Endoplasmic reticulum (ER) stress and oxidative stress lead to protein misfolding, and the resulting accumulation of protein aggregates is often associated with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion disease. Small molecules preventing these pathogenic processes may be effective interventions for such neurodegenerative disorders. In this paper, we identify several novel oxindole compounds that can prevent ER stress-and oxidative stress-induced cell death. Among them, derivatives of the lead compound GIF-0726-r in which a hydrogen atom at the oxindole ring 5 position is substituted with a methyl (GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) group potently suppressed global ER stress. Furthermore, GIF-0854-r and -0856-r prevented protein aggregate accumulation in vitro and in cultured hippocampal HT22 neuronal cells, indicating that these two compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamateinduced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-r and -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying the molecular mechanisms of ER and oxidative stress.
Estimation for a density ratio has an important role in statistical inference. We can use the estimator for testing homogeneity of two samples, detecting change point etc. Let f (x) and g(x) denote probability density functions and g(x0) ̸ = 0 (x0 ∈ R). There are several ways to estimate the density ratio f (x0)/g(x0). In this paper we discuss a kernel estimation that is a popular method in nonparametric statistical inference. A naive estimator is constituted from separate estimators of f (x0) and g(x0), which we call an indirect estimator. Another estimator is proposed byĆwik and Mielniczuk (1989), which we call a direct estimator. ExtendingĆwik and Mielniczuk (1989)'s method, we propose a new direct estimator, and derive an asymptotic mean squared error. We also prove central limit theorem of the new estimator, and compare mean squared errors of the proposed estimator and the direct estimator by simulation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.