- Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics -
We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of S protein compared to the closed form. In particular, the CAP sites control the dynamics binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly compensatory variants. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.
- Low-coverage whole genome sequencing for a highly selective cohort of severe COVID-19 patients -
Despite advances in identifying genetic markers associated to severe COVID-19, the full genetic characterisation of the disease remains elusive. This study explores the use of imputation in low-coverage whole genome sequencing for a severe COVID-19 patient cohort. We generated a dataset of 79 imputed variant call format files using the GLIMPSE1 tool, each containing an average of 9.5 million single nucleotide variants. Validation revealed a high imputation accuracy (squared Pearson correlation {approx}0.97) across sequencing platforms, showing GLIMPSE1's ability to confidently impute variants with minor allele frequencies as low as 2% in Spanish ancestry individuals. We conducted a comprehensive analysis of the patient cohort, examining hospitalisation and intensive care utilisation, sex and age-based differences, and clinical phenotypes using a standardised set of medical terms developed to characterise severe COVID-19 symptoms. The methods and findings presented here may be leveraged in future genomic projects, providing vital insights for health challenges like COVID-19.
- Discovery of orally active SARS-CoV-2 papain-like protease (PLpro) inhibitors -
Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
- Multiple layers of innate immune response antagonism of SARS-CoV-2 -
Several SARS-CoV-2 proteins have been shown to counteract the host innate immune response, mostly using in vitro protein expression, which may not fully reflect their role in the context of viral infection. In addition, while each viral protein was characterized in a different experimental system, their relative contribution in immunosuppression remains unclear. Here we used a SARS-CoV-2 bacterial artificial chromosome with en passant mutagenesis to recover a panel of twelve infectious recombinant SARS-CoV-2 viruses, each with mutations in either NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, NSP14, NSP15, NSP16, ORF3a, ORF6 or ORF8. We used the interferon-stimulated response element (ISRE)-driven luciferase assay in 293T-ACE2/TMPRSS2 cells to test the panel, demonstrating that mutations in many proteins, especially in NSP1 and NSP15, increased the type I interferon response relative to the parental wild-type virus. RNA-seq analysis of mutant-virus infected Calu-3 cells showed that the mutations in NSP1 or NSP15 lead to higher expression of multiple genes involved in innate immune response, cytokine-mediated signaling and regulation of lymphocyte proliferation. Furthermore, mutations in either NSP1 or NSP15 resulted in a greater maturation of human monocyte-derived dendritic cells in vitro. Infection of K18 hACE2 transgenic mice with either NSP1 or NSP15 mutated viruses demonstrated attentuated respiratory tract replication. Analysis of lung immune cells from infected mice by single-cell RNA-seq identified 15 populations of major myeloid and lymphoid cells with changes in the pattern of their activation associated with viral infection. The effects of mutations in NSP1 or NSP15 on these responses are consistent with differences in the immunosuppressive mechanisms utilized by the two proteins. Overall, these data demonstrate different and redundant mechanisms of innate immune antagonism by SARS-CoV-2 and suppression of activation of antigen presenting cells and T and B lymphocytes mediated by multiple viral proteins.
- Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus -
To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune responses generated by vaccination or exposure to previous variants poses a significant challenge. A compelling new therapeutic strategy against SARS-CoV-2 is that of single domain antibodies, termed nanobodies, which address certain limitations of monoclonal antibodies. Here we demonstrate that our high-affinity nanobody repertoire, generated against wild-type SARS-CoV-2 spike protein (Mast, Fridy et al. 2021), remains effective against variants of concern, including omicron BA.4/BA.5; a subset is predicted to counter resistance in emerging XBB and BQ.1.1 sublineages. Furthermore, we reveal the synergistic potential of nanobody cocktails in neutralizing emerging variants. Our study highlights the power of nanobody technology as a versatile therapeutic and diagnostic tool to combat rapidly evolving infectious diseases such as SARS-CoV-2.
