Harringtonine: A more effective antagonist for Omicron variant.

Fusion with host cell membrane is the main mechanism of infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we propose that a new strategy to screen small-molecule antagonists blocking SARS-CoV-2 membrane fusion. Using cell membrane chromatography (CMC), we found that harringtonine (HT) simultaneously targeted SARS-CoV-2 S protein and host cell surface TMPRSS2 expressed by the host cell, and subsequently confirmed that HT can inhibit membrane fusion. HT effectively blocked SARS-CoV-2 original strain entry with the IC50 of 0.217 µM, while the IC50 in delta variant decreased to 0.101 µM, the IC50 in Omicron BA.1 variant was 0.042 µM. Due to high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, however, against BA.5, HT showed a surprising effectiveness. The IC50 in Omicron BA.5 was even lower than 0.0019 µM. The above results revealed the effect of HT on Omicron is very significant. In summary, we characterize HT as a small-molecule antagonist by direct targeting on the Spike protein and TMPRSS2.

SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria.

Autophagy plays an important role in the interaction between viruses and host cells. SARS-CoV-2 infection can disrupt the autophagy process in target cells. However, the precise molecular mechanism is still unknown. In this study, we discovered that the Nsp8 of SARS-CoV-2 could cause an increasing accumulation of autophagosomes by preventing the fusion of autophagosomes and lysosomes. From further investigation, we found that Nsp8 was present on mitochondria and can damage mitochondria to initiate mitophagy. The results of experiments with immunofluorescence revealed that Nsp8 induced incomplete mitophagy. Moreover, both domains of Nsp8 orchestrated their function during Nsp8-induced mitophagy, in which the N-terminal domain colocalized with mitochondria and the C-terminal domain induced auto/mitophagy. This novel finding expands our understanding of the function of Nsp8 in promoting mitochondrial damage and inducing incomplete mitophagy, which helps us to understand the etiology of COVID-19 as well as open up new pathways for creating SARS-CoV-2 treatment methods.

Mechanical thrombectomy for acute multivessel occlusions with duplicated middle cerebral artery: A case report.

Acute multivessel occlusions generally have multisite clot burden with lower successful reperfusion rates, and cerebrovascular anatomical variants increase the challenge of endovascular clot retrieval. We report a case of acute anterior multivessel occlusions patient with duplicated middle cerebral artery. Combined balloon guide catheter with stent retriever and aspiration approach has gained complete revascularization and good functional outcomes at 3 months follow-up.

Estimation and sensitivity analysis of a COVID-19 model considering the use of face mask and vaccination.

To model the COVID-19 infection and develop effective control measures, this paper proposes an SEIR-type epidemic model considering the impact of face-mask wearing and vaccination. Firstly, the effective reproduction number and the threshold conditions are obtained. Secondly, based on the data of South Korea from January 20, 2022 to March 21, 2022, the model parameters are estimated. Finally, a sensitivity analysis and the numerical study are conducted. The results show that the face-mask wearing is associated with [Formula: see text] and [Formula: see text] reductions in the numbers of cumulative cases and newly confirmed cases, respectively, after a period of 60 days, when the face mask wearing rate increases by [Formula: see text]. Furthermore, the vaccination rate is associated with [Formula: see text] and [Formula: see text] reductions in the numbers of cumulative cases and the newly confirmed cases, respectively, after the same period of 60 days when the vaccination rate is increased by [Formula: see text]. A combined measure involving face-mask wearing and vaccination may be more effective and reasonable in preventing and controlling this infection. It is also suggested that disease control departments should strongly recommended the wearing of face masks s as well as vaccination to prevent the unvaccinated people from becoming infected.

Delivery and neonatal outcomes of pregnant women during the Shanghai lockdown: A retrospective analysis.

