Molecular mechanism study of the structural regulation of the N-terminal domain binding antibody on the receptor binding domain of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the global spread of the coronavirus disease (COVID-19), which has caused great loss of life and property worldwide. We investigated the regulatory mechanism with the antibody targeting the N-terminal domain (NTD) of the S protein by molecular dynamic simulation. It was found that the structure of the S1-4A8 complex experienced the largest change when the receptor binding domain (RBD) of S1 was in the Up state. By calculating the angle between domains of S1 in the Down and Up states, we found that the RBD angle changed more in the Up state. We further performed binding free energy calculations for S1-4A8 complexes in both Up and Down states, and the results showed that 4A8 has a stronger affinity with NTD in the Up state. These results indicate that 4A8 plays a stronger regulatory role in the RBD Up state. The N3 and N5 loops on the NTD are the main antigen-antibody binding sites, and residues on the antibody complementarity determining region 3 (CDR3) in the Up state can penetrate deeper into the hydrophobic pocket at the bottom of the N5 loop to form a tighter binding. Through the tICA method, we found that except the residues at the binding interface, distant residues including A609, V610, G652, and A653 at the linker region of subdomain 2, and residues S359 and N360 near the bottom of RBD are able to influence the regulatory effect in the long-range. This work provides new insights into the neutralization mechanism of targeting NTD antibodies in SARS-CoV-2.

Advances in developing ACE2 derivatives against SARS-CoV-2.

Extensive immune evasion of SARS-CoV-2 rendered therapeutic antibodies ineffective in the COVID-19 pandemic. Propagating SARS-CoV-2 variants are characterised by immune evasion capacity through key amino acid mutations, but can still bind human angiotensin-converting enzyme 2 (ACE2) through the spike protein and are, thus, sensitive to ACE2-mimicking decoys as inhibitors. In this Review, we examine advances in the development of ACE2 derivatives from the past 3 years, including the recombinant ACE2 proteins, ACE2-loaded extracellular vesicles, ACE2-mimicking antibodies, and peptide or mini-protein mimetics of ACE2. Several ACE2 derivatives are granted potent neutralisation efficacy against SARS-CoV-2 variants that rival or surpass endogenous antibodies by various auxiliary techniques such as chemical modification and practical recombinant design. The derivatives also represent enhanced production efficiency and improved bioavailability. In addition to these derivatives of ACE2, new effective therapeutics against SARS-CoV-2 variants are expected to be developed.

Advances in developing ACE2 derivatives against SARS-CoV-2

Extensive immune evasion of SARS-CoV-2 rendered therapeutic antibodies ineffective in the COVID-19 pandemic. Propagating SARS-CoV-2 variants are characterised by immune evasion capacity through key amino acid mutations, but can still bind human angiotensin-converting enzyme 2 (ACE2) through the spike protein and are, thus, sensitive to ACE2-mimicking decoys as inhibitors. In this Review, we examine advances in the development of ACE2 derivatives from the past 3 years, including the recombinant ACE2 proteins, ACE2-loaded extracellular vesicles, ACE2-mimicking antibodies, and peptide or mini-protein mimetics of ACE2. Several ACE2 derivatives are granted potent neutralisation efficacy against SARS-CoV-2 variants that rival or surpass endogenous antibodies by various auxiliary techniques such as chemical modification and practical recombinant design. The derivatives also represent enhanced production efficiency and improved bioavailability. In addition to these derivatives of ACE2, new effective therapeutics against SARS-CoV-2 variants are expected to be developed.

Application of estimand framework in ICH E9 (R1) to safety evaluation.

Defining the right question of interest is important to a clinical study. ICH E9 (R1) introduces the framework of an estimand and its five attributes, which provide a basis for connecting different components of a study with its clinical questions. Most of the applications of the estimand framework focus on efficacy instead of safety assessment. In this paper, we expand the estimand framework into the safety evaluation and compare/contrast the similarity and differences between safety and efficacy estimand. Furthermore, we present and discuss applications of a safety estimand to oncology trials and pooled data analyses. At last, we also discuss the potential usage of safety estimand to handle the impacts of COVID-19 pandemic on safety assessment.

High-Affinity Antibodies Designing of SARS-CoV-2 Based on Molecular Dynamics Simulations.

