Emerging role of endosomal toll-like receptors in rheumatoid arthritis

Toll-like receptors (TLRs) and their downstream signaling pathways have been comprehensively characterized in innate immunity. In addition to this function, these receptors have also been suggested to be involved in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Murine in vivo models and human in vitro tissue models of RA have provided a wealth of information on the potential activity of TLRs and components of the downstream signaling pathways. Whilst most early work investigated the cell surface TLRs, more recently the focus has moved to the endosomal TLRs 3, 7, 8, and 9. These receptors recognize self and foreign double-stranded RNA and single-stranded RNA and DNA. The development of therapeutics to inhibit the endosomal TLRs or components of their signaling cascades may represent a way to target inflammation upstream of cytokine production. This may allow for greater specificity than existing therapies including cytokine blockade. Here, we review the current information suggesting a role for the endosomal TLRs in RA pathogenesis and the efforts to target these receptors therapeutically

Simulation of Arbitrary Level Contrast Dose in MRI Using an Iterative Global Transformer Model

Deep learning (DL) based contrast dose reduction and elimination in MRI imaging is gaining traction, given the detrimental effects of Gadolinium-based Contrast Agents (GBCAs). These DL algorithms are however limited by the availability of high quality low dose datasets. Additionally, different types of GBCAs and pathologies require different dose levels for the DL algorithms to work reliably. In this work, we formulate a novel transformer (Gformer) based iterative modelling approach for the synthesis of images with arbitrary contrast enhancement that corresponds to different dose levels. The proposed Gformer incorporates a sub-sampling based attention mechanism and a rotational shift module that captures the various contrast related features. Quantitative evaluation indicates that the proposed model performs better than other state-of-the-art methods. We further perform quantitative evaluation on downstream tasks such as dose reduction and tumor segmentation to demonstrate the clinical utility.Comment: Accepted in MICCAI 202

Convective Vortices on Mars: A Reanalysis of Viking Lander 2 Meteorological Data, Sols 1-50

On 7th August 1976 the Viking 2 lander touched down at Utopia Planitia, Mars. We have reanalysed Viking lander 2 meteorological data, and it is the object of this research to give not only annual but diurnal statistics of convective vortex formation for the Viking 2 landing site

Implementing FATF standards in developing countries and financial inclusion : findings and guidelines

This report, emanating from a project commissioned by the FIRST Initiative, considers the impact of the implementation of Anti-Money Laundering (AML) and Combating the Financing of Terrorism (CFT) controls on financial inclusion in five countries (Indonesia, Kenya, Mexico, Pakistan and South Africa). Based on these findings, it develops a set of guidelines to assist the authorities in developing countries to design effective AML/CFT regimes that are compliant with Financial Action Task Force (FATF) standards and supports financial inclusion. The report and guidelines will be of benefit to countries striving towards the dual goals of protecting their institutions against money laundering and the financing of terrorism as well as extending financial inclusion, irrespective of whether protective measures are being considered in the process of implementing or amending AML/CFT controls to meet the Forty Nine Recommendations of the FATF or in order to meet other, related international requirements, such as those set out in the 2000 United Nations Convention on Transnational Organised Crime or the 2003 United Nations Convention Against Corruption.The project was supervised and guided by a steering committee consisting of representatives from the FIRST Management Unit, World Bank, International Monetary Fund (IMF), the UK&rsquo;s Department for International Development (DFID), the Consultative Group to Assist the Poor (CGAP), the South African National Treasury, the FinMark Trust and Professor Nikos Passas, an acknowledged world expert on AML/CFT standards and implementation.<br /

TLR1/2 and 5 induce elevated cytokine levels from rheumatoid arthritis monocytes independent of ACPA or RF autoantibody status

Objective RA is an autoimmune inflammatory joint disease. Both RF and ACPA are associated with more progressive disease and higher levels of systemic inflammation. Monocyte activation of toll-like receptors (TLRs) by endogenous ligands is a potential source of increased production of systemic cytokines. RA monocytes have elevated TLRs, some of which are associated with the disease activity score using 28 joints (DAS28). The aim of this study was to measure TLR-induced cytokine production from monocytes, stratified by autoantibody status, to assess if their capacity to induce cytokines is related to autoantibody status or DAS28. Methods Peripheral blood monocytes isolated from RA patients and healthy controls were stimulated with TLR1/2, TLR2/6, TLR4, TLR5, TLR7, TLR8 and TLR9 ligands for 18 h before measuring IL-6, TNFα and IL-10. Serum was used to confirm the autoantibody status. Cytokine levels were compared with RF, ACPA and DAS28. Results RA monocytes demonstrated significantly increased IL-6 and TNFα upon TLR1/2 stimulation and IL-6 and IL-10 upon TLR5 activation. TLR7 and TLR9 activation did not induce cytokines and no significant differences were observed between RA and healthy control monocytes upon TLR2/6, TLR4 or TLR8 activation. When stratified by ACPA or RF status there were no correlations between autoantibody status and elevated cytokine levels. However, TLR1/2-induced IL-6 did correlate with DAS28. Conclusions Elevated TLR-induced cytokines in RA monocytes were not related to ACPA or RF status. However, TLR1/2-induced IL-6 was associated with disease activity

Pilot In-Trail Procedure Validation Simulation Study

A Human-In-The-Loop experiment was conducted at the National Aeronautics and Space Administration (NASA) Langley Research Center (LaRC) to investigate the viability of the In-Trail Procedure (ITP) concept from a flight crew perspective, by placing participating airline pilots in a simulated oceanic flight environment. The test subject pilots used new onboard avionics equipment that provided improved information about nearby traffic and enabled them, when specific criteria were met, to request an ITP flight level change referencing one or two nearby aircraft that might otherwise block the flight level change. The subject pilots subjective assessments of ITP validity and acceptability were measured via questionnaires and discussions, and their objective performance in appropriately selecting, requesting, and performing ITP flight level changes was evaluated for each simulated flight scenario. Objective performance and subjective workload assessment data from the experiment s test conditions were analyzed for statistical and operational significance and are reported in the paper. Based on these results, suggestions are made to further improve the ITP