Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus' evolution.

SARS-CoV-2 ORF3a sensitizes cells to ferroptosis via Keap1-NRF2 axis.

Viral infection-induced cell death has long been considered as a double-edged sword in the inhibition or exacerbation of viral infections. Patients with severe Coronavirus Disease 2019 (COVID-19) are characterized by multiple organ dysfunction syndrome and cytokine storm, which may result from SARS-CoV-2-induced cell death. Previous studies have observed enhanced ROS level and signs of ferroptosis in SARS-CoV-2 infected cells or specimens of patients with COVID-19, but the exact mechanism is not clear yet. Here, we find SARS-CoV-2 ORF3a sensitizes cells to ferroptosis via Keap1-NRF2 axis. SARS-CoV-2 ORF3a promotes the degradation of NRF2 through recruiting Keap1, thereby attenuating cellular resistance to oxidative stress and facilitated cells to ferroptotic cell death. Our study uncovers that SARS-CoV-2 ORF3a functions as a positive regulator of ferroptosis, which might explain SARS-CoV-2-induced damage in multiple organs in COVID-19 patients and imply the potential of ferroptosis inhibition in COVID-19 treatment.

Differential media exposure and perceptions of fear and behavior change in China and Israel during the COVID-19 pandemic

Understanding the media effect on behavioral outcomes is critical during a health crisis. Mechanisms explaining the mediation effect of media induced risk perception on individual fears and preventive behavior adoption rarely attend to the assumptions and methods to make a causal inference, nor to explore how the effect differs by socioeconomic status. We applied a causal framework to estimate how differential media exposure motivates fear and behavioral reaction, and to what extent these effects can be explained by risk susceptibility and risk severity perceptions in Israel and China, and whether the effects are conditional on socioeconomic situation. Our results suggest that media consumptions are explanatory predictors for increased fear and behavior through provoked risk perceptions. Moreover, socioeconomic status is a pronounced moderator in differentiating the media effect. These findings emphasize the media effects in the context of pandemic and have potential implications for media campaign and policy making. [ FROM AUTHOR] Copyright of New Media & Society is the property of Sage Publications, Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Biomimetic Nanotechnology for SARS-CoV-2 Treatment.

More than 600 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in the pandemic of coronavirus disease 2019 (COVID-19). In particular, new waves of COVID-19 caused by emerging SARS-CoV-2 variants pose new health risks to the global population. Nanotechnology has developed excellent solutions to combat the virus pandemic, such as ACE2-based nanodecoys, nanobodies, nanovaccines, and drug nanocarriers. Lessons learned and strategies developed during this battle against SARS-CoV-2 variants may also serve as inspiration for developing nanotechnology-based strategies to combat other global infectious diseases and their variants in the future.

Multiple Fibroblast Subtypes Contribute to Matrix Deposition in Pulmonary Fibrosis.

Progressive pulmonary fibrosis results from a dysfunctional tissue repair response and is characterized by fibroblast proliferation, activation, and invasion and extracellular matrix accumulation. Lung fibroblast heterogeneity is well recognized. With single-cell RNA sequencing, fibroblast subtypes have been reported by recent studies. However, the roles of fibroblast subtypes in effector functions in lung fibrosis are not well understood. In this study, we incorporated the recently published single-cell RNA-sequencing datasets on murine lung samples of fibrosis models and human lung samples of fibrotic diseases and analyzed fibroblast gene signatures. We identified and confirmed the novel fibroblast subtypes we reported recently across all samples of both mouse models and human lung fibrotic diseases, including idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and coronavirus disease (COVID-19). Furthermore, we identified specific cell surface proteins for each fibroblast subtype through differential gene expression analysis, which enabled us to isolate primary cells representing distinct fibroblast subtypes by flow cytometry sorting. We compared matrix production, including fibronectin, collagen, and hyaluronan, after profibrotic factor stimulation and assessed the invasive capacity of each fibroblast subtype. Our results suggest that in addition to myofibroblasts, lipofibroblasts and Ebf1+ (Ebf transcription factor 1+) fibroblasts are two important fibroblast subtypes that contribute to matrix deposition and also have enhanced invasive, proliferative, and contraction phenotypes. The histological locations of fibroblast subtypes are identified in healthy and fibrotic lungs by these cell surface proteins. This study provides new insights to inform approaches to targeting lung fibroblast subtypes to promote the development of therapeutics for lung fibrosis.

