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In this paper, the problem of multiplayer hierarchical decision-making problem for non-affine systems is solved by adaptive dynamic programming. Firstly, the control dynamics are obtained according to the theory of dynamic feedback and combined with the original system dynamics to construct the affine augmented system. Thus, the non-affine multiplayer system is transformed into a general affine form. Then, the hierarchical decision problem is modeled as a Stackelberg game. In the Stackelberg game, the leader makes a decision based on the information of all followers, whereas the followers do not know each other's information and only obtain their optimal control strategy based on the leader's decision. Then, the augmented system is reconstructed by a neural network (NN) using input–output data. Moreover, a single critic NN is used to approximate the value function to obtain the optimal control strategy for each player. An extra term added to the weight update law makes the initial admissible control law no longer needed. According to the Lyapunov theory, the state of the system and the error of the weights of the NN are both uniformly ultimately bounded. Finally, the feasibility and validity of the algorithm are confirmed by simulation. [ABSTRACT FROM AUTHOR]

Kruppel-like factor 9 (KLF9) plays a key role as an inducer of cellular oxidative stress in the modulation of cell death and in oxidant-dependent tissue injury. Our previous study indicated that lncRNA-T199678 (T199678) affected the expression of KLF9 in an α-synuclein (α-syn) induced cellular model. However, the roles of interactions among α-syn, T199678, KLF9 and related microRNAs (miRNAs) in the Parkinson's disease (PD)-related α-syn pathology are unclear and were therefore investigated in this study. An α-syn-injected mouse model and an α-syn exposed SY-SH5Y cellular model were used in this study. We confirmed the utility of these established models with morphological and behavioral methods. We checked how expression of T199678 and KLF9 were affected by α-syn and demonstrated their interaction by fluorescence in situ hybridization (FISH) staining and western blots. We analyzed expression in ROS+ cells by immunohistochemistry. Finally, we obtained seven miRNAs through bioinformatic analysis simultaneously affected by T199678 and α-syn and verified these with RT-PCR. We found that expression of KLF9 was regulated by T199678, whereas expression of T199678 was not affected by KLF9 in the α-syn exposed SY-SH5Y cells. These findings suggest that KLF9 is the downstream gene regulated by T199678, whereas miR-519–3p may play a contributing role. We also confirmed that α-syn injection upregulated the expression of ROS, which could be downregulated by upregulation of T199678, indicating an anti-oxidative role of T199678 in the α-syn-related mechanisms. Our results indicate the existence of a potential α-syn/T199678/miR-519–3p /KLF9 pathway in PD-related α-syn pathology. This pathway might explain oxidative stress processes in α-syn-related mechanisms, which requires further verification. [Display omitted] • We confirmed that expression of KLF9 was regulated by T199678. • We confirmed that expression of T199678 was unchanged by KLF9 in the α-syn exposed SY-SH5Y cells. • KLF9 is the downstream gene regulated by T199678 whereas miR-519–3p may play a contributing role. • The anti-oxidative role of T199678 in the α-syn-induced neurotoxicity were also confirm. • Existence of an α-syn/T199678/miR-519–3p /KLF9 pathway were indicated. [ABSTRACT FROM AUTHOR]

Background and Objective: The cardiac safety of digoxin therapy for congestive heart failure (CHF) is a source of concern, especially among those with renal impairment.Methods: Using a case–control design, we examined the risk of primary cardiac arrest (PCA) associated with digoxin therapy within three levels of renal function.Results: After adjustment for other clinical characteristics, digoxin therapy for CHF was not associated with an increased risk of PCA [odds ratio (OR) = 0.97, 95% confidence interval (CI) 0.59–1.62] among patients with normal renal function (serum creatinine ⩽1.1 mg/dL). In contrast, digoxin therapy was associated with a modest increase in risk (OR = 1.58, CI 0.89–2.80) among patients with mild renal impairment (serum creatinine = 1.2–1.4 mg/dL); and a twofold increase in risk (OR = 2.39, CI 1.37–4.18) among patients with moderate renal impairment (serum creatinine = 1.5–3.5 mg/dL).Conclusions: These findings suggest that the risks of digoxin may offset the benefits among patients with moderately impaired renal function, but not among patients with normal renal function. [Copyright &y& Elsevier]

