922017 research outputs found
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Characterisation of C101248: a novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome
No full textNeuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that NLRP3 activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing of purified cell types from human post-mortem brain tissue, demonstrated a highly specific expression of the tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) in microglia compared to other glial and neuronal cell types in the human brain. NETSseq also showed a significant increase of THIK-1 in microglia isolated from cortical regions of brains with Alzheimer’s disease (AD) relative to control donors. Herein, we report the discovery and pharmacological characterisation of C101248, the first selective small-molecule inhibitor of THIK-1. C101248 showed a concentration-dependent inhibition of both mouse and human THIK-1 (IC50: ~50 nM) and was inactive against K2P family members TREK-1 and TWIK-2, and Kv2.1. Whole-cell patch-clamp recordings of microglia from mouse hippocampal slices showed that C101248 potently blocked both tonic and ATP-evoked THIK-1 K+ currents. Notably, C101248 had no effect on other constitutively active resting conductance in slices from THIK-1-depleted mice. In isolated microglia, C101248 prevented NLRP3-dependent release of IL-1β, an effect not seen in THIK-1-depleted microglia.In conclusion, we demonstrated that inhibiting THIK-1 (a microglia specific gene that is upregulated in brains from donors with AD) using a novel selective modulator attenuates the NLRP3-dependent release of IL-1β from microglia, which suggests that this channel may be a potential therapeutic target for the modulation of neuroinflammation in AD
Looking into the IL-1 of the storm: Are inflammasomes the link between immunothrombosis and hyperinflammation in cytokine storm syndromes?
No full textInflammasomes and the interleukin (IL)-1 family of cytokines are key mediators of both inflammation and immunothrombosis. Inflammasomes are responsible for the release of the pro-inflammatory cytokines IL-1β and IL-18, as well as releasing tissue factor (TF), a pivotal initiator of the extrinsic coagulation cascade. Uncontrolled production of inflammatory cytokines results in what is known as a “cytokine storm” leading to hyperinflammatory disease. Cytokine storms can complicate a variety of diseases and results in hypercytokinemia, coagulopathies, tissue damage, multi-organ failure and death. Patients presenting with cytokine storm syndromes have a high mortality rate, driven in part by disseminated intravascular coagulation (DIC). Whilst our knowledge on the factors propagating cytokine storms is increasing, how cytokine storm influences DIC remains unknown, and therefore treatments for diseases, where these aspects are a key feature are limited, with most targeting specific cytokines. Currently, no therapies target the immunothrombosis aspect of hyperinflammatory syndromes. Here we discuss how targeting the inflammasome and pyroptosis may be a novel therapeutic strategy for the treatment of hyperinflammation and its associated pathologies
Potentials and Limits of Using Preconfigured Spatial Beams as Bandwidth Resources: Beam Selection vs Beam Aggregation
No full textThis letter studies how to use spatial beams preconfigured in a legacy spatial division multiple access (SDMA) network as bandwidth resources via the implementation of nonorthogonal multiple access (NOMA). Two different beam management schemes, namely beam selection and beam aggregation, are developed to improve the overall system throughput without consuming extra spectrum or changing the performance of the legacy network. Analytical and simulation results are presented to show that the two schemes realize different tradeoffs between system performance and complexity
Writing and Reading Together from Colonial Legacy to World-making:The case of Algerian bilingual authors
No full textKateb Yacine told Geneviève Serreau in 1956 that one does not use a universal language to humiliate a people in its very soul without consequences: sooner or later, the people seize that language and culture for themselves on their way towards freedom. Following this prophecy, Algerian intellectuals have in effect appropriated the French language, which they deploy with a high level of proficiency to address the colonizer in its own language. However, with decolonization, the French language was probed as a legacy of colonialism and an obstacle to Algerian self-realization and cultural authenticity. Algerian governments implemented a top-down Arabization policy, excluding national differences and subscribing wholly to the group of Arab nations. This process alienated those who did not read or speak Arabic in a country that is essentially comprised of a multiplicity of languages, cultures, and identities. This article delves into this bitter polemic as a painstaking search for national identity. It traces the position of the French language in the Algerian intellectual and literary landscape, from an initial gesture of rejection to a later move toward appropriation and nativization
