Evaluation of the Inhibition Potency of Nirmatrelvir against Main Protease Mutants of SARS-CoV-2 Variants.

SARS-CoV-2 continues to pose a threat to public health. Main protease (Mpro) is one of the most lucrative drug targets for developing specific antivirals against SARS-CoV-2 infection. By targeting Mpro, peptidomimetic nirmatrelvir is able to inhibit viral replication of SARS-CoV-2 and reduce the risk for progression to severe COVID-19. However, multiple mutations in the gene encoding Mpro of emerging SARS-CoV-2 variants raise a concern of drug resistance. In the present study, we expressed 16 previously reported SARS-CoV-2 Mpro mutants (G15S, T25I, T45I, S46F, S46P, D48N, M49I, L50F, L89F, K90R, P132H, N142S, V186F, R188K, T190I, and A191V). We evaluated the inhibition potency of nirmatrelvir against these Mpro mutants and solved the crystal structures of representative Mpro mutants of SARS-CoV-2 bound to nirmatrelvir. Enzymatic inhibition assays revealed that these Mpro variants remain susceptible to nirmatrelvir as the wildtype. Detailed analysis and structural comparison provided the inhibition mechanism of Mpro mutants by nirmatrelvir. These results informed the ongoing genomic surveillance of drug resistance of emerging SARS-CoV-2 variants to nirmatrelvir and facilitate the development of next-generation anticoronavirus drugs.

Immunology of SARS-CoV-2 infection and vaccination.

Comprehensive elucidation of humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination is critical for understanding coronavirus disease 2019 (COVID-19) pathogenesis in general and developing antibody-based diagnostic and therapeutic strategies specifically. Following the emergence of SARS-CoV-2, significant scientific research has been conducted worldwide using omics, sequencing and immunologic approaches. These studies have been critical to the successful development of vaccines. Here, the current understanding of SARS-CoV-2 immunogenic epitopes, humoral immunity to SARS-CoV-2 structural proteins and non-structural proteins, SARS-CoV-2-specific antibodies, and T-cell responses in convalescents and vaccinated individuals are reviewed. Additionally, we explore the integrated analysis of proteomic and metabolomic data to examine mechanisms of organ injury and identify potential biomarkers. Insight into the immunologic diagnosis of COVID-19 and improvements of laboratory methods are highlighted.

Food Sources May Affect the Symptom Rates of COVID-19, an Epidemiological Analysis Based on the Public Data in Gansu Province, China, During the Summer Epidemic Cycle in 2022.

According to the public data collected from the Health Commission of Gansu Province, China, regarding the COVID-19 pandemic during the summer epidemic cycle in 2022, the epidemiological analysis showed that the pandemic spread stability and the symptom rate (the number of confirmed cases divided by the sum of the number of asymptomatic cases and the number of confirmed cases) of COVID-19 were different among 3 main epidemic regions, Lanzhou, Linxia, and Gannan; both the symptom rate and the daily instantaneous symptom rate (daily number of confirmed cases divided by the sum of daily number of asymptomatic cases and daily number of confirmed cases) in Lanzhou were substantially higher than those in Linxia and Gannan. The difference in the food sources due to the high difference of the population ethnic composition in the 3 regions was probably the main driver for the difference of the symptom rates among the 3 regions. This work provides potential values for prevention and control of COVID-19 in different regions.

Summary of global surveillance data of infectious diseases in January 2023

In January 2023, a total of 64 infectious diseases were reported globally, affecting 235 countries and regions. Except for influenza, the top five infectious diseases affecting greatest number of countries and regions were COVID-19 (235), monkeypox (110), dengue fever (31), measles (27) and cholera (15). The top five infectious diseases with highest case fatality rates were Nipah virus disease (62.5%), Ebola virus disease (47.0%), Crimean-Congo haemorrhagic fever (37.5%), Lassa fever (15.1%) and West Nile fever (7.6%). The top five infectious diseases with greatest number of deaths were COVID-19, malaria, cholera, measles and dengue fever. The prevalent infectious diseases in Asia were COVID-19, cholera and dengue fever, the prevalent infectious diseases in Africa were COVID-19, cholera, yellow fever, Lassa fever, malaria and monkeypox, the prevalent infectious diseases in America were COVID-19, cholera, monkeypox, dengue fever and chikungunya fever, the prevalent infectious disease in Europe were COVID-19, monkeypox and invasive group A streptococcus infection.

