A Robust Wheel Interface With A Novel Adaptive Controller For Computer/robot-Assisted Motivating Rehabilitation

TheraDrive is a low-cost robotic system for post-stroke upper extremity rehabilitation. This system uses off-the-shelf computer gaming wheels with force feedback to help reduce motor impairment and improve function in the arms of stroke survivors. Preliminary results show that the TheraDrive system lacks a robust mechanical linkage that can withstand the forces exerted by patients, lacks a patient-specific adaptive controller to deliver personalized therapy, and is not capable of delivering effective therapy to severely low-functioning patients. A new low-cost, high-force haptic robot with a single degree of freedom has been developed to address these concerns. The resulting TheraDrive consists of an actuated hand crank with a compliant transmission. Actuation is provided by a brushed DC motor, geared to output up to 50 lbf (223 N) at the end effector. To enable safe human-machine interaction, a special compliant element was developed to function also as a failsafe torque limiter. A load cell is used to determine the human-machine interaction forces for use by the robot\u27s impedance controller. The impedance controller renders a virtual spring that attracts or repels the end effector from a moving target that the human must track during therapy exercises. As exercises are performed, an adaptive controller monitors patient performance and adjusts the spring stiffness to ensure that exercises are difficult but doable, which is important for maintaining patient motivation. Experiments with a computer model of a human and robot show the adaptive controller\u27s ability to maintain difficulty of exercises after a period of initial calibration. Seven human subjects (3 normal, 4 stroke-impaired) were used to test this system alongside the original TheraDrive system in order to compare both systems. Data showed that the new system produced a larger change in normalized trajectory tracking error when assistance/resistance was added to exercises when compared to the original TheraDrive. Data also showed that adaptive control led subject performance to be closer to a desired level. Motivation surveys showed no significant difference in subject motivation between the two systems. When asked to choose a preferred system, stroke subjects unanimously chose the new robot

Design and Development of an Affordable Haptic Robot with Force-Feedback and Compliant Actuation to Improve Therapy for Patients with Severe Hemiparesis

The study describes the design and development of a single degree-of-freedom haptic robot, Haptic Theradrive, for post-stroke arm rehabilitation for in-home and clinical use. The robot overcomes many of the weaknesses of its predecessor, the TheraDrive system, that used a Logitech steering wheel as the haptic interface for rehabilitation. Although the original TheraDrive system showed success in a pilot study, its wheel was not able to withstand the rigors of use. A new haptic robot was developed that functions as a drop-in replacement for the Logitech wheel. The new robot can apply larger forces in interacting with the patient, thereby extending the functionality of the system to accommodate low-functioning patients. A new software suite offers appreciably more options for tailored and tuned rehabilitation therapies. In addition to describing the design of the hardware and software, the paper presents the results of simulation and experimental case studies examining the system\u27s performance and usability

A Robust Wheel Interface With a Novel Adaptive Controller for Computer/Robot-Assisted Motivating Rehabilitation

TheraDrive is an effective system for post-stroke upper extremity rehabilitation. This system uses off-the-shelf computer gaming wheels with force feedback to help reduce motor impairment and improve function in the arms of stroke survivors. Preliminary results show that the TheraDrive system lacks a robust mechanical linkage that can withstand the large forces exerted by patients, and it lacks a patient-specific adaptive controller to deliver personalized therapy. It is also not capable of delivering effective therapy to severely low-functioning patients. A new low-cost, high-force haptic robot with a single degree of freedom has been developed to address these concerns. The resulting TheraDrive consists of an actuated hand crank with a compliant transmission. Actuation is provided by a brushed DC motor, geared to output up to 23 kgf at the end effector. To enable a human to interact with this system safely, a special compliant element was developed to double as a failsafe torque limiter. A set of strain gauges in the handle of the crank are used to determine the interaction forces between human and robot for use by the robot’s impedance controller. The impedance controller is used to render a one-dimensional force field that attracts or repels the end effector from a moving target point that the human must track during therapy exercises. As exercises are performed, an adaptive controller monitors patient performance and adjusts the force field accordingly. This allows the robot to compensate for gravity, variable mechanical advantage, limited range of motion, and other factors. More importantly, the adaptive controller ensures that exercises are difficult but doable, which is important for maintaining patient motivation. Experiments with a computer model of human and robot show the adaptive controller’s ability to maintain difficulty of exercises after a period of initial calibration

Discovery of Small-Molecule Enhancers of Reactive Oxygen Species That are Nontoxic or Cause Genotype-Selective Cell Death

Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers of ROS may selectively kill cancer cells in various in vitro and in vivo models. We used a high-throughput screening approach to identify several hundred small-molecule enhancers of ROS in a human osteosarcoma cell line. A minority of these compounds diminished the viability of cancer cell lines, indicating that ROS elevation by small molecules is insufficient to induce death of cancer cell lines. Three chemical probes (BRD5459, BRD56491, BRD9092) are highlighted that most strongly elevate markers of oxidative stress without causing cell death and may be of use in a variety of cellular settings. For example, combining nontoxic ROS-enhancing probes with nontoxic doses of l-buthionine sulfoximine, an inhibitor of glutathione synthesis previously studied in cancer patients, led to potent cell death in more than 20 cases, suggesting that even nontoxic ROS-enhancing treatments may warrant exploration in combination strategies. Additionally, a few ROS-enhancing compounds that contain sites of electrophilicity, including piperlongumine, show selective toxicity for transformed cells over nontransformed cells in an engineered cell-line model of tumorigenesis. These studies suggest that cancer cell lines are more resilient to chemically induced increases in ROS levels than previously thought and highlight electrophilicity as a property that may be more closely associated with cancer-selective cell death than ROS elevation.Chemistry and Chemical Biolog

Comparing the use of meat and clay during cutting and projectile research

Diverse disciplines investigate how muscular tissue (i.e. ‘meat’) responds to being cut and deformed, however, large-scale, empirically robust investigations into these matters are often impractical and expensive. Previous research has used clay as an alternative to meat. To establish whether clay is a reliable proxy for meat, we directly compare the two materials via a series of cutting and projectile tests. Results confirm that the two materials display distinct cutting mechanics, resistance to penetration and are not comparable. Under certain conditions clay can be used as an alternative to meat, although distinctions between the two may lead to experimental limitations

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.Peer reviewe

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

Many Labs 2: Investigating Variation in Replicability Across Samples and Settings

We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely highpowered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP

Identification of Inhibitors of PvdQ, an Enzyme Involved in the Synthesis of the Siderophore Pyoverdine

Pseudomonas aeruginosa produces the peptide siderophore pyoverdine, which is used to acquire essential Fe3+ ions from the environment. PvdQ, an Ntn hydrolase, is required for the biosynthesis of pyoverdine. PvdQ knockout strains are not infectious in model systems, suggesting that disruption of siderophore production via PvdQ inhibition could be exploited as a target for novel antibacterial agents, by preventing cells from acquiring iron in the low iron environments of most biological settings. We have previously described a high-throughput screen to identify inhibitors of PvdQ that identified inhibitors with IC50 values of ∼100 μM. Here, we describe the discovery of ML318, a biaryl nitrile inhibitor of PvdQ acylase. ML318 inhibits PvdQ in vitro (IC50 = 20 nM) by binding in the acyl-binding site, as confirmed by the X-ray crystal structure of PvdQ bound to ML318. Additionally, the PvdQ inhibitor is active in a whole cell assay, preventing pyoverdine production and limiting the growth of P. aeruginosa under iron-limiting conditions