Müller glia activation in response to inherited retinal degeneration is highly varied and disease-specific

Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Müller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (Crb1rd8/rd8, Prph2+/Δ307, Rho-/-, Pde6brd1/rd1). These features underwent very different changes, depending upon the disease-causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in Crb1rd8/rd8 and Prph2+/Δ307, but decreased in the Prph2+/Δ307 and Pde6brd1/rd1 models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in Rho-/- mice, the adherens junctions maintained the typical rod-Müller glia interactions, while in the Pde6brd1/rd1 model they formed predominantly between Müller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent

Random local strain effects in homovalent-substituted relaxor ferroelectrics: a first-principles study of BaTi0.74Zr0.26O3

We present first-principles supercell calculations on BaTi0.74Zr0.26O3, a prototype material for relaxors with a homovalent substitution. From a statistical analysis of relaxed structures, we give evidence for four types of Ti-atom polar displacements: along the , , or directions of the cubic unit cell, or almost cancelled. The type of a Ti displacement is entirely determined by the Ti/Zr distribution in the adjacent unit cells. The underlying mechanism involves local strain effects that ensue from the difference in size between the Ti4+ and Zr4+ cations. These results shed light on the structural mechanisms that lead to disordered Ti displacements in BaTi(1-x)Zr(x)O3 relaxors, and probably in other BaTiO3-based relaxors with homovalent substitution.Comment: 5 pages, 4 figure

Experimental study of the competition between Kondo and RKKY interactions for Mn spins in a model alloy system

The quasicrystal Al-Pd-Mn is a model system for an experimental study of the competition between Ruderman-Kittel-Kasuya-Yoshida (RKKY) and Kondo interactions. First, specific of such alloys, only a few Mn atoms carry an effective spin and their concentration x is tunable over several orders of magnitude, even though the Mn amount is almost constant. Second, the characteristic energy scales for the interactions lie in the Kelvin range. Hence we could study the magnetization on both side of these energy scales, covering a range of temperatures [0.1-100 K] and magnetic fields (mu_B H/k_B= 0 to 5 K) for 22 samples and x varying over 2 decades. Using very general Kondo physics arguments, and thus carrying out the data analysis with no preconceived model, we found a very robust and simple result: The magnetization is a sum of a pure Kondo (T_K=3.35K) and a pure RKKY contributions, whatever the moment concentration is and this surprisingly up to the concentration where the RKKY couplings dominate fully and thus cannot be considered as a perturbation.Comment: 18 pages, 18 figure

Gliosis Can Impede Integration Following Photoreceptor Transplantation into the Diseased Retina

Retinal degenerations leading to the loss of photoreceptor (PR) cells are a major cause of vision impairment and untreatable blindness. There are few clinical treatments and none can reverse the loss of vision. With the rapid advances in stem cell biology and techniques in cell transplantation, PR replacement by transplantation represents a broad treatment strategy applicable to many types of degeneration. The number of donor cells that integrate into the recipient retina determines transplantation success, yet the degenerating retinae presents a number of barriers that can impede effective integration. Here, we briefly review recent advances in the field of PR transplantation. We then describe how different aspects of gliosis may impact on cell integration efficiency

The Impact of Inherited Retinal Diseases in the Republic of Ireland (ROI) and the United Kingdom (UK) from a Cost-of-Illness Perspective

To date, there has been a global lack of data regarding the prevalence of conditions falling under the Inherited Retinal Diseases (IRD) classification, the impact on the individuals and families affected, and the cost burden to economies. The absence of an international patient registry, and equitable access to genetic testing, compounds this matter. The resulting incomplete knowledge of the impact of IRDs hinders the development and commissioning of clinical services, provision of treatments, and planning and implementation of clinical trials. Thus, there is a need for stronger evidence to support value for money to regulatory bodies for treatments approved, and progressing through clinical trials. To ensure a strategic approach to future research and service provision, it is necessary to learn more about the IRD landscape. This review highlights two recent cost-of-illness reports on the socio-economic impact of 10 IRDs in the Republic of Ireland (ROI) and the United Kingdom (UK), which demonstrate the comprehensive impact of IRDs on individuals affected, their families, friends and society. Total costs attributable to IRDs in the ROI were estimated to be £42.6 million in 2019, comprising economic (£28.8 million) and wellbeing costs (£13.8 million). Wellbeing costs were estimated using the World Health Organization (WHO) burden of disease methodology, a non-financial approach, where pain, suffering and premature mortality are measured in terms of disability-adjusted-life-years (DALYs). In the UK, wellbeing costs attributable to IRDs were £196.1 million, and economic costs were £327.2 million amounting to £523.3 million total costs in 2019. Accounting for over one-third of total costs, the wellbeing burden of persons affected by IRDs should be emphasized and factored into reimbursement processes for therapies and care pathways. This targeted review presents the most current and relevant data on IRD prevalence in the ROI and the UK, and the impacts (financial and non-financial) of IRDs in terms of diagnosis, wellbeing, employment, formal and informal care, health system costs, deadweight losses and issues surrounding payers and reimbursement. This review demonstrates IRD patients and their families have common issues including, the need for timely equitable access to genetic testing and counselling, equality in accessing employment, and a revision of the assessment process for reimbursement of therapies currently focused on the cost-of-illness to the healthcare system. This review reveals that IRD patients do not frequently engage the healthcare system and as such suggests a cost-of-illness model from a societal perspective may be a better format