Typical dreams of Chinese elderly people during COVID-19 pandemic

This study aimed at investigating the dream themes of Chinese elderly people during COVID-19 and its relationship with death anxiety. In this study, 264 participants from four cities in different regions of China were interviewed through one-on-one interviews. Nielsen's Typical Dream Questionnaire (TDQ) and Death Anxiety Scale (DAS) were also administered. The dream recall rate of the elderly was 48.48%;there were differences in TDQ35 and TDQ1 between the experimental group (EG) and control group (CG);the most common emotion in elderly people's dreams was fear;TDQ21 (flood) and TDQ28 (see Yourself Die) were two higher frequent dream themes in the high death anxiety group. The results support the dream continuity hypothesis and threat simulation theory (TST), dreams may help coping with death anxiety, and future research directions are also suggested. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

Structural basis of main proteases of HCoV-229E bound to inhibitor PF-07304814 and PF-07321332

PF-07321332 and PF-07304814, inhibitors against SARS-CoV-2 developed by Pfizer, exhibit broad-spectrum inhibitory activity against the main protease (Mpro) from various coronaviruses. Structures of PF-07321332 or PF-07304814 in complex with Mpros of various coronaviruses reveal their inhibitory mechanisms against different Mpros. However, the structural information on the lower pathogenic coronavirus Mpro with PF-07321332 or PF-07304814 is currently scarce, which hinders our comprehensive understanding of the inhibitory mechanisms of these two inhibitors. Meanwhile, given that some immunocompromised individuals are still affected by low pathogenic coronaviruses, we determined the structures of lower pathogenic coronavirus HCoV-229E Mpro with PF-07321332 and PF-07304814, respectively, and analyzed and defined in detail the structural basis for the inhibition of HCoV-229E Mpro by both inhibitors. Further, we compared the crystal structures of multiple coronavirus Mpro complexes with PF-07321332 or PF-07304814 to illustrate the differences in the interaction of Mpros, and found that the inhibition mechanism of lower pathogenic coronavirus Mpro was more similar to that of moderately pathogenic coronaviruses. Our structural studies provide new insights into drug development for low pathogenic coronavirus Mpro, and provide theoretical basis for further optimization of both inhibitors to contain potential future coronaviruses.

Structural basis of main proteases of HCoV-229E bound to inhibitor PF-07304814 and PF-07321332.

PF-07321332 and PF-07304814, inhibitors against SARS-CoV-2 developed by Pfizer, exhibit broad-spectrum inhibitory activity against the main protease (Mpro) from various coronaviruses. Structures of PF-07321332 or PF-07304814 in complex with Mpros of various coronaviruses reveal their inhibitory mechanisms against different Mpros. However, the structural information on the lower pathogenic coronavirus Mpro with PF-07321332 or PF-07304814 is currently scarce, which hinders our comprehensive understanding of the inhibitory mechanisms of these two inhibitors. Meanwhile, given that some immunocompromised individuals are still affected by low pathogenic coronaviruses, we determined the structures of lower pathogenic coronavirus HCoV-229E Mpro with PF-07321332 and PF-07304814, respectively, and analyzed and defined in detail the structural basis for the inhibition of HCoV-229E Mpro by both inhibitors. Further, we compared the crystal structures of multiple coronavirus Mpro complexes with PF-07321332 or PF-07304814 to illustrate the differences in the interaction of Mpros, and found that the inhibition mechanism of lower pathogenic coronavirus Mpro was more similar to that of moderately pathogenic coronaviruses. Our structural studies provide new insights into drug development for low pathogenic coronavirus Mpro, and provide theoretical basis for further optimization of both inhibitors to contain potential future coronaviruses.

Death Anxiety During COVID-19 and its Related Factors among Chinese Elderly People.

This study aimed at investigating death anxiety and its related factors in Chinese elderly people during COVID-19. This study totally interviewed 264 participants from four cities in different regions of China. Death anxiety scale (DAS), NEO-Five-Factor Inventory (Neo-FFI) and Brief COPE were scored on the basis of one-on-one interviews. Quarantine experience didn't make significant difference in death anxiety among the elderly; Elderly people with high death anxiety had higher scores of neuroticism, and were more likely to use a Behavior Disengagement coping strategy; Multiple linear regression analysis showed that neuroticism, openness and COVID impact predicted 44.6% of the variance in the death anxiety among elderly people. The results support both theories of vulnerability-stress model and terror management theory (TMT). In the post-epidemic era, we suggest to pay attention to the mental health status of elderly people with personality susceptibility to handling the stress of infection badly.

Durability of neutralization against Omicron subvariants after vaccination and breakthrough infection.

