- MixOmics Integration of Biological Datasets Identifies Highly Correlated Key Variables of COVID-19 severity. -
BackgroundDespite several years since the COVID-19 pandemic was declared, challenges remain in understanding the factors that can predict the severity of COVID-19 disease and complications of SARS-CoV-2 infection. While many large-scale Multiomic datasets have been published, integration of these datasets has the potential to substantially increase the biological insight gained allowing a more complex comprehension of the disease pathogenesis. Such insight may improve our ability to predict disease progression, detect severe cases more rapidly and develop effective therapeutics. MethodsIn this study we have applied an innovative machine learning algorithm to delineate COVID-severity based on integration of paired samples of proteomic and transcriptomic data from a small cohort of patients testing positive for SARS-CoV-2 infection with differential disease severity. Targeted plasma proteomics and an onco-immune targeted transcriptomic panel was performed on sequential samples from a cohort of 23 severe, 21 moderate and 10 mild COVID-19 patients. We applied DIABLO, a new integrative method, to identify multi- omics biomarker panels that can discriminate between multiple phenotypic groups, such as the varied severity of disease in COVID-19 patients. ResultsAs COVID-19 severity is known among our sample group, we can train models using this as the outcome variable and calculate features that are important predictors of severe disease. In this study, we detect highly correlated key variables of severe COVID-19 using transcriptomic discriminant analysis and multi-omics integration methods. ConclusionsThis approach highlights the power of data integration from a small cohort of patients offering a better biological understanding of the molecular mechanisms driving COVID-19 severity and an opportunity to improve prediction of disease trajectories and targeted therapeutics.
- Tracking SARS-CoV-2 variants of concern in wastewater: an assessment of nine computational tools using simulated genomic data -
Wastewater-based surveillance (WBS) is an important epidemiological and public health tool for tracking pathogens across the scale of a building, neighbourhood, city, or region. WBS gained widespread adoption globally during the SARS-CoV-2 pandemic for estimating community infection levels by qPCR. Sequencing pathogen genes or genomes from wastewater adds information about pathogen genetic diversity which can be used to identify viral lineages (including variants of concern) that are circulating in a local population. Capturing the genetic diversity by WBS sequencing is not trivial, as wastewater samples often contain a diverse mixture of viral lineages with real mutations and sequencing errors, which must be deconvoluted computationally from short sequencing reads. In this study we assess nine different computational tools that have recently been developed to address this challenge. We simulated 100 wastewater sequence samples consisting of SARS-CoV-2 BA.1, BA.2, and Delta lineages, in various mixtures, as well as a Delta-Omicron recombinant and a synthetic novel lineage. Most tools performed well in identifying the true lineages present and estimating their relative abundances, and were generally robust to variation in sequencing depth and read length. While many tools identified lineages present down to 1% frequency, results were more reliable above a 5% threshold. The presence of an unknown synthetic lineage, which represents an unclassified SARS-CoV-2 lineage, increases the error in relative abundance estimates of other lineages, but the magnitude of this effect was small for most tools. The tools also varied in how they labelled novel synthetic lineages and recombinants. While our simulated dataset represents just one of many possible use cases for these methods, we hope it helps users understand potential sources of noise or bias in wastewater sequencing data and to appreciate the commonalities and differences across methods.
- Deciphering Abnormal Platelet Subpopulations in Inflammatory Diseases through Machine Learning and Single-Cell Transcriptomics -
Introduction: The transcriptional heterogeneity of activated platelets, play a significant role in contributing to negative outcomes in sepsis, COVID-19, and autoimmune diseases such as systemic lupus erythematosus (SLE). Despite this, our understanding of these heterogeneous platelet responses remains limited. In this study, we aim to investigate the diverse transcriptional profiles of activated platelets in these diseases, with the goal of deciphering this platelet heterogeneity for new therapeutic strategies to target abnormal and pathogenic platelet subtypes. Materials and methods: We obtained the single cell transcriptional profiles of blood platelets from patients with COVID-19, sepsis, and SLE. Utilizing machine learning algorithms, Deep Neural Network (DNN) and eXtreme Gradient Boosting (XGB), we discerned the distinct transcriptomic signatures indicative of fatal versus survival clinical outcomes. Our methodological framework incorporated source data annotations and platelet markers and used SingleR and Seurat for detailed profiling. Additionally, we implemented Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and visualization, aiding in the detection of various platelet subtypes and their correlation with disease status and patient outcomes. Results: Our study identified distinct platelet subpopulations that are associated with disease severity. We demonstrated that alterations in platelet transcription patterns can exacerbate endotheliopathy, potentially heightening the risk of coagulation in fatal patients. Moreover, these changes can also influence lymphocyte function, indicating a more extensive role for platelets in inflammatory and immune responses. Conclusions: Enhanced transcriptional heterogeneity in activated platelets is linked to adverse outcomes in conditions such as sepsis, COVID-19, and autoimmune diseases. The discovery of these unique platelet subpopulations paves the way for innovative therapeutic strategies targeting platelet activation, which could potentially improve patient outcomes.
