Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2.

The emergence of SARS-CoV-2 variants represents a major threat to public health and requires identification of novel therapeutic agents to address the unmet medical needs. Small molecules impeding viral entry through inhibition of spike protein priming proteases could have potent antiviral effects against SARS-CoV-2 infection. Omicsynin B4, a pseudo-tetrapeptides identified from Streptomyces sp. 1647, has potent antiviral activity against influenza A viruses in our previous study. Here, we found omicsynin B4 exhibited broad-spectrum anti-coronavirus activity against HCoV-229E, HCoV-OC43 and SARS-CoV-2 prototype and its variants in multiple cell lines. Further investigations revealed omicsynin B4 blocked the viral entry and might be related to the inhibition of host proteases. SARS-CoV-2 spike protein mediated pseudovirus assay supported the inhibitory activity on viral entry of omicsynin B4 with a more potent inhibition of Omicron variant, especially when overexpression of human TMPRSS2. Moreover, omicsynin B4 exhibited superior inhibitory activity in the sub-nanomolar range against CTSL, and a sub-micromolar inhibition against TMPRSS2 in biochemical assays. The molecular docking analysis confirmed that omicsynin B4 fits well in the substrate binding sites and forms a covalent bond to Cys25 and Ser441 in CTSL and TMPRSS2, respectively. In conclusion, we found that omicsynin B4 may serve as a natural protease inhibitor for CTSL and TMPRSS2, blocking various coronavirus S protein-driven entry into cells. These results further highlight the potential of omicsynin B4 as an attractive candidate for broad-spectrum antiviral therapy that could rapidly respond to emerging variants of SARS-CoV-2.

Factors influencing parents' willingness to vaccinate their preschool children against COVID-19: Results from the mixed-method study in China.

During the COVID-19 pandemic, little is known about parental hesitancy to receive the COVID-19 vaccine for preschool children who are the potential vaccinated population in the future. The purpose of this mixed-method study was to explore the factors influencing Chinese parents' decision to vaccinate their children aged 3-6 years old against COVID-19. In July 2021, we conducted semi-structured interviews (n = 19) and a cross-sectional survey (n = 2605) with parents of kindergarten children in an urban-rural combination pilot area in China. According to the qualitative study, most parents were hesitant to vaccinate their children with the COVID-19 vaccine. In the quantitative study, we found that three-fifths of 2605 participants were unwilling to vaccinate their children against COVID-19. Furthermore, the main predictors of parents' intention to vaccinate their children were fathers, lower level of education, and positive attitudes toward vaccination. Based on our findings, targeted health education techniques may be able to boost childhood COVID-19 immunization rates.

Optimization and Operations Research in Mitigation of a Pandemic

The pandemic of COVID-19 initiated in 2019 and spread all over the world in 2020 has caused significant damages to the human society, making troubles to all aspects of our daily life. Facing the serious outbreak of the virus, we consider possible solutions from the perspectives of both governments and enterprises. Particularly, this paper discusses several applications of supply chain management, public resource allocation, and pandemic prevention using optimization and machine learning methods. Some useful insights in mitigating the pandemic and economy reopening are provided at the end of this paper. These insights might help governments to reduce the severity of the current pandemic and prevent the next round of outbreak. They may also improve companies’ reactions to the increasing uncertainties appearing in the business operations. Although the coronavirus imposes challenges to the entire society at the moment, we are confident to develop new techniques to prevent and eradicate the disease.

Multi-Omics-Guided Discovery of Omicsynins Produced by Streptomyces sp. 1647: Pseudo-Tetrapeptides Active Against Influenza A Viruses and Coronavirus HCoV-229E.

