Investigational neuroprotective compounds in clinical trials for retinal disease

INTRODUCTION: The death of retinal neurons causes permanent and irreversible vision loss, severely impairing quality of life. By targeting toxic conditions which cause neuronal death, such as oxidative stress and ischaemia, neuroprotective agents provide utility in slowing or stopping sight loss resulting from eye disease. While clinical use of neuroprotectants remains limited, there are a few promising compounds presently in early clinical trials (pre-phase III) which may fulfil exciting new therapeutic roles. Search terms relating to neuroprotection and eye disease were used on ClinicalTrials.gov to identify relevant compounds. AREAS COVERED: This review focuses research supporting neuroprotective compounds in eye diseases which range from preclinical stages to phase II, as listed on the clinicaltrials.gov database. The compounds under discussion, namely NGF, Saffron, Ubiquinone, and CNTF, are discussed in terms of potential clinical applications in the near future. EXPERT OPINION: Until recently, the major challenge in neuroprotection research has been the successful translation from basic research to the clinic. A number of potential neuroprotective molecules have progressed to ophthalmology clinical trials in the last few years, with defined mechanisms of action - saffron and CoQ10 - targeting the mitochondria, and both CNTF and NGF showing anti-apoptotic effects. Enhancements in trial design and choice of patient cohorts in these chronic diseases using proof-of-concept trials with enriched patient populations and surrogate endpoints should increase drug development speed. A further important consideration is optimising drug delivery approaches with improvements in individualised management and patient compliance. Progress in all these areas means that neuroprotective strategies have a much improved chance nowadays of translational success

Time Dynamics of the Down-Coupling Phenomenon in 3-D NAND Strings

We present a detailed analysis of the time dynamics of the down-coupling phenomenon (DCP) in 3-D NAND Flash memory strings. The transient time dynamics of the channel potential following the wordline (WL) bias transition fromthe pass voltage to zero is studied via numerical simulation, highlighting the existence of three temporal regimes controlledby different physical processes: electron emission from traps, hole injection from the string edges followed by capture, and propagation along the string. The impact of these processes is separately studied, followed by an analysis of the dependence of the DCP recovery time on architectural parameters. Results highlight the relevant physics and can be used as a design guideline for NAND strings with reduced sensitivity to the DCP

Comprehensive numerical simulation of threshold-voltage transients in nitride memories

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Variation in sexual dimorphism in a wind-pollinated plant: The influence of geographical context and life-cycle dynamics

Understanding the mechanisms causing phenotypic differences between females and males has long fascinated evolutionary biologists. An extensive literature exists on animal sexual dimorphism but less information is known about sex differences in plants, particularly the extent of geographical variation in sexual dimorphism and its life‐cycle dynamics. Here, we investigated patterns of genetically based sexual dimorphism in vegetative and reproductive traits of a wind‐pollinated dioecious plant, Rumex hastatulus, across three life‐cycle stages using open‐pollinated families from 30 populations spanning the geographic range and chromosomal variation (XY and XY1Y2) of the species. The direction and degree of sexual dimorphism was highly variable among populations and life‐cycle stages. Sex‐specific differences in reproductive function explained a significant amount of temporal change in sexual dimorphism. For several traits, geographical variation in sexual dimorphism was associated with bioclimatic parameters, likely due to the differential responses of the sexes to climate. We found no systematic differences in sexual dimorphism between chromosome races. Sex‐specific trait differences in dioecious plants largely result from a balance between sexual and natural selection on resource allocation. Our results indicate that abiotic factors associated with geographical context also play a role in modifying sexual dimorphism during the plant life‐cycle

Inherited Ocean-Continent Transition zones in deeply subducted terranes: Insights from Alpine Corsica

