EGFR core fucosylation, induced by enveloped viruses, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses (preprint)

Aberrant N-glycosylation has been implicated in viral diseases. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here we found that multiple viral envelope proteins (including HCV-E2, VSV-G, SARS-COV-2-Spike and HIV-gp120) enhanced FUT8 expression and core fucosylation. HCV-E2 manipulates host transcription factor SNAIL to induce FUT8 expression through EGFR-AKT-SNAIL activation and SNAIL nuclear translocation. These aberrant increased-FUT8 expression promotes TRIM40-mediated RIG-I K48-ubiquitination and suppresses the antiviral interferon (IFN)-I response through core fucosylated EGFR-JAK1-STAT3-RIG-I signaling. FUT8 inhibitor 2FF, N-glycosylation site-specific mutation (Q352AT) of EGFR, and tissue-targeted Fut8 silencing significantly increased antiviral IFN-I responses and suppressed RNA viral replication, suggesting that core fucosylation mediated by FUT8 is critical for antiviral innate immunity. These findings reveal an immune invasion mechanism in which virus-induced FUT8 suppresses endogenous RIG-I-mediated antiviral defenses by enhancing core fucosylated EGFR-mediated activation. FUT8 may be a promising target for RNA viral therapies.

Longitudinal analysis of memory T follicular helper cells and antibody response following CoronaVac vaccination (preprint)

The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by CoronaVac remains elusive compared to other vaccine platforms. Here, we recruited 88 healthy individuals that received 3 doses of CoronaVac vaccine. We longitudinally evaluated their polyclonal and antigen-specific CD4+ T cells and neutralizing antibody response after receiving each dose of vaccine for over 300 days. Both the 2nd and 3rd dose of vaccination induced robust spike-specific neutralizing antibodies, with a 3rd vaccine further increased the overall magnitude of antibody response, and neutralization against Omicron sub-lineages B.1.1.529, BA.2, BA.4/BA.5 and BA.2.75.2. Spike-specific CD4+ T cell and circulating T follicular helper (cTFH) cells were markedly increased by the 2nd and 3rd dose of CoronaVac vaccine, accompanied with altered composition of functional cTFH cell subsets with distinct effector and memory potential. Additionally, cTFH cells are positively correlated with neutralizing antibody titers. Our results suggest that CoronaVac vaccine-induced spike-specific T cells are capable of supporting humoral immunity for long-term immune protection.

Comparison of infection and human immune responses of two SARS-CoV-2 strains in a humanized AdV-hACE2 NIKO mouse model (preprint)

The COVID-19 pandemic has sickened millions, cost lives and has devastated the global economy. Various animal models for experimental infection with SARS-CoV-2 have played a key role in many aspects of COVID-19 research. Here, we describe a humanized AdV-hACE2 NOD-SCID IL2Rγ-/- (NIKO) mouse model and compared infection with ancestral and mutant (SARS-CoV-2-∆382) strains of SARS-CoV-2. Immune cell infiltration, inflammation, lung damage and pro-inflammatory cytokines and chemokines was observed in humanized AdV-hACE2 NIKO mice. Humanized AdV-hACE2 NIKO mice infected with the WT and mutant SARS-CoV-2 strain had lung inflammation and production of pro-inflammatory cytokines and chemokines. This model can aid in examining the pathological basis of SARS-CoV-2 infection in a human immune environment and evaluation of therapeutic interventions.

Systematic evaluation of emergency management capacity for rural public health emergencies

Rural areas' emergency response capacities are generally weaker when compared to tier one cities and this can have an adverse effect on residents' livelihood and health. Evaluation of rural emergency management is of great significance for improving the rural emergency management capacity. This paper innovatively constructs an evaluation system for the emergency management capabilities with the rural public health emergencies, which includes four dimensions: emergency subject, mechanism, resources and concept. A Projection Pursuit model for objectively processing high-dimensional is constructed, and data from 2010 to 2020 in the rural areas of Xiantao City are selected as samples for empirical research. The results show that: (1) Each dimension of emergency management of public health emergencies contributes more than 20% to the ability. Compared with the other three dimensions, contribution of the emergency concept accounted for the lowest proportion, which was 21.69%, and indicates that this dimension is the key factor restricting the improvement of the emergency management capabilities. (2) From 2010 to 2019, the average annual growth rate of comprehensive emergency management capacity in the rural areas of Xiantao City was 14.9%, and by 2020, the rural emergency management capacity, impacted by the COVID-19 epidemic, grew very rapidly with an annual growth rate of 33.8%. (3) The development of an effective rural emergency management capacity system is not sufficient and unbalanced, which leads to the "barrel effect.” This study can provide theoretical guidelines for the evaluation of rural emergency management capabilities, and provide methodological support for similar research in other regions.