- Economic precarity and changing levels of anxiety and stress among Canadians with disabilities and chronic health conditions throughout the COVID-19 pandemic -
Early in the COVID-19 pandemic, multiple event stressors converged to exacerbate a growing mental health crisis in Canada with differing effects across status groups. However, less is known about changing mental health situations throughout the pandemic, especially among individuals more likely to experience chronic stress because of their disability and health status. Using data from two waves of a targeted online survey of people with disabilities and chronic health conditions in Canada (N = 563 individuals, June 2020 and July 2021), we find that approximately 25% of respondents experienced additional increases in stress and anxiety levels in 2021. These increases were partly explained by worsening perceived financial insecurity and, in the case of stress, additional negative financial effects tied to the pandemic. This paper understands mental health disparities as a function of social status and social group membership. By linking stress process models and a minority stress framework with a social model of disability, we allude to how structural and contextual barriers make functional limitations disabling and in turn, life stressors.
- Impact of the COVID-19 Pandemic on Undergraduate Research in the Department of Biology at Western University: Effect on project types, learning outcomes, and student perceptions. -
Undergraduate research is a high impact practice that offers numerous benefits to students, academic institutions, and the wider scientific community. Unfortunately, undergraduate research has faced restrictions due to the COVID-19 pandemic. This study aimed to assess how the COVID-19 pandemic has impacted: (1) the number and types of undergraduate research projects performed in the Department of Biology at the University of Western Ontario, and (2) the satisfaction-levels and perceived learning outcomes of students performing these projects. This study also aimed to incorporate a One Health framework through an emphasis on stakeholder involvement and the need for future action. A survey of 33 students who completed an undergraduate research project in the Department of Biology in the 2020/2021 academic year, and 68 students who completed an undergraduate research project in the 5 years prior was conducted. In keeping with the One Health approach, key stakeholders were identified, and a stakeholder map was constructed. The number of projects performed did not change dramatically despite COVID-19 restrictions. However, a shift towards dry research was observed with 87.9% of students in the 2020/2021 academic year conducting dry research, compared to 16.4% of students in the 5 years prior. Students who conducted research in the 2020/2021 academic year indicated lower overall levels of satisfaction and enjoyment, though their perceived learning outcomes were consistent with students who completed their projects in the 5 years prior. 53 key stakeholders from academia, government, industry, media, and the public were identified. Students provided invaluable feedback on their undergraduate research experiences that can be used to improve the quality of undergraduate research courses in the Department of Biology in the future. Findings may be of use to other departments and educational institutions that are seeking to improve their own undergraduate research courses amidst the COVID-19 pandemic or looking to incorporate experiential-based learning techniques into existing online courses.
- Case of Myocarditis, Pericarditis, and Fatal Aortic Dissection following Covid-19 mRNA Vaccination -
We present a case study of a 34-year-old male who was in apparent good health prior to his COVID-19 mRNA vaccination. Sixteen days after his first dose, he experienced acute inflammation, sudden thoracic aortic dissection, and pericardial tamponade, rapidly leading to his death. Studies suggest that young males, in particular, appear to be at increased risk of adverse cardiac events following COVID-19 mRNA vaccination. However, we propose that certain information gaps exist in the criteria that inform both public health agencies and the public on incidence rates in certain presentations of even severe myocarditis and cardiac adverse events following COVID-19 vaccination, as is often mentioned within COVID-19 vaccine myocarditis studies and is evident within the findings of this young man’s important case presentation.
- nf-core/airrflow: an adaptive immune receptor repertoire analysis workflow employing the Immcantation framework -
Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) is a valuable experimental tool to study the immune state in health and following immune challenges such as infectious diseases, (auto)immune diseases, and cancer. Several tools have been developed to reconstruct B cell and T cell receptor sequences from AIRR-seq data and infer B and T cell clonal relationships. However, currently available tools offer limited parallelization across samples, scalability or portability to high-performance computing infrastructures. To address this need, we developed nf-core/airrflow, an end-to-end bulk and single-cell AIRR-seq processing workflow which integrates the Immcantation Framework following BCR and TCR sequencing data analysis best practices. The Immcantation Framework is a comprehensive toolset, which allows the processing of bulk and single-cell AIRR-seq data from raw read processing to clonal inference. nf-core/airrflow is written in Nextflow and is part of the nf-core project, which collects community contributed and curated Nextflow workflows for a wide variety of analysis tasks. We assessed the performance of nf-core/airrflow on simulated sequencing data with sequencing errors and show example results with real datasets. To demonstrate the applicability of nf-core/airrflow to the high-throughput processing of large AIRR-seq datasets, we validated and extended previously reported findings of convergent antibody responses to SARS-CoV-2 by analyzing 97 COVID-19 infected individuals and 99 healthy controls, including a mixture of bulk and single-cell sequencing datasets. Using this dataset, we extended the convergence findings to 20 additional subjects, highlighting the applicability of nf-core/airrflow to validate findings in small in-house cohorts with reanalysis of large publicly available AIRR datasets. nf-core/airrflow is available free of charge, under the MIT license on GitHub (https://github.com/nf-core/airrflow). Detailed documentation and example results are available on the nf-core website at (https://nf-co.re/airrflow).
