Blockade of Endothelin Receptors Mitigates SARS-CoV-2-induced Osteochondral Damage (preprint)

Joint pain is a common post-acute COVID sequelae. Although pathological bone loss has been documented after SARS-CoV-2 infection, little is known about the damage to articular cartilage capping bone ends. Hereby, we characterise temporal changes of the bone-cartilage functional unit after SARS-CoV-2 infection in a golden Syrian hamster model. We observed cyst formation at osteochondral junction, chondrocyte senescence and subchondral bone loss in infected animals at 4 and 30 days post-infection. Endothelin signalling was upregulated with endothelial dysfunction and leakage of viral spike proteins to subchondral bone, triggering osteoclasts activation and chondrocytes senescence. Blockade of endothelin receptors using macitentan, an FDA-approved medication, alleviated cystic lesions and preserved chondrocyte number in acute phase of viral infection. Delayed macitentan treatment in post-acute infection phase still mitigated subchondral bone loss. Macitentan could also attenuate nociceptive pain induced by viral spike protein receptor binding domain injection in a mouse model. Collectively, macitentan is a repurposable drug candidate for treating SARS-CoV-2-induced joint damage and pain.

Remote Sensing Evidence for Significant Variations in the Global Gross Domestic Product during the COVID-19 Epidemic

Coronavirus disease 2019 (COVID-19) has been spreading rapidly and is still threatening human health currently. A series of measures for restraining epidemic spreading has been adopted throughout the world, which seriously impacted the gross domestic product (GDP) globally. However, details of the changes in the GDP and its spatial heterogeneity characteristics on a fine scale worldwide during the pandemic are still uncertain. We designed a novel scheme to simulate a 0.1°×0.1°resolution grid global GDP map during the COVID-19 pandemic. Simulated nighttime-light remotely sensed data (SNTL) was forecasted via a GM(1, 1) model under the assumption that there was no COVID-19 epidemic in 2020. We constructed a geographically weighted regression (GWR) model to determine the quantitative relationship between the variation of nighttime light (ΔNTL) and the variation of GDP (ΔGDP). The scheme can detect and explain the spatial heterogeneity of ΔGDP at the grid scale. It is found that a series of policies played an obvious role in affecting GDP. This work demonstrated that the global GDP, except for in a few countries, represented a remarkably decreasing trend, whereas the ΔGDP exhibited significant differences.

An overview of COVID-19

Pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection emerged in Wuhan City, Hubei Province, China in December 2019. By Feb. 11, 2020, the World Health Organization (WHO) officially named the disease resulting from infection with SARS-CoV-2 as coronavirus disease 2019 (COVID-19). COVID-19 represents a spectrum of clinical manifestations that typically include fever, dry cough, and fatigue, often with pulmonary involvement. SARS-CoV-2 is highly contagious and most individuals within the population at large are susceptible to infection. Wild animal hosts and infected patients are currently the main sources of disease which is transmitted via respiratory droplets and direct contact. Since the outbreak, the Chinese government and scientific community have acted rapidly to identify the causative agent and promptly shared the viral gene sequence, and have carried out measures to contain the epidemic. Meanwhile, recent research has revealed critical aspects of SARS-CoV-2 biology and disease pathogenesis;other studies have focused on epidemiology, clinical features, diagnosis, management, as well as drug and vaccine development. This review aims to summarize the latest research findings and to provide expert consensus. We will also share ongoing efforts and experience in China, which may provide insight on how to contain the epidemic and improve our understanding of this emerging infectious disease, together with updated guidance for prevention, control, and critical management of this pandemic.

Surveillance for Adverse Events Following Immunization With COVID-19 Vaccines in Dalian, China (preprint)