Dynamic Optimization of the Multi-Skilled Resource-Constrained Project Scheduling Problem with Uncertainty in Resource Availability

Multi-skilled resources have brought more flexibility to resource scheduling and have been a key factor in the research of resource-constrained project scheduling problems. However, existing studies are mainly limited to deterministic problems and neglect some uncertainties such as resource breakdowns, while resource availability may change over time due to unexpected risks such as the COVID-19 pandemic. Therefore, this paper focuses on the multi-skilled project scheduling problem with uncertainty in resource availability. Different from previous assumptions, multi-skilled resources are allowed a switch in their skills, which we call dynamic skill assignment. For this complex problem, a nested dynamic scheduling algorithm called GA-PR is proposed, which includes three new priority rules to improve the solving efficiency. Moreover, the algorithm's effectiveness is verified by an example, and the modified Project Scheduling Problem Library (PSPLIB) is used for numerical experimental analysis. Numerical experiments show that when the uncertainty in resource availability is considered, the more skills the resource has and the more resources are supplied, the better the dynamic scheduling method performs;on the other hand, the higher the probability of resource unavailability and the more skills are required, the worse the dynamic scheduling method performs.The results are helpful for improved decision making.

Updated progresses of acute hepatitis of unknown etiology in children and its management strategies

Acute hepatitis of unknown etiology in children has been reported in many countries all over the world since April 2022. As of May 27, there have been at least 650 cases of such patients reported by World Health Organization in 33 countries. The etiology of the hepatitis is still unknown. Adenovirus has been detected in samples of some cases, but it is also suspected that the immune response triggered by SARS-CoV-2 infection maybe contribute to the mechanism of the disease. In this paper, we overview the research and reports about the acute hepatitis of unknown etiology in children about its epidemiology, clinical features and possible etiology, then for the aim to make our country doing well in the monitoring and controlling of the acute hepatitis of unknown etiology in children. Here, we present some points of view from the perspective of infectious diseases and liver diseases in children.

Severe novel coronavirus pneumonia: a case report and literature review

Objective To describe the diagnosis and treatment of a patient with severe novel coronavirus pneumonia, and to improve the understanding and management of clinicians on novel coronavirus pneumonia. Methods The onset, development, treatment and outcome of a patient with severe 2019 novel coronavirus pneumonia were retrospectively analyzed and relevant literatures were reviewed. Results At the beginning of the disease, the patient presented fever and dry cough, and later the disease progressed to dyspnea. Chest CT showed bilateral exudation of the lung. Lopinavir/ritonavir, IFN-a and immunoglobulin were given to the patient according to the expert group's opinion. The pneumonia was cured and the patient was discharged two weeks later. Conclusion Appropriate management strategies are effective on diagnosis and treatment of new coronavirus pneumonia.

Gender-Specific Related Factors for Suicidal Ideation During COVID-19 Pandemic Lockdown Among 5,175 Chinese Adolescents

