Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K+ repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, noncanonical Hh signaling mediated by Gi proteins regulates K+ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias. © 2018 Cheng et al

Performance and Usability Evaluation Scheme for Mobile Manipulator Teleoperation

This article presents a standardized human–robot teleoperation interface (HRTI) evaluation scheme for mobile manipulators. Teleoperation remains the predominant control type for mobile manipulators in open environments, particularly for quadruped manipulators. However, mobile manipulators, especially quadruped manipulators, are relatively novel systems to be implemented in the industry compared to traditional machinery. Consequently, no standardized interface evaluation method has been established for them. The proposed scheme is the first of its kind in evaluating mobile manipulator teleoperation. It comprises a set of robot motion tests, objective measures, subjective measures, and a prediction model to provide a comprehensive evaluation. The motion tests encompass locomotion, manipulation, and a combined test. The duration for each trial is collected as the response variable in the objective measure. Statistical tools, including mean value, standard deviation, and T-test, are utilized to cross-compare between different predictor variables. Based on an extended Fitts' law, the prediction model employs the time and mission difficulty index to forecast system performance in future missions. The subjective measures utilize the NASA-task load index and the system usability scale to assess workload and usability. Finally, the proposed scheme is implemented on a real-world quadruped manipulator with two widely-used HRTIs, the gamepad and the wearable motion capture system

Characterisation of the guinea pig model of osteoarthritis by in vivo three-dimensional magnetic resonance imaging

AbstractObjective: To characterise longitudinal changes in joint integrity and cartilage volume in vivo in the guinea pig spontaneous osteoarthritis (OA) model by magnetic resonance imaging (MRI).Methods: Guinea pigs knee were imaged in vivo by high-resolution three-dimensional (3D) MRI between the ages of 3 and 12 months. Image analysis was performed to assess qualitative knee joint changes between 3 and 12 months (n=16) and quantitative volumetric changes of the medial tibial cartilage between 9 and 12 months (n=7). After imaging, animals were killed and knees were assessed macroscopically and histologically.Results: From 3 to 6 months qualitative observation by MRI and histopathology indicated localised cartilage swelling on the medial tibial plateau. At 6 months, bone cysts had developed in the epiphysis. At 9 months, we observed by MRI and histopathology, fragmentation of the medial tibial cartilage in areas not protected by the meniscus. Cartilage degeneration had intensified at 12 months with evidence of widespread loss of cartilage throughout the tibial plateau. Segmentation of the MR cartilage images showed a 36% loss of volume between 9 and 12 months.Conclusions: We have achieved 3D image acquisition and segmentation of knee cartilage in a guinea pig model of chronic OA, which permits measurements previously only possible in man. High resolution and short acquisition time allowed qualitative longitudinal characterisation of the entire knee joint and enabled us to quantify for the first time longitudinal tibial cartilage volume loss associated with disease progression

Frequentist and Bayesian measures of confidence via multiscale bootstrap for testing three regions

A new computation method of frequentist $p$-values and Bayesian posterior probabilities based on the bootstrap probability is discussed for the multivariate normal model with unknown expectation parameter vector. The null hypothesis is represented as an arbitrary-shaped region. We introduce new parametric models for the scaling-law of bootstrap probability so that the multiscale bootstrap method, which was designed for one-sided test, can also computes confidence measures of two-sided test, extending applicability to a wider class of hypotheses. Parameter estimation is improved by the two-step multiscale bootstrap and also by including higher-order terms. Model selection is important not only as a motivating application of our method, but also as an essential ingredient in the method. A compromise between frequentist and Bayesian is attempted by showing that the Bayesian posterior probability with an noninformative prior is interpreted as a frequentist $p$-value of ``zero-sided'' test

Progress and Trends in Artificial Silk Spinning: A Systematic Review

More than 400 million years of natural selection acting throughout the arthropoda has resulted in highly specialized and energetically efficient processes to produce protein-based fibers with properties that are a source of inspiration for all. As a result, for over 80 years researchers have been inspired by natural silk production in their attempts to spin artificial silks. While significant progress has been made, with fibers now regularly outperforming silkworm silks, surpassing the properties of superior silks, such as spider dragline, is still an area of considerable effort. This review provides an overview of the different approaches for artificial silk fiber spinning and compares all published fiber properties to date which has identified future trends and challenges on the road towards replicating high performance silks