Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.

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Surface electromyography signal plays an important role in hand function recovery training. In this paper, an IoT-enabled stroke rehabilitation system was introduced which was based on a smart wearable armband (SWA), machine learning (ML) algorithms, and a 3-D printed dexterous robot hand. User comfort is one of the key issues which should be addressed for wearable devices. The SWA was developed by integrating a low-power and tiny-sized IoT sensing device with textile electrodes, which can measure, pre-process, and wirelessly transmit bio-potential signals. By evenly distributing surface electrodes over user’s forearm, drawbacks of classification accuracy poor performance can be mitigated. A new method was put forward to find the optimal feature set. ML algorithms were leveraged to analyze and discriminate features of different hand movements, and their performances were appraised by classification complexity estimating algorithms and principal components analysis. According to the verification results, all nine gestures can be successfully identified with an average accuracy up to 96.20%. In addition, a 3-D printed five-finger robot hand was implemented for hand rehabilitation training purpose. Correspondingly, user’s hand movement intentions were extracted and converted into a series of commands which were used to drive motors assembled inside the dexterous robot hand. As a result, the dexterous robot hand can mimic the user’s gesture in a real-time manner, which shows the proposed system can be used as a training tool to facilitate rehabilitation process for the patients after stroke.

NKCC1 is highly expressed in dorsal root ganglion neurons, where it is involved in gating sensory information. In a recent study, it was shown that peripheral nerve injury results in increased NKCC1 activity, not due to an increase in cotransporter expression, but to increased phosphorylation of the cotransporter (Pieraut, S., Matha, V., Sar, C., Hubert, T., Méchaly, I., Hilaire, C., Mersel, M., Delpire, E., Valmier, J., and Scamps, F. (2007) J. Neurosci. 27, 6751-6759). Our laboratory has also identified two Ste20-like kinases that bind and phosphorylate NKCC1: Ste20-related proline-alanine-rich kinase (SPAK) and oxidative-stress response 1 (OSR1). In this study, we show that both kinases are expressed at similar expression levels in spinal cord and dorsal root ganglion neurons, and that both kinases participate equally in the regulation of NKCC1. Using a novel fluorescence method to assay NKCC1 activity in single cells, we show a 50% reduction in NKCC1 activity in DRG neurons isolated from SPAK knockout mice, indicating that another kinase, e.g. OSR1, is present to phosphorylate and activate the cotransporter. Using a nociceptive dorsal root ganglion sensory neuronal cell line, which expresses the same cationchloride cotransporters and kinases as native DRG neurons, and gene silencing via short hairpin RNA, we demonstrate a direct relationship between kinase expression and cotransporter activity. We show that inactivation of either kinase significantly affects NKCC1 activity, whereas inactivation of both kinases results in an additive effect. In summary, our study demonstrates redundancy of kinases in the regulation of NKCC1 in dorsal root ganglion neurons. The regulation of intracellular ClϪ in neurons is a critical determinant of inhibitory synaptic neurotransmission. Sensory or peripheral neurons express, in abundance, an inwardly poised Na ϩ -and K ϩ -dependent Cl Ϫ transport mechanism, NKCC1, 2 whose activity drives the uphill accumulation of Cl Ϫ ions (2, 3). High intracellular Cl Ϫ concentration in dorsal root ganglion (DRG) neurons permits depolarizing ␥-aminobutyric acid responses, which mediate presynaptic inhibition and filtration of sensory noise (4). Consequently, the knockout of NKCC1 exhibits a redistribution of internal Cl Ϫ in DRG neurons and a pain perception phenotype (3, 5). In addition, peripheral inflammation or nerve injury results in increased NKCC1 function in primary afferents (6, 7). Using a phosphopeptide-specific NKCC1 antibody, it was recently shown that NKCC1 phosphorylation instead of expression level increased in DRG neurons upon nerve injury (1). This observation points to the importance of NKCC1 regulation in the neuropathic pain pathway.In recent work, our laboratory identified two Ste20-like kinases that directly bind to the cytosolic N-terminal tail of NKCC1 (8). The binding is a pre-requisite for NKCC1 phosphorylation and activation (9 -13). The kinases, named SPAK (Ste20-related proline-alanine-rich kinase) and OSR1 (oxidative-stress response 1), share high homology in b...