Characterisation of Ferritic to Austenitic Steel Functional Grading via Powder Hot Isostatic Pressing
No full textThe application of functionally graded components produced via the powder hot isostatic pressing (HIP) process is considered for the next generation nuclear reactors as an alternative to dissimilar metal welding. This work is focused on functional grading of an SA508 Grade 3 ferritic low-alloy steel and 316L austenitic stainless steel, typically present in the pressure vessel and the piping or the pressure vessel cladding, respectively. Material was supplied in powder form, mixed and consolidated via the HIP process. Five different powder fractions were studied and, in some cases, significant change in the ferrite over austenite ratio is found to take place, due to dilution of austenite stabilizing elements. In contrast, the enrichment of alloying elements within the ferritic phase promotes the formation of laths, greatly affecting the material properties. The strengthening effect of the ferritic lath zone is assessed and the mechanism for its formation in the ferritic-austenitic system studied (throughout this work the term ferritic laths refers to a ferritic phase of unknown structure which is likely to consist of martensite, bainite or a mixture of both).KeywordsHot isostatic pressing, Functional grading, SA508, 316
Scaling CO2 Convection in Confined Aquifers: Effects of Dispersion, Permeability Anisotropy and Geochemistry
No full textStein factors for variance-gamma approximation in the Wasserstein and Kolmogorov distances
No full textWe obtain new bounds for the solution of the variance-gamma (VG) Stein equation that are of the correct form for approximations in terms of the Wasserstein and Kolmorogorov metrics. These bounds hold for all parameters values of the four parameter VG class. As an application we obtain explicit Wasserstein and Kolmogorov distance error bounds in a six moment theorem for VG approximation of double Wiener-It^o integrals
ADBSat: Methodology of a novel panel method tool for aerodynamic analysis of satellites
No full textADBSat is a novel software that determines the aerodynamic properties of any body in free-molecular flow. Its main advantage is the fast approximation of the aerodynamics of spacecraft in the lower end of the low-Earth orbit altitude range. It is a novel implementation of a panel method, where the body is represented as a set of fundamental elements and the sum of their individual aerodynamic properties makes up the properties of the whole. ADBSat’s approach treats the shape as a set of flat triangular plates. These are read from a CAD geometry file in the Wavefront format, which can be created with most common CAD programs. A choice of gas-surface interaction models is available to represent the physics of free-molecular flow under different conditions. Its modular design means that other models can be easily and quickly implemented. It also benefits from a new shading algorithm for fast determination of elemental flow exposure. An example case is presented to show the capability and functionality of the program
Determination of substrate addition order strategy for bespok Polyhydroxyalkanoates production: a Molecular Modeling based approach
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Ageing in Place over time::The making and unmaking of home
No full text‘Ageing in place’ is a key component of UK policy, aimed at supporting older people to remain living in their own homes and communities for as long as possible. Although wide-ranging, the scholarly literature in this field has not sufficiently examined the interconnections between ageing in place and the changing experience of ‘home’ over time. This paper addresses this gap in a novel way by bringing together qualitative secondary analysis of longitudinal data with critical literature on ‘home’ and Mason’s (2018) cutting-edge theories of ‘affinities’ to understand the multi-dimensionality of home in relation to ageing in place. The paper makes significant methodological, empirical, and theoretical contributions to the field of scholarship on home, by demonstrating how homes are made and unmade over time. Discussions of home emerged organically in the longitudinal data that focused on people’s travel and transport use, allowing our qualitative secondary analysis approach to look anew at how experiences of home are dynamically shaped by people’s potent connections inside and outside the dwelling. Presenting an empirical analysis of four case studies, the paper suggests that future discussions in the field of ageing in place should pay closer attention to the factors which shape experiences of the un/making of home over time, such as how deteriorating physical and mental health can shape how people experience their dwelling and neighbourhood as well as their relationships across these settings.<br/