First, we found that Wnt signaling was activated in SGNs after cisplatin treatment. Next, we discovered that overexpression (OE) of Wnt signaling in SGNs reduced cisplatin-induced SGN loss by inhibiting caspase-associated apoptosis, thus preventing the loss of SGN function after cisplatin treatment. In contrast, inhibition of Wnt signaling increased apoptosis, made SGNs more vulnerable to cisplatin treatment, and exacerbated hearing loss. TP53-induced glycolysis and apoptosis regulator (TIGAR), which scavenges intracellular reactive oxygen species (ROS), was upregulated in SGNs in response to cisplatin administration. Wnt/β-catenin activation increased TIGAR expression and reduced ROS level, while inhibition of Wnt/β-catenin in SGNs reduced TIGAR expression and increased the ROS level. Moreover, OE of TIGAR reduced ROS and decreased caspase 3 expression, as well as increased the survival of SGNs in Wnt-inhibited SGNs. Finally, antioxidant treatment rescued the more severe SGN loss induced by β-catenin deficiency after cisplatin treatment. Innovation and Conclusion: This study is the first to indicate that Wnt signaling activates TIGAR and protects SGNs against cisplatin-induced damage through the inhibition of oxidative stress and apoptosis in SGNs, and this might offer novel therapeutic targets for the prevention of SGN injury. Antioxid. Redox Signal. 00, 000-000.

We study recovery of piecewise-constant signals on graphs by the estimator minimizing an l 0 -edge-penalized objective. Although exact minimization of this objective may be computationally intractable, we show that the same statistical risk guarantees are achieved by the α-expansion algorithm which computes an approximate minimizer in polynomial time. We establish that for graphs with small average vertex degree, these guarantees are minimax rate-optimal over classes of edge-sparse signals. For spatially inhomogeneous graphs, we propose minimization of an edge-weighted objective where each edge is weighted by its effective resistance or another measure of its contribution to the graph's connectivity. We establish minimax optimality of the resulting estimators over corresponding edge-weighted sparsity classes. We show theoretically that these risk guarantees are not always achieved by the estimator minimizing the l 1 /total-variation relaxation, and empirically that the l 0 -based estimates are more accurate in high signal-to-noise settings.

Hearing loss is the most common sensory disorder in humans, and a significant number of cases is due to the ototoxicity of drugs such as cisplatin that cause hair cell (HC) damage. Thus, there is great interest in finding agents and mechanisms that protect HCs from ototoxic drug damage. It has been proposed that epigenetic modifications are related to inner ear development and play a significant role in HC protection and HC regeneration; however, whether the m6A modification and the ethyl ester form of meclofenamic acid (MA2), which is a highly selective inhibitor of FTO (fatmass and obesity-associated enzyme, one of the primary human demethylases), can affect the process of HC apoptosis induced by ototoxic drugs remains largely unexplored. In this study, we took advantage of the HEI-OC1 cell line, which is a cochlear HC-like cell line, to investigate the role of epigenetic modifications in cisplatin-induced cell death. We found that cisplatin injury caused reactive oxygen species accumulation and increased apoptosis in HEI-OC1 cells, and the cisplatin injury was reduced by co-treatment with MA2 compared to the cisplatin-only group. Further investigation showed that MA2 attenuated cisplatin-induced oxidative stress and apoptosis in HEI-OC1 cells. We next found that the cisplatin-induced upregulation of autophagy was significantly inhibited after MA2 treatment, indicating that MA2 inhibited the cisplatin-induced excessive autophagy. Our findings show that MA2 has a protective effect and improves the viability of HEI-OC1 cells after cisplatin treatment, and they provide new insights into potential therapeutic targets for the amelioration of cisplatin-induced ototoxicity.