To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Expression of all Yersinia pathogenicity factors encoded on the virulence plasmid, including the yop effector and the ysc type III secretion genes, is controlled by the transcriptional activator LcrF in response to temperature. Here, we show that a protein- and RNA-dependent hierarchy of thermosensors induce LcrF synthesis at body temperature. Thermally regulated transcription of lcrF is modest and mediated by the thermo-sensitive modulator YmoA, which represses transcription from a single promoter located far upstream of the yscW-lcrF operon at moderate temperatures. The transcriptional response is complemented by a second layer of temperature-control induced by a unique cis-acting RNA element located within the intergenic region of the yscW-lcrF transcript. Structure probing demonstrated that this region forms a secondary structure composed of two stemloops at 25°C. The second hairpin sequesters the lcrF ribosomal binding site by a stretch of four uracils. Opening of this structure was favored at 37°C and permitted ribosome binding at host body temperature. Our study further provides experimental evidence for the biological relevance of an RNA thermometer in an animal model. Following oral infections in mice, we found that two different Y. pseudotuberculosis patient isolates expressing a stabilized thermometer variant were strongly reduced in their ability to disseminate into the Peyer's patches, liver and spleen and have fully lost their lethality. Intriguingly, Yersinia strains with a destabilized version of the thermosensor were attenuated or exhibited a similar, but not a higher mortality. This illustrates that the RNA thermometer is the decisive control element providing just the appropriate amounts of LcrF protein for optimal infection efficiency.

This paper presents two robot devices for use in the rehabilitation of upper limb movements and reports the quantitative parameters obtained to characterize the rate of improvement, thus allowing a precise monitoring of patient's recovery. A one degree of freedom (DoF) wrist manipulator and a two-DoF elbow-shoulder manipulator were designed using an admittance control strategy; if the patient could not move the handle, the devices completed the motor task. Two groups of chronic post-stroke patients (G1 n = 7, and G2 n = 9) were enrolled in a three week rehabilitation program including standard physical therapy (45 min daily) plus treatment by means of robot devices, respectively, for wrist and elbow-shoulder movements (40 min, twice daily). Both groups were evaluated by means of standard clinical assessment scales and a new robot measured evaluation metrics that included an active movement index quantifying the patient's ability to execute the assigned motor task without robot assistance, the mean velocity, and a movement accuracy index measuring the distance of the executed path from the theoretic one. After treatment, both groups improved their motor deficit and disability. In G1, there was a significant change in the clinical scale values (p < 0.05) and range of motion wrist extension (p < 0.02). G2 showed a significant change in clinical scales (p < 0.01), in strength (p < 0.05) and in the robot measured parameters (p < 0.01). The relationship between robot measured parameters and the clinical assessment scales showed a moderate and significant correlation (r > 0.53 p < 0.03). Our findings suggest that robot-aided neurorehabilitation may improve the motor outcome and disability of chronic post-stroke patients. The new robot measured parameters may provide useful information about the course of treatment and its effectiveness at discharge.

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Background: Motivation is an important factor in rehabilitation and frequently used as a determinant of rehabilitation outcome. Several factors can influence patient motivation and so improve exercise adherence. This paper presents the design of two robot devices for use in the rehabilitation of upper limb movements, that can motivate patients during the execution of the assigned motor tasks by enhancing the gaming aspects of rehabilitation. In addition, a regular review of the obtained performance can reinforce in patients' minds the importance of exercising and encourage them to continue, so improving their motivation and consequently adherence to the program. In view of this, we also developed an evaluation metric that could characterize the rate of improvement and quantify the changes in the obtained performance.