- Development and validation of a federated learning framework for detection of subphenotypes of multisystem inflammatory syndrome in children -
Background Multisystem inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection. The highly diverse clinical features of MIS-C necessities characterizing its features by subphenotypes for improved recognition and treatment. However, jointly identifying subphenotypes in multi-site settings can be challenging. We propose a distributed multi-site latent class analysis (dMLCA) approach to jointly learn MIS-C subphenotypes using data across multiple institutions. Methods We used data from the electronic health records (EHR) systems across nine U.S. childrens hospitals. Among the 3,549,894 patients, we extracted 864 patients < 21 years of age who had received a diagnosis of MIS-C during an inpatient stay or up to one day before admission. Using MIS-C conditions, laboratory results, and procedure information as input features for the patients, we applied our dMLCA algorithm and identified three MIS-C subphenotypes. As validation, we characterized and compared more granular features across subphenotypes. To evaluate the specificity of the identified subphenotypes, we further compared them with the general subphenotypes identified in the COVID-19 infected patients. Findings Subphenotype 1 (46.1%) represents patients with a mild manifestation of MIS-C not requiring intensive care, with minimal cardiac involvement. Subphenotype 2 (25.3%) is associated with a high risk of shock, cardiac and renal involvement, and an intermediate risk of respiratory symptoms. Subphenotype 3 (28.6%) represents patients requiring intensive care, with a high risk of shock and cardiac involvement, accompanied by a high risk of >4 organ system being impacted. Importantly, for hospital-specific clinical decision-making, our algorithm also revealed a substantial heterogeneity in relative proportions of these three subtypes across hospitals. Properly accounting for such heterogeneity can lead to accurate characterization of the subphenotypes at the patient-level. Interpretation Our identified three MIS-C subphenotypes have profound implications for personalized treatment strategies, potentially influencing clinical outcomes. Further, the proposed algorithm facilitates federated subphenotyping while accounting for the heterogeneity across hospitals.
- In silico assessment of immune cross protection between BCoV and SARS-CoV-2 -
Background: Humans have long shared infectious agents with cattle, and the bovine-derived human common cold OC-43 CoV is a not-so-distant example of cross-species viral spill over of coronaviruses. Human exposure to the Bovine Coronavirus (BCoV) is certainly common, as the virus is endemic in most high-density cattle-raising regions. Since BCoVs are phylogenetically close to SARS-CoV-2, it is possible that cross-protection against COVID-19 occurs in people exposed to BCoV. Methods: This article shows an in silico investigation of human cross-protection to SARS-CoV-2 due to BCoV exposure. We determined HLA recognition and human B lymphocyte reactivity to BCoV epitopes using bioinformatics resources. A retrospective geoepidemiological analysis of COVID-19 was then performed to verify if BCoV/SARS-CoV-2 cross-protection could have occurred in the field. Brazil was used as a model for the epidemiological analysis of the impact of livestock density, as a proxy for human exposure to BCoV, on the prevalence of COVID-19 in people. Results: As could be expected from their classification in the same Betacoronavirus genus, we show that several human B and T epitopes are shared between BCoV and SARS-CoV-2. This raised the possibility of cross-protection of people from exposure to the bovine coronavirus. Analysis of field data added partial support to the hypothesis of viral cross-immunity from human exposure to BCoV. There was a negative correlation between livestock geographical density and COVID-19. Whole-Brazil data showed areas in the country in which COVID-19 prevalence was disproportionally low (controlled by normalization by transport infrastructure). Areas with high cattle density had lower COVID-19 prevalence in these low-risk areas. Conclusions: These data are hypothesis-raising indications that cross-protection is possibly being induced by human exposure to the Bovine Coronavirus.