In the Schistes Lustrés of Alpine Corsica (France) serpentinized mantle rocks are associated with continental basement and meta-volcanic/-sedimentary cover rocks. The relationships among these different lithologies are especially well exposed in the Monte San Petrone unit, where Alpine metamorphism reached lawsonite-eclogite conditions. The contact between serpentinites and slivers of continental basement, relatively flat-lying over several kilometers, is characterized by evidence of cataclastic deformation pre-dating Alpine High-Pressure ductile fabrics. The serpentinite/continental basement pair is stratigraphically overlain by metasediments with a typical Jurassic-Cretaceous supra-ophiolitic lithostratigraphy, with metaradiolarites passing upward to marbles and calcschists. Noticeably, no evidence of cataclastic deformation is found in metasediments. These observations indicate that the lithostratigraphy of the Monte San Petrone unit was established during a pre-Alpine polyphase evolution, which culminated in extensive brittle deformation along a flat-lying detachment fault prior to the deposition of Jurassic sediments. We suggest that the inferred Mesozoic extensional tectonics were related to the opening of the Western Tethys. The Mesozoic architecture of the Monte San Petrone area, which is typical of an Ocean-Continent Transition (OCT) zone, was preserved despite Alpine deformation and metamorphism, when the different lithologies (i.e. meta-ophiolites, continent-derived rocks and metasediments) underwent a common metamorphic evolution, culminating at T=490-550. °C and P=2.2-2.6. GPa. Similar tectono-stratigraphic associations are observed in other high-pressure terranes of Alpine Corsica, suggesting that inherited OCT-type domains may be common in Alpine-type orogens. © 2011 Elsevier B.V

Electrode-dependent asymmetric conduction mechanisms in K0.5Na0.5NbO3 micro-capacitors

The ultimate performance of devices employing lead-free piezoelectrics is determined not only by the intrinsic properties of the piezo, but also by processes and materials employed to create the electric contacts. In this paper, we investigate the impact of different metallic electrodes with increasing chemical reactivity (Pt, Ni, Ti, Cr), on the asymmetric behavior of the leakage current in M/K0.5Na0.5NbO3/Pt(111) micro-capacitors, where M stands for the top metallic electrode. For all electrodes we found a marked leakage asymmetry that we ascribed to the presence of a Schottky-like rectifying junction at the M/K0.5Na0.5NbO3/Pt(111) bottom interface, while the corresponding junction at the top interface is deeply affected by the creation of oxygen vacancies due to oxygen scavenging during the growth of the top metallic electrodes, leading to an almost ohmic top contact. The leakage increases with the reactivity of the electrodes, while the asymmetry decreases, thus suggesting that the creation of the top metal/K0.5Na0.5NbO3 interface generates oxygen vacancies diffusing down to the bottom interface and impacting on the rectifying behavior of the Schottky-like junction. Noteworthy, this asymmetric conduction can reflect in an asymmetric piezoelectric and ferroelectric behavior, as a sizable portion of the applied voltage drops across the rectifying junction in reverse bias, thus hampering symmetric bipolar operation, especially in leaky materials

Secretome of bovine amniotic and endometrial cells : application for in vitro embryo production

Some maternal miRNAs are involved in early stage embryos [Abd El Naby, 2011]. Microvesicles (MVs) have been suggested as carrier of miRNAs for maternal - to - embryonic communication during the first days of early development [Mondou, 2012]. MVs, together with soluble factors, are components of conditioned media (CM) produced by cells during their culture. Aim of this study was to understand the role of CM, MVs and supernatant (SN, obtained from CM deprived of MVs) secreted by bovine endometrial and amnion cells on embryo development. In vitro produced embryos were cultured in SOFaa alone (CTR) or su pplemented on day 5 post-fertilization with 10% of endometrial or amniotic CM or SN or 100x106 MVs/ml. The blastocyst rate obtained culturing embryos with amniotic CM and MVs was not significantly different from the CTR (34.17\ub13.29%, 32.82\ub13.26% and 35.45\ub1 2.53% respectively). The rate obtained by amniotic SN was 25.80\ub12.83% and statistically lower (P<0.05) than the other groups. The rate obtained by endometrial products were lower than CTR and the other conditions. The ICM of embryos cultured in medium supplemented with amniotic components had a higher number of cells than the CTR group: 30.4\ub11.83 and 29.42\ub11.27 for CM and MVs respectively compared to 27.6\ub11.44 for CTR (P<0.05). Our data showed that exposing the embryos to the amniotic secretome does not imp rove the blastocyst rate, but increases their quality. The hypothesis is that miRNAs contained into MVs may contribute to the production of better quality embryos and that amniotic secretome supplies a more physiological environment for the embryo development

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