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2 WU(IQR1.9-2.7). Baseline 6MWD was 352 m(IQR280-416) and 77% were in NYHA 3 or 4 functional class. All patients were commenced on initial monotherapy with an endothelin receptor antagonist(n=66) or phosphodiesterase-5 inhibitor(n=16). At first re-evaluation, 6MWD increased by 46 m(IQR7-96) and 35% demonstrated improvement in NYHA functional class. After a median follow-up of 65 months (IQR32-101), 18/82(22.0%) had died, with estimated 1-yr and 5-yr survivals of 98% and 84%, respectively. Death attributed to PAH occurred in 6/18(33.3%) of these patients (7% of total cohort).Patients with precapillary PH and "borderline" PVR falling outside the current definition have adverse outcomes. Such patients appear to respond to PAH therapy however this requires further study in randomised trials. Copyright ©ERS 2020.IMPORTANCE Coronavirus Disease 19 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV-2-axis (RAAS-SCoV-axis). There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV-axis, informed by prior studies of SARS-CoV, how this rlternative approach is the modulation of the specific downstream pathophysiologic effects caused by virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV-axis on acute lung injury in COVID-19. Copyright ©ERS 2020.INTRODUCTION Allergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis, however, clinical relevance in COPD remains unclear. METHODS Patients with stable COPD (n=446) and non-diseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assess outdoor and indoor environmental allergen exposure in COPD. We identify key fungi in outdoor air and develop specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of n=11 COPD patients and linked to clinical outcome. RESULTS High frequencies of sensitisation to a broad range of allergens occurs in COPD. Fungal sensitisation associates with frequent exacerbations, and, unsupervised clustering reveals a "highly sensitised fungal predominant" sub-group demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD, and, promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function illustrating the importance of environmental exposures on clinical outcomes in COPD. CONCLUSION Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD. Copyright ©ERS 2020.BRAG2/Iqsec1 is a guanine nucleotide exchange factor (GEF) for ADP ribosylation factor 6 (Arf6), a small GTPase implicated in the membrane trafficking between the plasma membrane and endosomes. BRAG2 regulates Arf6-dependent endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) through the direct interaction during the hippocampal long-term depression (LTD). selleck chemicals llc However, the molecular mechanism by which the BRAG2-Arf6 pathway links AMPARs to the endocytic machinery remains elusive. Herein, using mouse brains of both sexes, we demonstrated that BRAG2a, an alternative isoform with a long C-terminal insert containing a proline-rich domain and type I PDZ-binding motif, was selectively localized to the excitatory postsynaptic density (PSD). Using yeast two-hybrid screening, we identified PSD-95 and endophilin 1/3 as BRAG2a-binding partners in the brain. The interaction with PSD-95 was required for synaptic targeting of BRAG2a. In cultured hippocampal neurons, stimulation of group I metrf6-dependent endocytosis of AMPARs through the direct interaction during hippocampal long-term depression, one of the synaptic plasticity related to learning and memory. However, the molecular mechanism by which the BRAG2-Arf6 pathway links AMPARs to the endocytic machinery remains elusive. Here, we identified isoform-specific mechanisms of BRAG2-mediated AMPAR internalization. We demonstrated that the interaction of BRAG2a isoform with PSD-95 and endophilin 3 was required for the mGluR-dependent decrease in surface AMPARs in hippocampal neurons. These results unveiled a novel molecular mechanism by which BRAG2 links AMPARs to the clathrin-mediated endocytic machinery at postsynaptic sites. Copyright © 2020 the authors.Beta-amyloid (Aβ) is thought to play a critical role in Alzheimer's disease (AD), and application of soluble oligomeric forms of Aβ produce AD-like impairments in cognition and synaptic plasticity in experimental systems. We found previously that transgenic over expression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, altered the sensitivity of mice to Aβ-induced impairments, suggesting that PME-1 inhibition may be an effective approach for preventing or treating these impairments. To explore this possibility, we examined the behavioral and electrophysiological effects of acutely-applied synthetic Aβ oligomers in male and female mice heterozygous for either a PME-1 knockout (KO) or an LCMT-1 gene-trap mutation. We found that heterozygous PME-1 KO mice were resistant to Aβ-induced impairments in cognition and synaptic plasticity while LCMT-1 gene-trap mice showed increased sensitivity to Aβ-induced impairments. The heterozygous PME-1 KO mice produced normal levels of endogenous Aβ and exhibited normal electrophysiological responses to picomolar concentrations of Aβ suggesting that reduced PME-1 expression in these animals protects against Aβ-induced impairments without impacting normal physiological Aβ functions.