μ-Opioid receptor (MOR) level is directly related to the function of opioid drugs, such as morphine and fentanyl. Although agonist treatment generally does not affect transcription of mor, previous studies suggest that morphine can affect the translation efficiency of MOR transcript via microRNAs (miRNAs). On the basis of miRNA microarray analyses of the hippocampal total RNA isolated from mice chronically treated with μ-opioid agonists, we found a miRNA (miR-339-3p) that was consistently and specifically increased by morphine (2-fold) and by fentanyl (3.8-fold). miR-339-3p bound to the MOR 3'-UTR and specifically suppressed reporter activity. Suppression was blunted by adding miR-339-3p inhibitor or mutating the miR-339-3p target site. In cells endogenously expressing MOR, miR-339-3p inhibited the production of MOR protein by destabilizing MOR mRNA. Up-regulation of miR-339-3p by fentanyl (EC(50)=0.75 nM) resulted from an increase in primary miRNA transcript. Mapping of the miR-339-3p primary RNA and its promoter revealed that the primary miR-339-3p was embedded in a noncoding 3'-UTR region of an unknown host gene and was coregulated by the host promoter. The identified promoter was activated by opioid agonist treatment (10 nM fentanyl or 10 μM morphine), a specific effect blocked by the opioid antagonist naloxone (10 μM). Taken together, these results suggest that miR-339-3p may serve as a negative feedback modulator of MOR signals by regulating intracellular MOR biosynthesis.
Two-component signal transduction systems involving histidine autophosphorylation and phosphotransfer to an aspartate residue on a receiver molecule have only recently been discovered in eukaryotes, although they are well studied in prokaryotes. The Sln1 protein of Saccharomyces cerevisiae is a two-component regulator involved in osmotolerance. Phosphorylation of Sln1p leads to inhibition of the Hog1 mitogen-activated protein kinase osmosensing pathway. We have discovered a second function of Sln1p by identifying recessive activated alleles (designated nrp2) that regulate the essential transcription factor Mcm1. nrp2 alleles cause a 5-fold increase in the activity of an Mcm1-dependent reporter, whereas deletion of SLN1 causes a 10-fold decrease in reporter activity and a corresponding decrease in expression of Mcm1-dependent genes. In addition to activating Mcm1p, nrp2 mutants exhibit reduced phosphorylation of Hog1p and increased osmosensitivity suggesting that nrp2 mutations shift the Sln1p equilibrium toward the phosphorylated state. Two nrp2 mutations map to conserved residues in the receiver domain (P1148S and P1196L) and correspond to residues implicated in bacterial receivers to control receiver phosphorylation state. Thus, it appears that increased Sln1p phosphorylation both stimulates Mcm1p activity and diminishes signaling through the Hog1 osmosensing pathway.
Quadruped robots require compliance to handle unexpected external forces, such as impulsive contact forces from rough terrain, or from physical human-robot interaction. This paper presents a locomotion controller using Cartesian impedance control to coordinate tracking performance and desired compliance, along with Quadratic Programming (QP) to satisfy friction cone constraints, unilateral constraints, and torque limits. First, we resort to projected inverse-dynamics to derive an analytical control law of Cartesian impedance control for constrained and underactuated systems (typically a quadruped robot). Second, we formulate a QP to compute the optimal torques that are as close as possible to the desired values resulting from Cartesian impedance control while satisfying all of the physical constraints. When the desired motion torques lead to violation of physical constraints, the QP will result in a trade-off solution that sacrifices motion performance to ensure physical constraints. The proposed algorithm gives us more insight into the system that benefits from an analytical derivation and more efficient computation compared to hierarchical QP (HQP) controllers that typically require a solution of three QPs or more. Experiments applied on the ANYmal robot with various challenging terrains show the efficiency and performance of our controller.
Legged robots have many potential applications in real-world scenarios where the tasks are too dangerous for humans, and compliance is needed to protect the system against external disturbances and impacts. In this paper, we propose a model-based controller for hierarchical tasks of legged systems subject to external disturbance. The control framework is based on projected inverse dynamics controller, such that the control law is decomposed into two orthogonal subspaces, i.e., the constrained and the unconstrained subspaces. The unconstrained component controls multiple desired tasks with impedance responses. The constrained space controller maintains the contact subject to unknown external disturbances, without the use of any force/torque sensing at the contact points. By explicitly modelling the external force, our controller is robust to external disturbances and errors arising from incorrect dynamic model information. The main contributions of this paper include (1) incorporating an impedance controller to control external disturbances and allow impedance shaping to adjust the behaviour of the motion under external disturbances, (2) optimising contact forces within the constrained subspace that also takes into account the external disturbances without using force/torque sensors at the contact locations. The techniques are evaluated on the ANYmal quadruped platform under a variety of scenarios.
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