Booster immunizations and breakthrough infections can elicit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant neutralizing activity. However, the durability of the neutralization response is unknown. We characterize the sensitivity of BA.1, BA.2, BA.2.75, BA.4/BA.5, BF.7, BQ.1.1, and XBB against neutralizing antibodies from vaccination, hybrid immunity, and breakthrough infections 4-6 months after vaccination and infection. We show that a two-dose CoronaVac or a third-dose ZF2001 booster elicits limited neutralization against Omicron subvariants 6 months after vaccination. Hybrid immunity as well as Delta, BA.1, and BA.2 breakthrough infections induce long-term persistence of the antibody response, and over 70% of sera neutralize BA.1, BA.2, BA.4/BA.5, and BF.7. However, BQ.1.1 and XBB, followed by BA.2.75, are more resistant to neutralization, with neutralizing titer reductions of ∼9- to 41-fold, ∼16- to 63-fold, and ∼4- to 25-fold, respectively. These data highlight additional vaccination in CoronaVac- or ZF2001-vaccinated individuals and provide insight into the durability of neutralization against Omicron subvariants.

Durability of neutralization against Omicron subvariants after vaccination and breakthrough infection

Booster immunizations and breakthrough infections can elicit SARS-CoV-2 Omicron subvariants neutralizing activity. However, the durability of the neutralization response is unknown. We characterize the sensitivity of BA.1, BA.2, BA.2.75, BA.4/BA.5, BF.7, BQ.1.1, and XBB against neutralizing antibodies from vaccination, hybrid immunity, and breakthrough infections 4–6 months after vaccination and infection. We show that a two-dose CoronaVac or a third-dose ZF2001 booster elicits limited neutralization against Omicron subvariants 6 months after vaccination. Hybrid immunity as well as Delta, BA.1, and BA.2 breakthrough infections induce long-term persistence of the antibody response, and over 70% of sera neutralize BA.1, BA.2, BA.4/BA.5, and BF.7. However, BQ.1.1 and XBB, followed by BA.2.75, are more resistant to neutralization, with neutralizing titer reductions of ∼9- to 41-fold, ∼16- to 63-fold, and ∼4- to 25-fold, respectively. These data highlight additional vaccination in CoronaVac- or ZF2001-vaccinated individuals and provide insight into the durability of neutralization against Omicron subvariants. Graphical Zhu et al. report that a two-dose CoronaVac or ZF2001 booster elicits limited neutralization against Omicron subvariants 6 months after vaccination. Hybrid immunity and Delta, BA.1 and BA.2 breakthrough infection induce neutralization against earlier Omicron variants, but not for BQ.1.1 and XBB, up to 5 months after vaccination or infection.

Past, present and future prospective of global carbon fibre composite developments and applications

Carbon fibre and carbon fibre reinforced polymer matrix composites (CFRPs) are important lightweight materials for aerospace, automotive, rail transport, infrastructure, and renewable energy applications. This paper provides a comprehensive review on the history of carbon fibres and carbon fibre composites, the current global CFRPs consumption, and trends for future developments in the aerospace, wind turbine, automotive, pressure vessels, sports and leisure, and construction sectors. The history of carbon fibres and CFRPs is discussed over four representative periods including their early development (1950–60's), growth of carbon fibre composites industry (1970–80's), major adoption of carbon fibre composites (the first wave, 1990–2000's), and expanded use of carbon fibre composites (the second wave, 2010's and beyond). Despite a 37% decline of carbon fibre consumption in the aerospace industry in 2021 caused by COVID-19, the global CFRP demand was around 181 kt which more than doubled its value in 2014. There is tangible projected increase over the next five years and the demand for CFRPs is expected to reach 285 kt in 2025, mainly attributed from the fast expansion of non-aerospace industries such as the wind energy sector. Lower cost carbon fibres (e.g., large tow) and associated manufacturing technologies are continually evolving. Finally, the implications of emerging materials and manufacturing methods in conjunction with recycling and reuse for carbon fibre composites are discussed. [ FROM AUTHOR]

Risk and Protective Factors for COVID-19 Morbidity, Severity, and Mortality.

The outbreak of the coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an evolving global health crisis. Currently, a number of risk factors have been identified to have a potential impact on increasing the morbidity of COVID-19 in adults, including old age, male sex, pre-existing comorbidities, and racial/ethnic disparities. In addition to these factors, changes in laboratory indices and pro-inflammatory cytokines, as well as possible complications, could indicate the progression of COVID-19 into a severe and critical stage. Children predominantly suffer from mild illnesses due to COVID-19. Similar to adults, the main risk factors in pediatric patients include age and pre-existing comorbidities. In contrast, supplementation with a healthy diet and sufficient nutrition, COVID-19 vaccination, and atopic conditions may act as protective factors against the infection of SARS-CoV-2. COVID-19 vaccination not only protects vulnerable individuals from SARS-CoV-2 infection, more importantly, it may also reduce the development of severe disease and death due to COVID-19. Currently used therapies for COVID-19 are off-label and empiric, and their impacts on the severity and mortality of COVID-19 are still unclear. The interaction between asthma and COVID-19 may be bidirectional and needs to be clarified in more studies. In this review, we highlight the clinical evidence supporting the rationale for the risk and protective factors for the morbidity, severity, and mortality of COVID-19.

