Accumulation of intracellular misfolded or damaged proteins is associated with both normal aging and late-onset degenerative diseases. Two cellular clearance mechanisms, the ubiquitin-proteasome system (UPS) and the macroautophagy/autophagy-lysosomal pathway, work in concert to degrade harmful protein aggregates and maintain protein homeostasis. Here we show that Mask, an Ankyrin-repeat and KH-domain containing protein, plays a key role in promoting autophagy flux and mitigating degeneration caused by protein aggregation or impaired UPS function. In Drosophila eye models of human tauopathy or amyotrophic lateral sclerosis diseases, loss of Mask function enhanced, while gain of Mask function mitigated, eye degenerations induced by eye-specific expression of human pathogenic MAPT/TAU or FUS proteins. The fly larval muscle, a more accessible tissue, was then used to study the underlying molecular mechanisms in vivo. We found that Mask modulates the global abundance of K48- and K63-ubiquitinated proteins by regulating autophagy-lysosome-mediated degradation, but not UPS function. Indeed, upregulation of Mask compensated the partial loss of UPS function. We further demonstrate that Mask promotes autophagic flux by enhancing lysosomal function, and that Mask is necessary and sufficient for promoting the expression levels of the proton-pumping vacuolar (V)-type ATPases in a TFEB-independent manner. Moreover, the beneficial effects conferred by Mask expression on the UPS dysfunction and neurodegenerative models depend on intact autophagy-lysosomal pathway. Our findings highlight the importance of lysosome acidification in cellular surveillance mechanisms and establish a model for exploring strategies to mitigate neurodegeneration by boosting lysosomal function. 相似文献
Functional & Integrative Genomics - The mRNA levels of C2CD4A and C2CD4B were dysregulation in lung cancer (LC). We aimed to evaluate the role of C2CD4A/B variants in LC susceptibility. There... 相似文献
In this paper, a graphene strip is introduced into a metal-insulator-metal (MIM)-integrated square cavity hybrid structure; the transmission spectra are theoretically investigated by the finite different time domain (FDTD) methods. An asymmetric Fano resonance dip that has high figure of merit (FOM) value appears in the transmission band. According to the multimode interference coupled mode theory (MICMT) analytical method, the Fano resonance originates from the coherent coupling between TM10 cavity magnetic mode and graphene plasmonic resonance electric mode. The center wavelength, full width at half maximum (FWHM), and FOM value of the Fano resonance can be tuned dynamically by altering the Fermi level of the graphene. Through breaking the symmetry of the hybrid structure or introducing double graphene strips with different Fermi level into hybrid structure, double Fano resonance are realized. This study can provide some theoretical basis and design reference for designing ultrahigh sensitivity plasmonic sensor.
Recent advances of experimental methods and neuroscience research have made neural signals constantly massive and analysis of these signals highly compute-intensive. This study explore the possibility proposes a massively parallel approach for analysis of neural signals using General-purpose computing on the graphics processing unit (GPGPU). We demonstrate the uses and correctness of the proposed approach via a case of analyzing EEG with focal epilepsy. An experimental examination has been carried out to investigate (1) the GPGPU-aided approach’s performance and (2) energy costs of the GPGPU-aided application versus the original CPU-only systems. Experimental results indicate that the proposed approach excels in both aspects. 相似文献