Objectives: Shanghai witnessed an unprecedented outbreak of COVID-19 and experienced a strict lockdown from March 28, 2022 to May 31, 2022. Most studies to date are on the first lockdown after the outbreak in December 2019. This study aimed to examine the impact of lockdown on delivery and neonatal outcomes among uninfected pregnant women in the new phase of the COVID-19 outbreak. Methods: A retrospective analysis was conducted in the Obstetrics and Gynecology Hospital of Fudan University. Pregnant women without COVID-19 who delivered from March 28, 2022 to May 31, 2022 (lockdown group) and the same period in 2021 (non-lockdown group) were recruited for this study. Logistic regression models and 1 : 1 propensity score matching (PSM) were used to assess the effect of lockdown on delivery outcomes. Results: A total of 2,962 patients were included in this study, 1,339 of whom were from the lockdown group. Compared with the non-lockdown group, pregnant women giving birth during lockdown had an increased risk of term prelabor rupture of membranes (TPROM) (aOR = 1.253, 95% CI: 1.026-1.530), and decreased risks of postpartum hemorrhage (PPH) (aOR = 0.362, 95% CI: 0.216-0.606) and fetal malformation (aOR = 0.309, 95% CI: 0.164-0.582). The risk of large for gestational age (LGA) (aOR = 0.802, 95% CI: 0.648-0.992) and rate of admission to the neonatal intensive care unit (NICU) (aOR = 0.722, 95% CI: 0.589-0.885) also significantly declined. After 1 : 1 PSM, the impact of lockdown on the risk of TPROM (aOR = 1.501, 95% CI: 1.083-2.080), PPH (aOR = 0.371, 95% CI: 0.211-0.654), fetal malformation (aOR = 0.332, 95% CI: 0.161-0.684), LGA (aOR = 0.749, 95% CI: 0.594-0.945) and rate of admission to the NICU (aOR = 0.700, 95% CI: 0.564-0.869) all remained. There were no other delivery or neonatal outcomes affected by the lockdown after the COVID-19 outbreak. Conclusion: This study indicated a significant increase in the risk of term PROM, significant decreases in the risk of PPH, fetal malformation and LGA, and a marked decline in the rate of admission to the NICU during Shanghai Lockdown.

Corrigendum to "Comprehensive Humoral and Cellular Immune Responses to SARS-CoV-2 Variants in Diverse Chinese Population".

[This corrects the article DOI: 10.34133/2022/9873831.].

A receptor-binding domain-based nanoparticle vaccine elicits durable neutralizing antibody responses against SARS-CoV-2 and variants of concern.

Numerous vaccines have been developed to address the current COVID-19 pandemic, but safety, cross-neutralizing efficacy, and long-term protectivity of currently approved vaccines are still important issues. In this study, we developed a subunit vaccine, ASD254, by using a nanoparticle vaccine platform to encapsulate the SARS-CoV-2 spike receptor-binding domain (RBD) protein. As compared with the aluminum-adjuvant RBD vaccine, ASD254 induced higher titers of RBD-specific antibodies and generated 10- to 30-fold more neutralizing antibodies. Mice vaccinated with ASD254 showed protective immune responses against SARS-CoV-2 challenge, with undetectable infectious viral loads and reduced typical lesions in lung. Besides, neutralizing antibodies in vaccinated mice lasted for at least one year and were effective against various SARS-CoV-2 variants of concern, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, particle size, polydispersity index, and zeta potential of ASD254 remained stable after 8-month storage at 4°C. Thus, ASD254 is a promising nanoparticle vaccine with good immunogenicity and stability to be developed as an effective vaccine option in controlling upcoming waves of COVID-19.

A mathematical model reveals the influence of NPIs and vaccination on SARS-CoV-2 Omicron Variant.

An SVEIR SARS-CoV-2 Omicron variant model is proposed to provide some insights to coordinate non-pharmaceutical interventions (NPIs) and vaccination. Mathematically, we define the basic reproduction number R 0 and the effective reproduction number R e to measure the infection potential of Omicron variant and formulate an optimal disease control strategy. Our inversion results imply that the sick period of Omicron variant in the United States is longer than that of Delta variant in India. The decrease in the infectious period of the infection with infectiousness implies that the risk of hospitalization is reduced; but the increasing period of the infection with non-infectiousness signifies that Omicron variant lengthens the period of nucleic acid test being negative. Optimistically, Omicron's death rate is only a quarter of Delta's. Moreover, we forecast that the cumulative cases will exceed 100 million in the United States on February 28, 2022, and the daily confirmed cases will reach a peak on February 2, 2022. The results of parameters sensitivity analysis imply that NPIs are helpful to reduce the number of confirmed cases. In particular, NPIs are indispensable even if all the people were vaccinated when the efficiency of vaccine is relatively low. By simulating the relationships of the effective reproduction number R e , the vaccination rate and the efficacy of vaccine, we find that it is impossible to achieve the herd immunity without NPIs while the efficiency of vaccine is lower than 88.7 % . Therefore, the herd immunity area is defined by the evolution of relationships between the vaccination rate and the efficacy of vaccine. Finally, we present that the disease-induced mortality rate demonstrates the periodic oscillation and an almost periodic function is deduced to match the curve. A discussion completes the paper.

Compromised skin barrier induced by prolonged face mask usage during the COVID-19 pandemic and its remedy with proper moisturization.