Load forecasting in electrical distribution: grid of medium voltage

Trabalho apresentado no 7th Advanced Doctoral Conference on Computing, Electrical and Industrial Systems (DoCEIS’16), 11-13 abril de 2016, Caparica, PortugalThe importance of forecasting has become more evident with the appearance of the open electricity market and the restructuring of the national energy sector. This paper presents a new approach to load forecasting in the medium voltage distribution network in Portugal. The forecast horizon is short term, from 24 hours up to a week. The forecast method is based on the combined use of a regression model and artificial neural networks (ANN). The study was done with the time series of telemetry data of the DSO (EDP Distribution) and climatic records from IPMA (Portuguese Institute of Sea and Atmosphere), applied for the urban area of Évora - one of the first Smart Cities in Portugal. The performance of the proposed methodology is illustrated by graphical results and evaluated with statistical indicators. The error (MAPE) was lower than 5%, meaning that chosen methodology clearly validate the feasibility of the test

EXAFS study of lead-free relaxor ferroelectric BaTi(1-x)Zr(x)O3 at the Zr K-edge

Extended X-ray absorption fine structure (EXAFS) experiments at the Zr K-edge were carried out on perovskite relaxor ferroelectrics BaTi(1-x)Zr(x)O3 (BTZ) (x = 0.25, 0.30, 0.35), and on BaZrO3 for comparison. Structural information up to 4.5 A around the Zr atoms is obtained, revealing that the local structure differs notably from the average Pm-3m cubic structure deduced from X-ray diffraction. In particular, our results show that the distance between Zr atoms and their first oxygen neighbors is independent of the Zr substitution rate x and equal to that measured in BaZrO3, while the X-ray cubic cell parameter increases linearly with x. Furthermore, we show that the Zr atoms tend to segregate in Zr-rich regions. We propose that the relaxor behavior in BTZ is linked to random elastic fields generated by this particular chemical arrangement, rather than to random electric fields as is the case in most relaxors.Comment: 13 pages, 12 figures, 4 tables. Submitted to Phys. Rev.

GA-ANN Short-Term Electricity Load Forecasting

This paper presents a methodology for short-term load forecasting based on genetic algorithm feature selection and artificial neural network modeling. A feed forward artificial neural network is used to model the 24-h ahead load based on past consumption, weather and stock index data. A genetic algorithm is used in order to find the best subset of variables for modeling. Three data sets of different geographical locations, encompassing areas of different dimensions with distinct load profiles are used in order to evaluate the methodology. The developed approach was found to generate models achieving a minimum mean average percentage error under 2 %. The feature selection algorithm was able to significantly reduce the number of used features and increase the accuracy of the models

RNAi-mediated suppression of vimentin or glial fibrillary acidic protein prevents the establishment of Müller glial cell hypertrophy in progressive retinal degeneration.

Gliosis is a complex process comprising upregulation of intermediate filament (IF) proteins, particularly glial fibrillary acidic protein (GFAP) and vimentin, changes in glial cell morphology (hypertrophy) and increased deposition of inhibitory extracellular matrix molecules. Gliosis is common to numerous pathologies and can have deleterious effects on tissue function and regeneration. The role of IFs in gliosis is controversial, but a key hypothesized function is the stabilization of glial cell hypertrophy. Here, we developed RNAi approaches to examine the role of GFAP and vimentin in vivo in a murine model of inherited retinal degeneration, the Rhodopsin knockout (Rho-/- ) mouse. Specifically, we sought to examine the role of these IFs in the establishment of Müller glial hypertrophy during progressive degeneration, as opposed to (more commonly assessed) acute injury. Prevention of Gfap upregulation had a significant effect on the morphology of reactive Müller glia cells in vivo and, more strikingly, the reduction of Vimentin expression almost completely prevented these cells from undergoing degeneration-associated hypertrophy. Moreover, and in contrast to studies in knockout mice, simultaneous suppression of both GFAP and vimentin expression led to severe changes in the cytoarchitecture of the retina, in both diseased and wild-type eyes. These data demonstrate a crucial role for Vimentin, as well as GFAP, in the establishment of glial hypertrophy and support the further exploration of RNAi-mediated knockdown of vimentin as a potential therapeutic approach for modulating scar formation in the degenerating retina

The role of C and N dopants incorporation in phase change materials

Phase change memory (PCM) technology is considered to be among the most promising alternatives to conventional technologies in embedded memories [1]. To allow operation at relatively high temperatures in embedded applications, it is crucial to improve the stability of the amorphous phase. Carbon and nitrogen doping have been shown to significantly increase the crystallization temperature [1-3]. Moreover, the high RESET current requirement [2], which is a limit to the scalability of GeTe and GST, can be reduced by the incorporation of a dopant element [4]. In this presentation we focus on correlating experimental results and ab initio simulations to understand the effect of C and N incorporation in GeTe and GST PCM devices. Understanding the effect of dopants on the change of electronic properties and the mechanisms of the phase transformation requires analysis of the local order and structure of the amorphous to crystalline phases. In this context, we demonstrate that carbon and nitrogen deeply affects the structure and the dynamical properties of the amorphous phase of GeTe. In particular, the inclusion of N and C dopant elements in GeTe has a drastic effect on the vibrational modes of GeTe therefore improving the stability of the glass. This effect goes with an increased mechanical rigidity explaining why these doped GeTe compounds have a higher crystallization temperature than the undoped ones. Finally we will explore, mainly by FTIR and XRD measurements, the effect of C and N dopants during the annealing of amorphous PCMaterials towards their crystalline phases. These results will be discussed in order to understand the origin of the differences of the doped PCMaterials amorphous phase stability (data retention) observed between full sheet materials and the materials integrated in PCM devices. [1] A. Fantini et al., 2010 IEEE International Electron Devices Meeting (IEDM), 2010, pp. 29.21.21-29.21.24. [2] G. Betti Beneventi et al., Solid-State Electronics, 65-66 (2011) 197-204. [3] V. Sousa et al., EPCOS 2011. [4] Q. Hubert et al., IMW 2012.A.R.C. Themoter