- Persistence of an infectious form of SARS-CoV-2 post protease inhibitor treatment of permissive cells in vitro -
Reports have described SARS-CoV-2 rebound in COVID-19 patients treated with nirmatrelvir, a 3CL protease inhibitor. The cause remains a mystery, although drug resistance, re-infection, and lack of adequate immune responses have been excluded. We now present virologic findings that provide a clue to the cause of viral rebound, which occurs in ~20% of the treated cases. The persistence of an intermediary form of infectious SARS-CoV-2 was experimentally documented in vitro after treatment with nirmatrelvir or another 3CL protease inhibitor, but not with a polymerase inhibitor, remdesivir. This infectious intermediate decayed slowly with a half-life of ~1 day, suggesting that its persistence could outlive the treatment course to re-ignited SARS-CoV-2 infection as the drug is eliminated. Additional studies are needed to define the nature of this viral intermediate, but our findings point to a particular direction for future investigation and offer a specific treatment recommendation that should be tested clinically.
- Humoral immune responses to the monovalent XBB.1.5-adapted BNT162b2 mRNA booster -
Continued SARS-CoV-2 evolution and immune escape necessitated the development of updated vaccines, and a monovalent vaccine incorporating the XBB.1.5 variant spike protein is currently being rolled out. Amidst the emergence of the highly mutated BA.2.86 lineage and against the backdrop of pronounced immune imprinting, it is important to characterize the antibody responses following vaccination, particularly in the elderly. Here, we show that the monovalent XBB.1.5-adapted booster vaccination substantially enhanced both binding and neutralising antibody responses against a panel of variants, including BA.2.86, in an older population with four or more previous vaccine doses. Furthermore, neutralizing antibody titers to XBB.1.5 and BA.2.86 were boosted more strongly than titers to historical variants were. Our findings thereby suggest increased vaccine induced protection against both antigenically matched variants, as well as the more distant BA.2.86 variant, and support current vaccine policies recommending a monovalent XBB.1.5 booster dose to older individuals.
- Appraising the decision-making process concerning COVID-19 policy in postsecondary education in Canada: A critical scoping review protocol -
Responses to COVID-19 in Canadian postsecondary education have overhauled usual norms and practices, with policies of unclear rationale implemented under the pressure of a public health emergency. However, despite the unprecedented nature of these policies and their dramatic impact on millions of lives, the decision-making process leading to them has not been documented or appraised. Drawing from macro and micro theories of public policy, specifically the critical tradition in policy studies exemplified by Carol Bacchi’s approach “What is the problem represented to be” (WPR), we will conduct a scoping review of COVID-19 policies in Canadian postsecondary education, guided by Arksey and O’Malley’s framework for scoping reviews and by the team-based approach of Levan and colleagues. Data will include diverse and publicly available documents to capture multiple stakeholders’ perspectives on the phenomenon of interest, and will be retrieved from university, newsletter, and legal websites through combinations of search terms adapted to specific data types. Two reviewers will independently screen, chart, analyse and synthesize the data and disagreements will be resolved through full team discussion. By identifying, summarizing, and appraising the evidence, our review should inform practices that can contribute to effective and equitable public health policies in postsecondary institutions moving forward.
