Option Valuation with Business Conditions and Skewness (preprint)

This paper exploits business conditions and skewness to improve option pricing. We construct a user-friendly affine framework that incorporates the observable model-free macroeconomic variables and latent skewed innovations, and this new configuration nests and outperforms a wide range of empirically well-tested models. To facilitate practical implementations, we obtain closed-form formulas for pricing SPX options under a variance-dependent kernel. Several sets of empirical studies over the 2008 Great Recession and the ongoing COVID-19 recession demonstrate significant and robust improvements in option pricing brought about by macroeconomic variables, and we find that these improvements are enhanced by the introduction of innovation skewness.

Comparison of the levels of mental health at the different times of coronavirus disease 2019 in China college student (preprint)

Objective: Comparing levels of mental health including general psychological symptoms, stress and insomnia among college students at different times during the 2019 coronavirus (COVID-19) epidemic in China. Methods: Two cross-sectional survey studies were conducted with 503 isolated college students through the questionnaire STAR platform. Of these, 300 students participated in February 2020 and 203 students participated in May 2022. Information collected included demographic and psychological stress measures, mental health scales including the Athens Insomnia Scale (AIS) to assess sleep, the Self-Report Questionnaire (SRQ-20) to assess general psychological symptoms, and the China Perceived Stress Scale (CPSS) to assess stress. ANOVAs were conducted on factors associated with mental health outcomes. Results: From 2020 to 2022, levels of insomnia (p=0.001), anxiety/depression (p=0.001) and stress (p<0.001) decreased significantly. in February 2020, 42.67% of participants exhibited symptoms of insomnia, 16.67% exhibited anxiety/depression symptoms and 96.67% exhibited stress symptoms. in May 2022, the percentage of insomnia decreased to 28.08%, anxiety/depressive symptoms to 6.90% and stressful situations to 68.97%. Conclusions: During the COVID-19 disease pandemic, college students participating in the survey had significantly better sleep, significantly lower levels of anxiety and depression, and lower levels of stress in 2022 compared to 2020. Despite this, high levels of stress remain, indicating that college students are suffering from a high psychological burden, and targeted interventions to promote mental health are recommended.

Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against Omicron (preprint)

The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the antibodies' epitopes and genotypes. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of one class of antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments show that such antibodies can effectively inhibit the immune escape of Omicron. Cryo-EM results show that this class of antibodies utilizes a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. At the same time, it also provides guidance and insights for developing Omicron antibodies and vaccines.

Structural basis for the enhanced infectivity and immune evasion of Omicron subvariants (preprint)

The Omicron variants of SARS-CoV-2 have recently become the globally dominant variants of concern in the COVID-19 pandemic. At least five major Omicron sub-lineages have been characterized: BA.1, BA.2, BA.3, BA.4 and BA.5. They all possess over 30 mutations on the Spike (S) protein. Here we report the cryo-EM structures of the trimeric S proteins from the five subvariants, of which BA.4 and BA.5 share the same mutations of S protein, each in complex with the surface receptor ACE2. All three receptor binding domains of S protein from BA.2 and BA.4/BA.5 are up, while the BA.1 S protein has two up and one down. The BA.3 S protein displays increased heterogeneity, with the majority in the all up RBD state. The differentially preferred conformations of the S protein are consistent with their varied transmissibilities. Analysis of the well defined S309 and S2K146 epitopes reveals the underlie immune evasion mechanism of Omicron subvariants.

Reduced Neutralization of SARS-CoV-2 Omicron Variant in Sera from SARS-CoV-1 Survivors after 3-dose of Vaccination (preprint)

Recent studies found that Omicron variant escapes vaccine-elicited immunity. Interestingly, potent cross-clade pan-sarbecovirus neutralizing antibodies were found in survivors of the infection by SARS-CoV-1 after BNT162b2 mRNA vaccination (N Engl J Med. 2021 Oct 7;385(15):1401-1406). These pan-sarbecovirus neutralizing antibodies were observed to efficiently neutralize the infection driven by the S protein from both SARS-CoV and multiple SARS-CoV-2 variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) (N Engl J Med. 2021 Oct 7;385(15):1401-1406). However, whether these cross-reactive antibodies could neutralize the Omicron variant is still unknown. Based on the data collected from a cohort of SARS-CoV-1 survivors received 3-dose of immunization, our studies reported herein showed that a high level of neutralizing antibodies against both SARS-CoV-1 and SARS-CoV-2 were elicited by a 3rd-dose of booster vaccination of protein subunit vaccine ZF2001. However, a dramatically reduced neutralization of SARS-CoV-2 Omicron Variant (B.1.1.529) is observed in sera from these SARS-CoV-1 survivors received 3-dose of Vaccination. Our results indicates that the rapid development of pan-variant adapted vaccines is warranted.

