A network pharmacology for predicting the key targets and potential mechanism of Paxlovid in treating COVID-19 (preprint)

Background: Paxlovid has been widely used to treat COVID-19 in global pandemics. The aim of this study is to discover the main targets of SARS-CoV-2 and to explore therapeutic mechanism of Paxlovid. Methods: The targets of Paxlovid were predicted by SwissTargetPrediction. Meanwhile, COVID-19 related targets were collected from GeneCards and OMIM. Then, PPI networks, GO and KEGG enrichment analysis were constructed to discover the potential mechanism by STRING, Cytoscape and DAVID. Finally, AutoDock Vina and Pymol were performed to visualize the interactions between Paxlovid and targets. Results: A total of 22 Paxlovid-related targets of were collected, and 1191 remained therapeutic genes for COVID-19. 23 targets were retained for the further study by PPI network and data integration. The GO and KEGG indicated that 23 targets were significantly enriched to inflammatory response, immune response and so forth. Paxlovid was successfully docked to the active of ALB, CXCL8, HLA-A, IL1B, IL6, KNG1, TNF, VEGFA, CD8A and CTSL. In addition, Paxlovid easily bind with the active pocket of3CLpro and PLpro. Conclusions: Paxlovid could directly target 3CLproand PLpro, and also regulate the immune system. Meanwhile, it may affect the interaction between spike protein RBD and ACE2.

Heparan sulfate promotes ACE2 super-cluster assembly to enhance SARS-CoV-2-associated syncytium formation (preprint)

The mechanism of syncytium formation, caused by spike-induced cell-cell fusion in severe COVID-19, is largely unclear. Here we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical host factor exploited by SARS-CoV-2 to enhance spike’s fusogenic activity. HS binds spike to facilitate ACE2 clustering, generating synapse-like cell-cell contacts to promote fusion pore formation. ACE2 clustering, and thus, syncytium formation is significantly mitigated by chemical or genetic elimination of cell surface HS, while in a cell-free system consisting of purified HS, spike, and lipid-anchored ACE2, HS directly induces ACE2 clustering. Importantly, the interaction of HS with spike allosterically enables a conserved ACE2 linker in receptor clustering, which concentrates spike at the fusion site to overcome fusion-associated activity loss. This fusion-boosting mechanism can be effectively targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice.

Semiparametric estimation of expected shortfall and its application in finance

Measuring risk effectively is crucial for managing risk in financial markets. The expected shortfall has become an increasingly popular metric for risk in recent years. How to estimate it is important in statistics and financial econometrics. Based on the single index quantile regression, we introduce a new semiparametric approach, namely, weighted single index quantile regression. We assess the performance of the proposed expected shortfall estimator with backtesting. Our simulation results indicate that the estimator has a good finite sample performance and often outperforms existing methods. By applying the new method to both a market index and individual stocks, we show that it not only exhibits the best performance but also reveals an insight about the effect of the COVID pandemic, that is, the pandemic increases the market risk.

The impact of the COVID‐19 pandemic on the care of pulmonary hypertension patients outside the Hubei province in China

The Coronavirus disease 2019 (COVID‐19) pandemic has severely affected the lives of people around the world, especially some patients with severe chronic diseases. This study aims to evaluate the impact of the COVID‐19 outbreak from December 2019 to April 2020 on treating patients with PH. A questionnaire regarding the medical condition of PH patients during the COVID‐19 pandemic was designed by PH diagnostic experts in The First Affiliated Hospital of Guangzhou Medical University, China Respiratory Center. One hundred and fifty‐six subjects with PH from non‐Hubei regions in China were invited to participate in this survey online. 63.4% (n = 99) of them had difficulty seeing a doctor, and the main reason was fear of contracting severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in the hospital. Medical treatment was affected in 25% (n = 39) of patients, and who lived in rural areas, and discontinued medical therapy for financial reasons were at a higher risk of medical treatment being affected. Patients who reduced nutrition, and had difficulty seeing a doctor were more likely to get deteriorated. During the epidemic, the hospitalization rate of PH patients was 33.33%. Patients with aggravated PH had a high risk of hospitalization (odds ratio [OR] = 2.844), while patients who visited a doctor during the epidemic reduced the risk of hospitalization (OR = 0.33). In conclusion, during the COVID‐19 pandemic, PH patients had difficulty seeing a doctor, and their medical treatment was affected, even worsened, and increased the risk of hospitalization.

