Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.     

Two LCOS full color projector with efficient LED illumination engine

LED-based projectors have numerous advantages compared to traditional projectors, but their light output is limited by the limited brightness of the LEDs. With an efficient illumination engine design we can build an LED projector with a moderate light output and with superior properties. In this paper we present a compact LED projector with two ‘Liquid Crystal On Silicon’ panels and four LEDs (R, 2 × G, B). We use two panels instead of the classical three panels and will still have the same performance and moreover a reduced volume and cost. The illumination system consists of a custom made monolithic component (GTLP) that is combining many functions. We have also integrated some methods to increase the brightness of the LEDs by pulsing them. Additional methods, such as using an extra PBS to combine both color channels, are implemented to increase the contrast. After investigating the promising simulation results (119 lm D65 light with very high contrast and uniformity), we built a demonstrator setup. Our demonstrator produces a moderate light output (37.3 lm) on screen with a sufficient contrast ratio and a very good uniformity. In spite of semi color sequential working, the color breakup and crosstalk are negligible. The difference in performance and possible improvements will be discussed in the paper.     

Parallel partitioning method (PPM): A new exact method to solve bi-objective problems

In this paper, we propose a new exact method, called the parallel partitioning method (PPM), able to solve efficiently bi-objective problems. This method is based on the splitting of the search space into several areas leading to elementary exact searches. We compare this method with the well-known two-phase method (TPM). Experiments are carried out on a bi-objective permutation flowshop problem (BOFSP). During experiments the proposed PPM is compared with two versions of TPM: the basic TPM and an improved TPM dedicated to scheduling problems. Experiments show the efficiency of the new proposed method.     

Quantitative Proteomics to Characterize Specific Histone H2A Proteolysis in Chronic Lymphocytic Leukemia and the Myeloid THP-1 Cell Line

Proteome studies on hematological malignancies contribute to the understanding of the disease mechanism and to the identification of new biomarker candidates. With the isobaric tag for relative and absolute quantitation (iTRAQ) method we analyzed the protein expression between B-cells of healthy people and chronic lymphocytic leukemia (CLL) B-cells. CLL is the most common lymphoid cancer of the blood and is characterized by a variable clinical course. By comparing samples of patients with an aggressive vs. indolent disease, we identified a limited list of differentially regulated proteins. The enhanced sensitivity attributed to the iTRAQ labels led to the discovery of a previously reported but still not clarified proteolytic product of histone H2A (cH2A) which we further investigated in light of the suggested functional properties of this modification. In the exploratory proteome study the Histone H2A peptide was up-regulated in CLL samples but a more specific and sensitive screening of a larger patient cohort indicated that cH2A is of myeloid origin. Our subsequent quantitative analysis led to a more profound characterization of the clipping in acute monocytic leukemia THP-1 cells subjected to induced differentiation.     

GGM: efficient navigation and mining in distributed genomedical data

The integration of genomics and patient related data is considered as one of the most promising investigation topic in health care research. Started in 2004, the Grid for Geno Medicine (GGM) project aims at providing a comprehensive grid software infrastructure designed to allow biologists to mine and analyze relationships between medical, genetic, and genomic data stored in distributed datawarehouses. The proposed layered service oriented architecture offers a number of independent but compliant services that can be deployed in a grid environment. This paper presents these services insisting on their integration into a common software platform, the use case that is carried out. It also presents the current state of the developments and of the performance evaluations.     

CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials.     

Solving a dial-a-ride problem with a hybrid evolutionary multi-objective approach: Application to demand responsive transport

Demand responsive transport allows customers to be carried to their destination as with a taxi service, provided that the customers are grouped in the same vehicles in order to reduce operational costs. This kind of service is related to the dial-a-ride problem. However, in order to improve the quality of service, demand responsive transport needs more flexibility. This paper tries to address this issue by proposing an original evolutionary approach. In order to propose a set of compromise solutions to the decision-maker, this approach optimizes three objectives concurrently. Moreover, in order to intensify the search process, this multi-objective evolutionary approach is hybridized with a local search. Results obtained on random and realistic problems are detailed to compare three state-of-the-art algorithms and discussed from an operational point of view.     

Oxidation of NH3 on polycrystalline copper and Cu(1 1 0): a combined FT-IRAS and kinetics investigation

The kinetics of the reaction of oxidation of ammonia on polycrystalline copper, has been investigated, in a re-circulating reactor, and correlated to a characterisation of the catalyst surface at different extent of conversions.

The rapid formation of a nitride or oxynitride phase and its reactivity have been demonstrated. Under oxidising conditions, P_NH3=P_O2, and up to 650 K, dinitrogen is the only product of the reaction; N₂O being formed when T or P_O2 increases further. The correlation of these kinetics results to an in situ characterisation of the same reaction at RT by Fourier-transformed infrared reflection-absorption spectroscopy (FT-IRAS), on a well defined Cu(1 1 0) surface, led to the following conclusion: two reaction pathways contribute to the conversion of ammonia: (i) its decomposition on copper; (ii) the reaction between ammonia molecules and oxygen adsorbed from the gas phase. The major adsorbed species is oxygen; intermediate species are NH₂, NH and possibly HNO formed when the oxygen surface concentration is sufficient. Increasing the pressure of oxygen induces, at high T, the formation of nitrous oxide; N₂O results from an oxidation of the surface copper nitride or from the interaction of two surface HNO intermediates.