Inherited Retinal Diseases Due to RPE65 Variants: From Genetic Diagnostic Management to Therapy

Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6–6% of RP and 3–16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants (RPE65-IRDs). Therefore, the accurate molecular diagnosis of RPE65-IRDs is crucial to identify ‘actionable’ genotypes—i.e., genotypes that may benefit from the treatment—and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients’ access to available therapeutic options.     

Design and implementation of a new scheduler for enhancing multi-rate fairness in IEEE 802.16

Without the definition of a mandatory scheduling algorithm for channel resource assignment, WiMAX is open to Quality of Service (QoS) enhancements by research groups and developers, at the aim of managing heterogeneous flows with different QoS requirements. Furthermore, besides performance enhancement, another key issue arises for QoS delivery: it is known as multi-rate fairness and it deals with efficient resource allocation for providing sufficient bandwidth to high rate flows, without penalizing low rate ones. In this paper, uplink scheduling algorithms are studied and an innovative solution is proposed to achieve performance enhancement, multi-rate fairness and improved QoS management. After an overview of the state of the art, two scheduling algorithms based on Deficit Round Robin are studied, implemented and tested in NS2 simulator. The schedulers are validated and compared through exhaustive simulations, showing the benefits coming from the adoption of the proposed scheduling mechanism.     

Capacitance DNA bio-chips improved by new probe immobilization strategies

Label-free DNA detection plays a crucial role in developing point-of-care biochips. Capacitance detection is a promising technology for label-free detection. However, data published in literature often show evident time drift, large standard deviation, scattered data points, and poor reproducibility. To address these problems, mercapto-hexanol or similar alkanethiols are usually considered as blocking agents. The aim of the present paper is to investigate new blocking agents to further improve DNA probe surfaces. Data from AFM, SPR, florescence microscopy, and capacitance measurements are used to investigate new lipoate and ethylene-glycol molecules. The new surfaces offer further improvements in terms of diminished detection errors. Film structures are investigated at the nano-scale to justify the detection improvements in terms of probe surface quality. This study demonstrates the superiority of lipoate and ethylene-glycol molecules as blocking candidates when immobilizing molecular probes onto spot surfaces in label-free DNA biochip.     

Design of an integrated low-noise read-out system for DNA capacitive sensors

This paper presents an electronic system for a fast DNA label-less detection. The sensitivity of the capacitive sensor in use is improved by depositing an insulating self-assembled monolayer (SAM) over the golden electrodes. The capacitance shift due to the hybridization effect is monitored by means of a charge-sensitive amplifier and digitalized by means of a comparator and a counter. The read-out solution demonstrates the ability to identify a 0.01% variation on the capacitive value of the sensor. Results from measurements with the optimized sensor show the reliability of the electronics. The investigated solution is suitable for monolithic systems or for a micro-fabricated array of sensors. An example of the integrated front-end is described and performances and noise evaluation are reported here.     

Thermal analysis in coated cutting tools

This work studies the heat influence in cutting tools considering the variation of the coating thickness and the heat flux. K10 and diamond tools substrate with TiN and Al₂O₃ coatings were used. The numerical methodology utilizes the ANSYS^® CFX software. Boundary conditions and constant thermo physical properties of the solids involved in the numerical analysis are known. To validate the proposed methodology an experiment is used. The TiN and Al₂O₃ coatings did not show satisfying results during a continuous cutting process. It showed a slight reduction in the heat flux for the 10 (µm) TiN and Al₂O₃ coatings.     

Recursive partial realization for 2-D data arrays

In this paper an attempt is made to provide a proper formalization to the partial realization problem for discrete linear causal shift invariant 2-D systems. The approach falls into the class of 2-D Padé approximations; the results, however, are new, since the rational representation matches all the samples of a 2-D partial sequence. The realization algorithm, though characterized by a high complexity, exhibits a recursive structure and allows for a good computational economy.     

A systematic review on the functional testing of semantic web services

Semantic web services are gaining more attention as an important element of the emerging semantic web. Therefore, testing semantic web services is becoming a key concern as an essential quality assurance measure. The objective of this systematic literature review is to summarize the current state of the art of functional testing of semantic web services by providing answers to a set of research questions. The review follows a predefined procedure that involves automatically searching 5 well-known digital libraries. After applying the selection criteria to the results, a total of 34 studies were identified as relevant. Required information was extracted from the studies and summarized. Our systematic literature review identified some approaches available for deriving test cases from the specifications of semantic web services. However, many of the approaches are either not validated or the validation done lacks credibility. We believe that a substantial amount of work remains to be done to improve the current state of research in the area of testing semantic web services.     

Overlapping Schwarz and Spectral Element Methods for Linear Elasticity and Elastic Waves

The classical overlapping Schwarz algorithm is here extended to the spectral element discretization of linear elastic problems, for both homogeneous and heterogeneous compressible materials. The algorithm solves iteratively the resulting preconditioned system of linear equations by the conjugate gradient or GMRES methods. The overlapping Schwarz preconditioned technique is then applied to the numerical approximation of elastic waves with spectral elements methods in space and implicit Newmark time advancing schemes. The results of several numerical experiments, for both elastostatic and elastodynamic problems, show that the convergence rate of the proposed preconditioning algorithm is independent of the number of spectral elements (scalability), is independent of the spectral degree in case of generous overlap, otherwise it depends inversely on the overlap size. Some results on the convergence properties of the spectral element approximation combined with Newmark schemes for elastic waves are also presented.