Molecular hydrogen is a potential protective agent in the management of acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.

Highly efficacious and safe neutralizing DNA aptamer of SARS-CoV-2 as an emerging therapy for COVID-19 disease.

BACKGROUND: The paucity of SARS-CoV-2-specific virulence factors has greatly hampered the therapeutic management of patients with COVID-19 disease. Although available vaccines and approved therapies have shown tremendous benefits, the continuous emergence of new variants of SARS-CoV-2 and side effects of existing treatments continue to challenge therapy, necessitating the development of a novel effective therapy. We have previously shown that our developed novel single-stranded DNA aptamers not only target the trimer S protein of SARS-CoV-2, but also block the interaction between ACE2 receptors and trimer S protein of Wuhan origin, Delta, Delta plus, Alpha, Lambda, Mu, and Omicron variants of SARS-CoV-2. We herein performed in vivo experiments that administer the aptamer to the lungs by intubation as well as in vitro studies utilizing PBMCs to prove the efficacy and safety of our most effective aptamer, AYA2012004_L. METHODS: In vivo studies were conducted in transgenic mice expressing human ACE2 (K18hACE2), C57BL/6J, and Balb/cJ. Flow cytometry was used to check S-protein expressing pseudo-virus-like particles (VLP) uptake by the lung cells and test the immuogenicity of AYA2012004_L. Ames test was used to assess mutagenicity of AYA2012004_L. RT-PCR and histopathology were used to determine the biodistribution and toxicity of AYA2012004_L in vital organs of mice. RESULTS: We measured the in vivo uptake of VLPs by lung cells by detecting GFP signal using flow cytometry. AYA2012004_L specifically neutralized VLP uptake and also showed no inflammatory response in mice lungs. In addition, AYA2012004_L did not induce inflammatory response in the lungs of Th1 and Th2 mouse models as well as human PBMCs. AYA2012004_L was detectable in mice lungs and noticeable in insignificant amounts in other vital organs. Accumulation of AYA2012004_L in organs decreased over time. AYA2012004_L did not induce degenerative signs in tissues as seen by histopathology and did not cause changes in the body weight of mice. Ames test also certified that AYA2012004_L is non-mutagenic and proved it to be safe for in vivo studies. CONCLUSIONS: Our aptamer is safe, effective, and can neutralize the uptake of VLPs by lung cells when administered locally suggesting that it can be used as a potential therapeutic agent for COVID-19 management.

SARS-CoV-2 induces "cytokine storm" hyperinflammatory responses in RA patients through pyroptosis.

Background: The coronavirus disease (COVID-19) is a pandemic disease that threatens worldwide public health, and rheumatoid arthritis (RA) is the most common autoimmune disease. COVID-19 and RA are each strong risk factors for the other, but their molecular mechanisms are unclear. This study aims to investigate the biomarkers between COVID-19 and RA from the mechanism of pyroptosis and find effective disease-targeting drugs. Methods: We obtained the common gene shared by COVID-19, RA (GSE55235), and pyroptosis using bioinformatics analysis and then did the principal component analysis(PCA). The Co-genes were evaluated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ClueGO for functional enrichment, the protein-protein interaction (PPI) network was built by STRING, and the k-means machine learning algorithm was employed for cluster analysis. Modular analysis utilizing Cytoscape to identify hub genes, functional enrichment analysis with Metascape and GeneMANIA, and NetworkAnalyst for gene-drug prediction. Network pharmacology analysis was performed to identify target drug-related genes intersecting with COVID-19, RA, and pyroptosis to acquire Co-hub genes and construct transcription factor (TF)-hub genes and miRNA-hub genes networks by NetworkAnalyst. The Co-hub genes were validated using GSE55457 and GSE93272 to acquire the Key gene, and their efficacy was assessed using receiver operating curves (ROC); SPEED2 was then used to determine the upstream pathway. Immune cell infiltration was analyzed using CIBERSORT and validated by the HPA database. Molecular docking, molecular dynamics simulation, and molecular mechanics-generalized born surface area (MM-GBSA) were used to explore and validate drug-gene relationships through computer-aided drug design. Results: COVID-19, RA, and pyroptosis-related genes were enriched in pyroptosis and pro-inflammatory pathways(the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex, death-inducing signaling complex, regulation of interleukin production), natural immune pathways (Network map of SARS-CoV-2 signaling pathway, activation of NLRP3 inflammasome by SARS-CoV-2) and COVID-19-and RA-related cytokine storm pathways (IL, nuclear factor-kappa B (NF-κB), TNF signaling pathway and regulation of cytokine-mediated signaling). Of these, CASP1 is the most involved pathway and is closely related to minocycline. YY1, hsa-mir-429, and hsa-mir-34a-5p play an important role in the expression of CASP1. Monocytes are high-caspase-1-expressing sentinel cells. Minocycline can generate a highly stable state for biochemical activity by docking closely with the active region of caspase-1. Conclusions: Caspase-1 is a common biomarker for COVID-19, RA, and pyroptosis, and it may be an important mediator of the excessive inflammatory response induced by SARS-CoV-2 in RA patients through pyroptosis. Minocycline may counteract cytokine storm inflammation in patients with COVID-19 combined with RA by inhibiting caspase-1 expression.

