Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in conscious rats, central pathways activated by AA using Fos as a marker of neuronal activation; to characterize primary afferent fibres involved in this activation; and to investigate the effect of fedotozine on AA-induced Fos expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar spinal cord (laminae I, V, VII and X) and numerous brain structures such as the nucleus tractus solitarius, and paraventricular nucleus (PVN) of the hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin pretreatment blocked AA-induced Fos in all structures tested. Fedotozine significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA induces Fos in the spinal cord and numerous brain nucuei, some of which are involved in the control of digestive motility in rats. This effect is mediated through capsaicin-sensitive afferent fibres and prevented by fedotozine most likely through a peripheral action on visceral afferents.

Abstract-Active compensation of physiological tremor for handheld micromanipulators depends on fast control and actuation responses. Because of real-world latencies, real-time compensation is usually not completely effective at eliminating unwanted hand motion. By modeling tremor, more effective cancellation is possible by anticipating future hand motion. We propose a feedforward control strategy that utilizes tremor velocity from a state-estimating Kalman filter. We demonstrate that estimating hand motion in a feedforward controller overcomes real-world latencies in micromanipulator actuation. In hold-still tasks with a fully handheld micromanipulator, the proposed feedforward approach improves tremor rejection by over 50%.

Heart failure resulting from myocardial infarct, oxygen-deprived tissue death, is a serious disease that affects over 20 million patients in the world. The precise injection of tissue-engineered materials into the infarct site is emerging as a treatment strategy to improve cardiac function for patients with heart failure. We have developed a novel miniature robotic device (HeartLander) that can act as a manipulator for precise and stable interaction with the epicardial surface of the beating heart by mounting directly to the organ. The robot can be delivered to and operate within the intrapericardial space with the chest closed, through a single small incision below the sternum. The tethered crawling device uses vacuum pressure to maintain prehension of the epicardium, and a drive wire transmission motors for actuation. An onboard electromagnetic tracking sensor enables the display of the robot location on the heart surface to the surgeon, and closed-loop control of the robot positioning to targets. In a closed-chest animal study with the pericardium intact, HeartLander demonstrated the ability to acquire a pattern of targets located on the posterior surface of the beating heart within an average of 1.7 ± 1.0 mm. Dye injections were performed following the target acquisitions to simulate injection therapy for heart failure. HeartLander may prove useful in the delivery of intrapericardial treatments, like myocardial injection therapy, in a precise and stable manner, which could be performed on an outpatient basis.

The N6-methylation of RNA adenosines (m6A) is an important regulator of gene expression with critical implications in vertebrate and insect development. However, the developmental significance of epitranscriptomes in lophotrochozoan organisms remains unknown. Using MeRIP-seq, we generated transcriptome-wide m6A-RNA methylomes covering the whole development of the oyster from oocytes to juveniles. Oyster RNA classes display specific m6A signatures, with mRNAs and lncRNAs exhibiting distinct profiles and being highly methylated compared to transposon transcripts. Epitranscriptomes are dynamic and correspond to chronological steps of development (cleavage, gastrulation, organogenesis and metamorphosis), with a minimal mRNA and lncRNA methylation at the morula stage followed by a global increase. mRNA m6A levels are correlated to transcript levels and shifts in methyladenine profiles correspond to expression kinetics. Differentially methylated transcripts cluster according to embryo-larval stages and bear the corresponding developmental functions (cell division, signal transduction, morphogenesis and cell differentiation). The m6A level of transposon transcripts is also regulated and peaks during the gastrulation. We demonstrate that m6A-RNA methylomes are dynamic and associated to gene expression regulation during oyster development. The putative epitranscriptome implication in the cleavage, maternal-to-zygotic transition and cell differentiation in a lophotrochozoan model brings new insights into the control and evolution of developmental processes.