Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis.

The loss of photoreceptors is the defining characteristic of many retinal degenerative diseases, but the mechanisms that regulate photoreceptor cell death are not fully understood. Here we have used the 661W cone photoreceptor cell line to ask whether exposure to the terminal complement complex C5b-9 induces cell death and/or modulates the sensitivity of these cells to other cellular stressors. 661W cone photoreceptors were exposed to complete normal human serum following antibody blockade of CD59. Apoptosis induction was assessed morphologically, by flow cytometry, and on western blotting by probing for cleaved PARP and activated caspase-3. Necroptosis was assessed by flow cytometry and Sirtuin 2 inhibition using 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furyl]-N-5-quinolinylacrylamide (AGK2). The sensitivity of 661W cells to ionomycin, staurosporine, peroxide and chelerythrine was also investigated, with or without prior formation of C5b-9. 661W cells underwent apoptotic cell death following exposure to C5b-9, as judged by poly(ADP-ribose) polymerase 1 cleavage and activation of caspase-3. We also observed apoptotic cell death in response to staurosporine, but 661W cells were resistant to both ionomycin and peroxide. Interestingly, C5b-9 significantly increased 661W sensitivity to staurosporine-induced apoptosis and necroptosis. These studies show that low levels of C5b-9 on 661W cells can induce apoptosis, and that C5b-9 specifically sensitizes 661W cells to certain apoptotic and necroptotic pathways. Our observations provide new insight into the potential role of the complement system in photoreceptor loss, with implications for the molecular aetiology of retinal disease

Unreliable Retrial Queues in a Random Environment

This dissertation investigates stability conditions and approximate steady-state performance measures for unreliable, single-server retrial queues operating in a randomly evolving environment. In such systems, arriving customers that find the server busy or failed join a retrial queue from which they attempt to regain access to the server at random intervals. Such models are useful for the performance evaluation of communications and computer networks which are characterized by time-varying arrival, service and failure rates. To model this time-varying behavior, we study systems whose parameters are modulated by a finite Markov process. Two distinct cases are analyzed. The first considers systems with Markov-modulated arrival, service, retrial, failure and repair rates assuming all interevent and service times are exponentially distributed. The joint process of the orbit size, environment state, and server status is shown to be a tri-layered, level-dependent quasi-birth-and-death (LDQBD) process, and we provide a necessary and sufficient condition for the positive recurrence of LDQBDs using classical techniques. Moreover, we apply efficient numerical algorithms, designed to exploit the matrix-geometric structure of the model, to compute the approximate steady-state orbit size distribution and mean congestion and delay measures. The second case assumes that customers bring generally distributed service requirements while all other processes are identical to the first case. We show that the joint process of orbit size, environment state and server status is a level-dependent, M/G/1-type stochastic process. By employing regenerative theory, and exploiting the M/G/1-type structure, we derive a necessary and sufficient condition for stability of the system. Finally, for the exponential model, we illustrate how the main results may be used to simultaneously select mean time customers spend in orbit, subject to bound and stability constraints

Software-defined networking: guidelines for experimentation and validation in large-scale real world scenarios

Part 1: IIVC WorkshopInternational audienceThis article thoroughly details large-scale real world experiments using Software-Defined Networking in the testbed setup. More precisely, it provides a description of the foundation technology behind these experiments, which in turn is focused around OpenFlow and on the OFELIA testbed. In this testbed preliminary experiments were performed in order to tune up settings and procedures, analysing the encountered problems and their respective solutions. A methodology consisting of five large-scale experiments is proposed in order to properly validate and improve the evaluation techniques used in OpenFlow scenarios

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

Molecular dynamics study of the interface between water and 2-nitrophenyl octyl ether

We present results of molecular dynamics simulations of the interface between water and 2-nitrophenyl octyl ether (NPOE). This system is analyzed in detail using a procedure to calculate intrinsic profiles of several important properties (density, radial distribution functions, hydrogen bonds, molecular orientation, self-diffusion). The interface was found to be molecularly sharp but corrugated by thermal fluctuations. Using a method based on capillary wave theory, we have estimated the interfacial tension and obtained good agreement with values calculated from the virial route. The results were compared to simulations of the water/nitrobenzene interface. The presence of an alkyl chain in NPOE introduces an added degree of hydrophobicity, which causes an increase in the interfacial tension. Furthermore, interfacial NPOE molecules are less organized than nitrobenzene and show a distinct dynamic response. These results shed light on the observed differences between these two organic liquids in electrochemical studies

Características biométricas e indicadores tecnológicos da castanha em quatro clones de cajueiro anão precoce.

Neste trabalho, as caracteristicas biometricas incluiram peso, comprimento e diametro; e os indicadores tecnologicos compreenderam relacao peso da amendoa/peso da castanha, facilidade de abertura, mdida pela percentagem de amendoas inteiras apos o corte; facilidade de remocao da pelicula, medida pela percentagem de amendoas duras e quebradas apos a despeliculagem; estado de sanidade; e um perfil de classificacao das amendoas.bitstream/CNPAT-2010/2253/1/Pa-012.pd