Many microorganisms have mechanisms that protect cells against attack from viruses. The fermentation components of Streptomyces sp. 1647 exhibit potent anti-influenza A virus (IAV) activity. This strain was isolated from soil in southern China in the 1970s, but the chemical nature of its antiviral substance(s) has remained unknown until now. We used an integrated multi-omics strategy to identify the antiviral agents from this streptomycete. The antibiotics and Secondary Metabolite Analysis Shell (antiSMASH) analysis of its genome sequence revealed 38 biosynthetic gene clusters (BGCs) for secondary metabolites, and the target BGCs possibly responsible for the production of antiviral components were narrowed down to three BGCs by bioactivity-guided comparative transcriptomics analysis. Through bioinformatics analysis and genetic manipulation of the regulators and a biosynthetic gene, cluster 36 was identified as the BGC responsible for the biosynthesis of the antiviral compounds. Bioactivity-based molecular networking analysis of mass spectrometric data from different recombinant strains illustrated that the antiviral compounds were a class of structural analogues. Finally, 18 pseudo-tetrapeptides with an internal ureido linkage, omicsynins A1-A6, B1-B6, and C1-C6, were identified and/or isolated from fermentation broth. Among them, 11 compounds (omicsynins A1, A2, A6, B1-B3, B5, B6, C1, C2, and C6) are new compounds. Omicsynins B1-B4 exhibited potent antiviral activity against IAV with the 50% inhibitory concentration (IC50) of approximately 1 µmol∙L-1 and a selectivity index (SI) ranging from 100 to 300. Omicsynins B1-B4 also showed significant antiviral activity against human coronavirus HCoV-229E. By integrating multi-omics data, we discovered a number of novel antiviral pseudo-tetrapeptides produced by Streptomyces sp. 1647, indicating that the secondary metabolites of microorganisms are a valuable source of novel antivirals.

Limiting potential COVID-19 contagion in squatting public toilets.

BACKGROUND: Since the outbreak of the SARS-CoV-2 virus in December 2019, the COVID-19 pandemic continues to threaten global stability. Transmission of SARS-CoV-2 is mostly by respiratory droplets and direct contact but viral RNA fragments have also been detected in the faecal waste of patients with COVID-19. Cleanliness and effective sanitation of public toilets is a concern, as flushing the toilet is potentially an aerosol generating procedure. When the toilets are of the squatting type and without a cover, there exists a risk of viral contamination through the splashing of toilet water and aerosol generation. OBJECTIVE: This study aims to determine whether the cleanliness of public toilets was a concern to the general population during the COVID-19 pandemic, and whether a squatting toilet was preferred to a seated design. METHODS: A questionnaire was designed and posted on "WeChat" contact groups of the investigators. RESULTS: The survey showed that 91% of participants preferred squatting toilets, but that 72% were apprehensive of personal contamination when using public toilets. Over 63% of the respondents had encountered an incidence of water splash and would prefer public toilets to be covered during flushing and 83% of these respondents preferred a foot-controlled device. CONCLUSION: This survey suggests that consideration should be given to the installation of a simple foot-controlled device to cover public squatting toilets to help restrict potential COVID-19 contamination and to meet hygienic expectations of the public.

Efficacy of early prone or lateral positioning in patients with severe COVID-19: a single-center prospective cohort.

Background: Position intervention has been shown to improve oxygenation, but its role in non-invasively ventilated patients with severe COVID-19 has not been assessed. The objective of this study was to investigate the efficacy of early position intervention on non-invasively ventilated patients with severe COVID-19. Methods: This was a single-center, prospective observational study in consecutive patients with severe COVID-19 managed in a provisional ICU at Renmin Hospital of Wuhan University from 31 January to 15 February 2020. Patients with chest CT showing exudation or consolidation in bilateral peripheral and posterior parts of the lungs were included. Early position intervention (prone or lateral) was commenced for > 4 hours daily for 10 days in these patients, while others received standard care. Results: The baseline parameters were comparable between the position intervention group (n = 17) and the standard care group (n = 35). Position intervention was well-tolerated and increased cumulative adjusted mean difference of SpO2/FiO2 (409, 95% CI 86 to 733) and ROX index (26, 95% CI 9 to 43) with decreased Borg scale (-9, 95% CI -15 to -3) during the first 7 days. It also facilitated absorption of lung lesions and reduced the proportion of patients with high National Early Warning Score 2 (≥ 7) on days 7 and 14, with a trend toward faster clinical improvement. Virus shedding and length of hospital stay were comparable between the two groups. Conclusions: This study provides the first evidence for improved oxygenation and lung lesion absorption using early position intervention in non-invasively ventilated patients with severe COVID-19, and warrants further randomized trials.