Tax enforcement and corporate employment: Evidence from a quasi-natural experiment in China

This study investigates how tax enforcement affects corporate employment in China. We utilize the merger of the State Tax Bureau and Local Tax Bureaus as a quasi-natural experiment and adopt a difference-in-differences framework to identify causality. The results show that tougher tax enforcement has a significant and negative effect on corporate employment and that this effect is more pronounced for firms with higher labor intensity, greater financial constraints, more severe labor market frictions, a lower initial tax rate, lower tax transfer ability, and greater credit market imperfections. Further, the mechanism tests demonstrate that tougher tax enforcement leads to increases in the effective income tax rate, cash holdings, and the cash flow sensitivity of real investment but decreases in accounts receivable and dividend payments. These results are consistent with the liquidity constraints channel. In addition, we exclude several alternative explanations and conduct a series of robustness checks. Overall, our findings indicate that corporate tax enforcement has large effects on the local labor demand, which provides some useful insights for local governments to stabilize employment during the COVID-19 pandemic.

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1β, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with ACE2 interface, which gives 2G1 ability to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar IC50 in vitro. In SARS-CoV-2 and Beta- and Delta-variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 could be potentially capable of dealing with emerging SARS-CoV-2 variants in future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

Learning from the Pandemic: the Future of Meetings in HEP and Beyond (preprint)

The COVID-19 pandemic has by-and-large prevented in-person meetings since March 2020. While the increasing deployment of effective vaccines around the world is a very positive development, the timeline and pathway to "normality" is uncertain and the "new normal" we will settle into is anyone's guess. Particle physics, like many other scientific fields, has more than a year of experience in holding virtual meetings, workshops, and conferences. A great deal of experimentation and innovation to explore how to execute these meetings effectively has occurred. Therefore, it is an appropriate time to take stock of what we as a community learned from running virtual meetings and discuss possible strategies for the future. Continuing to develop effective strategies for meetings with a virtual component is likely to be important for reducing the carbon footprint of our research activities, while also enabling greater diversity and inclusion for participation. This report summarizes a virtual two-day workshop on Virtual Meetings held May 5-6, 2021 which brought together experts from both inside and outside of high-energy physics to share their experiences and practices with organizing and executing virtual workshops, and to develop possible strategies for future meetings as we begin to emerge from the COVID-19 pandemic. This report outlines some of the practices and tools that have worked well which we hope will serve as a valuable resource for future virtual meeting organizers in all scientific fields.

Expression Profiles of Plasma IFN Signaling-Related miRNAs (ISR-miRNAs) at the Acute and Recovery Phase of COVID-19 (preprint)

BackgroundCoronavirus disease 2019 (COVID-19) has brought major harm and challenges to the world. Although many studies have suggested that IFN-I could affect the life cycle of the virus by regulating the expression level of microRNAs, the expression characteristics of plasma IFN-I signaling-related miRNAs at the acute and recovery phase of COVID-19 remain unclear.MethodsDemographic characteristics and fasting blood samples were collected from the acute and recovery phases of 29 COVID-19 patients and 29 healthy controls matched by age (± 5years) and gender (1:1). Expression levels of 12 IFN signaling-related miRNAs were analyzed using RT-qPCR. The receptor-binding domain (RBD) IgG antibody in the convalescent plasma samples was detected using competitive ELISA.ResultsCompared with healthy controls, patients with COVID-19 presented increased levels of miR-29b-3p (~ 5.91-fold), miR-497-5p (~ 2.28-fold), and miR-1246 (~ 7.97-fold), and decreased expression levels of miR-186-5p (~ 6.39-fold) and miR-15a-5p (~ 3.26-fold) at the acute phase of infection. However, the expression levels of miR-29b-3p and miR-1246, which significantly elevated at the acute phase, were not different between individuals at the recovery phase and healthy controls. The expression levels of miR-30b-5p, miR-497-5p, miR-409-3p and miR-548c-5p in convalescent plasma samples were significantly lower than those in healthy controls. However, the concentration of miR-186-5p in the convalescent plasma samples was significantly higher than that in healthy controls and patients with acute infection. Furthermore, competitive ELISA results showed that the plasma level of miR-497-5p at the acute phase positively correlated with RBD-IgG antibody response (r=0.48, P=0.038).ConclusionsThe present study firstly reported that timely and appropriate regulation of IFN signaling-related miRNA expression plays a critical role during both acute and recovery phase of SARS-CoV-2 infection. Furthermore, the circulating miR-497-5p level was positively correlated to RBD-IgG antibody response in COVID-19 patients.