Occupational low back pain prevention capacity of nurses in China: A multicenter cross-sectional study.

Introduction: Nurses have a high prevalence of occupational low back pain, especially since the outbreak of the COVID-19 pandemic, which has increased the nurses' workloads. It has brought a huge burden on nurses and their professional development. Nurses' occupational low back pain prevention capacity is the logical starting point and core of interventions to prevent its occurrence. To date, there is no study investigating it with a scientific scale. Therefore, a multicenter cross-sectional study was conducted to explore the current status of nurses' capacity in occupational low back pain prevention and its influencing factors in China. Methods: Using a two-stage, purposive and convenience mixed sampling method, 1331 nurses from 8 hospitals across 5 provinces (Hubei, Zhejiang, Shandong, Henan, and Sichuan) in the southern, western, northern, and central areas of mainland China were involved in this study. The demographic questionnaire and occupational low back pain prevention behavior questionnaire were used for data collection. The descriptive analysis, univariate analysis, and multiple stepwise linear regression were used for data analysis. Results: The results showed that the occupational low back pain prevention behavior questionnaire score was 89.00 (80.00, 103.00) [M (Q1, Q3)], which indicated that nurses' ability was at a moderate level. Participation in prevention training before, perceived stress at work, and working hours per week were predictors for nurses' occupational low back pain prevention capacity. Discussion: To improve nurses' prevention ability, nursing managers should organize various training programs, strengthen regulations to reduce nurses' workload and stress, provide a healthy workplace, and offer incentives to motivate nurses.

Pandemic policy assessment by artificial intelligence.

Mobility-control policy is a controversial nonpharmacological approach to pandemic control due to its restriction on people's liberty and economic impacts. Due to the computational complexity of mobility control, it is challenging to assess or compare alternative policies. Here, we develop a pandemic policy assessment system that employs artificial intelligence (AI) to evaluate and analyze mobility-control policies. The system includes three components: (1) a general simulation framework that models different policies to comparable network-flow control problems; (2) a reinforcement-learning (RL) oracle to explore the upper-bound execution results of policies; and (3) comprehensive protocols for converting the RL results to policy-assessment measures, including execution complexity, effectiveness, cost and benefit, and risk. We applied the system to real-world metropolitan data and evaluated three popular policies: city lockdown, community quarantine, and route management. For each policy, we generated mobility-pandemic trade-off frontiers. The results manifest that the smartest policies, such as route management, have high execution complexity but limited additional gain from mobility retention. In contrast, a moderate-level intelligent policy such as community quarantine has acceptable execution complexity but can effectively suppress infections and largely mitigate mobility interventions. The frontiers also show one or two turning points, reflecting the safe threshold of mobility retention when considering policy-execution errors. In addition, we simulated different policy environments and found inspirations for the current policy debates on the zero-COVID policy, vaccination policy, and relaxing restrictions.

Effects of the COVID-19 Lockdown on Air Pollutant Levels and Associated Reductions in Ischemic Stroke Incidence in Shandong Province, China.