Background Suicide was an urgent issue during the pandemic period in adolescents. However, few studies were focused on suicide during the coronavirus disease 2019 (COVID-19) pandemic lockdown. Methods An online survey was conducted among 5,175 Chinese adolescents from June 9th to 29th in 2020 to investigate the prevalence of suicidal ideation (SI) during COVID-19 pandemic lockdown. A gender-specific stepwise logistic regression model was used. All analyses were performed with STATA 15.0. Results About 3% of the participants had reported having SI during the COVID-19 pandemic lockdown period. The prevalence of female SI (3.64%, 95% CI: 2.97–4.45%) was higher than that of males (2.39%, 95% CI: 1.88–3.05%) (χ2 = 6.87, p = 0.009). Quarreling with parents [odds ratio (OR) = 9.73, 95% CI: 5.38–17.59], insomnia (OR = 5.28, 95% CI: 2.81–9.93), previous suicide attempt history (OR = 3.68, 95% CI: 1.69–8.03), previous SI history (OR = 2.81, 95% CI: 1.30–6.06), and feeling depressed during pandemic lockdown (OR = 2.26, 95% CI: 1.22–4.18) were positively associated with the males' SI. However, having emptiness inside (OR = 4.39, 95% CI: 2.19–8.79), quarreling with parents (OR = 3.72, 95% CI: 2.16–6.41), insomnia (OR = 3.28, 95% CI: 1.85–5.80), feeling anxious (OR = 2.62, 95% CI: 1.46–4.70), and longing for father's emotional warmth (OR = 0.38, 0.20–0.72) were associated mostly with females' SI. Conclusions Female adolescents, who felt emptiness from their families and their fathers' emotional warmth, were at much higher risk of having SI during COVID-19 lockdown. We must specify a suicide prevention policy and interventions for adolescents in the pandemic crisis based on gender gaps.

Four doses of the inactivated SARS-CoV-2 vaccine redistribute humoral immune responses away from the Receptor Binding Domain (preprint)

A recent MMWR reported that the effectiveness of a 3rd dose of SARS-CoV-2 mRNA vaccine waned quickly in the Omicron-predominant period. Similarly, a substantial decline of immune responses induced by a 3rd dose of inactivated vaccines was also observed in our study. In response to the fast waning immune response and the great threat of Omicron variant of concern (VOC) to frontline healthcare workers (HCWs), 38 HCWs who were in our previous cohort investigating responses to the first three doses of inactivated vaccines participated in the current study and volunteered to receive a 4th homologous booster. Here, we demonstrated that the 4th dose is safe and capable of recalling waned immune responses 6 months after the 3rd dose. However, a greater suppression on the induction of overall Neutralizing antibodies (NAbs) and NAbs targeting the receptor-binding domain (RBD) was found in participants with stronger immune responses after the 3rd dose. As a result, a stepwise elevation of RBD-NAbs from the 1st to the 3rd vaccination achieved a "turning point". The peak RBD-NAbs level induced by the 4th dose was inferior to the peak of the 3rd dose. Accompanied with reduced induction of RBD-NAbs, the immune system shifted responses to the nucleocapsid protein (NP) and the N-terminal domain (NTD) of the spike protein. Although NTD directed antibodies are capable of neutralization, they only compensated the loss of RBD-NAbs to ancestral SARS-CoV-2 virus but not to the Omicron variant due to a substantial conformational change of Omicron NTD. This longitudinal clinical study monitored the immune response of the same cohort for every doses, shaping a relationship between the trajectory of immune focus and the dynamics of the neutralizing potency against the evolving virus. Our data reveal that immune responses could not be endlessly elevated, while suppression of heightened immune responses focusing on one subunit together with a shift of immune responses to other subunits would occur after repeated vaccination. Thus, an updated vaccine with more diverse epitopes capable of inducing NAbs against VOCs would be a future direction for boosters.

Network-Based Approach to Repurpose Approved Drugs for COVID-19 by Integrating GWAS and Text Mining Data

The coronavirus disease 19 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a rapidly increasing prevalence and has caused significant morbidity/mortality. Despite the availability of many vaccines that can offer widespread immunization, it is also important to reach effective treatment for COVID-19 patients. However, the development of novel drug therapeutics is usually a time-consuming and costly process, and therefore, repositioning drugs that were previously approved for other purposes could have a major impact on the fight against COVID-19. Here, we first identified lung-specific gene regulatory/interaction subnetworks (COVID-19-related genes modules) enriched for COVID-19-associated genes obtained from GWAS and text mining. We then screened the targets of 220 approved drugs from DrugBank, obtained their drug-induced gene expression profiles in the LINCS database, and constructed lung-specific drug-related gene modules. By applying an integrated network-based approach to quantify the interactions of the COVID-19-related gene modules and drug-related gene modules, we prioritized 13 approved drugs (e.g., alitretinoin, clocortolone, terazosin, doconexent, and pergolide) that could potentially be repurposed for the treatment of COVID-19. These findings provide important and timely insights into alternative therapeutic options that should be further explored as COVID-19 continues to spread.

