Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ

Abstract Background Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants ( e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic ( e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. Results We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. Conclusions The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ

Path planning for image based visual servoing

This thesis deals with Visual Servoing and its strictly connected disciplines like projective geometry, image processing, robotics and non-linear control. More specifically the work addresses the problem to control a robotic manipulator through one of the largely used Visual Servoing techniques: the Image Based Visual Servoing (IBVS). In Image Based Visual Servoing the robot is driven by on-line performing a feedback control loop that is closed directly in the 2D space of the camera sensor. The work considers the case of a monocular system with the only camera mounted on the robot end effector (eye in hand configuration). Through IBVS the system can be positioned with respect to a 3D fixed target by minimizing the differences between its initial view and its goal view, corresponding respectively to the initial and the goal system configurations: the robot Cartesian Motion is thus generated only by means of visual informations. However, the execution of a positioning control task by IBVS is not straightforward because singularity problems may occur and local minima may be reached where the reached image is very close to the target one but the 3D positioning task is far from being fulfilled: this happens in particular for large camera displacements, when the the initial and the goal target views are noticeably different. To overcame singularity and local minima drawbacks, maintaining the good properties of IBVS robustness with respect to modeling and camera calibration errors, an opportune image path planning can be exploited. This work deals with the problem of generating opportune image plane trajectories for tracked points of the servoing control scheme (a trajectory is made of a path plus a time law). The generated image plane paths must be feasible i.e. they must be compliant with rigid body motion of the camera with respect to the object so as to avoid image jacobian singularities and local minima problems. In addition, the image planned trajectories must generate camera velocity screws which are smooth and within the allowed bounds of the robot. We will show that a scaled 3D motion planning algorithm can be devised in order to generate feasible image plane trajectories. Since the paths in the image are off-line generated it is also possible to tune the planning parameters so as to maintain the target inside the camera field of view even if, in some unfortunate cases, the feature target points would leave the camera images due to 3D robot motions. To test the validity of the proposed approach some both experiments and simulations results have been reported taking also into account the influence of noise in the path planning strategy. The experiments have been realized with a 6DOF anthropomorphic manipulator with a fire-wire camera installed on its end effector: the results demonstrate the good performances and the feasibility of the proposed approach

VISUAL SERVOING WITH A PAIR OF COAXIAL CIRCLES

Abstract: An uncalibrated approach to visual servoing with respect to non planar targets modeled through a pair of coaxial circles plus one point is discussed. Full calibration data (fixed internal parameters) are obtained from two views, and used to recover Euclidean target structure and camera relative pose. Pose disambiguation is achieved without requiring any real third view of the target. The approach benefits of an off-line planning strategy by which the camera follows a 3D helicoidal path around the target axis. Simulations results demonstrate that the approach is robust with respect to a noisy calibration. Copyright c ○ 2006 IFA

Development and Experimental Validation of Auxiliary Rolling Bearing Models for Active Magnetic Bearings (AMBs) Applications

Nowadays, the search for increasing performances in turbomachinery applications has led to a growing utilization of active magnetic bearings (AMBs), which can bring a series of advantages thanks to their features: AMBs allow the machine components to reach higher peripheral speeds; in fact there are no wear and lubrication problems as the contact between bearing surfaces is absent. Furthermore, AMBs characteristic parameters can be controlled via software, optimizing machine dynamics performances. However, active magnetic bearings present some peculiarities, as they have lower load capacity than the most commonly used rolling and hydrodynamic bearings, and they need an energy source; for these reasons, in case of AMBs overload or breakdown, an auxiliary bearing system is required to support the rotor during such landing events. During the turbomachine design process, it is fundamental to appropriately choose the auxiliary bearing type and characteristics, because such components have to resist to the rotor impact; so, a supporting design tool based on accurate and efficient models of auxiliary bearings is very useful for the design integration of the Active Magnetic Bearing System into the machine. This paper presents an innovative model to accurately describe the mechanical behavior of a complete rotor-dynamic system composed of a rotor equipped with two auxiliary rolling bearings. The model, developed and experimentally validated in collaboration with Baker Hughes a GE company (providing the test case and the experimental data), is able to reproduce the key physical phenomena experimentally observed; in particular, the most critical phenomenon noted during repeated experimental combined landing tests is the rotor forward whirl, which occurs in case of high friction conditions and greatly influences the whole system behavior. In order to carefully study some special phenomena like rotor coast down on landing bearings (which requires long period of time to evolve and involves many bodies and degrees of freedom) or other particular events like impacts (which occur in a short period of time), a compromise between accuracy of the results and numerical efficiency has been pursued. Some of the elements of the proposed model have been previously introduced in literature; however the present work proposes some new features of interest. For example, the lateral and the axial models have been properly coupled in order to correctly reproduce the effects observed during the experimental tests and a very important system element, the landing bearing compliant suspension, has been properly modelled to more accurately describe its elastic and damping effects on the system. Furthermore, the model is also useful to characterize the frequencies related to the rotor forward whirl motion