Cytoplasmic ATP Inhibition of CLC-1 Is Enhanced by Low pH

The CLC-1 Cl− channel is abundantly expressed on the plasma membrane of muscle cells, and the membrane potential of muscle cells is largely controlled by the activity of this Cl− channel. Previous studies showed that low intracellular pH increases the overall open probability of recombinant CLC-1 channels in various expression systems. Low intracellular pH, however, is known to inhibit the Cl− conductance on the native muscle membrane, contradicting the findings from the recombinant CLC-1 channels in expressed systems. Here we show that in the presence of physiological concentrations of ATP, reduction of the intracellular pH indeed inhibits the expressed CLC-1, mostly by decreasing the open probability of the common gate of the channel

Accurate Single Stage Detector Using Recurrent Rolling Convolution

Most of the recent successful methods in accurate object detection and localization used some variants of R-CNN style two stage Convolutional Neural Networks (CNN) where plausible regions were proposed in the first stage then followed by a second stage for decision refinement. Despite the simplicity of training and the efficiency in deployment, the single stage detection methods have not been as competitive when evaluated in benchmarks consider mAP for high IoU thresholds. In this paper, we proposed a novel single stage end-to-end trainable object detection network to overcome this limitation. We achieved this by introducing Recurrent Rolling Convolution (RRC) architecture over multi-scale feature maps to construct object classifiers and bounding box regressors which are "deep in context". We evaluated our method in the challenging KITTI dataset which measures methods under IoU threshold of 0.7. We showed that with RRC, a single reduced VGG-16 based model already significantly outperformed all the previously published results. At the time this paper was written our models ranked the first in KITTI car detection (the hard level), the first in cyclist detection and the second in pedestrian detection. These results were not reached by the previous single stage methods. The code is publicly available.Comment: CVPR 201

AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease

AbstractHuntington's disease (HD) is an autosomal dominant neurological disorder that is induced by a CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. We previously reported that the abnormal activation of an important energy sensor, AMP-activated protein kinase α1 (AMPK-α1), occurs in the brains of mice and patients with HD, which suggests that this abnormal activation may contribute to neuronal degeneration in HD. In the present study, we demonstrated that the elevated oxidative stress that was evoked by a polyQ-expanded mutant HTT (mHTT) caused the abnormal activation of AMPK-α1 and, subsequently, resulted in neurotoxicity in a striatal progenitor cell line (STHdhQ109) and in the striatum of a transgenic mouse model of HD (R6/2). The systematic administration of an antioxidant (N-acetyl-cysteine, NAC) to R6/2 mice suppressed the activation of AMPK-α1, reduced neuronal toxicity, which was assessed by the activation of caspases, increased neuronal density, ameliorated ventricle enlargement, and improved motor dysfunction. This beneficial effect of NAC in vivo appears to be direct because NAC also reduced the activation of AMPK-α1 and the death of STHdhQ109 cells upon elevated oxidative stress. Moreover, the activation of AMPK enhanced the level of oxidative stress in STHdhQ109 cells, in primary neurons of R6/2 mice, and in the striatum of two different HD mouse models (R6/2 and Hdh150Q/+), whereas the inhibition of AMPK reduced the level of oxidative stress. Collectively, our findings suggest that positive feedback regulation between the elevated oxidative stress and the activation of AMPK-α1 contributes to the progression of HD