- Comparison of SARS-CoV-2 variants of concern in primary human nasal cultures demonstrates Delta as most cytopathic and Omicron as fastest replicating -
The SARS-CoV-2 pandemic was marked with emerging viral variants, some of which were designated as variants of concern (VOCs) due to selection and rapid circulation in the human population. Here we elucidate functional features of each VOC linked to variations in replication rate. Patient-derived primary nasal cultures grown at air-liquid-interface (ALI) were used to model upper-respiratory infection and human lung epithelial cell lines used to model lower-respiratory infection. All VOCs replicated to higher titers than the ancestral virus, suggesting a selection for replication efficiency. In primary nasal cultures, Omicron replicated to the highest titers at early time points, followed by Delta, paralleling comparative studies of population sampling. All SARS-CoV-2 viruses entered the cell primarily via a transmembrane serine protease 2 (TMPRSS2)-dependent pathway, and Omicron was more likely to use an endosomal route of entry. All VOCs activated and overcame dsRNA-induced cellular responses including interferon (IFN) signaling, oligoadenylate ribonuclease L degradation and protein kinase R activation. Among the VOCs, Omicron infection induced expression of the most IFN and IFN stimulated genes. Infections in nasal cultures resulted in cellular damage, including a compromise of cell-barrier integrity and loss of nasal cilia and ciliary beating function, especially during Delta infection. Overall, Omicron was optimized for replication in the upper-respiratory system and least-favorable in the lower-respiratory cell line; and Delta was the most cytopathic for both upper and lower respiratory cells. Our findings highlight the functional differences among VOCs at the cellular level and imply distinct mechanisms of pathogenesis in infected individuals.
- Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19 -
The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 donor lungs with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage (DAD). We identify changes in cellular composition across progressive DAD, including waves of molecularly distinct macrophages and depleted epithelial and endothelial populations throughout different types of tissue damage. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early DAD, and fibrosis-related collagens in organised DAD. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early DAD. These results provide the first comprehensive, spatially resolved atlas of DAD stages, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways across alveolar damage progression.
- Deep profiling of antigen-specific B cells from different pathogens identifies novel compartments in the IgG memory B cell and antibody-secreting cell lineages -
A better understanding of the bifurcation of human B cell differentiation into memory B cells (MBC) and antibody-secreting cells (ASC) and identification of MBC and ASC precursors is crucial to optimize vaccination strategies or block undesired antibody responses. To unravel the dynamics of antigen-induced B cell responses, we compared circulating B cells reactive to SARS-CoV-2 (Spike, RBD and Nucleocapsid) in COVID-19 convalescent individuals to B cells specific to Influenza-HA, RSV-F and TT, induced much longer ago. High-dimensional spectral flow cytometry indicated that the decision point between ASC- and MBC-formation lies in the CD43+CD71+IgG+ Activated B cell compartment, showing properties indicative of recent germinal center activity and recent antigen encounter. Within this Activated B cells compartment, CD86+ B cells exhibited close phenotypical similarity with ASC, while CD86- B cells were closely related to IgG+ MBCs. Additionally, different activation stages of the IgG+ MBC compartment could be further elucidated. The expression of CD73 and CD24, regulators of survival and cellular metabolic quiescence, discerned activated MBCs from resting MBCs. Activated MBCs (CD73- CD24lo) exhibited phenotypical similarities with CD86- IgG+ Activated B cells and were restricted to SARS-CoV-2 specificities, contrasting with the resting MBC compartment (CD73-/CD24hi) that exclusively encompassed antigen-specific B cells established long ago. Overall, these findings identify novel stages for IgG+ MBC and ASC formation and bring us closer in defining the decision point for MBC or ASC differentiation.