BACKGROUND: Prolonged face mask usage, a daily practice for the public due to the COVID-19 pandemic, creates high levels of humidity underneath the mask, which may cause unexpected skin concerns. OBJECTIVE: To investigate the impact of repeated mask usage on the face by comparing skin properties inside and outside of the mask-covered areas. METHODS: A double-blinded, randomized, split-face clinical study was conducted with 21 healthy female participants who wore face masks at least 6 h every day for 1 week, with one side of their face treated with a moisturizer three times daily. On day 8, after 5 h of wearing the mask, skin properties (sebum, hydration, and trans-epidermal water loss [TEWL]) were evaluated at 15, 60, and 120 min post-mask removal, followed by barrier disruption and recovery assessment. RESULTS: Mask usage weakened stratum corneum (SC) on facial skin compared to uncovered areas, including reduced SC hydration (p < 0.02 at 15 min) and increased TEWL in response to tape stripping challenge (p < 0.03 after stripping). In addition, sebum production also increased after mask removal (p < 0.01 at 15 min). Notably, a daily moisturizer mitigated these effects by increasing SC hydration (p < 0.001) and improving SC resilience against barrier disruption. CONCLUSION: Daily prolonged usage of a facial mask, essential due to the COVID-19 situation, generated a high-humidity microenvironment and led to compromised SC, which was revealed by a barrier challenge technique. Moreover, proper facial moisturization may help to maintain skin homeostasis and prevent the barrier impairment caused by repeated mask usage.

Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Antibody resistance dampens neutralizing antibody therapy and threatens current global Coronavirus (COVID-19) vaccine campaigns. In addition to the emergence of resistant SARS-CoV-2 variants, little is known about how SARS-CoV-2 evades antibodies. Here, we report a novel mechanism of extracellular vesicle (EV)-mediated cell-to-cell transmission of SARS-CoV-2, which facilitates SARS-CoV-2 to escape from neutralizing antibodies. These EVs, initially observed in SARS-CoV-2 envelope protein-expressing cells, are secreted by various SARS-CoV-2-infected cells, including Vero E6, Calu-3, and HPAEpiC cells, undergoing infection-induced pyroptosis. Various SARS-CoV-2-infected cells produce similar EVs characterized by extra-large sizes (1.6-9.5 µm in diameter, average diameter > 4.2 µm) much larger than previously reported virus-generated vesicles. Transmission electron microscopy analysis and plaque assay reveal that these SARS-CoV-2-induced EVs contain large amounts of live virus particles. In particular, the vesicle-cloaked SARS-CoV-2 virus is resistant to neutralizing antibodies and able to reinfect naïve cells independent of the reported receptors and cofactors. Consistently, the constructed 3D images show that intact EVs could be taken up by recipient cells directly, supporting vesicle-mediated cell-to-cell transmission of SARS-CoV-2. Our findings reveal a novel mechanism of receptor-independent SARS-CoV-2 infection via cell-to-cell transmission, provide new insights into antibody resistance of SARS-CoV-2 and suggest potential targets for future antiviral therapeutics.

Integrating Chatbot and Augmented Reality Technology into Biology Learning during COVID-19

The novel coronavirus (COVID-19) pandemic is rampant around the world, and teachers and students are unable to attend physical classes in the midst of a serious outbreak. This study aims to design a user-friendly, educational chatbot application interface that can be used as an after-school self-learning tool for students to enhance their interest and comprehension and increase the effectiveness of their learning at home. The system adopts the Chatfuel platform as the core interface and incorporates augmented reality technology to build a chatbot that allows users to interact with it after they have logged in to Facebook. The content is based on the biology subject of the first year of junior high school and is integrated into the online teaching with augmented reality teaching materials. A user survey is conducted to understand students' attitudes towards learning biology with the aid of the ARCS motivation model, with 102 valid questionnaires received. The results show that the AR-based chatbot system developed in this study significant influenced the indicators in the ARCS motivation model;therefore, the intention to use the system is presumed to result in a noticeable increase in student learning outcomes when using the system. Accordingly, this study proposes new online learning tools for students to use at home during the pandemic, and the system also provides references for the future development and modification of educational chatbots.

Sertraline Is an Effective SARS-CoV-2 Entry Inhibitor Targeting the Spike Protein.