Background: Local governments in China took restrictive measures after the outbreak of COVID-19 to control its spread, which unintentionally resulted in reduced anthropogenic emission sources of air pollutants. In this study, we intended to examine the effects of the COVID-19 lockdown policy on the concentration levels of particulate matter with aerodynamic diameters of ≤1 µm (PM1), ≤2.5 µm (PM2.5), and ≤10 µm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO) and the potential subsequent reductions in the incidence of ischemic and hemorrhagic stroke in Shandong Province, China. Methods: A difference-in-difference model combining the daily incidence data for ischemic and hemorrhagic stroke and air pollutant data in 126 counties was used to estimate the effect of the COVID-19 lockdown on the air pollutant levels and ischemic and hemorrhagic stroke incident counts. The avoided ischemic stroke cases related to the changes in air pollutant exposure levels were further estimated using concentration-response functions from previous studies. Results: The PM1, PM2.5, PM10, NO2, and CO levels significantly decreased by -30.2, -20.9, -13.5, -46.3, and -13.1%, respectively. The O3 level increased by 11.5% during the lockdown compared with that in the counterfactual lockdown phase of the past 2 years. There was a significant reduction in population-weighted ischemic stroke cases (-15,315, 95% confidence interval [CI]: -27,689, -2,942), representing a reduction of 27.6% (95% CI: -49.9%, -5.3%). The change in the number of hemorrhagic stroke cases was not statistically significant. The total avoided PM1-, PM2.5-, PM10-, NO2-, and CO-related ischemic stroke cases were 739 (95% CI: 641, 833), 509 (95% CI: 440, 575), 355 (95% CI: 304, 405), 1,132 (95% CI: 1,024, 1,240), and 289 (95% CI: 236, 340), respectively. Conclusion: The COVID-19 lockdown indirectly reduced the concentration levels of PM1, PM2.5, PM10, NO2, and CO and subsequently reduced the associated ischemic stroke incidence. The health benefits due to the lockdown are temporary, and long-term measures should be implemented to increase air quality and related health benefits in the post-COVID-19 period.

Genome-Wide Analysis of the Indispensable Role of Non-structural Proteins in the Replication of SARS-CoV-2.

Understanding the process of replication and transcription of SARS-CoV-2 is essential for antiviral strategy development. The replicase polyprotein is indispensable for viral replication. However, whether all nsps derived from the replicase polyprotein of SARS-CoV-2 are indispensable is not fully understood. In this study, we utilized the SARS-CoV-2 replicon as the system to investigate the role of each nsp in viral replication. We found that except for nsp16, all the nsp deletions drastically impair the replication of the replicon, and nsp14 could recover the replication deficiency caused by its deletion in the viral replicon. Due to the unsuccessful expressions of nsp1, nsp3, and nsp16, we could not draw a conclusion about their in trans-rescue functions. Our study provided a new angle to understand the role of each nsp in viral replication and transcription, helping the evaluation of nsps as the target for antiviral drug development.

The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, we report that esterification of the 5'-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5'-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.

A comprehensive evolutionary and epidemiological characterization of insertion and deletion mutations in SARS-CoV-2 genomes.

SARS-CoV-2, which causes the current pandemic of respiratory illness, is evolving continuously and generating new variants. Nevertheless, most of the sequence analyses thus far focused on nucleotide substitutions despite the fact that insertions and deletions (indels) are equally important in the evolution of SARS-CoV-2. In this study, we analyzed 1,099,664 high-quality sequences of SARS-CoV-2 genomes to re-construct the evolutionary and epidemiological histories of indels. Our analysis revealed 289 circulating indel types (237 deletion and 52 insertion types, each represented by more than ten genomic sequences), among which eighteen were recurrent indel types, each represented by more than 500 genome sequences. Although indels were identified across the entire genome, most of them were identified in nsp6, S, ORF8, and N genes, among which ORF8 indel types had the highest frequencies of frameshift. Geographical and temporal analyses of these variants revealed a few alterations of dominant indel types, each accompanied by geographic expansion to different countries and continents, which resulted in the fixation of several types of indels in the field, including the current variants of concern. Evolutionary and structural analyses revealed that indels involving S N-terminal domain regions were linked to the 3/4 variants of concern, resulting in significantly altered S protein that might contribute to the selective advantage of the corresponding variant. In sum, our study highlights the important role of insertions and deletions in the evolution and spread of SARS-CoV-2.

The Impact of Accumulated Mutations in SARS-CoV-2 Variants on the qPCR Detection Efficiency.

