (PSEN1), and Cyclin-Dependent Kinase 5 (CDK5), and we have experimentally confirmed that miR-650 is able to significantly reduce the expression of APOE, PSEN1, and CDK5 in vitro . Importantly, the overexpression of miR-650 was further shown to significantly alter the CDK5 level and ameliorate AD pathologies in APP-PSEN1 transgenic mice. Overall, our results indicate that miR-650 influences AD pathogenesis through regulation of CDK5.
Objective To discuss the harm to patients with systemic lupus erythematosus caused by improper treatment.Methods The occurence,development and hazard of a case with Amoxicillin-induced systemic lupus erythematosus were analyzed and the relevant literature was reviewed.Results The major factor of the case happening was that the characteristics of systemic lupus erythematosus,especially drug-induced was to be known very little.Conclusion To prevent the case happening,we must not only understand the diagnosis and treatment of disease,but also be familiar with its characteristics.
Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi). TREM2hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.
Measuring the diffusivity of molecules is the first step toward understanding their dependence and controlling diffusion, but the challenge increases with the decrease of molecular size, particularly for non-fluorescent and non-reactive molecules such as solvents. Here, the capability to monitor the solvent exchange process within the micropores of silica with millisecond time resolution is demonstrated, by simply embedding a rotor-based fluorophore (thioflavin T) in colloidal silica nanoparticles. Basically, the silica provides an extreme case of viscous microenvironment, which is affected by the polarity of the solvents. The fluorescence intensity traces can be well fitted to the Fickian diffusion model, allowing analytical solution of the diffusion process, and revealing the diffusion coefficients. The validation experiments, involving the water-to-ethanol and ethanol-to-water solvent exchange, the comparison of different drying conditions, and the variation in the degree of cross-linking in silica, confirmed the effectiveness and sensitivity of this method for characterizing diffusion in silica micropores. This work focuses on the method development of measuring diffusivity and the high temporal resolution in tracking solvent exchange dynamics over a short distance (within 165 nm) opens enormous possibilities for further studies.
Objective To investigate the roles of Notch1 and Jagged1 protein in the occurrence and development of colorectal adenocarcinoma(CA).Methods Immunohistochemical PV-9000 method and Western blot were used to detect the expression of Notch1 protein and Jagged1 protein in 78 cases of CA(CA group),40 cases of colorectal adenoma(adenoma group) and 40 cases of normal colorectal tissue(5 cm far from the CA,normal group),and their relationship with the clinic pathological parameters were analyzed.Results The positive expression rate of Notch1 and Jagged1 protein in CA group were significantly higher than those in adenoma group and normal group(P0.05);the expression intensity of Notch1 and Jagged1 protein were closely associated with histological grading,Dukes stage and lymph nodemetastasis of CA(P0.05).There was positive correlation between the expression of Notch1 and Jagged1 protein in CA group(r=0.407,P0.05).Conclusion Notch1 and Jagged1 protein play important roles in the pathway of carcinogenesis and progression of CA.
Abstract The ten-eleven translocation (Tet) family of dioxygenases convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Previous studies have shown that 5hmC-mediated epigenetic modifications play essential roles in diverse biological processes and diseases. Here, we show that Tet proteins and 5hmC display dynamic features during postnatal cardiac development and that Tet2 is the predominant dioxygenase present in heart. Tet2 knockout results in abnormal cardiac function, progressive cardiac hypertrophy and fibrosis. Mechanistically, Tet2 deficiency leads to reduced hydroxymethylation in the cardiac genome and alters the cardiac transcriptome. Mechanistically, Tet2 loss leads to a decrease of Hspa1b expression, a regulator of the extracellular signal-regulated protein kinase (Erk) signaling pathway, which leads to over-activation of Erk signaling. Acute Hspa1b knock down (KD) increased the phosphorylation of Erk and induced hypertrophy of cardiomyocytes, which could be blocked by Erk signaling inhibitor. Consistently, ectopic expression of Hspa1b was able to rescue the deficits of cardiomyocytes induced by Tet2 depletion. Taken together, our study’s results reveal the important roles of Tet2-mediated DNA hydroxymethylation in cardiac development and function.
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