- No Substitute for the Real Thing? Physical and Digital Cultural Participation in Denmark during the COVID-19 Pandemic: A Research Note -
In this research note, we analyze the impact of the COVID-19 pandemic on cultural participation. We use rich survey data from Denmark to construct pooled time-series cross-sectional data for each month of the years 2019-2021 and report three findings. First, participation in physical cultural activities (e.g., attending a concert or a museum) plummeted during two lockdowns and did not return to its pre-pandemic level by the end of 2021. Second, participation in digital activities (e.g., reading a digital book or following a museum on social media) did not change much during the pandemic. Overall, we find little evidence of substitution from physical to digital cultural participation during the COVID-19 lockdown in Denmark. Third, socioeconomic gradients in cultural participation decreased during the pandemic for physical cultural participation, but did not change for digital cultural participation. We end by discussing what we can learn from our results about how social disruptions affect patterns of cultural participation and inequality.
- Stratification in Parents’ Selection of Developmentally Appropriate Books for Children: Register-based Evidence from Danish Public Libraries -
This paper studies socioeconomic gradients in selecting developmentally appropriate children’s books from public libraries. I draw on research on developmental gradients in parental inputs to hypothesize that families with high socioeconomic status (SES) are more likely to select books that match children’s developmental stage in order to best improve children’s learning environments. In contrast to previous survey-based research, I use behavioral data on the actual books families have selected from libraries. Based on Danish registry data that cover all books borrowed from public libraries in 2020, I find that highly educated families are more likely to use libraries and borrow more books when they use libraries, but they do not select a larger share of developmentally appropriate books; in fact, they select a slightly lower share. In contrast, I find only a weak positive income gradient for the amount of books borrowed and the share of developmentally appropriate books. The supplementary analyses show that results are robust across families with children of different ages and to account for nonrandom selection into the sample of library users, socioeconomic differences in children’s reading skills, and the impact of library lockdowns due to Covid-19. I conclude that stratification in library book selection is more prominent concerning the voraciousness with which highly educated parents provide reading inputs (more books) than how discriminating they are in terms of selecting developmentally appropriate books.
- Safety Monitoring of Bivalent COVID-19 mRNA Vaccines Among Recipients 6 months and Older in the United States -
Importance Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes post-licensure. Objective To evaluate health outcomes following bivalent COVID-19 Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273.222) vaccination among individuals 6 months and older in the United States. Design Monthly monitoring of health outcomes from August 2022 to July 2023 in four administrative claims databases. Descriptive analyses monitored vaccine uptake, outcome counts and coadministration of bivalent COVID-19 and influenza vaccines. Sequential analyses tested for elevated risk of each outcome in a prespecified post-vaccination risk interval, or a period of hypothesized elevation based on clinical guidance, compared to a historical baseline. Participants and Exposures Persons 6 months and older who received a bivalent COVID-19 BNT162b2 or mRNA-1273.222 vaccine during the study period, with continuous enrollment in a medical insurance plan from the start of an outcome-specific clean interval to the COVID-19 vaccination date. Vaccines were identified using product-specific codes from medical coding systems. Health Outcomes Twenty outcomes were monitored in BNT162b2 vaccine recipients 6 months-4 years, and mRNA-1273.222 vaccine recipients 6 months-5 years. Twenty-one outcomes were monitored in BNT162b2 vaccine recipients 5-17 years and mRNA-1273.222 vaccine recipients 6-17 years. Eighteen outcomes were monitored in persons 18 years and older for both mRNA vaccines. Results Overall, 13.9 million individuals 6 months and older received a single bivalent COVID-19 mRNA vaccine. The statistical threshold for a signal was met for two outcomes in one database: anaphylaxis following bivalent BNT162b2 and mRNA-1273.222 vaccines in persons 18-64 years and myocarditis/pericarditis following bivalent BNT162b2 vaccines in individuals 18-35 years. There were no signals identified in young children. Conclusions Results were consistent with prior observations from published studies on COVID-19 vaccine safety. This study supports the safety profile of bivalent COVID-19 mRNA vaccines and the conclusion that the benefits of vaccination outweigh the risks.
