Notes

Elucidating the actual Spatial Characteristics of Charge Carriers within Quasi-Two-Dimensional Perovskites.
Survival of patients with congenital heart defects including increased right ventricular pressure load (i.e. Tetralogy of Fallot) or pulmonary hypertension is dependent on the function of the right ventricle (RV). RV remodeling has several effects with progressive transition from compensated status to heart failure. Transient receptor potential melastatin 4 (TRPM4) forms cation channels expressed in myocardium, which was shown to modulate cardiac remodeling in the left ventricle of mice. Aim of this study was to identify the role of TRPM4 for contractile function and remodeling of the right ventricle in a rat model of right ventricular pressure load. We performed experiments with untreated rats and under Monocrotaline (MCT)-induced pressure load comparing wild type (Trpm4+/+) and TRPM4-deficient (Trpm4-/-) rats. RV function was characterized by echocardiography and contractility measurements of isolated papillary muscles. RV hypertrophy was investigated by echocardiography and by determination of hypertrophy treatment in rats leads to a prominent downregulation of TRPM4 protein expression in the right ventricle and complete deletion of TRPM4 expression aggravates right ventricular hypertrophy. Thus, therapeutic modulation of TRPM4 expression and activity might represent a novel approach to target right ventricular remodeling in patients with pulmonary hypertension or otherwise loaded RV. PURPOSE The aim of this study was to determine if radiation-induced lymphopenia (RIL) affects survival of patients with breast cancer. METHODS AND MATERIALS Post-hoc analysis of data of 598 breast cancer patients from a randomized controlled trial comparing postmastectomy hypofractionated radiotherapy (HFRT; 43.5 Gy in 15 fractions over 3 weeks) with conventional fractionated radiotherapy (CFRT; 50 Gy in 25 fractions over 5 weeks). Mean peripheral lymphocyte count (PLC) at different time points in the two groups were compared by the t-test. Disease-free survival (DFS) and overall survival (OS) were analyzed by the Kaplan-Meier method and compared between groups by the log-rank test. RESULTS Baseline PLC (pre-PLC) was comparable between HFRT and CFRT patients (1.60 ± 0.57 × 109/L vs. 1.56 ± 0.52 × 109/L; P = .33). In both groups, the PLC declined steadily during the course of radiotherapy but started to recover at 1 month after radiotherapy. Incidence of lymphopenia was significantly lower in HFRT patients (45.4% vs. 55.7%; P = .01). Nadir PLC (nadir-PLC) was significantly higher in HFRT patients (1.08 ± 0.37 × 109/L vs. 0.97 ± 0.31× 109/L; P less then .001), as also the nadir-PLC/pre-PLC ratio (0.72 ± 0.28 vs. 0.67 ± 0.28; P = .02). Median follow-up was for 57.6 months (IQR 38.5-81.4). The 5-year DFS was significantly lower in patients with nadir-PLC/pre-PLC ratio less then 0.8 than in those with ratio ≥0.8 (71.8% vs. 82.6%; P = .01); however, OS was comparable between the groups (85.8% vs. 90.6%; P = .24). CONCLUSIONS The risk of RIL in breast cancer patients is lower with HFRT than with CFRT. Low nadir-PLC/pre-PLC ratio may predict poor prognosis. Patients with type 2 diabetes mellitus (T2DM) are more susceptible to acute myocardial ischemia/reperfusion (MI/R) injury. However, the mechanism remains largely elusive. Clinical observation showed that high levels of hepatokine fetuin-B (FetB) in plasma are significantly associated with both diabetes and coronary artery diseases. This study was aimed to determine whether FetB mostly derived from liver exacerbates MI/R-induced injury and the underlying mechanisms in T2DM. Mice were given high-fat diet and streptozotocin to induce T2DM model and subjected to 30 min MI followed by reperfusion. Diabetes caused increased hepatic FetB expression and greater myocardial injury as evidenced by increased apoptosis and myocardial enzymes release following MI/R. In T2DM hearts, insulin-induced phosphorylations of insulin receptor substrate 1 at Tyr608 site and Akt at Ser473 site and glucose transporter 4 membrane translocation were markedly reduced. Interaction between FetB and insulin receptor-β subunit (IRβ) was enhanced assessed by immunoprecipitation analysis. More importantly, FetB knockdown via AAV9 alleviated MI/R injury and improved cardiac insulin-induced signaling in T2DM mice. Conversely, upregulation of FetB in normal mice caused exacerbated MI/R injury and impairment of insulin-mediated signaling. In cultured neonatal mouse cardiomyocytes, incubation of FetB significantly reduced tyrosine kinase activity of IR and insulin-induced glucose uptake, and increased hypoxia/reoxygenation-induced apoptosis. Furthermore, FoxO1 knockdown by siRNA suppressed FetB expressions in hepatocytes treated with palmitic acid. In conclusion, upregulated FetB in diabetic liver contributes to increased MI/R injury and cardiac dysfunction via directly interacting with IRβ and consequently impairing cardiac insulin signaling. The large conductance Ca2+-activated K+ (BK) channels, composed of the pore-forming α subunits (BK-α, encoded by KCNMA1 gene) and the regulatory β1 subunits (BK-β1, encoded by KCNMB1 gene), play a unique role in the regulation of coronary vascular tone and myocardial perfusion by linking intracellular Ca2+ homeostasis with excitation-contraction coupling in coronary arterial smooth muscle cells (SMCs). The nuclear factor erythroid 2-related factor 2 (Nrf2) belongs to a member of basic leucine zipper transcription factor family that regulates the expression of antioxidant and detoxification enzymes by binding to the antioxidant response elements (AREs) of these target genes. We have previously reported that vascular BK-β1 protein expression was tightly regulated by Nrf2. However, the molecular mechanism underlying the regulation of BK channel expression by Nrf2, particularly at transcription level, is unknown. In this study, we hypothesized that KCNMA1 and KCNMB1 are the target genes of Nrf2 transcriptional regulation. We found that BK channel protein expression and current density were diminished in freshly isolated coronary arterial SMCs of Nrf2 knockout (KO) mice. However, BK-α mRNA expression was reduced, but not that of BK-β1 mRNA expression, in the arteries of Nrf2 KO mice. Promoter-Nrf2 luciferase reporter assay confirmed that Nrf2 binds to the ARE of KCNMA1 promoter, but not that of KCNMB1. Adenoviral expression and pharmacological activation of Nrf2 increased BK-α and BK-β1 protein levels and enhanced BK channel activity in coronary arterial SMCs. Hence, our results indicate that Nrf2 is a key determinant of BK channel expression and function in vascular SMCs. Nrf2 facilitates BK-α expression through a direct increase in gene transcription, whereas that on BK-β1 is through a different mechanism. PKI 14-22 amide,myristoylated solubility dmso
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