SARS-CoV-2 has led to a global pandemic of new crown pneumonia, which has had a tremendous impact on human society. Antibody drug therapy is one of the most effective way of combating SARS-CoV-2. In order to design potential antibody drugs with high affinity, we used antibody S309 from patients with SARS-CoV as the target antibody and RBD of S protein as the target antigen. Systems with RBD glycosylated and non-glycosylated were constructed to study the influence of glycosylation. From the results of molecular dynamics simulations, the steric effects of glycans on the surface of RBD plays a role of "wedge", which makes the L335-E340 region of RBD close to the CDR3 region of the heavy chain of antibody and increases the contact area between antigen and antibody. By mutating the key residues of antibody at the interaction interface, we found that the binding affinities of antibody mutants G103A, P28W and Y100W were all stronger than that of the wild-type, especially for the G103A mutant. G103A significantly reduces the distance between the binding region of L335-K356 in the antigen and P28-Y32 of heavy chain in the antibody through structural transition. Taken together, the antibody design method described in this work can provide theoretical guidance and a time-saving method for antibody drug design.

Genetically predicted high IGF-1 levels showed protective effects on COVID-19 susceptibility and hospitalization: a Mendelian randomisation study with data from 60 studies across 25 countries.

Background: Epidemiological studies observed gender differences in COVID-19 outcomes, however, whether sex hormone plays a causal in COVID-19 risk remains unclear. This study aimed to examine associations of sex hormone, sex hormones-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and COVID-19 risk. Methods: Two-sample Mendelian randomization (TSMR) study was performed to explore the causal associations between testosterone, estrogen, SHBG, IGF-1, and the risk of COVID-19 (susceptibility, hospitalization, and severity) using genome-wide association study (GWAS) summary level data from the COVID-19 Host Genetics Initiative (N=1,348,701). Random-effects inverse variance weighted (IVW) MR approach was used as the primary MR method and the weighted median, MR-Egger, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test were conducted as sensitivity analyses. Results: Higher genetically predicted IGF-1 levels have nominally significant association with reduced risk of COVID-19 susceptibility and hospitalization. For one standard deviation increase in genetically predicted IGF-1 levels, the odds ratio was 0.77 (95% confidence interval [CI], 0.61-0.97, p=0.027) for COVID-19 susceptibility, 0.62 (95% CI: 0.25-0.51, p=0.018) for COVID-19 hospitalization, and 0.85 (95% CI: 0.52-1.38, p=0.513) for COVID-19 severity. There was no evidence that testosterone, estrogen, and SHBG are associated with the risk of COVID-19 susceptibility, hospitalization, and severity in either overall or sex-stratified TSMR analysis. Conclusions: Our study indicated that genetically predicted high IGF-1 levels were associated with decrease the risk of COVID-19 susceptibility and hospitalization, but these associations did not survive the Bonferroni correction of multiple testing. Further studies are needed to validate the findings and explore whether IGF-1 could be a potential intervention target to reduce COVID-19 risk. Funding: We acknowledge support from NSFC (LR22H260001), CRUK (C31250/A22804), SHLF (Hjärt-Lungfonden, 20210351), VR (Vetenskapsrådet, 2019-00977), and SCI (Cancerfonden).

A Mendelian randomization study of genetic predisposition to autoimmune diseases and COVID-19.

Autoimmune diseases and coronavirus disease 2019 (COVID-19) share many similarities. Concerns have arisen that autoimmune diseases may increase the susceptibility and severity of COVID-19. We used Mendelian randomization to investigate whether liability to autoimmune diseases is related to COVID-19 susceptibility and severity. Genetic instruments for 8 autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis and juvenile idiopathic arthritis, were obtained from published genome-wide association studies. Two-sample Mendelian randomization analyses of the associations of liability to each autoimmune disease with COVID-19 infection, hospitalized COVID-19, and very severe COVID-19 were performed using the latest publicly available genome-wide association study for COVID-19. Genetic liability to each of the autoimmune diseases was largely not associated with COVID-19 infection, hospitalized COVID-19, or very severe COVID-19 after accounting for multiple comparison. Sensitivity analysis excluding genetic variants in the human leukocyte antigen gene, which has an important role in the immune response, showed similar results. The autoimmune diseases examined were largely not genetically associated with the susceptibility or severity of COVID-19. Further investigations are warranted.

Protein Kinase C Inhibitors Reduce SARS-CoV-2 Replication in Cultured Cells.

Infection by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has posed a severe threat to global public health. The current study revealed that several inhibitors of protein kinases C (PKCs) possess protective activity against SARS-CoV-2 infection. Four pan-PKC inhibitors, Go 6983, bisindolylmaleimide I, enzastaurin, and sotrastaurin, reduced the replication of a SARS-CoV-2 replicon in both BHK-21 and Huh7 cells. A PKCδ-specific inhibitor, rottlerin, was also effective in reducing viral infection. The PKC inhibitors acted at an early step of SARS-CoV-2 infection. Finally, PKC inhibitors blocked the replication of wild-type SARS-CoV-2 in ACE2-expressing A549 cells. Our work highlights the importance of the PKC signaling pathway in infection by SARS-CoV-2 and provides evidence that PKC-specific inhibitors are potential therapeutic agents against SARS-CoV-2. IMPORTANCE There is an urgent need for effective therapeutic drugs to control the pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). We found that several inhibitors of protein kinases C (PKCs) dramatically decrease the replication of SARS-CoV-2 in cultured cells. These PKC inhibitors interfere with an early step of viral infection. Therefore, the rapid and prominent antiviral effect of PKC inhibitors underscores that they are promising antiviral agents and suggests that PKCs are important host factors involved in infection by SARS-CoV-2.

Coronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition.

Coronaviruses have brought severe challenges to public health all over the world in the past 20years. SARS-CoV-2, the causative agent of the COVID-19 pandemic that has led to millions of deaths, belongs to the genus beta-coronavirus. Alpha- and beta-coronaviruses encode a unique protein, nonstructural protein 1 (Nsp1) that both suppresses host immune responses and reduces global gene expression levels in the host cells. As a key pathogenicity factor of coronaviruses, Nsp1 redirects the host translation machinery to increase synthesis of viral proteins. Through multiple mechanisms, coronaviruses impede host protein expression through Nsp1, while escaping inhibition to allow the translation of viral RNA. In this review, we discuss current data about suppression of the immune responses and inhibition of protein synthesis induced by coronavirus Nsp1, as well as the prospect of live-attenuated vaccine development with virulence-attenuated viruses with mutations in Nsp1.

Self-Interest Bias in the COVID-19 Pandemic: A Cross-Cultural Comparison between the United States and China

In the global crisis of the COVID-19 pandemic, many countries attempt to enforce new social norms to prevent the further spread of the coronavirus. A key to the success of these measures is the individual adherence to norms that are collectively beneficial to contain the spread of the pandemic. However, individuals? self-interest bias (i.e., the prevalent tendency to license own but not others? self-serving acts or norm violations) can pose a challenge to the success of such measures. The current research examines COVID-19-related self-interest bias from a cross-cultural perspective. Two studies (N?=?1,558) sampled from the United States and China consistently revealed that participants from the United States evaluated their own self-serving acts (exploiting test kits in Study 1;social gathering and sneezing without covering the mouth in public in Study 2) as more acceptable than identical deeds of others, while such self-interest bias did not emerge among Chinese participants. Cultural underpinnings of independent versus interdependent self-construal may influence the extent to which individuals apply self-interest bias to justifications of their own self-serving behaviors during the pandemic.

Association of glycosylated haemoglobin HbA1c levels with outcome in patients with COVID-19: A Retrospective Study.

Patients with hyperglycemia tend to be susceptible to Coronavirus disease 2019 (COVID-19). However, the association of HbA1c level with outcome of COVID-19 patients was unclear. We performed a retrospective study of 2880 cases of COVID-19 admitted in Tongji Hospital, Wuhan, China, among which 922 had detected the HbA1c levels. We found that COVID-19 patients with either lower levels of HbAlc (3%-4.9%) or higher levels of HbAlc (≥6%) were associated with elevated all-cause mortality. Meanwhile, we observed that HbAlc levels were highly correlated with haemoglobin (Hb) and total cholesterol (TC) (P < .0001), moderately correlated with albumin (ALB) and high-sensitive C reaction protein (hs-CRP) (0.0001 < P<.001), and relatively low correlated with low-density lipoprotein cholesterol (LDL-C) (.001 < P<.01). These associated cofactors might together contribute to the clinical outcome of COVID-19 patients. Furthermore, the mortality was higher in COVID-19 patients with newly diagnosed diabetes mellitus (DM) compared with COVID-19 patients with history of DM. Moreover, in patients with history of DM, the mortality was decreased in patients treated with anti-hyperglycaemic drugs. In summary, our data showed that the in-hospital mortality was increased in COVID-19 patients with lower or higher levels of HbAlc. Meanwhile, initiation of appropriate anti-hyperglycaemic treatment might improve the clinical outcome in COVID-19 patients.

Mortality and pre-hospitalization use of low-dose aspirin in COVID-19 patients with coronary artery disease.

To determine whether pre-hospitalization use of aspirin is associated with all-cause mortality in coronavirus disease 2019 (COVID-19) patients with coronary artery disease (CAD). We recruited 183 adult patients with CAD diagnosed with COVID-19, including 52 taking low-dose aspirin (mean [SD] age, 69.7 [1.1] years; 59.6% men) and 131 without using aspirin (mean [SD] age, 71.8 [0.9] years; 51.9% men), who were admitted in the Tongji hospital in Wuhan, China from January 10, 2020 to March 30, 2020. There was no difference on in-hospital mortality between aspirin group and non-aspirin group (21.2% vs. 22.1%, P = .885). Similarly, for critically severe COVID-19 patients, the mortality in aspirin group was close to that in non-aspirin group (44% vs. 45.9%, P = .872). Moreover, the percentage of patients with CAD taking low-dose aspirin did not differ between those survivors and non-survivors (28.7% vs. 27.5%, P = .885). Meanwhile, the usage of aspirin was not correlated with all-cause mortality in multivariate analysis (OR = 0.944, 95% CI: 0.411-2.172, P = .893). Collectively, our study suggested that the pre-hospitalization use of low-dose aspirin was not associated with the clinical outcome of patients with CAD hospitalized with COVID-19 infections.

Nonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting Host Protein Synthesis Machinery toward Viral RNA.

The causative virus of the COVID-19 pandemic, SARS-CoV-2, uses its nonstructural protein 1 (Nsp1) to suppress cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the cellular transcriptome. Our cryo-EM structure of the Nsp1-40S ribosome complex shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the structure of the 48S preinitiation complex formed by Nsp1, 40S, and the cricket paralysis virus internal ribosome entry site (IRES) RNA, which shows that it is nonfunctional because of the incorrect position of the mRNA 3' region. Our results elucidate the mechanism of host translation inhibition by SARS-CoV-2 and advance understanding of the impacts from a major pathogenicity factor of SARS-CoV-2.

Comparison of the Indicators of Psychological Stress in the Population of Hubei Province and Non-Endemic Provinces in China During Two Weeks During the Coronavirus Disease 2019 (COVID-19) Outbreak in February 2020.

BACKGROUND During February 2020, the coronavirus disease 2019 (COVID-19) epidemic in Hubei Province, China, was at its height, requiring isolation of the population. This study aimed to compare the emotional state, somatic responses, sleep quality, and behavior of people in Hubei Province with non-endemic provinces in China during two weeks in February 2020.  MATERIAL AND METHODS Questionnaires were completed by 939 individuals (357 men; 582 women), including 33 from Hubei and 906 from non-endemic provinces. The Stress Response Questionnaire (SRQ) determined the emotional state, somatic responses, and behavior. The Pittsburgh Sleep Quality Index (PSQI) was used to measure the duration of sleep and sleep quality. RESULTS There were 939 study participants, aged 18-24 years (35.89%) and 25-39 years (35.57%); 65.92% were university students. During a two week period in February 2020, the emotional state and behavior of participants in Hubei improved, but the quality of sleep did not. Health workers and business people became increasingly anxious, but other professionals became less anxious. The data showed that most people in Hubei Province developed a more positive attitude regarding their risk of infection and the chances of surviving the COVID-19 epidemic. CONCLUSIONS During a two-week period, front-line health workers and people in Hubei Province became less anxious about the COVID-19 epidemic, but sleep quality did not improve. Despite public awareness, levels of anxiety exist that affect the quality of life during epidemics, including periods of population quarantine. Therefore, health education should be combined with psychological counseling for vulnerable individuals.

Construction of Integrated Emergency Management Model for Novel Coronavirus Pneumonia Epidemic Prevention and Control in Hospital Pharmacy Department / 中国药房

OBJECTIVE： To provide reference for improving emergency capacity of the hospital pharmacy department in response to the novel coronavirus pneumonia （COVID-19） epidemic. METHODS ：According to the related regulations and requirements of Law of the People ’s Republic of China on the Prevention and Control of Infectious Diseases ，combined with the situation of COVID- 19 epidemic prevention and control ，and management experience of relevant hospitals ，on the basis of in-depth analysis of drug supply and quality assurance ，drug dispensing management ，provision of clinical pharmaceutical services and other related material support of hospital pharmacy department，integrated emergency management model was constructed for COVID- 19 epidemic prevention and control ，and the precautions and response measures of each link were sorted out. RESULTS ：Integruted emergency management mode for COVID-19 epidemic prevention and control in hospital pharmacy department included but was not limited to human resource management，drug and disinfection products supply management （mainly including key treatment drugs and disinfection product list formulation，control，inventory increase ，etc.）；drug dispensing management （mainly including prescription ，pharmacy window ， planning quantitative reserve ， drug return ， etc.）；clinical pharmaceutical care management （mainly including providing pharmaceutical information support ，online pharmaceutical service ，monitoring drug safety ，etc.）；personnel protection and disinfection （mainly including personnel protection ，environment and window ，equipment and container ，paper prescription disinfection，etc.）；special management of donated drugs ；prevention and control knowledge training ；pharmaceutical education and scientific research management ，etc. CONCLUSIONS ：The integrated emergency management model for epidemic prevention and control is helpful for hospital pharmacy to manage public health emergencies. During the outbreak of COVID- 19，hospital pharmacy department should start integrated emergency management mode for epidemic prevention and control ，strengthen the risk control of each link ，and play a good role in the key functional departments in the special period.