ACE2-Targeting Monoclonal Antibody As A "Pan" Coronavirus Blocker In Vitro and In A Mouse Model (preprint)

Coronaviruses have caused three major outbreaks of infectious disease since the beginning of 21st century. Broad-spectrum strategies that can be utilized in both current and future coronavirus outbreaks and mutation-tolerant are sought after. Here we report a monoclonal antibody 3E8 targeting human angiotensin-converting enzyme 2 (ACE2) neutralized pseudo-typed coronaviruse SARS-CoV-2, SARS-CoV-2-D614G, SARS-CoV and HCoV-NL63, without affecting physiological activities of ACE2 or causing toxicity in mouse model. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a mouse model of COVID-19. Cryo-EM studies revealed the binding site of 3E8 on ACE2 and identified Histone 34 of ACE2 as a critical site of anti-viral epitope. Overall, our work has provided a potential pan coronavirus management strategy and disclosed a pan anti-coronavirus epitope on human ACE2 for the first time.

Antibody-dependent enhancement (ADE) of SARS-CoV-2 infection in recovered COVID-19 patients: studies based on cellular and structural biology analysis (preprint)

Antibody-dependent enhancement (ADE) has been reported in several virus infections including dengue fever virus, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus infection. To study whether ADE is involved in COVID-19 infections, in vitro pseudotyped SARS-CoV-2 entry into Raji cells, K562 cells, and primary B cells mediated by plasma from recovered COVID-19 patients were employed as models. The enhancement of SARS-CoV-2 entry into cells was more commonly detected in plasma from severely-affected elderly patients with high titers of SARS-CoV-2 spike protein-specific antibodies. Cellular entry was mediated via the engagement of Fc{gamma}RII receptor through virus-cell membrane fusion, but not by endocytosis. Peptide array scanning analyses showed that antibodies which promote SARS-CoV-2 infection targeted the variable regions of the RBD domain. To further characterize the association between the spike-specific antibody and ADE, an RBD-specific monoclonal antibody (7F3) was isolated from a recovered patient, which potently inhibited SARS-Cov-2 infection of ACE-2 expressing cells and also mediated ADE in Raji cells. Site-directed mutagenesis the spike RBD domain reduced the neutralization activity of 7F3, but did not abolish its binding to the RBD domain. Structural analysis using cryo-electron microscopy (Cryo-EM) revealed that 7F3 binds to spike proteins at a shift-angled pattern with one up and two down RBDs, resulting in partial overlapping with the receptor binding motif (RBM), while a neutralizing monoclonal antibody that lacked ADE activity binds to spike proteins with three up RBDs, resulting in complete overlapping with RBM. Our results revealed that ADE mediated by SARS-CoV-2 spike-specific antibodies could result from binding to the receptor in slightly different pattern from antibodies mediating neutralizations. Studies on ADE using antibodies from recovered patients via cell biology and structural biology technology could be of use for developing novel therapeutic and preventive measures for control of COVID-19 infection.