- Predicting the Trend of SARS-CoV-2 Mutation Frequencies Using Historical Data -
As the SARS-CoV-2 virus rapidly evolves, predicting the trajectory of viral variations has become a critical yet complex task. A deep understanding of future mutation patterns, in particular the mutations that will prevail in the near future, is vital in steering diagnostics, therapeutics, and vaccine strategies in the coming months. In this study, we developed a model to forecast future SARS-CoV-2 mutation surges in real-time, using historical mutation frequency data from the USA. To improve upon the accuracy of traditional time-series models, we transformed the prediction problem into a supervised learning framework using a sliding window approach. This involved breaking the time series of mutation frequencies into very short segments. Considering the time-dependent nature of the data, we focused on modeling the first-order derivative of the mutation frequency. We predicted the final derivative in each segment based on the preceding derivatives, employing various machine learning methods including random forest, XGBoost, support vector machine, and neural network models, in this supervised learning setting. Empowered by the novel transformation strategy and the high capacity of machine learning models, we witnessed low prediction error that is confined within 0.1% and 1% when making predictions for future 30 and 80 days respectively. In addition, the method also led to a notable increase in prediction accuracy compared to traditional time-series models, as evidenced by lower MAE, and MSE for predictions made within different time horizons. To further assess the method's effectiveness and robustness in predicting mutation patterns for unforeseen mutations, we categorized all mutations into three major patterns. The model demonstrated its robustness by accurately predicting unseen mutation patterns when training on data from two pattern categories while testing on the third pattern category, showcasing its potential in forecasting a variety of mutation trajectories. To enhance accessibility and utility, we built our methodology into an R-shiny app (https://swdatpredicts.shinyapps.io/rshiny_predict/), a tool with potential applicability in studying other infectious diseases, thus extending its relevance beyond the current pandemic.
- Inverse folding of protein complexes with a structure-informed language model enables unsupervised antibody evolution -
Large language models trained on sequence information alone are capable of learning high level principles of protein design. However, beyond sequence, the three-dimensional structures of proteins determine their specific function, activity, and evolvability. Here we show that a general protein language model augmented with protein structure backbone coordinates and trained on the inverse folding problem can guide evolution for diverse proteins without needing to explicitly model individual functional tasks. We demonstrate inverse folding to be an effective unsupervised, structure-based sequence optimization strategy that also generalizes to multimeric complexes by implicitly learning features of binding and amino acid epistasis. Using this approach, we screened ~30 variants of two therapeutic clinical antibodies used to treat SARS-CoV-2 infection and achieved up to 26-fold improvement in neutralization and 37-fold improvement in affinity against antibody-escaped viral variants-of-concern BQ.1.1 and XBB.1.5, respectively. In addition to substantial overall improvements in protein function, we find inverse folding performs with leading experimental success rates among other reported machine learning-guided directed evolution methods, without requiring any task-specific training data.
- Cell type-specific adaptation of the SARS-CoV-2 spike -
SARS-CoV-2 can infect various human tissues and cell types, principally via interaction with its cognate receptor ACE2. However, how the virus evolves in different cellular environments is poorly understood. Here, we used experimental evolution to study the adaptation of the SARS-CoV-2 spike to four human cell lines expressing different levels of key entry factors. After 20 passages, cell type-specific phenotypic changes were observed. Selected spike mutations were identified and functionally characterized in terms of entry efficiency, ACE2 affinity, spike processing, TMPRSS2 usage, entry pathway and syncytia formation. We found that the effects of these mutations varied across cell types. Interestingly, two spike mutations (L48S and A372T) that emerged in cells expressing low ACE2 levels increased receptor affinity, syncytia induction, and entry efficiency under low-ACE2 conditions. Our results demonstrate specific adaptation of the SARS-CoV-2 spike to different cell types and have implications for understanding SARS-CoV-2 tissue tropism and evolution.
- Temperature impacts SARS-CoV-2 spike fusogenicity and evolution -
SARS-CoV-2 infects both the upper and lower respiratory tracts, which are characterized by different temperatures (33 degrees C and 37 degrees C, respectively). In addition, fever is a common COVID-19 symptom. SARS-CoV-2 has been shown to replicate more efficiently at low temperatures but the effect of temperature on different viral proteins remains poorly understood. Here, we investigate how temperature affects the SARS-CoV-2 spike function and evolution. We first observed that rising temperature from 33 degrees C to 37 degrees C or 39 degrees C increased spike-mediated cell-cell fusion. We then experimentally evolved a recombinant vesicular stomatitis virus expressing the SARS-CoV-2 spike at these different temperatures. We found that spike-mediated cell-cell fusion was maintained during evolution at 39 degrees C, but was lost in a high proportion of viruses evolved at 33 degrees C or 37 degrees C. Consistently, sequencing of the spikes evolved at 33 degrees C or 37 degrees C revealed the accumulation of mutations around the furin cleavage site, a region that determines cell-cell fusion, whereas this did not occur in spikes evolved at 39 degrees C. Finally, using site-directed mutagenesis, we found that disruption of the furin cleavage site had a temperature-dependent effect on spike-induced cell-cell fusion and viral fitness. Our results suggest that variations in body temperature may affect the activity and diversification of the SARS-CoV-2 spike.