A bibliometric analysis of COVID-19's impact on the sharing economy

A rapidly growing body of scholarly research discusses the impact of the COVID-19 pandemic on the sharing economy (SE). This study aims to employ bibliometric analysis to examine the research themes, scholarly communities, evolution paths and research hotspots of the developing domain of COVID-19's SE research. Adopting an integrated bibliometric approach, this study analyses articles published on Web of Science from 2008 to 2019 and from 2020 to 2021. The outcomes of this study reveal that four new research themes including the COVID-19's impact were updated for the post-pandemic SE research. The scholarly communities' analysis identifies research changes of documents and published journals communities of COVID-19. The results also dig into the evolution path of the topic and instigate further research hotspots toward SE activities. Thus, we contribute to point out the research directions for the opportunities and challenges of SE after the COVID-19 pandemic.

Chapter 17 - COVID-19 Boon or Bane: A case study of Air pollutant transport in the Yangtze River Delta region and its consequent health effects during the COVID-19 lockdown period

This study investigates the transport of air pollutants around the Yangtze River Delta with an aim to identify if there would be a relationship towards health effects during the COVID-19 lockdown period. It is well-known that due to lockdown, the number of socio-economical activities are reduced and hence there is an observable reduction in air pollution. We would like to investigate if this consequential reduction of air pollution would lead to improvement in health amongst its population. A number of integrated methodologies are utilized, including collection and correlation of statistical data and numerical modeling to correlate the mortality rates difference with and without COVID-19 lockdown. In particular air quality changes during the COVID-19 lockdown period are compared with similar periods of the previous years using Brute Force Method. It is found that in general there is significant reduction in air-pollution related mortality, like stroke, ischemic cardio diseases, obstructive pulmonary disease, lung cancer and acute lower respiratory infection are all reduced as a result of relative improvement in PM2.5 level during the lockdown period. Further investigation of the trajectories suggests that these PM2.5 originate from afar with multiple sources, and do not suggest COVID-19 are transported to the region via long-range transport. Our results demonstrate the need for more stringent policy measure to tackle air pollution as it has strong evidence that it increases mortality rate.

Development and utilization of a surrogate SARS-CoV-2 viral neutralization assay to assess mRNA vaccine responses. (preprint)

BackgroundTests for SARS-CoV-2 immunity are needed to help assess responses to vaccination, which can be heterogeneous and may wane over time. The plaque reduction neutralization test (PRNT) is considered the gold standard for measuring serum neutralizing antibodies but requires high level biosafety, live viral cultures and days to complete. We hypothesized that competitive enzyme linked immunoassays (ELISAs) based on SARS-CoV-2 spike proteins receptor binding domain (RBD) attachment to its host receptor, the angiotensin converting enzyme 2 receptor (ACE2r), would correlate with PRNT, given the central role of RBD-ACE2r interactions in infection and published studies to date, and enable evaluation of vaccine responses. Methods and FindingsConfiguration and development of a competitive ELISA with plate-bound RBD and soluble biotinylated ACE2r was accomplished using pairs of pre/post vaccine serum. When the competitive ELISA was used to evaluate N=32 samples from COVID-19 patients previously tested by PRNT, excellent correlation in IC50 results were observed (rs= .83, p < 0.0001). When the competitive ELISA was used to evaluate N=41 vaccinated individuals and an additional N=14 unvaccinated recovered COVID-19 patients, significant differences in RBD-ACE2r inhibitory activity were associated with prior history of COVID-19 and type of vaccine received. In longitudinal analyses pre and up to 200 days post vaccine, surrogate neutralizing activity increased markedly after primary and booster vaccine doses, but fell substantially, up to <12% maximal levels within 6 months. ConclusionsA competitive ELISA based on inhibition of RBD-ACE2r attachment correlates well with PRNT, quantifies significantly higher activity among vaccine recipients with prior COVID (vs. those without), and highlights marked declines in surrogate neutralizing activity over a 6 month period post vaccination. The findings raise concern about the duration of vaccine responses and potential need for booster shots.

