Jaleel, A. | Search bioRxiv

bioRxiv2020

Protein tyrosine phosphatase-PEST (PTP-PEST) mediates hypoxia-induced endothelial autophagy and angiogenesis through AMPK activation

Global and endothelial loss of PTP-PEST is associated with impaired cardiovascular development and embryonic lethality. Although hypoxia is implicated in vascular morphogenesis and remodelling, its effect on PTP-PEST remains unexplored. Here we report that hypoxia (1% oxygen)increases protein levels and catalytic activity of PTP-PEST in primary endothelial cells. Immunoprecipitation followed by mass spectrometry (LC/MS/MS) revealed that AMP-activated protein kinase alpha subunits (AMPK 1 and 2) interact with PTP-PEST under normoxia but not in hypoxia. Co-immunoprecipitation experiments confirmed this observation and determined that AMPK subunits interact with the catalytic domain of PTP-PEST. Knock-down of PTP-PEST abrogated hypoxia mediated tyrosine dephosphorylation and activation of AMPK (Thr172 phosphorylation). Absence of PTP-PEST also blocked hypoxia-induced autophagy (measured as LC3 degradation and puncta formation) which was rescued by AMPK activator, metformin (500{micro}M). Since endothelial autophagy is a pre-requisite for angiogenesis, knock-down of PTP-PEST also attenuated endothelial cell migration and capillary tube formation with autophagy inducer rapamycin (200nM) rescuing these effects. In conclusion, this work identifies for the first time PTP-PEST as a regulator of hypoxia-induced AMPK activation and endothelial autophagy to promote angiogenesis.

cell biology↗

bioRxiv2019

Saccade vigor as an implicit measure of subjective economic value

Decisions are made based on the subjective value that the brain assigns to options. However, subjective value is a mathematical construct that cannot be measured directly, but rather inferred from choices. Recent results have demonstrated that reaction time and velocity of movements are modulated by reward, raising the possibility that there is a link between how the brain evaluates an option, and how it controls movements toward that option. Here, we asked people to choose among risky options represented by abstract stimuli, some associated with gain, others with loss. From their choices in decision trials we estimated the subjective value that they assigned to each stimulus. In probe trials, they were presented with a single stimulus at center and made a saccade to a peripheral location. We found that the reaction time and peak velocity of that saccade varied roughly linearly from loss to gain with the subjective value of the stimulus. Naturally, participants differed in how much they valued a given stimulus. Remarkably, those who valued a stimulus more, as evidenced by their choices in decision trials, tended to move with greater vigor in response to that stimulus in probe trials. Thus, saccade vigor partly reflected the subjective value that the brain assigned the stimulus. However, the influence of subjective value on vigor was only a modest predictor of preference: vigor in probe trials allowed us to predict choice in decision trials with roughly 60% accuracy. New and NoteworthyWe found that saccade vigor tends to vary monotonically with subjective value: smallest for stimuli that predict a loss, and highest for stimuli that predict a gain. Notably, between-subject differences in valuation could be gleaned from the between-subject differences in their patterns of vigor. However, the influence of subjective value on vigor was modest, allowing partial ability to infer subjective value for the purpose of predicting choice in decision trials.

neuroscience↗