- An ecological study of COVID-19 outcomes among Florida counties -
Background: During the COVID-19 pandemic, Florida reported some of the highest number of cases and deaths in the US; however, county-level variation in COVID-19 outcomes has not been comprehensively investigated. The present ecological study aimed to assess corelates of COVID-19 outcomes among Florida counties that explain variation in case rates, mortality rates, and case fatality rates (CFR) across pandemic waves. Method: We obtained county-level administrative data and COVID-19 case reports from public repositories. We tested spatial autocorrelation to assess geographic clustering in COVID-19 outcomes: case rate, mortality rate, and CFR. Stepwise linear regression was employed to test the association between case, death, and CFR and 18 demographic, socioeconomic, and health-related county-level predictors. Results: We found mortality rate and CFR were significantly higher in rural counties compared to urban counties, among which significant differences in vaccination coverage was also observed. Multivariate analysis found that the percentage of the population aged over 65 years, the percentage of the obese people, and the percentage of rural population were significant predictors of COVID-19 case rate. Median age, vaccination coverage, percentage of people who smoke, and percentage of the population with diabetes were significant influencing factors for CFR. Importantly, vaccination coverage was significantly associated with a reduction in case rate (R = -0.26, p = 0.03) and mortality (R = -0.51, p < 0.001). Last, we found that spatial dependencies play a role in explaining variations in COVID-19 CFR among Florida counties. Conclusion: Our findings emphasize the need for targeted, equitable public health strategies to reduce disparities and enhance population resilience during public health crises. We further inform future spatial-epidemiological analyses and present actionable data for policies related to preparedness and response to current and future epidemics in Florida and elsewhere.
Predict + Protect: A Randomized Controlled Trial Exploring the Effectiveness of a Predictive Health Education Intervention on the Adoption of Protective Behaviors Related to Influenza-like Illness (ILI) - Conditions: Influenza; Influenza A; Influenza B; COVID-19; Respiratory Syncytial Virus (RSV)
Interventions: Behavioral: ILI Predictive Alerts, Reactive Content, and Proactive Content; Behavioral: ILI Predictive Alerts, Reactive Content; Behavioral: Proactive Content; Behavioral: No Intervention
Sponsors: Evidation Health; Biomedical Advanced Research and Development Authority
Not yet recruiting
Long COVID-19 [11C]CPPC Study - Conditions: COVID Long-Haul
Interventions: Drug: [11C]CPPC Injection; Drug: [11C]CPPC Injection
Sponsors: Johns Hopkins University; Radiological Society of North America
Not yet recruiting
Thrombohemorrhagic Complications of COVID-19 - Conditions: COVID-19 (Coronavirus Disease 2019)
Interventions: Diagnostic Test: Prevention algorithm
Sponsors: Volgograd State Medical University
Active, not recruiting
Combined Use of Immunoglobulin and Pulse Steroid Therapies in Severe Covid-19 Patients - Conditions: Pulse Steroid and Immunoglobulins Drugs in Covid 19 Patients
Interventions: Drug: pulse steroid and nanogam
Sponsors: Konya City Hospital
Completed
Beneficial Effects of Natural Products on Management of Xerostomia - Conditions: Xerostomia; Diabetes Mellitus; Hypertension; Post COVID-19 Condition
Interventions: Other: (Manuka honey-green tea- ginger)
Sponsors: British University In Egypt
Completed
Eficacia Ventilatoria y Remolacha - Conditions: SARS CoV 2 Infection; Muscle Disorder; Fatigue
Interventions: Dietary Supplement: Remolacha
Sponsors: Hospital de MatarĂł
Recruiting
Diet and Fasting for Long COVID - Conditions: Long Covid19; Long COVID
Interventions: Other: Low sugar diet and 10-12 hour eating window; Other: Low sugar diet, 8 hour eating window and fasting
Sponsors: Pacific Northwest University of Health Sciences
Recruiting
The Effectiveness of a Health Promotion Program for Older People With Post-Covid-19 Sarcopenia - Conditions: Post COVID-19 Condition
Interventions: Other: Protein powder and Resistance exercise
Sponsors: Mahidol University; National Health Security Office, Thailand
Not yet recruiting
Chronic-disease Self-management Program in Patients Living With Long-COVID in Puerto Rico - Conditions: Long Covid19
Interventions: Other: “Tomando control de su salud” (Spanish Chronic Disease Self-Management)
Sponsors: University of Puerto Rico; National Institutes of Health (NIH)
