Erythrocyte phospholipid and polyunsaturated fatty acid composition in diabetic retinopathy

Background: Long chain polyunsaturated fatty acids (LCPUFAs) including docosahexaenoic acid and arachidonic acid are suspected to play a key role in the pathogenesis of diabetes. LCPUFAs are known to be preferentially concentrated in specific phospholipids termed as plasmalogens. This study was aimed to highlight potential changes in the metabolism of phospholipids, and particularly plasmalogens, and LCPUFAs at various stages of diabetic retinopathy in humans. Methodology and Principal Findings: We performed lipidomic analyses on red blood cell membranes from controls and mainly type 2 diabetes mellitus patients with or without retinopathy. The fatty acid composition of erythrocytes was determined by gas chromatography and the phospholipid structure was determined by liquid chromatography equipped with an electrospray ionisation source and coupled with a tandem mass spectrometer (LC-ESI-MS/MS). A significant decrease in levels of docosahexaenoic acid and arachidonic acid in erythrocytes of diabetic patients with or without retinopathy was observed. The origin of this decrease was a loss of phosphatidyl-ethanolamine phospholipids esterified with these LCPUFAs. In diabetic patients without retinopathy, this change was balanced by an increase in the levels of several phosphatidyl-choline species. No influence of diabetes nor of diabetic retinopathy was observed on the concentrations of plasmalogen-type phospholipids. Conclusions and Significance: Diabetes and diabetic retinopathy were associated with a reduction of erythrocyte LCPUFAs in phosphatidyl-ethanolamines. The increase of the amounts of phosphatidyl-choline species in erythrocytes of diabetic patients without diabetic retinopathy might be a compensatory mechanism for the loss of LC-PUFA-rich phosphatidyl-ethanolamines

Physical Realization of a Supervised Learning System Built with Organic Memristive Synapses

International audienceMultiple modern applications of electronics call for inexpensive chips that can perform complex operations on natural data with limited energy. A vision for accomplishing this is implementing hardware neural networks, which fuse computation and memory, with low cost organic electronics. A challenge, however, is the implementation of synapses (analog memories) composed of such materials. In this work, we introduce robust, fastly programmable, nonvolatile organic memristive nanodevices based on electrografted redox complexes that implement synapses thanks to a wide range of accessible intermediate conductivity states. We demonstrate experimentally an elementary neural network, capable of learning functions, which combines four pairs of organic memristors as synapses and conventional electronics as neurons. Our architecture is highly resilient to issues caused by imperfect devices. It tolerates inter-device variability and an adaptable learning rule offers immunity against asymmetries in device switching. Highly compliant with conventional fabrication processes, the system can be extended to larger computing systems capable of complex cognitive tasks, as demonstrated in complementary simulations

Flow photochemistry: a meso-scale reactor for industrial applications

Developing flow photochemistry, especially at meso-scale where significant productivity is required, remains challenging. There is a need for innovative equipments generating highly controlled flow under light irradiation. In this work, a commercial solution, developed by Corning, is presented and studied by LGC and MEPI on an intramolecular (2+2) photo-cycloaddition. Detailed experimental and modelling analysis has been performed to emphasize the flow reactor behaviour and performances, and demonstrate its capability in producing up to 30g.h-1 of the desired molecule. Through this simple model reaction, the G1 photo-reactor is shown to be an efficient meso-scale reactor for industrial photo-applications development and production

A new HPLC-ESI-MS/MS method to characterize and quantify phosphatidyl-choline with VLC-PUFA: Application to human retina

Purpose: Mutations in the ELOVL4 gene have been found in Stargardt-like macular dystrophy or STD3. Previous studies have shown that ELOVL4 is involved in the biosynthesis of very long chain polyunsaturated fatty acids (VLC-PUFA). The aim of this work was to develop a HPLC-ESI-MS/MS method of characterization and quantification of dipolyunsaturated phosphatidyl-choline (PC) molecular species containing VLC-PUFA and to apply it on retinas from human donors. Methods: Eyeballs were collected from calf as well as from nine human donors (body donation to Science). The neural retina was dissected from the RPE/choroid. Following lipid extraction, phosphorus content of total phospholipids was determined.Using a triple quadrupole MS instrument, PC molecular species were structurally characterized by collision-induced dissociation in the negative mode with a method based on normal-HPLC-ESIMS/MS. PC molecular species were then quantified using precursor ion scanning of m/z 184amu in the positive mode. Results: The characterization of PC species was done on bovine retinas. Among them, 28 were dipolyunsaturated PC species containing one VLC-PUFA (C24 to C36) with three to six double bonds. VLC-PUFA were always in the sn-1 position whilst PUFA at the sn-2 position was exclusively docosahexaenoic acid (DHA, C22:6.n-3). Most of these VLC-PUFA-containing dipolyunsaturated PC were detected and quantified in human retinas. The main represented compounds were those having VLC-PUFA of 32 carbon atoms (C32:3, C32:4, C32:5 and C32:6) and 34 carbon atoms (C34:3, C34:4, C34:5 and C34:6). Dipolyunsaturated PC with 36:5 and 36:6 were detected in lower quantities. Conclusions: This new HPLC-ESI-MS/MS method is sensitive and specific enough to structurally characterize and quantify all molecular species of PC, including those esterified with VLC-PUFA. This technique is valuable for a precise characterization of PC containingVLC-PUFA in retina and may be useful for better understanding their implication in the pathogenesis of STD3

Lipid Composition of the Human Eye: Are Red Blood Cells a Good Mirror of Retinal and Optic Nerve Fatty Acids?