Although excess adiposity appears to increase the risk of coronary heart disease in the general population, its importance in patients with established coronary disease is less defined. We evaluated a population-based inception cohort of survivors to hospital discharge following first acute myocardial infarction (AMI) (n = 2,541) to assess the association between body mass index (BMI) and the risk of recurrent coronary events and to explore the mechanisms for this relation. Using Cox proportional-hazards regression, we assessed the risk of recurrent coronary events associated with levels of adiposity as defined by BMI and then investigated potential mechanisms through which adiposity conferred risk by examining how adjustment for diabetes mellitus, systemic hypertension, and dyslipidemia affected the association. Forty-one percent of the cohort were overweight (BMI 25 to 29.9), and 27.8% were obese (BMI > or =30). After adjustment for other risk factors, the risk of recurrent coronary events (n = 418) increased as BMI increased, especially among those who were obese. Using a BMI of 16 to 24.9 as the reference group, for mildly overweight patients (BMI 25 to 27.4), the relative risk (RR) was 0.93 (95% confidence interval [CI] 0.70 to 1.24); it was 1.16 for more severe overweight patients (BMI 27.5 to 29.9; 95% CI 0.87 to 1.55). For patients with class I obesity (BMI 30 to 34.9), the RR was 1.49 (95% CI 1.12 to 1.98), and for class II to III obesity (BMI > or =35), the RR was 1.80 (95% CI 1.30 to 2.48). We estimated that clinical measurements of diabetes, hypertension, and dyslipidemia explained approximately 43% of this risk. Thus, excess adiposity as measured by BMI was associated with an increased risk of recurrent coronary events following AMI, particularly among those who were obese. [ABSTRACT FROM AUTHOR]

Mounting evidence suggests that lysosome dysfunction promotes the progression of several neurodegenerative diseases via hampering autophagy flux. While regulation of autophagy in microglia may affect chronic inflammation involved in Parkinson's disease (PD). Our previous studies have reported rifampicin inhibits rotenone-induced microglia inflammation by enhancing autophagy, however the precise mechanism remains unclear. Human microglia (HM) cells were pretreated with 100 μM rifampicin for 2 h followed by exposure to 0.1 μM rotenone. We found that rifampicin pretreatment suppressed the gene expression of IL-1β and IL-6 via inhibiting activation of JNK after rotenone induction, but the anti-inflammatory effect of rifampicin was reversed by chloroquine. Moreover, rifampicin pretreatment not only improved the ratio of LC3-II/LC3-I in rotenone-treated cells, but also increased autolysosomes and decreased autophagosomes in RFP-GFP-LC3B transfected HM cells exposed to rotenone, thus indicating rifampicin improves autophagy flux in rotenone-treated HM cells. Finally, we verified rifampicin pretreatment enhanced ATP6V0A1 expression when compared to that exposed to rotenone alone. ATP6V0A1 knockdown inhibited the effect of rifampicin on maintaining lysosome acidification and autophagosome-lysosome fusion in rotenone-treated microglia. Taken together, our results indicated that rifampicin attenuates rotenone-induced microglia inflammation partially via elevating ATP6V0A1. Modulation of lysosomal function by rifampicin may be a novel therapeutic strategy for PD. • Autophagy inhibitor attenuated rifampicin's anti-inflammatory effect. • Rifampicin improved autophagy flux in rotenone-treated microglia. • Rifampicin enhanced expression of ATP6V0A1 in rotenone-treated microglia. • Rifampicin improved lysosomal function by increasing ATP6V0A1 expression. [ABSTRACT FROM AUTHOR]