The global spread of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the continuously emerging new variants underscore an urgent need for effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). Here, we screened several FDA-approved amphiphilic drugs and determined that sertraline (SRT) exhibits potent antiviral activity against infection of SARS-CoV-2 pseudovirus (PsV) and authentic virus in vitro. It effectively inhibits SARS-CoV-2 spike (S)-mediated cell-cell fusion. SRT targets the early stage of viral entry. It can bind to the S1 subunit of the S protein, especially the receptor binding domain (RBD), thus blocking S-hACE2 interaction and interfering with the proteolysis process of S protein. SRT is also effective against infection with SARS-CoV-2 PsV variants, including the newly emerging Omicron. The combination of SRT and other antivirals exhibits a strong synergistic effect against infection of SARS-CoV-2 PsV. The antiviral activity of SRT is independent of serotonin transporter expression. Moreover, SRT effectively inhibits infection of SARS-CoV-2 PsV and alleviates the inflammation process and lung pathological alterations in transduced mice in vivo. Therefore, SRT shows promise as a treatment option for COVID-19. IMPORTANCE The study shows SRT is an effective entry inhibitor against infection of SARS-CoV-2, which is currently prevalent globally. SRT targets the S protein of SARS-CoV-2 and is effective against a panel of SARS-CoV-2 variants. It also could be used in combination to prevent SARS-CoV-2 infection. More importantly, with long history of clinical use and proven safety, SRT might be particularly suitable to treat infection of SARS-CoV-2 in the central nervous system and optimized for treatment in older people, pregnant women, and COVID-19 patients with heart complications, which are associated with severity and mortality of COVID-19.

A bispecific nanobody dimer broadly neutralizes SARS-CoV-1 & 2 variants of concern and offers substantial protection against Omicron via low-dose intranasal administration.

Current SARS-CoV-2 Omicron subvariants impose a heavy burden on global health systems by evading immunity from most developed neutralizing antibodies and vaccines. Here, we identified a nanobody (aSA3) that strongly cross-reacts with the receptor binding domain (RBD) of both SARS-CoV-1 and wild-type (WT) SARS-CoV-2. The dimeric construct of aSA3 (aSA3-Fc) tightly binds and potently neutralizes both SARS-CoV-1 and WT SARS-CoV-2. Based on X-ray crystallography, we engineered a bispecific nanobody dimer (2-3-Fc) by fusing aSA3-Fc to aRBD-2, a previously identified broad-spectrum nanobody targeting an RBD epitope distinct from aSA3. 2-3-Fc exhibits single-digit ng/mL neutralizing potency against all major variants of concerns including BA.5. In hamsters, a single systemic dose of 2-3-Fc at 10 mg/kg conferred substantial efficacy against Omicron infection. More importantly, even at three low doses of 0.5 mg/kg, 2-3-Fc prophylactically administered through the intranasal route drastically reduced viral RNA loads and completely eliminated infectious Omicron particles in the trachea and lungs. Finally, we discovered that 2(Y29G)-3-Fc containing a Y29G substitution in aRBD-2 showed better activity than 2-3-Fc in neutralizing BA.2.75, a recent Omicron subvariant that emerged in India. This study expands the arsenal against SARS-CoV-1, provides potential therapeutic and prophylactic candidates that fully cover major SARS-CoV-2 variants, and may offer a simple preventive approach against Omicron and its subvariants.

COVID-19 excess deaths in Eastern European countries associated with weaker regulation implementation and lower vaccination coverage.

Background: Since winter 2020, excess deaths due to COVID-19 have been higher in Eastern Europe than most of Western Europe, partly because regulatory enforcement was poor. Methods: This paper analysed data from 50 countries in the WHO European Region, in addition to data from USA and Canada. Excess mMortality and vaccination data were retrieved from "Our World In Data" and regulation implementation was assessed using standard methods. Multiple linear regression was used to assess the association between mortality and each covariate. Results: Excess mortality increased by 4.1 per 100 000 (P = 0.038) for every percentage decrease in vaccination rate and with 6/100 000 (p=0.011) for every decreased unit in the regulatory implementation score a country achieved in the Rule of Law Index. Conclusion: Degree of regulation enforcement, likely including public health measure enforcement, may be an important factor in controlling COVID-19's deleterious health impacts.

Emergence of SARS-CoV-2 Omicron variant and strategies for tackling the infection.

INTRODUCTION: Nowadays, emerging SARS-CoV-2 Omicron, the novel highly mutated VOC, has quickly spread as the dominant variant in over 190 countries worldwide through the first part of 2022, which is influencing the infectivity, transmissibility, pathogenicity, and severity of COVID-19 pandemic. Additionally, clinical cases and experimental studies have reported that Omicron variant likely leads to weakened immune protection elicited by infection, antibody therapies, and vaccines. The new wave, from late February, 2022, was escalated abruptly by higher levels of transmission of Omicron BA.2 sublineage in China. METHODS AND RESULTS: Following a systematic database search, this review summarizes the salient features of Omicron sublineages, and their impact on transmissibility, disease severity as well as the efficacy of the available vaccines and treatment against the Omicron. CONCLUSION: We hope this study will provide a scientific reference for alleviating the burden of COVID-19.

