Molecular recognition of SARS-CoV-2 spike protein with three essential partners: exploring possible immune escape mechanisms of viral mutants.

OBJECTIVE: The COVID-19 epidemic is raging around the world, with the emergence of viral mutant strains such as Delta and Omicron, posing severe challenges to people's health and quality of life. A full understanding life cycle of the virus in host cells helps to reveal inactivation mechanism of antibody and provide inspiration for the development of a new-generation vaccines. METHODS: In this work, molecular recognitions and conformational changes of SARS-CoV-2 spike protein mutants (i.e., Delta, Mu, and Omicron) and three essential partners (i.e., membrane receptor hACE2, protease TMPRSS2, and antibody C121) both were compared and analyzed using molecular simulations. RESULTS: Water basin and binding free energy calculations both show that the three mutants possess higher affinity for hACE2 than WT, exhibiting stronger virus transmission. The descending order of cleavage ability by TMPRSS2 is Mu, Delta, Omicron, and WT, which is related to the new S1/S2 cutting site induced by transposition effect. The inefficient utilization of TMPRSS2 by Omicron is consistent with its primary entry into cells via the endosomal pathway. In addition, RBD-directed antibody C121 showed obvious resistance to Omicron, which may have originated from high fluctuation of approaching angles, high flexibility of I472-F490 loop, and reduced binding ability. CONCLUSIONS: According to the overall characteristics of the three mutants, high infectivity, high immune escape, and low virulence may be the future evolutionary selection of SARS-CoV-2. In a word, this work not only proposes the possible resistance mechanism of SARS-CoV-2 mutants, but also provides theoretical guidance for the subsequent drug design against COVID-19 based on S protein structure.

Emergency hospitalization caused by non-COVID-19 respiratory diseases before and during the COVID-19 pandemic: A retrospective observational cohort study.

Background: The coronavirus disease 2019 (COVID-19) pandemic as well as the subsequent prevention and control measures is like a quasi-experiment intervention that might have changed the features of emergency hospitalizations. Mortality is high in patient hospitalization due to emergency respiratory diseases (ERD). Therefore, we compared the characteristics of these patients before and during the pandemic. Exploring this issue might contribute to decision-making of emergency management when most of the resources and attention has been devoted to combat COVID-19. Methods: This study was a retrospective observational cohort study. All emergency hospitalizations due to ERD from January 1, 2019 to December 31, 2020 in a tertiary hospital in China were included. Data including patients' age, sex, and clinical outcomes were extracted. Air quality was collected from the official online platform. Clinical characteristics were compared and odds ratios were calculated. Results: The ERD hospitalization rate was lower in 2020 than in 2019 (6.4 vs. 4.3%, χ2 = 55.449, P = 0.000) with a 50.65% reduction; however, the patients were older in 2020 than in 2019 (P = 0.000) with a higher proportion of admission to the intensive care unit (ICU) (46 vs. 33.5%, χ2 = 20.423, P = 0.000) and a longer ICU stay (P = 0.000). The overall intubation rate, hospital mortality, and rate of discharge due to ineffective treatment in 2020 were higher than those in 2019 (15.6 vs. 8%, χ2 = 18.578, P = 0.000; 4.2 vs. 1.1%, χ2 = 4.122, P = 0.000; 5.5 vs. 2.4%, χ2 = 8.93, P = 0.000, respectively). The logistic regression analysis indicated hospitalizations due to ERD were mainly associated with PM2.5 and sulfur dioxide on the day, and on the 4th and 5th days before admission (P = 0.034 and 0.020, 0.021 and 0.000, 0.028, and 0.027, respectively) in 2019. However, in 2020, the relationship between parameters of air quality and hospitalization changed. Conclusion: The COVID-19 pandemic has changed the characteristics of emergency hospitalization due to ERD with a larger proportion of severe patients and poorer prognosis. The effect of air quality on emergencies were weakened. During the COVID-19 pandemic, it is necessary to pay more attention to the non-COVID-19 emergency patients.

