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Summary: Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status, but the underlying molecular mechanisms are incompletely understood. Protein S-nitrosylation, the nitric-oxide-mediated cysteine thiol protein modification, plays important roles in cellular redox regulation. Here we show that diet-induced obesity (DIO) and acute cold exposure elevate BAT protein S-nitrosylation, including UCP1. This thermogenic-induced nitric oxide bioactivity is regulated by S-nitrosoglutathione reductase (GSNOR; alcohol dehydrogenase 5 [ADH5]), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 in BAT impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction. Mechanistically, we demonstrate that Adh5 expression is induced by the transcription factor heat shock factor 1 (HSF1), and administration of an HSF1 activator to BAT of DIO mice increases Adh5 expression and significantly improves UCP1-mediated respiration. Together, these data indicate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis, which may be therapeutically targeted to improve metabolic health.

Background & Aims: The lysosome is an acidic organelle that is important for maintaining cellular and metabolic homeostasis in hepatocytes. Lysosomal dysfunction and chronic inflammation coexist, and both contribute to obesity-associated hepatic insulin resistance. However, in the context of obesity, the interplay between inflammatory signals and hepatic lysosomal function remains largely unknown. Inducible nitric oxide synthase (iNOS) is a hallmark for inflammation, and is activated in obesity. The aim of this study is to understand the molecular link between iNOS-mediated lysosomal nitric oxide (NO) production, hepatic lysosomal function, and autophagy in the context of obesity-associated insulin resistance. Methods: The role of iNOS in hepatic autophagy, as related to insulin and glucose homeostasis were studied in mice with diet-induced obesity (DIO). The effects and mechanisms of iNOS-mediated lysosomal NO production on lysosomal function and hepatic autophagy were studied in primary hepatocytes as well as in a mouse model of DIO. Results: We demonstrate that obesity promotes iNOS localization to the lysosome and decreases levels of lysosomal arginine, resulting in an accumulation of NO in hepatic lysosomes. This lysosomal NO production is attenuated by treatment with a NO scavenger, while co-overexpression of mTOR and a lysosomal arginine transporter (SLC38A9) enhances lysosomal NO production and suppresses autophagy. In addition, we show that deletion of iNOS ameliorates lysosomal nitrosative stress in the livers of DIO mice, promotes lysosomal biogenesis by activating transcription factor EB (TFEB), and enhances lysosomal function and autophagy. Lastly, deletion of iNOS in mice with DIO improves hepatic insulin sensitivity, which is diminished by suppression of TFEB or autophagy related 7 (Atg7). Conclusions: Our studies suggest that lysosomal iNOS-mediated NO signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance. Keywords: Autophagy, Insulin Resistance, Inducible Nitric Oxide Synthase, Lysosome, Nitric Oxide

BACE1 is a key enzyme facilitating the generation of neurotoxic β-amyloid (Aβ) peptide. However, given that BACE1 has multiple substrates we explored the importance of BACE1 in the maintenance of retinal pigment epithelial (RPE) cell homeostasis under oxidative stress. Inhibition of BACE1 reduced mitochondrial membrane potential, increased mitochondrial fragmentation, and increased cleaved caspase-3 expression in cells under oxidative stress. BACE1 inhibition also resulted in significantly lower levels of mitochondrial fusion proteins OPA1 and MFN1 suggesting a higher rate of mitochondrial fission while increasing the levels of mitophagic proteins Parkin and PINK1 and autophagosome numbers. In contrast, BACE2 had minimal effect on cellular response to oxidative stress. In summary, our results emphasize the importance of BACE1 in augmenting cellular defense against oxidative stress by protecting mitochondrial dynamics.