SARS-CoV-2 is evolving with mutations throughout the genome all the time and a number of major variants emerged, including several variants of concern (VOC), such as Delta and Omicron variants. In this study, we demonstrated that mutations in the regions corresponding to the sequences of the probes and 3'-end of primers have a significant impact on qPCR detection efficiency. We also found that the G28916T mutation of the N gene accounts for 78.78% sequenced genomes of Delta variant. It was found that detection sensitivity of G28916T mutant was 2.35 and 1.74 times less than that of the wt sequence and detection limit was reduced from 1 copy/µl to 10 copies/µl for the commercially available CP3 and CP4 primer/probe sets. These results indicate that the detection probes and primers should be optimized to keep maximal detection efficiency in response to the emergence of new variants.

A comprehensive evolutionary and epidemiological characterization of insertion and deletion mutations in SARS-CoV-2 genomes

SARS-CoV-2, which causes the current pandemic of respiratory illness, is evolving continuously and generating new variants. Nevertheless, most of the sequence analyses thus far focused on nucleotide substitutions despite the fact that insertions and deletions (indels) are equally important in the evolution of SARS-CoV-2. In this study, we analyzed 1,099,664 high-quality sequences of SARS-CoV-2 genomes to re-construct the evolutionary and epidemiological histories of indels. Our analysis revealed 289 circulating indel types (237 deletion and 52 insertion types, each represented by more than ten genomic sequences), among which eighteen were recurrent indel types, each represented by more than 500 genome sequences. Although indels were identified across the entire genome, most of them were identified in nsp6, S, ORF8, and N genes, among which ORF8 indel types had the highest frequencies of frameshift. Geographical and temporal analyses of these variants revealed a few alterations of dominant indel types, each accompanied by geographic expansion to different countries and continents, which resulted in the fixation of several types of indels in the field, including the current variants of concern. Evolutionary and structural analyses revealed that indels involving S N-terminal domain regions were linked to the 3/4 variants of concern, resulting in significantly altered S protein that might contribute to the selective advantage of the corresponding variant. In sum, our study highlights the important role of insertions and deletions in the evolution and spread of SARS-CoV-2.

Development of septic shock and prognostic assessment in critically ill patients with coronavirus disease outside Wuhan, China.

BACKGROUND: The study aims to illustrate the clinical characteristics and development of septic shock in intensive care unit (ICU) patients confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to perform a comprehensive analysis of the association between septic shock and clinical outcomes in critically ill patients with coronavirus disease (COVID-19). METHODS: Patients confirmed with SARS-CoV-2 infection, who were admitted to the ICU of the Third People's Hospital of Shenzhen from January 1 to February 7, 2020, were enrolled. Clinical characteristics and outcomes were compared between patients with and without septic shock. RESULTS: In this study, 35 critically ill patients with COVID-19 were included. Among them, the median age was 64 years (interquartile range [IQR] 59-67 years), and 10 (28.4%) patients were female. The median ICU length of stay was 16 days (IQR 8-23 days). Three (8.6%) patients died during hospitalization. Nine (25.7%) patients developed septic shock in the ICU, and these patients had a significantly higher incidence of organ dysfunction and a worse prognosis than patients without septic shock. CONCLUSIONS: Septic shock is associated with a poor outcome in critically ill COVID-19 patients and is one of the hallmarks of the severity of patients receiving ICU care. A dysregulated immune response, uncontrolled inflammation, and coagulation disorders are strongly associated with the development and progression of COVID-19-related septic shock.

Some characteristics of clinical sequelae of COVID-19 survivors from Wuhan, China: A multi-center longitudinal study.