Emergency hospitalization caused by non-COVID-19 respiratory diseases before and during the COVID-19 pandemic: A retrospective observational cohort study

Background The coronavirus disease 2019 (COVID-19) pandemic as well as the subsequent prevention and control measures is like a quasi-experiment intervention that might have changed the features of emergency hospitalizations. Mortality is high in patient hospitalization due to emergency respiratory diseases (ERD). Therefore, we compared the characteristics of these patients before and during the pandemic. Exploring this issue might contribute to decision-making of emergency management when most of the resources and attention has been devoted to combat COVID-19. Methods This study was a retrospective observational cohort study. All emergency hospitalizations due to ERD from January 1, 2019 to December 31, 2020 in a tertiary hospital in China were included. Data including patients’ age, sex, and clinical outcomes were extracted. Air quality was collected from the official online platform. Clinical characteristics were compared and odds ratios were calculated. Results The ERD hospitalization rate was lower in 2020 than in 2019 (6.4 vs. 4.3%, χ2 = 55.449, P = 0.000) with a 50.65% reduction;however, the patients were older in 2020 than in 2019 (P = 0.000) with a higher proportion of admission to the intensive care unit (ICU) (46 vs. 33.5%, χ2 = 20.423, P = 0.000) and a longer ICU stay (P = 0.000). The overall intubation rate, hospital mortality, and rate of discharge due to ineffective treatment in 2020 were higher than those in 2019 (15.6 vs. 8%, χ2 = 18.578, P = 0.000;4.2 vs. 1.1%, χ2 = 4.122, P = 0.000;5.5 vs. 2.4%, χ2 = 8.93, P = 0.000, respectively). The logistic regression analysis indicated hospitalizations due to ERD were mainly associated with PM2.5 and sulfur dioxide on the day, and on the 4th and 5th days before admission (P = 0.034 and 0.020, 0.021 and 0.000, 0.028, and 0.027, respectively) in 2019. However, in 2020, the relationship between parameters of air quality and hospitalization changed. Conclusion The COVID-19 pandemic has changed the characteristics of emergency hospitalization due to ERD with a larger proportion of severe patients and poorer prognosis. The effect of air quality on emergencies were weakened. During the COVID-19 pandemic, it is necessary to pay more attention to the non-COVID-19 emergency patients.

Omicron-included mutation-induced changes in epitopes of SARS-CoV-2 spike protein and effectiveness assessments of current antibodies.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading globally and continues to rage, posing a serious threat to human health and life quality. Antibody therapy and vaccines both have shown great efficacy in the prevention and treatment of COVID-19, whose development progress and adaptation range have attracted wide attention. However, with the emergence of variant strains of SARS-CoV-2, the neutralization activity of therapeutic or vaccine-induced antibodies may be reduced, requiring long-term virus monitoring and drug upgrade in response to its evolution. In this paper, conformational changes including continuous epitopes (CPs), discontinuous epitopes (DPs) and recognition interfaces of the three representative SARS-CoV-2 spike protein (SP) mutants (i.e., the Delta (B.1.617.2), Mu (B.1.621) and Omicron (B.1.1.529) strains), were analyzed to evaluate the effectiveness of current mainstream antibodies. The results showed that the conformation of SP wild type (WT) and mutants both remained stable, while the local antigenic epitopes underwent significant changes. Sufficient flexibility of SP CPs is critical for effective antibody recognition. The DPs of Delta, Mu and Omicron variants have showed stronger binding to human angiotensin converting enzyme-2 (hACE2) than WT; the possible drug resistance mechanisms of antibodies against three different epitopes (i.e., NTD_DP, RBD1_DP and RBD2_DP) were also proposed, respectively; the RBD2 of Delta, NTD of Mu, NTD and RBD2 of Omicron are deserve more attention in the subsequent design of next-generation vaccines. The simulation results not only revealed structural characteristics of SP antigenic epitopes, but also provided guidance for antibody modification, vaccine design and effectiveness evaluation.