Background: Coronavirus disease 2019 (COVID-19) vaccines have been administered in priority populations in China since December 15, 2020. This study aims to assess the safety of the COVID-19 vaccination programme in Dalian, China.Methods: Passive surveillance for adverse events following immunization (AEFIs) with COVID-19 vaccines was performed by the Dalian Center for Disease Control and Prevention (CDC). Data were collected through June 8, 2021, from the Chinese National Adverse Events Following Immunization System (CNAEFIS) and were verified by local and upper-level CDCs.Findings: A total of 7.12 million doses of vaccine were administered from November 27, 2020, through June 8, 2021, and 623 vaccinees reported adverse events, resulting in a rate of 87.5 events per one million doses. The age-specific rates of AEFIs ranged from 74.0 per one million doses among persons aged 45 to 59 years to 102.0 per one million doses among persons aged 18 to 44 years; the manufacturer-specific rates ranged from 81.1 to 125.2 per one million doses. Among the 623 AEFIs, 544 (87.3%; rate, 76.4 per one million doses) were confirmed as common minor vaccine reactions. Very rare cases of anaphylaxis after vaccination were reported (5 cases; 0.7 per one million doses). Seven cases of AEFIs were classified as serious; however, available information indicated that there was no causal relationship with COVID-19 vaccination.Interpretation: No major safety concerns were identified during the COVID-19 vaccination campaign. There was no evidence of an increased risk of serious adverse events (SAEs).Funding Information: The study was supported by grants from the National Science Fund for Distinguished Young Scholars (No. 81525023), Key Emergency Project of Shanghai Science and Technology Committee (No. 20411950100).Declaration of Interests: H.Y. has received research funding from Sanofi Pasteur GlaxoSmithKline, Yichang HEC Changjiang Pharmaceutical Company, and Shanghai Roche Pharmaceutical Company. None of those research funding is related to development of COVID-19 vaccines. All other authors report no competing interests.

How to Improve Food Quality in the Domestic Market: The Role of “Same Line Same Standard Same Quality”—Evidence from a Consumer Choice Experiment in China

Consumers are increasingly concerned about food quality. The “Same line Same standard Same quality” (Santong) program has been implemented to improve food quality in the Chinese domestic market. The Santong program means that exporters are encouraged to produce goods on the same production line, following the same standards and the same quality requirements for both the export target market and the domestic market. Using data collected from an online choice experiment on tomatoes, we examine Chinese consumer preferences and their willingness to pay (WTP) for the Santong claim, export target market quality and organic certification. Three types of export target market, indicating different technical regulations and standards, are considered. Our results show that consumers are willing to pay for the Santong quality claim and for export goods with a target market of “EU”. Furthermore, we also identify the substitution effects between the Santong claim and organic certification. The results of our study provide solutions for both Chinese exporters and the Chinese government to meet the need for a high level of food quality accompanied by domestic consumption upgrade and achieve the transformation from export to domestic sales. Our results may also provide solutions for other emerging economies, where governments raise the level of food quality in domestic markets and support the domestic sales of exporters after the shock of the coronavirus (COVID-19) pandemic in 2019.

Discovery of Potential Compounds Against SARS-COV-2 Based on 3clpro/Rdrp Dual-Target an in Silico Approach (preprint)

Currently, Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) lacks clinically specific drugs. In this study, the new coronavirus SARS-CoV-2 3-chymotrypsin-like protease(3CLpro)and RNA-dependent RNA polymerase(RdRp)were used as targets for virtual screening. After analysis of molecular docking and molecular dynamics simulation results, ZINC04259665,ZINC12659533 and ZINC70705490 have good docking scores,and they are stable in combination with 3CLpro/RdRp. The prediction of drug-like properties found that ZINC04259665 has good druggability and has the potential to further explore its anti-SARS-CoV-2.

Aptamer Blocking Strategy Inhibits SARS-CoV-2 Virus Infection

Eine Aptamer-Blockierungsstrategie zur Hemmung der SARS-CoV-2-Infektion wird von Honglin Chen, Yanling Song, Chaoyong Yang et?al. in ihrem Forschungsartikel demonstriert (DOI: 10.1002/ange.202100225). Eine Aptamer-Sonde wurde so konstruiert, dass sie an das Spike-Protein von SARS-CoV-2 bindet, was die Infektion des Virus hemmt, indem es die Interaktion des Virus mit ACE2-Rezeptoren auf der Zellmembran blockiert.

Aptamer Blocking Strategy Inhibits SARS-CoV-2 Virus Infection.