- Is Covid-19 “vaccine uptake” in postsecondary education a “problem”? A critical policy inquiry -
Since the launch of the Covid-19 global vaccination campaign, postsecondary institutions have strongly promoted vaccination, often through mandates, and the academic literature has identified “vaccine uptake” among postsecondary students as a problem deserving monitoring, research, and intervention. However, with the admission that vaccines do not stop viral spread, that older-age and co-morbidities are major determinants of poor outcomes, and that many vaccine side effects disproportionately affect the young, it cannot be assumed that a risk-benefit analysis favours vaccinating postsecondary students. Drawing from critical policy studies, I appraise the literature on Covid-19 vaccine uptake in postsecondary education. I find that this literature reflects the “scientific consensus”, hardly acknowledging contradictory medical evidence, ignoring coercive elements underlying “vaccine acceptance”, and neglecting ethical tensions built into the very design of vaccination policies. I discuss potential explanations for my findings, and their implications for academia’s role in society in the COVID-19 era and beyond.
- COVID-19 vaccines and autoimmune disorders: A scoping review protocol -
Background Two years into the global vaccination program, important questions about the association between COVID-19 vaccines and autoimmune diseases have arisen. A growing number of reports have documented associations between COVID-19 vaccination and autoimmunity, suggesting, for example, a causal link between vaccination and new-onset and/or relapsing autoimmune disorders such as type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Graves disease, and Hashimoto’s thyroiditis. These autoimmune phenomena have occurred with various COVID-19 vaccines and research is required to elucidate the underlying mechanisms and causal directions, for example, whether persons with no history of autoimmune disorders may experience them upon vaccination or persons with autoimmune disorders may experience exacerbation or new adverse events post-vaccination. Methods and analysis Specific objectives of this scoping review will address the following questions: Can COVID-19 vaccination trigger and/or exacerbate autoimmune disorders? Are persons with autoimmune disorders at higher risk of experiencing additional autoimmune disorders? What are the mechanisms connecting autoimmune disorders with COVID-19 vaccination? Can COVID-19 vaccination interact with immunosuppressive therapy in persons with autoimmune disorders? Does the risk of autoimmune disorders following COVID-19 vaccination differ by vaccine type, age, gender, or other still unidentified characteristics (e.g., SES)? What is the consensus of care concerning COVID-19 vaccination in persons with autoimmune disorders and what evidence informs it? Our review will follow Arksey and O’Malley’s (2005) framework, enhanced by Levac et al.’s team-based approach (2010), and adhering to the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. To capture the broadest range of perspectives on the phenomenon of interest, data will be synthesized through numerical summaries describing general characteristics of included studies and thematic analysis. Subgroup analysis of primary outcomes will be performed to compare findings according to 1) the previous existence of autoimmune disorder, 2) the presence of relevant co-morbidities, 3) vaccine type; and other relevant factors that we may encounter as the research proceeds. Significance COVID-19 has triggered the largest vaccination campaign in history, targeting literally the global human community. Drug safety is a crucial aspect of any medical intervention, critical to a proper assessment of the balance of risks and benefits. Our investigation should yield information useful to improve medical and public health practice in multiple ways, including assisting in clinical decision-making, policy development, and ethical medical practice.
A Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Combined Modified RNA Vaccine Candidate Against COVID-19 and Influenza. - Conditions: Influenza; COVID-19
Interventions: Biological: Influenza and COVID-19 Combination A; Biological: Licensed influenza vaccine; Biological: COVID-19 Vaccine; Biological: Influenza and COVID-19 Combination B; Biological: Placebo
Sponsors: BioNTech SE; Pfizer
Not yet recruiting
Transcranial Pulse Stimulation (TPS) in Post-COVID-19 - Conditions: Post-COVID-19 Syndrome; Fatigue
Interventions: Device: Transcranial pulse stimulation Verum; Device: Transcranial pulse stimulation Sham
Sponsors: Medical University of Vienna; Campus Bio-Medico University
Not yet recruiting
A Phase 3 Clinical Study to Evaluate the Efficacy, Safety and Immunogenicity of Booster Vaccination With Recombinant COVID-19 (XBB) Trimer Protein Vaccine (Sf9 Cell) (WSK-V102D). - Conditions: COVID-19
Interventions: Biological: Recombinant COVID-19 (XBB) Trimer Protein Vaccine (Sf9 Cell) (WSK-V102D); Biological: Recombinant COVID-19 Variant Vaccine (Sf9 Cell) (WSK-V102); Biological: Placebo
Sponsors: WestVac Biopharma Co., Ltd.; WestVac Biopharma (Guangzhou) Co., Ltd.