A subset of Memory B-derived antibody repertoire from 3-dose vaccinees is ultrapotent against diverse and highly transmissible SARS-CoV-2 variants, including Omicron (preprint)

Omicron, the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. We examined whether sera from individuals who received two or three doses of inactivated vaccine, could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2/60) and 95% (57/60) for 2- and 3-dose vaccinees, respectively. For three-dose recipients, the geometric mean neutralization antibody titer (GMT) of Omicron was 15, 16.5-fold lower than that of the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in 3-dose vaccinees, half of which recognize the receptor binding domain (RBD) and show that a subset of them (24/163) neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron, potently. Therapeutic treatments with representative broadly neutralizing mAbs individually or antibody cocktails were highly protective against SARS-CoV-2 Beta infection in mice. Atomic structures of the Omicron S in complex with three types of all five VOC-reactive antibodies defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to one major class of antibodies bound at the right shoulder of RBD through altering local conformation at the binding interface. Our results rationalize the use of 3-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are a rational target for a universal sarbecovirus vaccine. One sentence summary A sub-set of antibodies derived from memory B cells of volunteers vaccinated with 3 doses of an inactivated SARS-CoV-2 vaccine work individually as well as synergistically to keep variants, including Omicron, at bay.

Air quality impacts of emissions from a typical iron and steel plant in Hebei Province during the coronavirus disease（COVID-19）

Based on the meteorological forecast data from the National Meteorological Bureau, this study developed an AERMOD-based pollution forecasting model for iron and steel plants, simulated air quality impacts of a typical iron and steel plant located in Hebei Province during the controlled period（from February to March in 2020） and the uncontrolled period（from April to October in 2020） of the COVID-19 epidemic, and validated the model with real monitoring air quality data. In case of adverse wind direction, the results showed that the average contribution of SO2, NOx and PM10 from the plant to three state-controlled monitoring stations were 20.19～33.81%, 17.49～23.46% and 2.02～2.69% respectively during the controlled period, and 13.43～21.01%, 11.09～20.92% and 1.20～2.22% during the uncontrolled period. The correlation coefficients between the forecast values of SO2, NOx and PM10 emission of the plant and the real monitoring values of the three state-controlled monitoring stations were higher in the controlled period（the highest values are 0.43,0.48 and 0.29, respectively, at individual monitoring station） compared with the uncontrolled period（the highest values are 0.42,0.39 and 0.07, respectively） due to the less interference from other anthropogenic emission sources during the controlled period.

Auricular Acupressure for Adverse Events Following Immunization Related To COVID-19 Vaccine Injection: Study Protocol for a Multicenter, Three-Arm, Blinded Randomized Controlled Trial (preprint)

Background: Some pain, fatigue, and gastrointestinal adverse reactions were observed in potential association with injection of COVID-19 vaccines. However, there were no preventive intervention for it. We aim to investigate efficacy of auricular acupressure (AA) therapy in preventing and (or) relieving AEFI after injection of COVID-19 vaccine. Methods/design: The study design is a randomized controlled, multicentre, three-arm, single-blind trial. Participants meeting the inclusion criteria will be advertised and enrolled, and assigned randomly in the medical institutions for post-injection observation. No less than 360 participants will be randomized into one of three groups: auricular acupressure group, sham auricular acupressure group and wait-list group. Interventions will be performed immediately, and will happen 4 to 5 times per day for 5 days. The primary clinical outcomes will be quality and quantity evaluation among participants who reported any AEFI and who reported local pain at injection site. Secondary outcomes will concern headache, muscle and (or) joint pain, fatigue, nausea, vomiting, diarrhoea, and other potential events. All the outcomes will be assessed at baseline, 1, 3, 5, 7, and 14 days after the injection. Both intention-to-treat and per-protocol analyses will be performed, with significance level determined at the 5 % level. Discussion Results of this trial will help clarify the value of auricular acupressure therapy in preventing and (or) relieving overall and certain adverse events following immunization after injection of COVID-19 vaccine. Trial registration: This trial was registered in the China Clinical Trial Registry (ChiCTR) (ChiCTR2100043210) on 8th February, 2021.

Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine (preprint)

SARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a non-randomized trial among the healthcare professionals (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccine and the potential need for a third booster dose for the HCWs. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 31.2 AU/ml to 9.2 AU/ml 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 66.8 AU/ml by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to 2 doses were not truly "no responders" but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term immunological memory by the inactivated vaccine, which has implications for future booster strategies that the frontline HCWs, individuals with low serological response to 2 dose of vaccine and immune compromised patients could benefit from a third dose of inactivated vaccine.