Study on mechanism of matrine in treatment of COVID-19 combined with liver injury by network pharmacology and molecular docking technology.

The aim of the present study was to investigate the pharmacological mechanism of matrine in treatment of COVID-19 combined with liver injury. Potential targets related to matrine, COVID-19 and liver injury were identified from several databases. We constructed PPI network and screened the core targets according to the degree value. Then, GO and KEGG enrichment were carried out. Molecular docking technology was used to verify the affinity between matrine and the crystal structure of core target protein. Finally, real-time RT-PCR was used to detect the effects of matrine on hub gene expression in liver tissue of liver injury mice and lung tissue of lung injury mice to further confirm the results of network pharmacological analysis. The results show that six core targets including AKT1, TP53, TNF, IL6, BCL2L1 and ATM were identified. The potential therapeutic mechanism of matrine on COVID-19 combined with liver injury is closely related to regulate antiviral process, improve immune system and regulate the level of inflammatory factors. Molecular docking showed that matrine could spontaneously bind to the receptor protein and had strong binding force. Real-time RT-PCR demonstrated that matrine could significantly reduce the expression of AKT1, TP53, TNF, IL6 and ATM in mice with liver injury or lung injury (P < 0.05), and increase the expression of BCL2L1 to a certain extent (P > 0.05). Our results indicate that matrine can achieve simultaneous intervention of COVID-19 combined with liver injury by multi-dimensional pharmacological mechanism.

Differences of inflammatory and non-inflammatory indicators in Coronavirus disease-19 (COVID-19) with different severity.

Background A variety of inflammatory and non-inflammatory indicators were increased in severe and critical Coronavirus disease-19 (COVID-19) and some of them were used to evaluate the severity and predict prognosis of community-acquired pneumonia. The aim of this study was to investigate the association of these indicators in COVID-19 with different severity. Methods Clinical data of 46 patients with severe COVID-19 and 31 patients with critical COVID-19 were collected. The general characteristics and comorbidities of the patients were retrospectively analyzed. The initial and peak concentrations of serum troponin I (cTnI), D-dimer (D-D), C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), initial and peak neutrophil counts and initial and trough lymphocyte counts were compared between two groups. The correlation between the variation of cTnI, D-D, CRP, IL-6, PCT, neutrophils, lymphocytes and the severity of the disease was analyzed. The efficacy of the initial concentrations of cTnI, D-D, CRP, IL-6, PCT, the initial neutrophil and lymphocyte counts in predicting critical COVID-19 were evaluated by receiver operating characteristic (ROC) curve. Results The initial and peak concentrations of cTnI, D-D, CRP, IL-6, PCT, initial and peak neutrophil counts in critical group were higher than those in severe group, the initial and trough counts of lymphocyte were lower than those in the severe group. Except for the initial level of PCT, the other differences were statistically significant (p < 0.05). The increase of cTnI, D-D, CRP, IL-6, PCT, neutrophils and the decrease of lymphocytes were related to the severity of the disease, OR values were 28.80, 2.20, 18.47, 10.80, 52.00, 9.60 and 21.08, respectively. Except for D-D, the other differences were statistically significant. The areas under ROC curves for predicting critical COVID-19 by initial concentrations of cTnI, D-D, CRP, IL-6, PCT, initial lymphocyte and neutrophil counts were 0.76, 0.78, 0.83, 0.95, 0.56, 0.68 and 0.62, respectively. Conclusions The severe and critical COVID-19 patients had significant differences in concentrations of serum cTnI, D-D, CRP, IL-6, PCT, neutrophil and lymphocyte counts. The increase of cTnI, CRP, IL-6, PCT, neutrophils and decrease of lymphocytes indicated severe condition. The initial IL-6 might be a good indicator of COVID-19 severity.