A novel design of the two-wheeled self-balancing robot (TWSR) was presented in this research. The robot was called two-wheeled self-balancing vehicle-pendulum system (TWSVPS). Compared with TWSR, the TWSVPS has a single pendulum (SP), which was passively jointed to the robot body through the O1 axis. The difficulty and complexity of control and modelling were increased due to the additional degree of freedom (DOF) which was offered by the SP rotated around the O1 axis. To simplify the analysis, the TWSVPS can be considered to be the mobile double inverted pendulum. Lagrangian dynamic formulation is used to derive the system dynamics due to its relative simplicity. The parallel double fuzzy controller based on information fusion technology was designed and simulated in MATLAB. The results show that the method is feasible and TWSVPS has excellent moving stability. The new developed configuration is of great importance in various applications including self-balance robots, wheelchairs on two wheels, stability analysis of multi links system etc.

Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra-physiologic levels of ω3-PUFAs produced by 12 weeks of ω3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload [transverse aortic constriction (TAC)], a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding ω3-concentration-dependent cardioprotection, the specific role of EPA and DHA, and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant ω3-levels and test individual ω3-PUFAs, we shortened the ω3-diet regimen and used EPA- and DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced ω3-PUFA levels closer to Western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither ω3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of ω3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, FFA receptor 4, a G protein-coupled receptor for ω3-PUFAs, was sufficient and required to block transforming growth factor β1-fibrotic signaling in cultured cardiac fibroblasts, suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF.

Objective To investigate the effect of salidroside (SAL) on the proliferation and migration of human vascular endothelial cell line EA.hy926. Methods The cells were divided into control group and test groups of 1,10 and 100 nmol/L SAL, 10 nmol/L SAL+2 μg/mL avastin (vascular endothelial growth factor(VEGF) blocker) group, 10 nmol/L SAL+2 μg/mL IgG (blocker negative control) group, 10 nmol/L SAL+8 μg/mL avastin group, 10 nmol/L SAL+8 μg/mL IgG group, 10 μmol/L YC-1[hypoxia inducible factor-1α(HIF-1α) blocker] group and 10 μmol/L YC-1+10 nmol/L SAL group. The proliferation and migration of EA.hy926 cells were detected by MTS assay and Transwell cell migration experiments. RT-qPCR and Western blot were used to measure the gene and protein level of HIF-1α and VEGF. The luciferase report gene experiment was used to find the effect of SAL on HIF-1α transcription activity of EA.hy926 cells.The guanylate cyclase activator (YC-1) was used as a HIF-1α blocker to verify potential effect of SAL on the expression of VEGF through HIF-1α. Results SAL significantly promoted proliferation of EA.hy926 cells (P＜0.05)and the proliferation promoting effect of SAL(10 nmol/L) was significantly reduced by the VEGF blocker bevacizumab avastin(2 μg/mL) (P＜0.05). SAL significantly promoted migration of EA.hy926 cells (P＜0.05), and this effect was significantly inhibited by avastin(8 μg/mL)(P＜0.05). SAL increased the expression of HIF-1α and VEGF gene and protein, and promoted the transcription of HIF-1α (P＜0.05).The level of HIF-1α and VEGF protein decreased by YC-1, a HIF-1α blocker(P＜0.05). Conclusions HIF-1α/VEGF pathway is potentially involved in SAL promoted proliferation and migration of EA.hy926 cells.

Background: Ambient air pollutants (PM2.5) are components of persistent haze in Beijing during the autumn and winter seasons. Materials: We collected hourly PM2.5 monitoring data for 35 days from 35 sites in Beijing during 2012. We also identified patients developing respiratory infections during the same time period in the same locale. A BME model was used to simulate environmental exposure concentrations over the course of each day. A medical accessibility analysis was performed to exclude the impact of medical availability on the analysis. A spatial analysis was included in the evaluation of the relationship between exposure duration and concentration of PM2.5 with the development of acute respiratory disease. Results: A low concentration of PM2.5 (greater than 35 pig/m² and less than 115 pig/m²) for at least 3 days was associated with an increased risk of acute respiratory disease. A high concentration of PM2.5 (greater than 115 pig/m²) was associated with an increased risk of infection even after 1 day of exposure. [ABSTRACT FROM AUTHOR]