Recruiting
Treatment of Persistent Post-Covid-19 Smell and Taste Disorders - Conditions: Post-covid-19 Persistent Smell and Taste Disorders
Interventions: Drug: Cerebrolysin; Other: olfactory and gustatory trainings
Sponsors: Sherifa Ahmed Hamed
Completed
A Study to Evealuate Safety and Immunogenicity of TI-0010 SARS-CoV-2 Vaccine in Healthy Adults - Conditions: COVID-19; COVID-19 Immunisation
Interventions: Biological: TI-0010; Biological: Placebo
Sponsors: National Drug Clinical Trial Institute of the Second Affiliated Hospital of Bengbu Medical College; Therorna
Recruiting
AI-driven covalent drug design strategies targeting main protease (mpro) against SARS-CoV-2: structural insights and molecular mechanisms - The emergence of new SARS-CoV-2 variants has raised concerns about the effectiveness of COVID-19 vaccines. To address this challenge, small-molecule antivirals have been proposed as a crucial therapeutic option. Among potential targets for anti-COVID-19 therapy, the main protease (M^(pro)) of SARS-CoV-2 is important due to its essential role in the virus’s life cycle and high conservation. The substrate-binding region of the core proteases of various coronaviruses, including SARS-CoV-2,…
Inhibition of multiple SARS-CoV-2 variants entry by Lycium barbarum L. polysaccharides through disruption of spike protein-ACE2 interaction - Viral respiratory infections are major human health concerns. The most striking epidemic disease, COVID-19 is still on going with the emergence of fast mutations and drug resistance of pathogens. A few polysaccharide macromolecules from traditional Chinese medicine (TCM) have been found to have direct anti-SARS-CoV-2 activity but the mechanism remains unclear. In this study, we evaluated the entry inhibition effect of Lycium barbarum polysaccharides (LBP) in vitro and in vivo. We found LBP…
Proposing of fungal endophyte secondary metabolites as a potential inhibitors of 2019-novel coronavirus main protease using docking and molecular dynamics - In this study, the inhibitory potential of 99 fungal derived secondary metabolites was predicted against SARS-CoV-2 main protease by using of computational approaches. This protein plays an important role in replication and is one of the important targets to inhibit viral reproduction. Among the 99 reported compounds, the 9 of them with the highest binding energy to Mpro obtained from the molecular docking method were selected for the molecular dynamic simulations. The compounds were then…
DON/DRP-104 as potent serine protease inhibitors implicated in SARS-CoV-2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach - Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off-site toxicity profiles remains limited. Therefore, probing the anti-TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become…
Fluoxetine exerts anti-inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release - Fluoxetine is a safe antidepressant with remarkable anti-inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic-polycytidylic acid (p(I:C))-induced inflammatory model. We found that a non-cytotoxic concentration (MTT-assay, CyQUANT-assay) of fluoxetine significantly suppressed p(I:C)-induced expression and release of several pro-inflammatory cytokines (Q-PCR, cytokine array, ELISA), and it…
Flavonoids derived from medicinal plants as a COVID-19 treatment - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 disease. Through its viral spike (S) protein, the virus enters and infects epithelial cells by utilizing angiotensin-converting enzyme 2 as a host cell’s receptor protein. The COVID-19 pandemic had a profound impact on global public health and economies. Although various effective vaccinations and medications are now available to prevent and treat COVID-19, natural compounds derived from medicinal plants,…
Mutational analysis of SARS-CoV-2 ORF6-KPNA2 binding interface and identification of potent small molecule inhibitors to recuse the host immune system - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surfaced on 31 December, 2019, and was identified as the causative agent of the global COVID-19 pandemic, leading to a pneumonia-like disease. One of its accessory proteins, ORF6, has been found to play a critical role in immune evasion by interacting with KPNA2 to antagonize IFN signaling and production pathways, resulting in the inhibition of IRF3 and STAT1 nuclear translocation. Since various mutations have been observed in ORF6,…