Not yet recruiting
Evaluate the Efficacy and Safety of “Formosa 1-Breath Free (NRICM101)” in Subjects With the Symptoms of COVID-19 or Influenza-like Disease - Conditions: Influenza Viral Infections; COVID-19
Interventions: Drug: Formosa 1-Breath Free (NRICM101); Drug: Placebo control drug
Sponsors: China Medical University Hospital; Tian-I Pharmaceutical,. Co. Ltd.; China Medical University, China; Qualitix Clinical Research Co., Ltd.
Not yet recruiting
Restoring Energy With Sub-symptom Threshold Optimized Rehabilitation Exercise for Long COVID - Conditions: Long Covid19; Exercise Intolerance, Riboflavin-Responsive
Interventions: Behavioral: Restoring Energy with Sub-symptom Threshold Aerobic Rehabilitation Exercise; Behavioral: Light Stretching/Breathing Exercises
Sponsors: Columbia University; New York University
Recruiting
A Pilot Study of Liraglutide (A Weight Loss Drug) in High Risk Obese Participants With Cognitive and Memory Issues - Conditions: Multiple Sclerosis; Long COVID; Long Covid19; Obese; Obesity; Obesity, Morbid; Acute Leukemia in Remission
Interventions: Drug: Liraglutide Pen Injector [Saxenda]; Other: Medication Diary
Sponsors: University of Chicago
Not yet recruiting
EXERCISE TRAINING USING AN APP ON PHYSICAL CARDIOVASCULAR FUNCTION INDIVIDUALS WITH POST-COVID-19 SYNDROME - Conditions: Post-Acute COVID-19 Syndrome
Interventions: Behavioral: Exercise; Behavioral: Control
Sponsors: University of Nove de Julho
Not yet recruiting
A Phase 1 Trial of Recombinant COVID-19 Trivalent Protein Vaccine （CHO Cell）LYB002V14 in Booster Vaccination - Conditions: SARS-CoV-2; COVID-19 Vaccine
Interventions: Biological: 30μg dose of LYB002V14; Biological: 60μg dose of LYB002V14; Biological: placebo
Sponsors: Guangzhou Patronus Biotech Co., Ltd.; Yantai Patronus Biotech Co., Ltd.
Not yet recruiting
COVID-19 Vaccine Effectiveness Against Recurrent Infection Among Lung Cancer Patients and Biomarker Research - Conditions: COVID-19 Recurrent; Lung Cancer; Vaccination; Antibody; Chemotherapy; Immune Checkpoint Inhibitor
Interventions: Biological: Any Chinese government-recommended COVID-19 booster vaccine
Sponsors: Peking Union Medical College Hospital
Recruiting
IMMUNERECOV CONTRIBUTES TO IMPROVEMENT OF RESPIRATORY AND IMMUNOLOGICAL RESPONSE IN POST-COVID-19 PATIENTS. - Conditions: Long Covid19; Dietary Supplements; Respiratory Tract Infections; Inflammation
Interventions: Dietary Supplement: Nutritional blend (ImmuneRecov).
