Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs

We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic

Long-Wavelength Instability in Marangoni Convection

Our experiments in thin liquid layers (approximately 0.1 mm thick) heated from below reveal a well-defined long-wavelength instability: at a critical temperature difference across the layer, the depth of the layer in the center of the cell spontaneously decreases until the liquid-air interface ruptures and a dry spot forms. The onset of this critical instability occurs at a temperature difference across the liquid layer that is 35% smaller than that predicted in earlier theoretical studies of a single layer model. Our analysis of a two-layer model yields predictions in accord with the observations for liquid layer depths greater than or equal to 0.15 mm, but for smaller depths there is an increasing difference between our predictions and observations (the difference is 25% for a layer 0.06 mm thick). In microgravity environments the long-wavelength instability observed in our terrestrial experiments is expected to replace cellular convection as the primary instability in thick as well as thin liquid layers heated quasistatically from below

Onset of hexagons in surface-tension-driven Benard convection

High resolution laboratory experiments with large aspect ratio are being conducted for thin fluid layers heated from below and bounded from above by a free surface. The fluid depths are chosen sufficiently small (less than 0.06 cm) so that surface tension is the dominant driving mechanisms; the Rayleigh number is less than 5 for the results reported here. Shadowgraph visualization reveals that the primary instability leading to hexagons is slightly hysteretic (approximately 1 percent). Preliminary measurements of the convection amplitude using infrared imaging are also presented

A dynamical approach to the spatiotemporal aspects of the Portevin-Le Chatelier effect: Chaos,turbulence and band propagation

Experimental time series obtained from single and poly-crystals subjected to a constant strain rate tests report an intriguing dynamical crossover from a low dimensional chaotic state at medium strain rates to an infinite dimensional power law state of stress drops at high strain rates. We present results of an extensive study of all aspects of the PLC effect within the context a model that reproduces this crossover. A study of the distribution of the Lyapunov exponents as a function of strain rate shows that it changes from a small set of positive exponents in the chaotic regime to a dense set of null exponents in the scaling regime. As the latter feature is similar to the GOY shell model for turbulence, we compare our results with the GOY model. Interestingly, the null exponents in our model themselves obey a power law. The configuration of dislocations is visualized through the slow manifold analysis. This shows that while a large proportion of dislocations are in the pinned state in the chaotic regime, most of them are at the threshold of unpinning in the scaling regime. The model qualitatively reproduces the different types of deformation bands seen in experiments. At high strain rates where propagating bands are seen, the model equations are reduced to the Fisher-Kolmogorov equation for propagative fronts. This shows that the velocity of the bands varies linearly with the strain rate and inversely with the dislocation density, consistent with the known experimental results. Thus, this simple dynamical model captures the complex spatio-temporal features of the PLC effect.Comment: 17 pages, 18 figure

Therapeutic and educational objectives in robot assisted play for children with autism

“This material is presented to ensure timely dissemination of scholarly and technical work. Copyright and all rights therein are retained by authors or by other copyright holders. All persons copying this information are expected to adhere to the terms and constraints invoked by each author's copyright. In most cases, these works may not be reposted without the explicit permission of the copyright holder." “Copyright IEEE. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from the IEEE.” DOI: 10.1109/ROMAN.2009.5326251This article is a methodological paper that describes the therapeutic and educational objectives that were identified during the design process of a robot aimed at robot assisted play. The work described in this paper is part of the IROMEC project (Interactive Robotic Social Mediators as Companions) that recognizes the important role of play in child development and targets children who are prevented from or inhibited in playing. The project investigates the role of an interactive, autonomous robotic toy in therapy and education for children with special needs. This paper specifically addresses the therapeutic and educational objectives related to children with autism. In recent years, robots have already been used to teach basic social interaction skills to children with autism. The added value of the IROMEC robot is that play scenarios have been developed taking children's specific strengths and needs into consideration and covering a wide range of objectives in children's development areas (sensory, communicational and interaction, motor, cognitive and social and emotional). The paper describes children's developmental areas and illustrates how different experiences and interactions with the IROMEC robot are designed to target objectives in these areas.Final Published versio

Universal Statistical Behavior of Neural Spike Trains

We construct a model that predicts the statistical properties of spike trains generated by a sensory neuron. The model describes the combined effects of the neuron's intrinsic properties, the noise in the surrounding, and the external driving stimulus. We show that the spike trains exhibit universal statistical behavior over short times, modulated by a strongly stimulus-dependent behavior over long times. These predictions are confirmed in experiments on H1, a motion-sensitive neuron in the fly visual system.Comment: 7 pages, 4 figure