Immunogenic Amino Acid Motifs and Linear Epitopes of COVID-19 mRNA Vaccines (preprint)

Reverse vaccinology is an evolving approach for improving vaccine effectiveness and minimizing adverse responses by limiting immunizations to critical epitopes. Towards this goal, we sought to identify immunogenic amino acid motifs and linear epitopes of the SARS-CoV-2 spike protein that elicit IgG in COVID-19 mRNA vaccine recipients. Paired pre/post vaccination samples from N=20 healthy adults, and post-vaccine samples from an additional N=13 individuals were used to immunoprecipitate IgG targets expressed by a bacterial display random peptide library, and preferentially recognized peptides were mapped to the spike primary sequence. The data identify several distinct amino acid motifs recognized by vaccine-induced IgG, a subset of those targeted by IgG from natural infection, which may mimic 3-dimensional conformation (mimotopes). Dominant linear epitopes were identified in the C-terminal domains of the S1 and S2 subunits (aa 558-569, 627-638, and 1148-1159) which have been previously associated with SARS-CoV-2 neutralization in vitro and demonstrate identity to bat coronavirus and SARS-CoV, but limited homology to non-pathogenic human coronavirus. The identified COVID-19 mRNA vaccine epitopes should be considered in the context of variants, immune escape and vaccine and therapy design moving forward.

Associations of SARS-CoV-2 serum IgG with occupation and demographics of military personnel (preprint)

ABSTRACT Background Countries across the globe have mobilized their armed forces in response to COVID-19, placing them at increased risk for viral exposure. Humoral responses to SARS-CoV-2 among military personnel serve as biomarkers of infection and provide a basis for disease surveillance and recognition of work-related risk factors. Methods Enzyme-linked immunosorbent assays (ELISA) were used to measure SARS-CoV-2 spike antigen-specific IgG in serum obtained from N=995 US National Guard soldiers between April-June 2020. Occupational information, e.g. military operating specialty (MOS) codes, and demographic data were obtained via questionnaire. Plaque assays with live SARS-CoV-2 were used to assess serum neutralizing capacity for limited subjects (N=12). Results The SARS-CoV-2 IgG seropositivity rate among the study population was 10.3% and significantly associated with occupation and demographics. Odds ratios were highest for those working in MOS 2T-Transportation (3.6; 95% CI 0.7-18) and 92F-Fuel specialist/ground and aircraft (6.8; 95% CI 1.5-30), as well as black race (2.2; 95% CI 1.2-4.1), household size ≥6 (2.5; 95% CI 1.3-4.6) and known COVID-19 exposure (2.0; 95% CI 1.2-3.3). Seropositivity tracked along major interstate highways and clustered near the international airport and the New York City border. SARS-CoV-2 spike IgG + serum exhibited low to moderate SARS-CoV-2 neutralizing capacity with IC 50s ranging from 1:15 to 1:280. In limited follow-up testing SARS-CoV-2 serum IgG levels remained elevated up to 7 months. Conclusions The data highlight increased SARS-CoV-2 seroprevalence among National Guard vs. the local civilian population in association with transportation-related occupations and specific demographics.

Benign Clinical and Epidemiological Outcomes-Associated Factors of COVID-19 from a Solved Epidemic with a Low Case Fatality Rate (preprint)

Background: Since December 2019, COVID-19 has been confirmed in more than18.8 million patients and leads to 0.70 million deaths worldwide. The mortality and disease severity predictors of COVID-19 have been investigated in many studies. However, they are based on early or partial datasets from high epidemic areas. Here, we retrospect benign clinical and epidemiological outcomes-associated factors from a solved epidemic in a low epidemic area. Methods: All 98 laboratory-confirmed COVID-19 patients in a local epidemic (Zhuhai, China) from January 17, 2020 to March 10, 2020 were enrolled. Data were updated until all patients having final outcomes. Results: Patients were all hospitalized. The case fatality rate was 1.0%. There were no local secondary infection cases. The median age was 46.3 years. Underlying diseases were found in 33.7% patients. The severe/critical rate was 19.4%. The mean period from disease onset to admission was 4.4 days. Compared with serious/critical cases, mild/common cases on admission were much younger, lacks of comorbidities and normal in functions of vital organs and indicators of secondary bacterial infections. The lymphocyte counts in serious/critical cases began to be significantly lower 3 days before their identification dates. The absence of lymphopenia before the eighth day from disease onset can exclude the possibility of 78.5% to be serious/critical ill. Most patients (88.8%) received antiviral treatments. Early antiviral treatment significantly shortened the viral RNA-negative conversion time. The delayed antiviral treatment was associated with critical patients.Conclusions: Younger age, lack of aging-related diseases and early hospitalization of all patients to conduct antiviral treatment and prevention of secondary epidemic were the important benign clinical and epidemiological outcomes-associated factors of COVID-19. In combating COVID-19, the active intervention strategies are crucial in low epidemic areas and the continuous monitoring of lymphocytes may be useful to sort patients reasonably in high epidemic areas.