Intraepithelial Inclusions on Urinalysis Screening among COVID-19 Cases: Are they Covicytes?-A Hospital-Based Cohort Study with Narrative Review - CONCLUSIONS: This study reported COVID-19-associated urinary cytomorphological abnormalities and interesting unique inclusions (Covicytes) that may be a result of underlying inflammatory changes, reactive hyperplasia, degenerative changes, or defective endocytosed vacuoles. The possible etiologies for renal inclusions were reviewed. We recommend compulsory baseline and follow-up urinary cytology screening for all COVID-19-suspected patients to detect and predict delayed AKI before clinical and…
Marine natural products and human immunity: novel biomedical resources for anti-infection of SARS-CoV-2 and related cardiovascular disease - Marine natural products (MNPs) and marine organisms include sea urchin, sea squirts or ascidians, sea cucumbers, sea snake, sponge, soft coral, marine algae, and microalgae. As vital biomedical resources for the discovery of marine drugs, bioactive molecules, and agents, these MNPs have bioactive potentials of antioxidant, anti-infection, anti-inflammatory, anticoagulant, anti-diabetic effects, cancer treatment, and improvement of human immunity. This article reviews the role of MNPs on…
Antibodies against SARS-CoV-2 non-structural protein 3 cross-react with human muscle cells and neuroglial cells - Coronavirus Disease 2019 (COVID-19) vaccines protect the public and limit viral spread. However, inactivated viral vaccines use the whole virus particle, which contains many non-capsid proteins that may cause adverse immune responses. A report has found that the ADP-ribose-binding domains of SARS-CoV-2 non-structural protein 3 (NSP3) and human poly(ADP-ribose) polymerase family member 14 (PARP14) share a significant degree of homology. Here, we further show that antibodies against 2019 novel…
Eculizumab led to beneficial clinical course in a patient with generalized myasthenia gravis who developed COVID 19-associated pneumonia - A 74-year-old woman developed myasthenia gravis (MG) at the age of 32. She had a thymoma removed the following year, but her MG symptoms did not stabilize, and she required frequent hospitalization for fast-acting treatment (FT). She started eculizumab in March of two years ago and was followed up on an outpatient basis as her MG symptoms became milder. In February of this year, she was admitted to our hospital due to mild COVID-19-associated pneumonia with general malaise and fever. Her…
Lower respiratory tract single-cell RNA sequencing and neutrophil extracellular trap profiling of COVID-19-associated pulmonary aspergillosis: a single centre, retrospective, observational study - BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) is a severe superinfection with the fungus Aspergillus affecting patients who are critically ill with COVID-19. The pathophysiology and the role of neutrophil extracellular traps (NETs) in this infection are largely unknown. We aimed to characterise the immune profile, with a focus on neutrophils and NET concentrations, of critically ill patients with COVID-19, with or without CAPA.
An ensemble docking-based virtual screening and molecular dynamics simulation of phytochemical compounds from Malaysian Kelulut Honey (KH) against SARS-CoV-2 target enzyme, human angiotensin-converting enzyme 2 (ACE-2) - The human angiotensin-converting enzyme 2 (ACE-2) receptor is a metalloenzyme that plays an important role in regulating blood pressure by modulating angiotensin II. This receptor facilitates SARS-CoV-2 entry into human cells via receptor-mediated endocytosis, causing the global COVID-19 pandemic and a major health crisis. Kelulut honey (KH), one of Malaysian honey recently gained attention for its distinct flavour and taste while having many nutritional and medicinal properties. Recent study…
Anti-COVID-19 Potential of Withaferin-A and Caffeic Acid Phenethyl Ester - CONCLUSION: Wi-A and CAPE possess multimodal anti-COVID-19 potential, and their combination (Wi-ACAPE) is expected to provide better activity and hence warrant further attention in the laboratory and clinic.
Recurrent viral capture of cellular phosphodiesterases that antagonize OAS-RNase L - Phosphodiesterases (PDEs) encoded by viruses are putatively acquired by horizontal transfer of cellular PDE ancestor genes. Viral PDEs inhibit the OAS-RNase L antiviral pathway, a key effector component of the innate immune response. Although the function of these proteins is well-characterized, the origins of these gene acquisitions are less clear. Phylogenetic analysis revealed at least five independent PDE acquisition events by ancestral viruses. We found evidence that PDE-encoding genes were…