International audienceBACKGROUND: The assessment of blood lipids is very frequent in clinical research as it is assumed to reflect the lipid composition of peripheral tissues. Even well accepted such relationships have never been clearly established. This is particularly true in ophthalmology where the use of blood lipids has become very common following recent data linking lipid intake to ocular health and disease. In the present study, we wanted to determine in humans whether a lipidomic approach based on red blood cells could reveal associations between circulating and tissue lipid profiles. To check if the analytical sensitivity may be of importance in such analyses, we have used a double approach for lipidomics. METHODOLOGY AND PRINCIPAL FINDINGS: Red blood cells, retinas and optic nerves were collected from 9 human donors. The lipidomic analyses on tissues consisted in gas chromatography and liquid chromatography coupled to an electrospray ionization source-mass spectrometer (LC-ESI-MS). Gas chromatography did not reveal any relevant association between circulating and ocular fatty acids except for arachidonic acid whose circulating amounts were positively associated with its levels in the retina and in the optic nerve. In contrast, several significant associations emerged from LC-ESI-MS analyses. Particularly, lipid entities in red blood cells were positively or negatively associated with representative pools of retinal docosahexaenoic acid (DHA), retinal very-long chain polyunsaturated fatty acids (VLC-PUFA) or optic nerve plasmalogens. CONCLUSIONS AND SIGNIFICANCE: LC-ESI-MS is more appropriate than gas chromatography for lipidomics on red blood cells, and further extrapolation to ocular lipids. The several individual lipid species we have identified are good candidates to represent circulating biomarkers of ocular lipids. However, further investigation is needed before considering them as indexes of disease risk and before using them in clinical studies on optic nerve neuropathies or retinal diseases displaying photoreceptors degeneration

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Caractérisation physique et approche numérique du rôle des aquitards dans les systèmes aquifères multicouches - Application au complexe tertiaire nord-aquitain

The development of hydrodynamic models at regional scale requires to take into account the aquitards layers and their hydrogeological behaviour on the long term. These leaky units have specific geological and hydrodynamical properties and sometimes large scale heterogeneities. The area of Bordeaux which is subject to large withdrawals, is used to support the study for understanding the role of aquitards in the hydrodynamic behavior of a multilayered complex. Various methods were used to assess the geological characteristics of these low permeability formations. The well logging tool allowed a reinterpretation of the geology and resulted in the updating of the geometry of the hydro-geological study area and a new vertical structure of aquifers and aquitards units. The installation of a specific borehole, with the analysis of core samples and permanent pressure monitoring device, at different levels, provided an estimation of the geological and hydrodynamical properties of the aquitard. Finally, the quantitative approach of the role of aquitards in the hydrodynamic behavior of the aquifer system was carried out using a hydrodynamic model. This model takes into account the new geometry obtained from the use of well loggings, and integrates the values of hydrodynamic parameters obtained by laboratory and in situ measurements. The model is used to identify the leakage flows in the multilayer system. The results demonstrate the impact and the role of a leaky unit within a thick aquitard. Ultimately, integration of heterogeneities within an aquitard is essential to the development of quantitative and qualitative management tools for groundwater resources, at different time scales, for complex multilayered aquifer systems.L'élaboration de modèles hydrodynamiques à des fins de gestion rationnelle des aquifères et des prélèvements à une échelle régionale nécessite la connaissance du fonctionnement hydrodynamique des aquitards.La caractérisation de ces formations semi-perméables implique de déterminer leurs propriétés géologiques, hydrodynamiques et leur degré d'hétérogénéité. La région de Bordeaux, soumise à d'importants prélèvements, sert ici de support d'étude pour appréhender le rôle des aquitards dans le fonctionnement hydrodynamique d'un multicouche complexe. La caractérisation de ces formations semi-perméables a été obtenue au travers d'approches directes, indirectes et numériques. L'outil diagraphique a permis une réinterprétation de la géologie et a abouti à la mise à jour de la géométrie hydro-géologique du domaine d'étude ainsi qu'à une nouvelle organisation verticale des unités aquifères et aquitards. Les propriétés hydrodynamiques des aquitards ont été approchées grâce à la réalisation d'un forage expérimental dédié à l'étude d'une éponte. Des mesures pétrophysiques et l'analyse des séries temporelles enregistrées en différents niveaux de l'aquitard ont été effectuées et ont fourni des estimations des paramètres de conductivité hydraulique et d'emmagasinement spécifique de l'aquitard. Enfin, l'approche quantitative du rôle des aquitards dans le fonctionnement hydrodynamique du système aquifère a été réalisée à l'aide d'un modèle hydrogéologique. Celui-ci prend en compte la géométrie revisitée, issue des données diagraphiques, et intègre les valeurs des paramètres hydrodynamiques obtenues par les mesures de laboratoire et in situ. Le modèle a été utilisé pour préciser les flux de drainance au sein du système multicouche ainsi que leurs proportions relatives. Les résultats démontrent l'impact et le rôle d'un horizon semi-perméable au sein d'un aquitard puissant. In fine, l'intégration des hétérogénéités d'un aquitard s'avère obligatoire dans l'élaboration d'outils de gestion raisonnée (quantitative et qualitative) à court et long terme des ressources en eau souterraines d'un système aquifère multicouche complexe