Analyzing the risk spillovers of international crude oil on China's corn and biofuel ethanol markets: A transition toward green economy and environmental sustainability

This study aims to analyze the risk spillover effects between the global crude oil market and the biofuel ethanol and corn markets in China, employing a DCC-GARCH-Copula-CoVaR model and basing the weekly price data from 2012 to 2021. The empirical results revealed that there were dynamic conditional correlations among international crude oil, China's biofuel ethanol, and corn markets. Following the COVID-19 outbreak, the CoVaR and Delta CoVaR changed, which caused a sharp increase in the mean values and volatility. Additionally, China's biofuel ethanol market is more vulnerable to the risk spillovers from the international crude oil market than China's corn market. However, China's markets do not appear to have obvious risk spillover effects on the global market. The implications of the results are discussed in financial market supervision, including the risk management and portfolio adjustment.

Past, present and future prospective of global carbon fibre composite developments and applications

Carbon fibre and carbon fibre reinforced polymer matrix composites (CFRPs) are important lightweight materials for aerospace, automotive, rail transport, infrastructure, and renewable energy applications. This paper provides a comprehensive review on the history of carbon fibres and carbon fibre composites, the current global CFRPs consumption, and trends for future developments in the aerospace, wind turbine, automotive, pressure vessels, sports and leisure, and construction sectors. The history of carbon fibres and CFRPs is discussed over four representative periods including their early development (1950–60's), growth of carbon fibre composites industry (1970–80's), major adoption of carbon fibre composites (the first wave, 1990–2000's), and expanded use of carbon fibre composites (the second wave, 2010's and beyond). Despite a 37% decline of carbon fibre consumption in the aerospace industry in 2021 caused by COVID-19, the global CFRP demand was around 181 kt which more than doubled its value in 2014. There is tangible projected increase over the next five years and the demand for CFRPs is expected to reach 285 kt in 2025, mainly attributed from the fast expansion of non-aerospace industries such as the wind energy sector. Lower cost carbon fibres (e.g., large tow) and associated manufacturing technologies are continually evolving. Finally, the implications of emerging materials and manufacturing methods in conjunction with recycling and reuse for carbon fibre composites are discussed.

COVID-19 vaccination boosts the potency and breadth of the immune response against SARS-CoV-2 among recovered patients in Wuhan.

The immunity of patients who recover from coronavirus disease 2019 (COVID-19) could be long lasting but persist at a lower level. Thus, recovered patients still need to be vaccinated to prevent reinfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or its mutated variants. Here, we report that the inactivated COVID-19 vaccine can stimulate immunity in recovered patients to maintain high levels of anti-receptor-binding domain (RBD) and anti-nucleocapsid protein (NP) antibody titers within 9 months, and high neutralizing activity against the prototype, Delta, and Omicron strains was observed. Nevertheless, the antibody response decreased over time, and the Omicron variant exhibited more pronounced resistance to neutralization than the prototype and Delta strains. Moreover, the intensity of the SARS-CoV-2-specific CD4+ T cell response was also increased in recovered patients who received COVID-19 vaccines. Overall, the repeated antigen exposure provided by inactivated COVID-19 vaccination greatly boosted both the potency and breadth of the humoral and cellular immune responses against SARS-CoV-2, effectively protecting recovered individuals from reinfection by circulating SARS-CoV-2 and its variants.