Impact of Glycosylation on SARS-CoV-2 Infection and Broadly Protective Vaccine Design (preprint)

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 167 million confirmed cases and over 3 million deaths so far. This global pandemic has led to great efforts directed toward the study of this virus and its infection mechanism as well as development of effective means to control this devastating infectious disease. Like many other viral surface proteins, the trimeric SARS-CoV-2 spike (S) protein is heavily glycosylated with 22 N- and 2 O-glycosites per monomer which are likely to influence S protein folding and evade host immune response. More than one million S protein sequences with over 1,000 sites of mutation in its 1,273 amino acids have been reported to the GISAID database, including the highly transmissible variant strains found in the UK and South Africa. This high frequency of transmission and mutation is a major challenge in the development of broadly protective vaccines to control the pandemic. We have studied the impact of glycosylation on receptor-ligand interaction through evaluation of ACE2 and S protein expressed in different cell lines. Of different S protein glycoforms, the one expressed from lung epithelial cells, the primary cells for infection, has more complex-type glycans and higher binding avidity to the receptor as compared with the S protein from HEK293T cells which have more high-mannose or hybrid-type glycoforms. We also found that most of the S protein glycosites are highly conserved and the glycosites at positions 801 and 1194 are essential for viral entry. In addition, the RBD of S1 and the HR regions of S2 contain most of highly conserved sequences, and removal of each glycosite on pseudotyped SARS-CoV-2 virus for evaluation of the impact on structure and function provides insights into the design of broadly protective vaccines. In an effort to develop such universal vaccines, we found that mice immunized with monoglycosylated S protein (Smg) elicited better antibody responses capable of neutralizing not only the wild type but also the variants from the UK and South Africa than those with the fully-glycosylated S protein (Sfg), and strikingly, Smg vaccination provides better survival for hACE2 transgenic mice when challenged with lethal dose of SARS-CoV-2. Moreover, using single B cell technology, we isolated a monoclonal antibody from Smg immunized mice which was also able to neutralize the wild type and variants, suggesting that removal of unnecessary glycans from S protein to better expose the highly conserved sequences is an effective approach to developing broadly protective vaccines against SARS-CoV-2 and variants.

AI-assisted quantitative lung CT evaluation following umbilical cord mesenchymal stem cell treatment in severe COVID-19 patients (preprint)

Background: The COVID-19 has high transmission and mortality. Previous studies support the efficacy and safety of mesenchymal stem cells (MSCs) in the treatment of lung injury. In this study, We aimed to evaluate the CT changes of lung lesions in severe COVID-19 patients treated with umbilical cord mesenchymal stem cells (UC-MSCs) by using AI-assisted quantification method.Methods46 patients with severe COVID-19 from March 5 to April 1, 2020 were selected by single-blind, non-randomized controlled clinical study and divided into three groups: 11 cases in UC-MSCs treatment group 1 (MSC-1, with cells infusion once), 26 cases in UC-MSCs treatment group 2 (MSC-2, with cells infusion twice or three times), and 9 cases in control group with routine treatment. Repeated measure ANOVA was used to compare the effects of treatment factors on chest CT parameters of COVID-19 patients between control and experimental groups, and pairwise comparison using LSD test.FindingsThe differences between the percentage of GGO in total lung or the percentage of total lung infection volume on day 0 and that in day 60 as well as in day 90 were statistically significant among the three groups. The P values were 0.034 and 0.018 respectively. Pairwise comparison results showed that the percentage difference of the whole lung GGO and total lung infection volume in MSC-1 group was smaller than that in control group and MSC-2 group respectively, but there was no statistical difference between control group and MSC-2 group. The distribution characteristics and other CT parameters post-proceeded by AI software were not significantly different among the three groups. There were no serious adverse events related to stem cell infusion in all treated patients.InterpretationUC-MSC infusion is safe for the treatment of severe COVID-19 patients. The absorption of lung lesions at 60 days and 90 days after UC-MSC infusion once was more obvious than that in the control group. AI quantification of lung lesions is more suitable for comparative studies before and after treatment.