Molecular characterization of SARS-CoV-2 from Bangladesh: Implications in genetic diversity, possible origin of the virus, and functional significance of the mutations (preprint)

In a try to understand the pathogenesis, evolution, and epidemiology of the SARS-CoV-2 virus, scientists from all over the world are tracking its genomic changes in real-time. Genomic studies can be helpful in understanding the disease dynamics. We have downloaded 324 complete and near-complete SARS-CoV-2 genomes submitted in the GISAID database from Bangladesh which were isolated between 30 March to 7 September 2020. We then compared these genomes with the Wuhan reference sequence and found 4160 mutation events including 2253 missense single nucleotide variations, 38 deletions, and 10 insertions. The C>T nucleotide change was most prevalent possibly due to selective mutation pressure to reduce CpG sites to evade CpG targeted host immune response. The most frequent mutation that occurred in 98% of the isolates was 3037C>T which is a synonymous change that almost always accompanied 3 other mutations that include 241C>T, 14408C>T (P323L in RdRp), and 23403A>G (D614G in spike protein). The P323L was reported to increase mutation rate and D614G is associated with increased viral replication and currently the most prevalent variant circulating all over the world. We identified multiple missense mutations in B-cell and T-cell predicted epitope regions and/or PCR target regions (including R203K and G204R that occurred in 86% of the isolates) that may impact immunogenicity and/or RT-PCR based diagnosis. Our analysis revealed 5 large deletion events in ORF7a and ORF8 gene products that may be associated with less severity of the disease and increased viral clearance. Our phylogeny analysis identified most of the isolates belonged to the Nextstrain clade 20B (86%) and GISAID clade GR (88%). Most of our isolates shared common ancestors either directly with European countries or jointly with middle eastern countries as well as Australia and India. Interestingly, the 19B clade (GISAID S clade) was unique to Chittagong which was originally prevalent in China. This reveals possible multiple introductions of the virus in Bangladesh via different routes. Hence more genome sequencing and analysis with related clinical data are needed to interpret the functional significance and better predict the disease dynamics that may be helpful for policymakers to control the COVID-19 pandemic in Bangladesh.

Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies (preprint)

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the "up" conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.

Influence of Convalescent Plasma Therapy on the Mortality in COVID-19 Patients: A Meta-Analysis (preprint)

As of August15, 2020, more than 21,155,600 people were infected and about 761,264 were expired due to SARS-CoV-2 infection worldwide. The extreme spread of the emerging virus makes the disease a serious problem for public health. However, a curative treatment or effective specific vaccine againstSARS-CoV-2 infection is unavailable. Recently, several studies have been performed to evaluate the effects of COVID-19 convalescent plasma transfusion on the clinical outcomes in patients with severe/critical COVID-19 [1-5]. However, the results from these studies aredatable, and thus its useremains investigational.

Engineered Trimeric ACE2 Binds and Locks "Three-up" Spike Protein to Potently Inhibit SARS-CoVs and Mutants (preprint)

SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered a de novo trimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (KD < 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to "three-up" RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants.

A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability (preprint)

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.

Clinical features and laboratory findings of SARS-CoV-2 infection in hospitalized patients (preprint)

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a new emerging public health crisis to the world. However, data are still limited on the clinical features and laboratory findings in COVID-19 patients.Methods: Medical records including demographics characteristics, clinical features, laboratory findings and radiological materials of 66 hospitalized COVID-19 patients were collected between Jan 23 and Mar 9, 2020. Symptoms/signs with potential association with the disease severity were analyzed.Results: Of 66 hospitalized COVID-19 patients, the male-to-female ratio was 44:22. There were eight cases potentially exposed to one single patient. The most common initial symptoms of SARS-CoV-2 infection were fever (77.3%) and cough (74.2%). Compared to those with non-severe infection, the severe patients were more likely to be older (62.6 ± 15.1 vs 46.9 ± 13.3 years. P = 0.001) and with more infected lobes. As the results shown, higher initial (on admission) and peak (during hospitalization) counts of lymphocyte were inversely associated with the severe SARS-CoV-2 infection (both OR: 0.01 every 1´109/L decrease). However, the elevated initial neutrophil counts (OR: 1.63 every 1´109/L increase), initial and peak levels of LDH (OR: 1.02 and 1.01 every 1 U/L increase), peak levels of CRP (OR: 1.03 every 1 mg/L increase), AST (OR: 1.06 every 1 U/L increase) and ALT (OR: 1.02 every 1 U/L increase) were significantly associated with COVID-19 severity.Conclusion: Our present study indicated that fever and cough were the most common initial symptoms of SARS-CoV-2 infection, and the virus could be efficiently spread by person-to-person transmission. In addition, lymphocyte and neutrophil counts, and serum levels of AST, ALT, CRP and LDH should be useful for the evaluation on COVID-19 severity.