The COVID-19 pandemic caused by SARS-CoV-2 is threating global health. Inhibiting interaction of the receptor-binding domain of SARS-CoV-2 S protein (SRBD ) and human ACE2 receptor is a promising treatment strategy. However, SARS-CoV-2 neutralizing antibodies are compromised by their risk of antibody-dependent enhancement (ADE) and unfavorably large size for intranasal delivery. To avoid these limitations, we demonstrated an aptamer blocking strategy by engineering aptamers' binding to the region on SRBD that directly mediates ACE2 receptor engagement, leading to block SARS-CoV-2 infection. With aptamer selection against SRBD and molecular docking, aptamer CoV2-6 was identified and applied to prevent, compete with, and substitute ACE2 from binding to SRBD . CoV2-6 was further shortened and engineered as a circular bivalent aptamer CoV2-6C3 (cb-CoV2-6C3) to improve the stability, affinity, and inhibition efficacy. cb-CoV2-6C3 is stable in serum for more than 12 h and can be stored at room temperature for more than 14 days. Furthermore, cb-CoV2-6C3 binds to SRBD with high affinity (Kd =0.13 nM) and blocks authentic SARS-CoV-2 virus with an IC50 of 0.42 nM.

Necessary problems in re-emergence of COVID-19.

The ongoing pandemic of coronavirus disease 2019 poses a great threat to human beings. Although numerous patients have recovered, re-positive cases have been reported in several countries. Till now, we still know very little about the disease and its pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, more attention should be paid to the following aspects, such as post-discharge surveillance, asymptomatic infection, re-evaluation of influenza-like symptoms, and dynamic monitoring of genomic mutation of SARS-CoV-2.

"Multimodal" Imaging Performance and Clinical Application of Coronavirus Disease 2019 (COVID-19) (preprint)

Background: To investigate the diagnostic value of three different examination methods of chest radiography (CXR), digital tomosynthesis (DTS) and Computed tomography (CT) scan on the diagnosis of novel coronavirus pneumonia (COVID-19).Methods: A retrospective analysis of three examination methods of chest: CXR, DTS, and CT scan of COVID-19 pneumonia patients diagnosed in our hospital from January, 23, 2020 to February, 29, 2020. And we compared three different imaging methods to COVID-19 display ability of pneumonia intrapulmonary lesions.Results: A total of 37 patients diagnosed as COVID-19 by nucleic acid testing were included. The CXR group (10/37) and DTS group (21/28) of 37 patients with COVID-19 pneumonia showed significant differences in intrapulmonary ground glass opacities (P<0.05); DTS group (21/28) and CT group (25/27) showed no statistically significant differences in intrapulmonary ground glass opacities (P> 0.05). Conclusion: Comparison of the three imaging methods of COVID-19 pneumonia, the diagnostic efficiency of CXR is low, which is easy to be false negative and miss lesions; diagnostic resolutions of DTS are higher than CXR, which can improve the ability to display the fine structure of intrapulmonary lesions; CT scan shows the intrapulmonary of COVID-19 pneumonia low-density ground glass opacities and internal structures have equal capacity compared with DTS. Therefore, DTS and CT are the best choices for the image diagnosis of COVID-19 pneumonia.

Large-scale single-cell analysis reveals critical immune characteristics of COVID-19 patients (preprint)

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic up-regulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19.

Modeling the Opening SARS-CoV-2 Spike: an Investigation of its Dynamic Electro-Geometric Properties (preprint)

The recent COVID-19 pandemic has brought about a surge of crowd-sourced initiatives aimed at simulating the proteins of the SARS-CoV-2 virus. A bottleneck currently exists in translating these simulations into tangible predictions that can be leveraged for pharmacological studies. Here we report on extensive electrostatic calculations done on an exascale simulation of the opening of the SARS-CoV-2 spike protein, performed by the Folding@home initiative. We compute the electric potential as the solution of the non-linear Poisson-Boltzmann equation using a parallel sharp numerical solver. The inherent multiple length scales present in the geometry and solution are reproduced using highly adaptive Octree grids. We analyze our results focusing on the electro-geometric properties of the receptor-binding domain and its vicinity. This work paves the way for a new class of hybrid computational and data-enabled approaches, where molecular dynamics simulations are combined with continuum modeling to produce high-fidelity computational measurements serving as a basis for protein bio-mechanism investigations.

