Royshaw2396

Protein citrullination was enhanced in the lung of CIA mice compared to naive mice, and citrullinated fibrinogen was primarily targeted by these autoantibodies. The elevation of autoantibodies against citrullinated proteins and their deposition in the lung with patchy subpleural preponderance suggest that CIA can serve as a model to study the pathogenesis of RA-ILD. © The Japanese Society for Immunology. 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.MOTIVATION Since December 2019, the newly identified coronavirus SARS-CoV-2 has caused a massive health crisis worldwide and resulted in over 70,000 COVID-19 infections so far. Clinical drugs targeting SARS-CoV-2 are urgently needed to decrease the high fatality rate of confirmed COVID-19 patients. Traditional de novo drug discovery needs more than 10 years, so drug repurposing seems the best option currently to find potential drugs for treating COVID-19. RESULTS Compared with traditional non-covalent drugs, covalent drugs have attracted escalating attention recent years due to their advantages in potential specificity upon careful design, efficiency, and patient burden. We recently developed a computational protocol named as SCAR for discovering covalent drugs. In this work, we used the SCAR protocol to identify possible covalent drugs (approved or clinically tested) targeting the main protease (3CLpro) of SARS-CoV-2. We identified 11 potential hits, among which at least 6 hits were exclusively enriched by the SCAR protocol. Cloperastine fendizoate in vivo Since the preclinical or clinical information of these identified drugs is already available, they might be ready for being clinically tested in the treatment of COVID-19. © The Author(s) (2020). Published by Oxford University Press. All rights reserved. For Permissions, please email journals.permissions@oup.com.The CA3 and CA1 principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and CA1 is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via CA1 network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and CA1 fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left CA1 and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by CA1 connectivity with prefrontal cortex. We additionally found that spatial learning and memory were associated with functional connectivity changes lateralized to the left CA3 and CA1 divisions. These results provide novel evidence that network-level dysfunction involving interactions of CA3 with CA1 is an early marker of poor cognitive outcome in aging. Published by Oxford University Press 2020.AIMS Clinical studies have demonstrated the efficacy of intensive statin therapy in lowering low-density lipoprotein cholesterol and cardiovascular (CV) events. Our objective was to examine statin titration patterns and the association between titration patterns and subsequent CV events in very high-risk patients. METHODS AND RESULTS Using Swedish national population-based registry data, we identified 192,435 patients with very high risk of atherosclerotic cardiovascular disease initiated on moderate-intensity statin therapy between 2006 and 2013. Outcomes of interest were titration to high-intensity therapy and the major adverse cardiovascular events (MACE) composite (myocardial infarction, ischemic stroke, CV death) outcome. Cumulative incidence of MACE was assessed by titration status one-year post treatment initiation in patients adherent to treatment during the first year, using a 12-week cut-off from initiation to define early, delayed and no up-titration to high-intensity statins. Cox regression analysis was used to estimate adjusted hazard ratios (HRs). In 144,498 eligible patients, early titration was associated with significantly lower risk of MACE in the subsequent two years compared to no up-titration (HR 0.76, p  less then  0.01). Delayed up-titration was associated with a smaller reduction (HR 0.88, p = 0.08). The majority of patients did not up-titrate. CONCLUSION Early up-titration to high-intensity statins was independently associated with lower risk of subsequent CV events compared to no up-titration. Delayed up-titration was not associated with the same benefit. Despite the higher risk associated with no up-titration, few patients at very high CV risk who started treatment on moderate-intensity up-titrated to high-intensity, indicating a potential need for more aggressive lipid management of these patients in clinical practice. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email journals.permissions@oup.com.The ability to act on knowledge about the value of stimuli or actions factors into simple foraging behaviors as well as complex forms of decision-making. In striatal regions, action representations are thought to acquire value through a gradual (reinforcement-learning based) process. It is unclear whether this is also true for anterior cingulate cortex (ACC) where neuronal representations tend to change abruptly. We recorded from ensembles of ACC neurons as rats deduced which of 3 levers was rewarded each day. The rat's lever preferences changed gradually throughout the sessions as they eventually came to focus on the rewarded lever. Most individual neurons changed their responses to both rewarded and nonrewarded lever presses abruptly ( less then 2 trials). These transitions occurred asynchronously across the population but peaked near the point where the rats began to focus on the rewarded lever. Because the individual transitions were asynchronous, the overall change at the population level appeared gradual.