Caractérisation physique et approche numérique du rôle des aquitards dans les systèmes aquifères multicouches (application au complexe tertiaire nord-aquitain)

L élaboration de modèles hydrodynamiques à des fins de gestion rationnelle des aquifères et des prélèvements à une échelle régionale nécessite la connaissance du fonctionnement hydrodynamique des aquitards. La caractérisation de ces formations semi-perméables implique de déterminer leurs propriétés géologiques, hydrodynamiques et leur degré d hétérogénéité. La région de Bordeaux, soumise à d importants prélèvements, sert ici de support d étude pour appréhender le rôle des aquitards dans le fonctionnement hydrodynamique d un multicouche complexe. La caractérisation de ces formations semi-perméables a été obtenue au travers d approches directes, indirectes et numériques. L outil diagraphique a permis une réinterprétation de la géologie et a abouti à la mise à jour de la géométrie hydro-géologique du domaine d étude ainsi qu à une nouvelle organisation verticale des unités aquifères et aquitards. Les propriétés hydrodynamiques des aquitards ont été approchées grâce à la réalisation d un forage expérimental dédié à l étude d une éponte. Des mesures pétrophysiques et l analyse des séries temporelles enregistrées en différents niveaux de l aquitard ont été effectuées et ont fourni des estimations des paramètres de conductivité hydraulique et d emmagasinement spécifique de l aquitard. Enfin, l approche quantitative du rôle des aquitards dans le fonctionnement hydrodynamique du système aquifère a été réalisée à l aide d un modèle hydrogéologique. Celui-ci prend en compte la géométrie revisitée, issue des données diagraphiques, et intègre les valeurs des paramètres hydrodynamiques obtenues par les mesures de laboratoire et in situ. Le modèle a été utilisé pour préciser les flux de drainance au sein du système multicouche ainsi que leurs proportions relatives. Les résultats démontrent l impact et le rôle d un horizon semi-perméable au sein d un aquitard puissant. In fine, l intégration des hétérogénéités d un aquitard s avère obligatoire dans l élaboration d outils de gestion raisonnée (quantitative et qualitative) à court terme des ressources en eau souterraines d un système aquifère multicouche complexe.BORDEAUX3-BU Lettres-Pessac (335222103) / SudocSudocFranceF

Groundwater management of large aquifers in southwestern France by regional hydrodynamic models

International audienceIn southwestern France, groundwater resources are withdrawn for various uses (drinkable water, irrigation, industry, geothermal energy, forestry, conservation of wetlands, shellfish breeding among others) which can sometimes cause conflicts between users. To help the management of these resources, regional hydrodynamic models have been developed. These models have been a support to the public policies for over 20 years.In the northern region, groundwater is in close relation with rivers, especially during periods of low-water levels. Indeed, groundwater used for irrigation impact not only the stream flows, but also the water supply for the second large wetland of France: the Marais Poitevin. The developed models have permitted to test the impact of several scenarios of water withdrawals. These tests help to determinate the amount of water that can be pumped to respect defined objectives as water levels in piezometer and river flows.These models were also used to test the impact of the eventual implementation of water tanks (400,000 to 800,000 m3). Further south, the major problem is the important reduction of the level of the Eocene aquifer in the department of Gironde. In this area, the regional hydrodynamic model has been developed since 1990. Its development allows the management of deep groundwater resources and contributes to validate strategies of exploitation based on different simulations. This model also allows to answer problems of overexploitation and to analyse areas where water savings could be done to avoid this overexploitation, and to estimate the impact of new resources.The extreme southern region has a significant particularity: on two different sites, groundwater is used for the storage of gas. The cyclic injection and withdrawal of gas impacts significantly the aquifer level. The proposed model is adapted for the groundwater resources knowledge and management of this case. Finally, these models were used to evaluate impacts of climate change on groundwater resources in order to allow authorities to evaluate strategies to adapt to this change (Project Explore 2070 for example)