A global assessment of the impact of school closure in reducing COVID-19 spread (preprint)

Prolonged school closure has been adopted worldwide to control COVID-19. Such preemptive implementation was predicated on the premise that school children are a core group for COVID-19 transmission. Using surveillance data from the Chinese cities of Shenzhen and Anqing, we inferred that children aged 18 or below are only around half as susceptible to COVID-19 infection as adults. Using transmission models parameterized with synthetic contact matrices for 152 jurisdictions around the world, we showed that the lower susceptibility of school children substantially limited the effectiveness of school closure in reducing COVID-19 transmissibility. Our results, together with recent findings that clinical severity of COVID-19 in children is lower, suggest that school closure may not be ideal as a sustained, primary intervention for controlling COVID-19. 

Studies on viral pneumonia related to novel coronavirus SARS-CoV-2, SARS-CoV, and MERS-CoV: a literature review.

Coronaviruses are a class of RNA viruses that can cause respiratory and intestinal infections in animals and humans. SARS-CoV, MERS-CoV, and a novel coronavirus (SARS-CoV-2 [2019-nCoV]) belong to the family Coronaviridae and the genus Betacoronavirus. At present, the understanding of SARS-CoV-2 is getting deeper and deeper. In order to better prevent and treat SARS-CoV-2, this article compares the infectivity, pathogenicity, and related clinical characteristics of the three human pathogenic coronaviruses, SARS-CoV-2, SARS-CoV, and MERS-CoV to help us further understand the pathogenic characteristics of novel coronaviruses.

Clinical Features of COVID‐19 in a Young Man with Massive Cerebral Hemorrhage: Case Report (preprint)

COVID-19 is currently a pandemic in the world, can invade multiple systems, and has a high morbidity and mortality. So far, no cases of acute cerebrovascular disease have been reported. This article reports the clinical features of a COVID-19 patient whose first symptom was cerebral hemorrhage. More importantly, after the craniotomy, the patient had high fever and it was difficult to retreat. After cerebrospinal fluid testing, it was determined that an intracranial infection had occurred. After anti-infection and plasma infusion of the recovered person, the patient's symptoms gradually improved. This case suggests that COVID-19 may infringe on cerebral blood vessels and cause cerebral hemorrhage. Transfusion of plasma from rehabilitation patients is effective for critically ill patients.

Effect of matrine sodium chloride injection on a mouse model combining disease with syndrome of human coronavirus pneumonia with cold-dampness pestilence attacking the lung / 药学学报

"TCM syndrome of plague attack lung" is a classification of traditional Chinese medicine syndromes of the novel coronavirus pneumonia by the Beijing Municipal Administration of Traditional Chinese Medicine. In this study, a mouse model combining disease with syndrome of human coronavirus pneumonia with cold-dampness pestilence attacking the lung was established for the first time, and the therapeutic effect of matrine sodium chloride injection was evaluated based on immune regulation and inflammatory damage. Lung index, lung index inhibition rate and HE stain were used to evaluate the therapeutic effect of matrine sodium chloride injection on the model mice; the viral load in lung tissue was measured by RT-PCR to evaluate its antiviral effect; the percentage of CD4+ T cells, CD8+ T cells and B cells were detected by flow cytometry to evaluate its immunomodulatory effect; the production of interleukin 6 (IL-6), IL-10, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured by ELISA to evaluate its anti-inflammatory effect. All interventions and operations in the experiment were approved by the Animal Ethics Committee of the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH) and Beijing Experimental Animal Ethics Committee. The results showed that intraperitoneal injection of the high-dose (36.67 mL·kg-1·d-1) and low-dose (18.33 mL·kg-1·d-1) of matrine sodium chloride injection significantly improved the pathological damage of lung tissue and reduced lung index. The lung index inhibition rates were 86.86% and 76.53%, respectively. The production of IL-6, IL-10, TNF-α, IFN-γ, as well as the viral load in lung tissue were reduced significantly compared to the model; the percentage of CD4+ T cells, CD8+ T cells and B cells in peripheral blood were increased compared to the model. These results indicated that the matrine sodium chloride injection has an evident therapeutic effect on the model, and its mechanism was related to the inhibition virus replication, regulation of immunity function and inhibition of inflammatory factor release. This study provided laboratory data support for matrine sodium chloride injection which was used to treat the novel coronavirus pneumonia in clinical in Hubei province. These results indicated that the matrine sodium chloride injection has a good prospect for prevention and treatment of the novel coronavirus pneumonia.