Potent and Selective Covalent Inhibition of the Papain-like Protease from SARS-CoV-2

Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibited PLpro with k inact /K I = 10,000 M - 1 s - 1 , achieved sub-microM EC 50 values against three SARS-CoV-2 variants in mammalian cell lines, and did not inhibit a panel of human deubiquitinases at > 30 microM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validated our design strategy and established the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.

Comparison of the levels of depression and anxiety during the first and fourth waves of coronavirus disease-2019 pandemic in Brazil.

OBJECTIVE: To compare the levels of depression, anxiety, physical activity, and mobility restrictions between the first wave in June 2020 and the fourth wave in January 2022 of the coronavirus disease-2019 (COVID-19) pandemic in Brazil. PATIENTS AND METHODS: Brazilian citizens answered a self-administered questionnaire that included questions related to personal information, mobility restriction levels, physical activity levels, and the status of mood disorders in June 2020 (n=1853) and January 2022 (n=728). RESULTS: The levels of mobility restrictions (p<0.001), anxiety (p<0.001), and depression (p<0.001) significantly decreased from 2020 to 2022. In June 2020, 23.2% of the participants presented moderate to severe anxiety, and in January 2022, this percentage decreased to 14.8%. In June 2020, 29.6% of the participants presented moderate to severe depressive symptoms, and in January 2022 this percentage decreased to 19.3%. On the contrary, physical activity levels significantly increased between 2020 and 2022 (p<0.001). CONCLUSIONS: During the fourth wave of the COVID-19 pandemic, participants were less restricted and more physically active than in the first wave. Furthermore, anxiety and depression levels were significantly lower in the fourth wave than in the first wave. Despite this reduction, levels of anxiety and depression remain high; therefore, the authors suggest measures to encourage physical activity and promote mental health.

CMR findings after COVID-19 and after COVID-19-vaccination-same but different?

Cardiac involvement has been described in varying proportions of patients recovered from COVID-19 and proposed as a potential cause of prolonged symptoms, often described as post-COVID or long COVID syndrome. Recently, cardiac complications have been reported from COVID-19 vaccines as well. We aimed to compare CMR-findings in patients with clinical cardiac symptoms after COVID-19 and after vaccination. From May 2020 to May 2021, we included 104 patients with suspected cardiac involvement after COVID-19 who received a clinically indicated cardiac magnetic resonance (CMR) examination at a high-volume center. The mean time from first positive PCR to CMR was 112 +/- 76 days. During their COVID-19 disease, 21% of patients required hospitalization, 17% supplemental oxygen and 7% mechanical ventilation. In 34 (32.7%) of patients, CMR provided a clinically relevant diagnosis: Isolated pericarditis in 10 (9.6%), %), acute myocarditis (both LLC) in 7 (6.7%), possible myocarditis (one LLC) in 5 (4.8%), ischemia in 4 (3.8%), recent infarction in 2 (1.9%), old infarction in 4 (3.8%), dilated cardiomyopathy in 3 (2.9%), hypertrophic cardiomyopathy in 2 (1.9%), aortic stenosis, pleural tumor and mitral valve prolapse each in 1 (1.0%). Between May 2021 and August 2021, we examined an additional 27 patients with suspected cardiac disease after COVID-19 vaccination. Of these, CMR provided at least one diagnosis in 22 (81.5%): Isolated pericarditis in 4 (14.8%), acute myocarditis in 9 (33.3%), possible myocarditis (acute or subsided) in 6 (22.2%), ischemia in 3 (37.5% out of 8 patients with stress test), isolated pericardial effusion (> 10 mm) and non-compaction-cardiomyopathy each in 1 (3.7%). The number of myocarditis diagnoses after COVID-19 was highly dependent on the stringency of the myocarditis criteria applied. When including only cases of matching edema and LGE and excluding findings in the right ventricular insertion site, the number of cases dropped from 7 to 2 while the number of cases after COVID-19 vaccination remained unchanged at 9. While myocarditis is an overall rare side effect after COVID-19 vaccination, it is currently the leading cause of myocarditis in our institution due to the large number of vaccinations applied over the last months. Contrary to myocarditis after vaccination, LGE and edema in myocarditis after COVID-19 often did not match or were confined to the RV-insertion site. Whether these cases truly represent myocarditis or a different pathological entity is to be determined in further studies.

Impact of the COVID-19 pandemic on competitive swimming performance.

OBJECTIVE: This article aims to conduct a comparison of swimming performance during short course national championships (25-m) from 2019 and 2020 (before and during the pandemic). MATERIALS AND METHODS: The data points from the championships will be compared for 5 European countries: Poland, Spain, Russia, Turkey, and Denmark. Times achieved in the finals were calculated by the analysis of variance. Post hoc pairwise comparison analysis was performed using Tukey's test. The analysis plan included the assessment of the main effects and the effect of interactions in the groups of women and men. The strength of the effect was expressed by the partial eta-squared ratio. RESULTS: Two main trends were observed in the results. The first was a greater variation in the results in the group of men than in women (12-5 differences). The second was the development and improvement of sports performance in symmetrical strokes (69% improvement in recorded times measured during the pandemic, e.g., in Poland, women on 50-m breaststroke and butterfly Δ = 0.52, p <0.001 and Δ = 0.32, p = 0.034, men on 50-m and 100-m butterfly Δ = 0.34, p = 0.003 and Δ = 1.21, p <0.001). CONCLUSIONS: The main conclusion of our analysis is that the pandemic influenced the development of sports performance in symmetrical techniques, i.e., in breaststroke and butterfly.

EDUCATION OF STUDENTS OF THE POLISH UNIVERSITIES IN THE FIRST WEEKS OF THE COVID-19 PANDEMIC CAUSED BY THE SARS-COV-2 CORONAVIRUS

The main aim of the research was to answer the research questions: how the science went - studying Polish university students in the first weeks of the COVID-19 pandemic caused by the SARS-CoV-2 coronavirus and what were the main barriers to learning for Polish students during the COVID-19 pandemic. A survey method has been applied to collect empirical material among students. In the survey, CAWI (Computer-Assisted Web Interview) Internet questionnaire, sent via e-mail to students in the form of the invitation to the survey with a link to the survey, has been used in the survey. Research shows that the vast majority of the students felt anxiety, uncertainty about taking their maturity examinations, bachelor's and master's degree examinations and having the academic year credited on time. The main inhibitor preventing the respondents from learning at home during the ongoing pandemic was a lack of silence - quietness due to the noise of the siblings as well as remote work of the parents who had to perform their remote work during the students' classes.