Sponsors: Federal University of São Paulo
Recruiting
Physical Activity Coaching in Patients With Post-COVID-19 - Conditions: Post-COVID-19 Syndrome
Interventions: Behavioral: Self-monitoring; Behavioral: Goal setting and review; Behavioral: Education; Behavioral: Feedback; Behavioral: Contact; Behavioral: Exercise; Behavioral: Report; Behavioral: Social support; Behavioral: Group activities; Behavioral: World Health Organization recommendations for being physically active
Sponsors: University of Alcala; Colegio Profesional de Fisioterapeutas de la Comunidad de Madrid
Not yet recruiting
Study on Post-Acute COVID-19 Syndrome in Improvement of COVID-19 Rehabilitated Patients by Respiratory Training - Conditions: COVID-19, Post-Acute COVID-19 Syndrome, Dyspnea, Incentive Spirometer
Interventions: Device: breathing training
Sponsors: Tri-Service General Hospital
Active, not recruiting
Ensitrelvir for Viral Persistence and Inflammation in People Experiencing Long COVID - Conditions: Long COVID; Post Acute Sequelae of COVID-19; Post-Acute COVID-19
Interventions: Drug: Ensitrelvir; Other: Placebo
Sponsors: Timothy Henrich; Shionogi Inc.
Not yet recruiting
Low-intensity Aerobic Training Associated With Global Muscle Strengthening in Post-COVID-19 - Conditions: COVID-19
Interventions: Procedure: muscle strengthening
Sponsors: Centro Universitário Augusto Motta
Completed
Repurposing ebselen as an inhalable dry powder to treat respiratory tract infections - Respiratory tract infections (RTIs) are one of the leading causes of death globally, lately exacerbated by the increasing prevalence of antimicrobial resistance. While antimicrobial resistance could be overcome by developing new antimicrobial agents, the use of a safe repurposed agent having potent antimicrobial activity against various RTIs can be an efficient and cost-effective alternative to overcome the long and complex process of developing and testing new drugs. Ebselen, a synthetic…
Inhibitory effects against SARSCoV-2 main protease (Mpro) of biflavonoids and benzophenones from the fruit of Platonia insignis - The SARS-CoV-2 mutation and the limitation of the approved drug against COVID-19 are still a challenge in many country healthcare systems and need to be affronted despite the set of vaccines to prevent this viral infection. To contribute to the identification of new antiviral agents, the present study focused on natural products from an edible fruit with potential inhibitory effects against the SARS-CoV-2 main protease (M^(pro)). First, LC-ESIMS analysis of Platonia insignis fruits was performed…
Evaluation of SARS-CoV-2 RNA Rebound After Nirmatrelvir/Ritonavir Treatment in Randomized, Double-Blind, Placebo-Controlled Trials - United States and International Sites, 2021-2022 - Rebound of SARS-CoV-2 shedding or COVID-19 signs and symptoms has been described after treatment with nirmatrelvir/ritonavir (Paxlovid). The direct association of nirmatrelvir/ritonavir to COVID-19 rebound remains unclear because most reports are based on individual cases or nonrandomized studies. Viral RNA shedding data from two phase 2/3, randomized, double-blind, placebo-controlled clinical trials of nirmatrelvir/ritonavir (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients…
Synthetic graphene-copper nanocomposites interact with the hACE-2 enzyme and inhibit its biochemical activity - This study demonstrates the copper nanocomposite-induced enzymatic inhibition of human angiotensin I-converting enzyme-2 (hACE-2) by complex stabilization through the formation of the enzyme nanocomposite. The immediate application of this work is related to ACE-2 as a mechanism of SARS-CoV-2 entry into cells. Moreover, ACE-2 enzyme regulation is a potential therapeutic strategy in hypertension and cardiovascular disease, diabetes, lung injury, and fibrotic disorders. Thus, inhibition of ACE-2…
A two-stage design enhanced biodegradation of high concentrations of a C16-alkyl quaternary ammonium compound in oxygen-based membrane biofilm reactors - Quaternary ammonia compounds (QAC), such as hexadecyltrimethyl-ammonium (CTAB), are widely used as disinfectants and in personal-care products. Their use as disinfectants grew during the SARS-CoV-2 (COVID-19) pandemic, leading to increased loads to wastewater treatment systems and the environment. Though low concentrations of CTAB are biodegradable, high concentrations are toxic to bacteria. Sufficient O(2) delivery is a key to achieve high CTAB removal, and the O(2)-based Membrane Biofilm…
CNP blocks mitochondrial depolarization and inhibits SARS-CoV-2 replication in vitro and in vivo - The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world’s healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus replication cycle have been developed however, effective late-stage therapeutical targets have yet to be identified. To that end, our lab identified that 2’,3’ cyclic-nucleotide 3’-phosphodiesterase (CNP) inhibits SARS-CoV-2 virion assembly. We show…