BACKGROUND: The pandemic of COVID-19 has a persistent impact on global health, yet its sequelae need to be addressed at a wide scale around the globe. This study aims to investigate the characteristics, prevalence, and risk factors for mid-term (>6 months) clinical sequelae in a cohort of COVID-19 survivors. METHODS: Totally 715 COVID-19 survivors discharged before April 1, 2020, from three medical centers in Wuhan, China, were included. The longitudinal study was conducted by telephone interviews based on a questionnaire including the clinical sequelae of general, respiratory, and cardiovascular systems. Demographics and some characteristics of clinical sequelae of the survivors were recorded and analyzed. Multivariate logistic regression analysis was applied to explore the risk factors for the sequelae. RESULTS: The median time interval from discharge to telephone interview was 225.0 days. The COVID-19 survivors' median ages were 69 years, and 51.3% were male. Among them, 29.9% had at least one clinical sequela. There were 19.2%, 22.7%, and 5.0% of the survivors reporting fatigue, respiratory symptoms, and cardiovascular symptoms, respectively. Comorbidities, disease severity, the application of mechanical ventilation and high-flow oxygen therapy, and the history of re-admission were associated with the presence of clinical sequelae. CONCLUSIONS: Our study provides further evidence for the prevalence and characteristics of clinical sequelae of COVID-19 survivors, suggesting long-term monitoring and management is needed for their full recovery.

Attitudes to Being Vaccinated Against COVID-19: A Survey of People With Epilepsy in China.

Objective: We conducted a survey to assess vaccination coverage, vaccination willingness, and variables associated with vaccination hesitancy to provide evidence on coronavirus disease (COVID-19) vaccination strategies. Methods: This anonymous questionnaire study conducted a multicenter, cross-sectional survey of outpatients and inpatients with epilepsy (PWE) registered in epilepsy clinics, in 2021, in 10 hospitals in seven cities of Shandong Province. Results: A total of 600 questionnaires were distributed, and 557 valid questionnaires were returned. A total of 130 people were vaccinated against COVID-19. Among 427 unvaccinated participants, 69.32% (296/427) were willing to receive the COVID-19 vaccine in the future, and the remaining 30.68% (131/427) were unwilling to receive vaccination. Most (89.9%) of the participants believed that the role of vaccination was crucial in response to the spread of COVID-19. A significant association was found between willingness to receive the COVID-19 vaccine and the following variables: age, marital status, level of education, occupation, residence, seizure type, and seizure control after antiepileptic drug therapy. It is noteworthy that education level, living in urban areas, and seizure freedom were significantly related to willingness to receive COVID-19 vaccination. Conclusions: Vaccination is a key measure for the prevention and control of COVID-19, and most PWE are willing to be vaccinated. Vaccine safety, effectiveness, and accessibility are essential in combatting vaccine hesitation and increasing vaccination rates.

Traditional Chinese medicine for COVID-19 pandemic and emerging challenges: An online cross-sectional survey in China.

BACKGROUND: We aimed to investigate use of infection control behaviours, preventative and therapeutic interventions, and outcomes among respondents to an online survey during the COVID-19 pandemic in China. METHODS: The survey was designed by an international team, translated and adapted to simplified Chinese, including 132 kinds of traditional Chinese medicine (TCM) preparation recommended by guidelines. It was distributed and collected from February to May 2021, with data analysed by WPS spreadsheet and wjx.cn. Descriptive statistics were used to describe demographics and clinical characteristics, diagnosis, treatments, preventative behaviours and interventions, and their associated outcomes. RESULTS: The survey was accessed 503 times with 341 (67.8%) completions covering 23 provinces and four municipalities in China. Most (282/341, 82.7%) respondents reported no symptoms during the pandemic and the majority (290/341, 85.0%) reported having a SARS-CoV-2 PCR test at some point. Forty-five (13.2%) reported having a respiratory infection, among which 19 (42.2%) took one or more categories of modern medicine, e.g. painkillers, antibiotics; 16 (35.6%) used TCM interventions(s); while seven respondents combined TCM with modern medicine. All respondents reported using at least one behavioural or medical approach to prevention, with 22.3% taking TCM and 5.3% taking modern medicines. No respondents reported having a critical condition related to COVID-19. CONCLUSION: We found evidence of widespread use of infection control behaviours, modern medicines and TCM for treatment and prevention of COVID-19 and other respiratory symptoms. Larger scale studies are warranted, including a more representative sample exploring TCM preparations recommended in clinical guidelines.