Causally Associations of Blood Lipids Levels with COVID-19 Risk: Mendelian Randomization Study (preprint)

Background: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). It has been found that coronary artery disease (CAD) is a comorbid condition for COVID-19. As the risk factors of CAD, whether blood lipids levels are causally related to increasing susceptibility and severity of COVID-19 is still unknown. Design: We performed two-sample Mendelian Randomization (MR) analyses to explore whether dyslipidemia, low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), triglyceride (TG) and total cholesterol (TC) were causally related to COVID-19 risk and severity. The GWAS summary data of blood lipids involving in 188,578 individuals and dyslipidemia in a total of 53,991 individuals were used as exposures, respectively. Two COVID-19 GWASs including 1,221 infected patients and 1,610 severe patients defined as respiratory failure were employed as outcomes. Based on the MR estimates, we further carried out gene-based and gene-set analysis to explain the potential mechanism for causal effect. Results: The MR results showed that dyslipidemia was casually associated with the susceptibility of COVID-19 and induced 27% higher odds for COVID-19 infection (MR-IVW OR = 1.27, 95% CI: 1.08 to 1.49, p-value = 3.18 x 10-3). Moreover, the increasing level of blood TC will raise 14 % higher odds for the susceptibility of COVID-19 (MR-IVW OR = 1.14, 95% CI: 1.04 to 1.25, p-value = 5.07 x 10-3). Gene-based analysis identified that ABO gene was associated with TC and the gene-set analysis found that immune processes were involved in the risk effect of TC. Conclusions: We obtained three conclusions: 1) Dyslipidemia is casually associated with the susceptibility of COVID-19; 2) TC is a risk factor for the susceptibility of COVID-19; 3) The different susceptibility of COVID-19 in specific blood group may be partly explained by the TC concentration in diverse ABO blood groups.

Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis (preprint)

ABSTRACTDespite the current devastation of the COVID-19 pandemic, several recent studies have suggested that the immunosuppressive drug Tocilizumab can powerfully treating inflammatory responses that occur in this disease. Here, by employing single-cell analysis of the immune cell composition of severe-stage COVID-19 patients and these same patients in post Tocilizumab-treatment remission, we have identified a monocyte subpopulation specific to severe disease that contributes to inflammatory storms in COVID-19 patients. Although Tocilizumab treatment attenuated the strong inflammatory immune response, we found that immune cells including plasma B cells and CD8+ T cells still exhibited an intense humoral and cell-mediated anti-virus immune response in COVID-19 patients after Tocilizumab treatment. Thus, in addition to providing a rich, very high-resolution data resource about the immune cell distribution at multiple stages of the COVID-19 disease, our work both helps explain Tocilizumab’s powerful therapeutic effects and defines a large number of potential new drug targets related to inflammatory storms.Competing Interest StatementJingwen Fang is the executive officer of HanGen BiotechView Full Text

Discovery of Aptamers Targeting Receptor-Binding Domain of the SARS-CoV-2 Spike Glycoprotein (preprint)

The World Health Organization has declared the outbreak of a novel coronavirus (SARS-CoV-2 or 2019-nCoV) as a global pandemic. However, the mechanisms behind the coronavirus infection are not yet fully understood, nor are there any targeted treatments or vaccines. In this study, we identified high-binding-affinity aptamers targeting SARS-CoV-2 RBD, using an ACE2 competition-based aptamer selection strategy and a machine learning screening algorithm. The K d values of the optimized CoV2-RBD-1C and CoV2-RBD-4C aptamers against RBD were 5.8 nM and 19.9 nM, respectively. Simulated interaction modeling, along with competitive with experiments, suggests that two aptamers may have partially identical binding sites at ACE2 on SARS-CoV-2 RBD. These aptamers present an opportunity for generating new probes for recognition of SARS-CoV-2, and could provide assistance in the diagnosis and treatment of SARS-CoV-2 while providing a new tool for in-depth study of the mechanisms behind the coronavirus infection.

Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation (preprint)

An excessive immune response contributes to SARS-CoV, MERS-CoV and SARS-CoV-2 pathogenesis and lethality, but the mechanism remains unclear. In this study, the N proteins of SARS-CoV, MERS-CoV and SARS-CoV-2 were found to bind to MASP-2, the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement activation and aggravated inflammatory lung injury. Either blocking the N protein:MASP-2 interaction or suppressing complement activation can significantly alleviate N protein-induced complement hyper-activation and lung injury in vitro and in vivo. Complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody. Complement suppression may represent a common therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.