Highlights d Piezo cell autonomously inhibits axon regeneration in Drosophila sensory neurons d Piezo channels are activated after axon injury or during axon regeneration d Piezo inhibits axon regeneration through calcium signaling, Nos, and PKG d Piezo1 also inhibits axon regeneration in mammals in vitro and in vivo

Highlights d A given stimulus preferentially activates a single TrpA1 isoform in vivo d Polymodal nociception requires co-expression of TrpA1 isoforms in nociceptors d Each TrpA1 isoform has a unique expression profile d isoEXPRESS is a new and versatile framework targeting alternative splicing

Currently, resistance to tyrosine kinase inhibitors, such as gefitinib, has become one major obstacle for improving the clinical outcome of patients with metastatic and advanced-stage non-small cell lung cancer (NSCLC). While cell behavior can be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs within extracellular vesicles (exosomes) are largely unknown. To this end, the involvement and regulatory functions of lncRNA H19 wrapped by exosomes during formation of gefitinib resistance in human NSCLC were investigated. Gefitinib-resistant cell lines were built by continuously grafting HCC827 and HCC4006 cells into gefitinib-contained culture medium. RT-qPCR assays indicated that H19 was increased in gefitinib-resistant cells when compared to sensitive parent cells. Functional experiments revealed that silencing of H19 potently promoted gefitinib-induced cell cytotoxicity. H19 was secreted by packaging into exosomes and this packaging process was specifically mediated by hnRNPA2B1. H19 wrapped in exosomes could be transferred to non-resistant cells, thus inducing gefitinib resistance. Moreover, treatment-sensitive cells with exosomes highly-expressing H19 induced gefitinib resistance, while knockdown of H19 abrogated this effect. In conclusion, H19 promoted gefitinib resistance of NSCLC cells by packaging into exosomes. Therefore, exosomal H19 may be a promising therapeutic target for EGFR+ NSCLC patients.

Abnormal activation of calpain is implicated in synaptic dysfunction and participates in neuronal death in Alzheimer disease (AD) and other neurological disorders. Pharmacological inhibition of calpain has been shown to improve memory and synaptic transmission in the mouse model of AD. However, the role and mechanism of calpain in AD progression remain elusive. Here we demonstrate a role of calpain in the neuropathology in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, an established mouse model of AD. We found that overexpression of endogenous calpain inhibitor calpastatin (CAST) under the control of the calcium/calmodulindependent protein kinase II promoter in APP/PS1 mice caused a remarkable decrease of amyloid plaque burdens and prevented Tau phosphorylation and the loss of synapses. Furthermore, CAST overexpression prevented the decrease in the phosphorylation of the memory-related molecules CREB and ERK in the brain of APP/PS1 mice and improved spatial learning and memory. Interestingly, treatment of cultured primary neurons with amyloid-␤ (A␤) peptides caused an increase in the level of ␤-site APP-cleaving enzyme 1 (BACE1), the key enzyme responsible for APP processing and A␤ production. This effect was inhibited by CAST overexpression. Consistently, overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1 and increased A␤ production. Finally, CAST transgene prevented the increase of BACE1 in APP/PS1 mice. Thus, calpain activation plays an important role in APP processing and plaque formation, probably by regulating the expression of BACE1. Aggregation of amyloid-␤ (A␤)3 peptides into compact plaques is a characteristic feature in the pathogenesis of Alzheimer disease (AD) (1, 2). Recently, it is suggested that soluble A␤ oligomers, in the process of aggregation, adversely affect synaptic structure and plasticity (2-9). A␤ peptides are generated in neurons by the sequential proteolytic cleavage of the transmembrane glycoprotein amyloid precursor protein (APP) that is cleaved initially by ␤-site APP-cleaving enzyme 1 (BACE1, also known as ␤-secretase) and subsequently by ␥-secretase, whose activity is associated with a presenilin (PS)-containing macromolecular complex (10 -12), in the transmembrane region of APP (13,14). Thus, BACE1 has been proposed to be a therapeutic target for AD (15).Calpains are a family of calcium-activated intracellular cysteine proteases that are involved in many physiological events including long term potentiation (16 -18) or neurotoxic insults ranging from ischemia to Alzheimer disease (19 -21). Inhibition of calpain by synthetic inhibitors exerts neuroprotection in various models of brain injuries, such as ischemia or excitotoxicity-induced neuronal death (22-24). Interestingly, A␤ aggregation is associated with neuronal and astrocytic calcium dysregulation (25-27). Treatment of cultured cortical neurons with A␤ oligomers caused calcium influx and subsequently calpain activation (21).A number of proteins hav...