No abstract

Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated production of vascular endothelial growth factor (VEGF) activated the receptor VEGFR2 on DRGs, which increased the abundance of the calcineurin inhibitor DSCR1, which, in turn, decreased calcineurin-mediated activation of the transcription factor NFAT, thereby reducing the transcription of the gene encoding TRESK. Intrathecal application of exogenous calcineurin to tumor-bearing rats rescued TRESK abundance and abrogated both DRG hyperexcitability and pain hypersensitivity, whereas either inhibition or knockdown of calcineurin in normal rats reduced TRESK abundance and increased DRG excitability and pain sensitivity. These findings identify a potentially targetable mechanism that may cause bone metastasis–associated pain in cancer patients.

The path-following problem for four-wheel independent driving and four-wheel independent steering electric autonomous vehicles is investigated in this paper. Owing to the over-actuated characters of four-wheel independent driving and four-wheel independent steering autonomous vehicles, a novel yaw rate tracking-based path-following controller is proposed. First, according to the kinematic relationships between vehicle and the reference path, the yaw rate generator is designed by linear matrix inequality theory, with the ability to minimize the disturbances caused by vehicle side slip and varying curvature of path. Considering that the path-following objective and dynamics stability are in conflict with each other in some extreme path-following conditions, a coordinating mechanism based on yaw rate prediction is proposed to satisfy the two conflicting objectives. Then, according to the desired yaw rate and longitudinal velocity, a hierarchical structure is introduced for motion control. The upper-level controller calculates the generalized tracking forces while the allocation layer optimally distributes the generalized forces to tires considering tire vertical load and adhesive utilization. Finally, simulation results indicate that the proposed method can achieve excellent path-following performances in different driving conditions, while both path-following objective and dynamics stability can be satisfied.

No abstract

No abstract