Molecular insights to the anti-COVID-19 potential of α-, β- and γ-cyclodextrins - SARS-CoV-2 viral infection is regulated by the host cell receptors ACE2 and TMPRSS2, and therefore the effect of various natural and synthetic compounds on these receptors has recently been the subject of investigations. Cyclodextrins, naturally occurring polysaccharides derived from starch, are soluble in water and have a hydrophobic cavity at their center enabling them to accommodate small molecules and utilize them as carriers in the food, supplements, and pharmaceutical industries to improve…
Combined in vitro/in silico approaches, molecular dynamics simulations and safety assessment of the multifunctional properties of thymol and carvacrol: A comparative insight - Bioactive compounds derived from medicinal plants have acquired immense attentiveness in drug discovery and development. The present study investigated in vitro and predicted in silico the antibacterial, antifungal, and antiviral properties of thymol and carvacrol, and assessed their safety. The performed microbiological assays against Pseudomonas aeruginosa, Escherichia coli, Salmonella enterica Typhimurium revealed that the minimal inhibitory concentration values ranged from (0.078 to 0.312…
Molecular dynamics, molecular docking, DFT, and ADMET investigations of the Co(II), Cu(II), and Zn(II) chelating on the antioxidant activity and SARS-CoV-2 main protease inhibition of quercetin - The natural flavonol quercetin (Q) is found in many vegetables, fruits, and beverages, and it is known as a strong antioxidant. Its metal ion chelation may increase its antioxidant activity. The present study aims to explore the Co(II), Cu(II), and Zn(II) chelating on the antioxidant effectiveness and severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) main protease (M^(pro)) inhibitory of quercetin using Density-functional theory (DFT), molecular docking, and molecular dynamics…
Integrated metabolomics and transcriptomics analyses reveal metabolic responses to TGEV infection in porcine intestinal epithelial cells - Transmissible gastroenteritis virus (TGEV) is a coronavirus that infects piglets with severe diarrhoea, vomiting, dehydration, and even death, causing huge economic losses to the pig industry. The underlying pathogenesis of TGEV infection and the effects of TGEV infection on host metabolites remain poorly understood. To investigate the critical metabolites and regulatory factors during TGEV infection in intestinal porcine epithelial cells (IPEC-J2), we performed metabolomic and transcriptomic…
Inhibition potential of natural flavonoids against selected omicron (B.1.19) mutations in the spike receptor binding domain of SARS-CoV-2: a molecular modeling approach - The omicron (B.1.19) variant of contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered a variant of concern (VOC) due to its increased transmissibility and highly infectious nature. The spike receptor-binding domain (RBD) is a hotspot of mutations and is regarded as a prominent target for screening drug candidates owing to its crucial role in viral entry and immune evasion. To date, no effective therapy or antivirals have been reported; therefore, there is an…
Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses - Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19),…
Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition - Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the wake of the COVID-19 pandemic. Increasing resistance to gyrase-targeting second-line fluoroquinolone antibiotics indicates the necessity to develop both novel therapeutics and our understanding of M. tuberculosis growth during infection. ParDE toxin-antitoxin systems also target gyrase and are regulated in response to both…
Unraveling viral drug targets: a deep learning-based approach for the identification of potential binding sites - The coronavirus disease 2019 (COVID-19) pandemic has spurred a wide range of approaches to control and combat the disease. However, selecting an effective antiviral drug target remains a time-consuming challenge. Computational methods offer a promising solution by efficiently reducing the number of candidates. In this study, we propose a structure- and deep learning-based approach that identifies vulnerable regions in viral proteins corresponding to drug binding sites. Our approach takes into…
Inhibition of SARS-CoV-2 NSP-15 by Uridine-5’-Monophosphate Analogues Using QSAR Modelling, Molecular Dynamics Simulations, and Free Energy Landscape - SARS-CoV-2 is accountable for severe social and economic disruption around the world causing COVID-19. Non-structural protein-15 (NSP15) possesses a domain that is vital to the viral life cycle and is known as uridylate-specific endoribonuclease (EndoU). This domain binds to the uridine 5’-monophosphate (U5P) so that the protein may carry out its native activity. It is considered a vital drug target to inhibit the growth of the virus. Thus, in this current study, ML-based QSAR and virtual…