Progression of myopia in a natural cohort of Chinese children during COVID-19 pandemic.

PURPOSE: To determine myopia progression in children during the COVID-19 and the related factors associated with myopia. METHODS: All subjects underwent three-timepoint ocular examinations that were measured in July 2019, January, and August 2020. We compared the changes in uncorrected visual acuity (UCVA), mydriatic spherical equivalent (SE), and axial length (AL) between two periods (before and during COVID-19). A questionnaire was performed to investigate risk factors for myopia. RESULTS: Compared with before the COVID-19, the mean (S.D.) myopia progression during the COVID-19 was significantly higher in right eyes (- 0.93 (0.65) vs. - 0.33 (0.47) D; p < 0.001). However, the differences in UCVA changes and the axial elongation between two periods were clinically insignificant. Through logistic regressive analysis, we found the difference of the SE changes was associated with the baseline AL (P = 0.028; 95% confidence interval [CI], 1.058, 2.632), online education (P = 0.02; 95% CI, 1.587, 8.665), and time of digital screen (p < 0.005; 95% CI, 1.587, 4.450). CONCLUSIONS: Children were at higher risk of myopia progression during COVID-19, which was associated with the baseline AL, the longtime online learning, and digital screen reading.

Is increased symptom interval associated with advanced stage and poorer outcome? A prospective multicenter study of 220 patients with osteosarcoma around the knee

OBJECTIVE: Osteosarcoma is rare disease and there is a strong controversy about the potential impact of symptom interval on the stage of disease and patients'outcomes. We want to assess whether increased symptom interval (SI) is associated with advanced tumor stage and poor prognosis for patients with osteosarcoma. METHODS: We analyzed prospectively collected data of 220 patients younger than 40 years who had osteosarcoma around the knee. Symptom interval was analyzed to evaluate its impact on metastases at diagnosis, tumor volume, chemotherapy response and overall survival. RESULTS: The median of SI was 64.5 (Q1-Q3: 42-88) days. The 5-year overall survival rate for patients with different length of symptom interval (<42 days, 42-64 days, 65-87 days, >= 88 days) were 0.78 (95 %CI: 0.67-0.89), 0.49 (95 %CI: 0.35-0.63), 0.52 (95 %CI:0.39-0.65), and 0.65 (95 %CI:0.53-0.77) respectively(p = 0.013). Nonparametric test showed increased SI was associated with metastases at diagnosis (p = 0.008), but not associated with large tumor volume or poor chemotherapy response. Cox regression mode test showed that patient with increased SI had higher hazard ratio (42-64 days HR: 2.586 (95 %CI:1.360-4.915);65-87 days, HR: 2.225 (95 %CI:1.170-4.233)) for poor outcomes compared to short SI (<42 days), though it was not significant in multivariate analysis (p = 0.182). CONCLUSION: Increased SI but not the longest SI is associated with higher incidence of metastases at diagnosis;patients can benefit from an earlier diagnosis in terms of survival.

COVID-19 Docking Server: a meta server for docking small molecules, peptides and antibodies against potential targets of COVID-19.

MOTIVATION: The coronavirus disease 2019 (COVID-19) caused by a new type of coronavirus has been emerging from China and led to thousands of death globally since December 2019. Despite many groups have engaged in studying the newly emerged virus and searching for the treatment of COVID-19, the understanding of the COVID-19 target-ligand interactions represents a key challenge. Herein, we introduce COVID-19 Docking Server, a web server that predicts the binding modes between COVID-19 targets and the ligands including small molecules, peptides and antibodies. RESULTS: Structures of proteins involved in the virus life cycle were collected or constructed based on the homologs of coronavirus, and prepared ready for docking. The meta-platform provides a free and interactive tool for the prediction of COVID-19 target-ligand interactions and following drug discovery for COVID-19. AVAILABILITY AND IMPLEMENTATION: http://ncov.schanglab.org.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.