The presence of heterogeneous nuclear ribonucleoproteins in frontotemporal lobar degeneration with FUS positive inclusions

Frontotemporal lobar degeneration with fused in sarcoma–positive inclusions (FTLD-FUS) is a disease with unknown cause. Transportin 1 is abundantly found in FUS-positive inclusions and responsible for the nuclear import of the FET proteins of which FUS is a member. The presence of all FET proteins in pathological inclusions suggests a disturbance of transportin 1–mediated nuclear import. FUS also belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) protein family. We investigated whether hnRNP proteins are associated with FUS pathology implicating dysfunctional nuclear export in the pathogenesis of FTLD-FUS. hnRNP proteins were investigated in affected brain regions in FTLD-FUS using immunohistochemistry, biochemical analysis, and the expression analysis. We demonstrated the presence of several hnRNP proteins in pathological inclusions including neuronal cytoplasmic inclusions and dystrophic neurites. The biochemical analysis revealed a shift in the location of hnRNP A1 from the nucleus to the cytoplasm. The expression analysis revealed an increase in several hnRNP proteins in FTLD-FUS. These results implicate a wider dysregulation of movement between intracellular compartments, than mechanisms only affecting the nuclear import of FUS proteins

Driving success towards zero carbon energy targets for UK's Local Authorities

This paper draws on three case studies which show feasible and economic results in meeting net zero carbon emissions targets through Smart Local Energy Systems (SLES) in different localities across England, exploring opportunities to utilise waste heat from industry. They are based on the GreenSCIES model for which the blueprint was developed in London, Study 1. It consists of a fifth generation (5G) ambient loop district heat network using waste heat from a data centre, integrated with electric vehicle charging, storage and solar PV. The network includes decentralised heat pumps and allows for (i) heat sharing between buildings and (ii) applications for heat recovery from local sources. Study 2 is based on a heat network with waste heat from a foundry and some cooling supply and heat storage in the aquifer. Study 3 explored waste heat from a glassworks and considered mine workings for providing heat storage. These SLES projects illustrate how to integrate local waste heat sources in 3G and 4G heat networks, adapting the original GreenSCIES concept, providing pathways towards net zero carbon for a diverse range of urban locations with different waste heat sources, and further demonstrate the importance of collaboration between researchers, local government and industry

Ambient loop district heating and cooling networks with integrated mobility, power and interseasonal storage

This paper describes a heat pump investigation for GreenSCIES (GS), a fifth Generation district heating and cooling (5DHC) network in Islington, London. The paper describes the GreenSCIES concept integrating Mobility, Power and Heat into a Smart Local Energy System (SLES). At the heart of the system is an ultra-low temperature ambient loop network, which permits bi-directional flow within the pipes to allow energy exchange between heating and cooling customers at different times and in different locations, depending on where demand is at any given time. An existing data centre provides the primary source of waste heat for the scheme. Heat pumps in distributed energy centres are utilised to amplify the temperature of the ambient loop to deliver heat in connected buildings. The energy centres integrate heat pumps with building-mounted solar photovoltaic (PV) systems and electric vehicle (EV) charging points. The paper provides an overview of the integrated SLES concept, focussing on the heat pump selection and the short and long-term thermal storage options designed for the scheme. The results show that even the smaller constructible ‘New River’ scheme will save 5,000 tons of CO2e annually. This will tend to 100% as the grid decarbonise further. Therefore, the GS SLES concept applied to urban areas could deliver significant carbon emission savings in the UK and elsewhere. Practical application: Project GreenSCIES, is a detailed design study to develop a Smart, Local Energy System (SLES) for a large community in the London Borough of Islington. Our consortium have developed an innovative SLES concept, centred around a fifth generation district heating and cooling network. The GS ambient loop systems have negligible losses and much greater efficiencies than traditional district heat networks. As recognised by the UK Government’s Heat and Buildings Strategy, ambient loop systems should be considered where large-scale neighbourhood regeneration occurs. The proposed SLES concept applied to wider urban areas could deliver significant carbon emission savings in the UK

Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice

The aggregation of abnormally phosphorylated tau protein in neurons and glia is a neuropathological hallmark of several neurodegenerative disorders, collectively known as tauopathies. They are further subclassified based on the preferential pathological aggregation of three carboxyl-terminal repeat domains (3R) and/or 4R tau. Corticobasal degeneration (CBD) is a rare neurodegenerative disorder classified as a 4R tauopathy. In the present study, we extend analysis of CBD-tau cell-type specific pathology transmission with 3R and 4R tau isoform distinguishable changes. We use a humanized tau (hTau) mouse line, which overexpress all six human tau isoforms in a murine tau knockout background and perform intrastriatal inoculation of control and CBD-tau enriched human brain homogenate. We show that CBD-tau causes hyperphosphorylation of tau at Ser202 predominantly in oligodendrocytes. Next, we demonstrate the spread of tau pathology from striatum to the overlaying corpus callosum and further to the contralateral side. Finally, we demonstrate that the almost exclusive oligodendrocyte-based transmission of hyperphosphorylated tau is reflected in the endogenous 4R tau isoform expression and corresponds to subclassification of CBD as a 4R tauopathy. Additionally, we identify functional changes in oligodendrocytes reflected by myelin basic protein abnormalities upon CBD-tau inoculation. These changes are not observed in murine tau knockout mice lacking both human and murine tau. Our study presents not only in vivo tau isoform–driven region- and cell-specific tau pathology, but also underlines that tau pathology seeding and transmission might be oligodendrocyte-based. These results, which need to be extended to more cases, give new insights into why tauopathies might vary greatly in both histopathological and neuroanatomical patterns

GEM-E3 Model Documentation

The computable general equilibrium model GEM-E3 has been used in a large set of climate policy applications supporting Commission policy proposals during the last decade, as well as in other environmental and economic policy areas. It can be considered a multi-purpose macroeconomic model, designed to estimate the effects of sector-specific policies on the economy as a whole. The main purpose of this publication is to provide extensive documentation of the model's equations and its underlying databases, in order to offer to the broader audience an accurate description of the model characteristics.JRC.J.1-Economics of Climate Change, Energy and Transpor

Globular glial tauopathy type II

The globular glial tauopathies (GGTs) are a rare group of neurodegenerative diseases with fewer than 90 autopsy-confirmed cases reported in the literature. Although there has been some uncertainty about whether GGT is entirely distinct from progressive supranuclear palsy, a recent study of tau filament structures supports the definition of GGT as a separate neuropathological entity. We present a sporadic case of GGT type II presenting with a progressive corticobasal-primary lateral sclerosis overlap syndrome in a 74-year-old woman. Neuropathological examination identified neuronal and glial tau inclusions, including globular astrocytic and oligodendroglial inclusions. We also discuss the clinical features and molecular pathophysiology of GGT. Increased awareness of this condition could become more important as patients with GGT may be candidates for anti-tau therapies currently undergoing clinical evaluation in patients with other tauopathies

The Importance of Heat Pump COP in the Economics of 5th Generation District Heating and Cooling Networks

This paper describes the investigation of heat pumps for GreenSCIES, a 5th Generation heat network in Islington, London. The paper describes the GreenSCIES concept integrating Mobility, Power and Heat into a local energy system. At the heart of the system is a 5th generation heat network, which utilises an ambient heat network to capture secondary heat and share heat between different applications. The GreenSCIES network, technology utilised and buildings connected are described. Heat pumps are used to amplify the temperature of the ambient loop to deliver heat at the required temperature in connected buildings. A number of different heat pumps using different refrigerants and configurations were appraised in this study. This considered the performance, safety, environmental impact, operational and capital expenditure point of view. The study shows the importance of heat pump COP on the economics of operating the system and suggests innovative series arrangements in order to improve performance and economics

Interprocedural Reachability for Flat Integer Programs

We study programs with integer data, procedure calls and arbitrary call graphs. We show that, whenever the guards and updates are given by octagonal relations, the reachability problem along control flow paths within some language w1* ... wd* over program statements is decidable in Nexptime. To achieve this upper bound, we combine a program transformation into the same class of programs but without procedures, with an Np-completeness result for the reachability problem of procedure-less programs. Besides the program, the expression w1* ... wd* is also mapped onto an expression of a similar form but this time over the transformed program statements. Several arguments involving context-free grammars and their generative process enable us to give tight bounds on the size of the resulting expression. The currently existing gap between Np-hard and Nexptime can be closed to Np-complete when a certain parameter of the analysis is assumed to be constant.Comment: 38 pages, 1 figur