Demographic disparities in COVID-19 vaccine hesitancy among U.S. adults: Analysis of household pulse survey data from Jul 21 to Oct 11 in 2021.

Monitoring COVID-19 vaccine hesitancy helps design and implement strategies to increase vaccine uptake. Utilizing the large scale cross-sectional Household Pulse Survey data collected between July 21 and October 11 in 2021, this study aims to construct measures of COVID-19 vaccine hesitancy and identify demographic disparities among U.S. adults (18y+). Factor analysis identified three factors of vaccine hesitancy: safety concerns (prevalence: 70.1 %). trust issues (53.5 %), and not seen as necessary (33.8 %). Among those who did not show willingness to receive COVID-19 vaccine, females were more likely to have safety concerns (73.7 %) compared to males (66.7 %), but less likely to have trust issues (female: 49.7 %; male: 57.1 %) or not seen as necessary (female: 23.8 %; male 43.4 %). Higher education was associated with higher prevalence of not seen as necessary. Younger adults and Whites had higher prevalence of having trust issues and not seen as necessary compared to their counter parts.

Identification of phytochemicals in Qingfei Paidu decoction for the treatment of coronavirus disease 2019 by targeting the virus-host interactome.

Qingfei Paidu decoction (QFPDD) has been clinically proven to be effective in the treatment of coronavirus disease 2019 (COVID-19). However, the bioactive components and therapeutic mechanisms remain unclear. This study aimed to explore the effective components and underlying mechanisms of QFPDD in the treatment of COVID-19 by targeting the virus-host interactome and verifying the antiviral activities of its active components in vitro. Key active components and targets were identified by analysing the topological features of a compound-target-pathway-disease regulatory network of QFPDD for the treatment of COVID-19. The antiviral activity of the active components was determined by a live virus infection assay, and possible mechanisms were analysed by pseudotyped virus infection and molecular docking assays. The inhibitory effects of the components tested on the virus-induced release of IL-6, IL-1ß and CXCL-10 were detected by ELISA. Three components of QFPDD, oroxylin A, hesperetin and scutellarin, exhibited potent antiviral activities against live SARS-CoV-2 virus and HCoV-OC43 virus with IC50 values ranging from 18.68 to 63.27 µM. Oroxylin A inhibited the entry of SARS-CoV-2 pseudovirus into target cells and inhibited SARS-CoV-2 S protein-mediated cell-cell fusion by binding with the ACE2 receptor. The active components of QFPDD obviously inhibited the IL-6, IL-1ß and CXCL-10 release induced by the SARS-CoV-2 S protein. This study supports the clinical application of QFPDD and provides an effective analysis method for the in-depth study of the mechanisms of traditional Chinese medicine (TCM) in the prevention and treatment of COVID-19.

TIMELESS is a key gene mediating thrombogenesis in COVID-19 and antiphospholipid syndrome.

Abnormal coagulation and increased risk of thrombosis are some of the symptoms associated with COVID-19 severity. Anti-phospholipid antibodies (aPLs) present in critically ill COVID-19 patients contribute to systemic thrombosis. The aim of this study was to identify key common genes to characterize genetic crosstalk between COVID-19 and antiphospholipid syndrome (APS) using bioinformatics analysis and explore novel mechanisms of immune-mediated thrombosis in critically ill COVID-19 patients. The transcriptome data of mononuclear cells from severe COVID-19 patients and APS patients were evaluated to obtain the common genes. The protein-protein interaction network and cytoHubba module analysis in Cytoscape software were used to find the associated hinge genes and hub genes. Among the common differentially expressed genes, TIMELESS depletion was identified only in patients with severe COVID-19 and not in patients with mild COVID-19, and it was validated with the GSE159678 dataset. Functional analyses using gene ontology terms and the Kyoto Encyclopedia of Genes and Genomes pathway suggested that TIMELESS might contribute to the production of antiphospholipid antibody and thrombosis in both COVID-19 and APS patients. The potential role of TIMELESS and autophagy genes in momonuclear cells were further investigated, and GSK3B was found to be associated with TIMELESS. Autophagy targeting agents have a therapeutic potential against COVID-19 and thrombogenesis in APS, which may be related to the role of autophagy genes in the modification of circadian clock proteins. Interference with TIMELESS and other genes associated with it to regulate autoantibody expression may be a potential strategy for immunotherapy against thrombogenesis in severe COVID-19 patients.