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171 lines
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<title>20 December, 2023</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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</ul>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>Coping with Covid 19 lockdown: Optimism and Intolerance of Uncertainty in India</strong> -
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Background: Kerala state in India has been hailed as an exceptional model in containing the Covid 19 pandemic within a low resource setting Insights from such a setting are valuable for mental health research during an epidemic situation, especially for resource poor countries. Aims:The study examined the relationship between optimism intolerance of uncertainty (IU), and socio- demographic factors among participants from Kerala, India. Methods: An observational design was used and data was collected using online survey. Snowball sampling method was employed. Sample consisted of 121 adults belonging to Kerala. Standardised tools and customised questionnaire were used for data collection. Descriptive and inferential statistics were employed. Results: A strong relationship existed between inhibitory anxiety and optimism. Socio-demographic factors did not determine either intolerance of uncertainty or optimism. The unprecedented uncertainty brought about by the pandemic needs further exploration. Conclusions: The present pandemic has presented an unprecedented situation regarding well being of individuals. Further studies on anxiety and related issues, and protective factors during situations of uncertainty are needed for policy and practice related to community level disaster preparedness.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://osf.io/bzfp7/" target="_blank">Coping with Covid 19 lockdown: Optimism and Intolerance of Uncertainty in India</a>
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<li><strong>PandoGen: Generating complete instances of future SARS-CoV-2 sequences using Deep Learning</strong> -
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Deep generative models have achieved breakthrough performance in generating computer code, instances of human language and images. We explore the use of these models to create as yet undiscovered instances of viral sequences in a pandemic situation. Towards this goal, we formulate a novel framework for training models to align the sequence generation problem to the characteristics of a pandemic. We applied our method to modeling the SARS-CoV2 Spike protein, the primary driver of the COVID-19 pandemic, and compared our method to models trained via prevalent practices applied to biological sequence modeling. Our method substantially outperforms a state-of-the-art generative model finetuned on SARS-CoV2 data, producing samples containing sequences which are four times as likely to be real, undiscovered sequences, and ten times as infectious. Our method can forecast novel lineages of the virus up to approximately 3 months in advance. Given a limited sequence budget, our method generates sequences belonging to the Delta variant and multiple dominant Omicron subvariants up to a month in advance.
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.05.10.540124v5" target="_blank">PandoGen: Generating complete instances of future SARS-CoV-2 sequences using Deep Learning</a>
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</div></li>
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<li><strong>Robust detection of SARS-CoV-2 exposure in population using T-cell repertoire profiling</strong> -
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The COVID-19 pandemic offers a powerful opportunity to develop methods for monitoring the spread of infectious diseases based on their signatures in population immunity. Adaptive immune receptor repertoire sequencing (AIRR-seq) has become the method of choice for identifying T cell receptor (TCR) biomarkers encoding pathogen specificity and immunological memory. AIRR-seq can detect imprints of past and ongoing infections and facilitate the study of individual responses to SARS-CoV-2, as shown in many recent studies. Here, we have applied a machine learning approach to two large AIRR-seq datasets with more than 1,200 high-quality repertoires from healthy and COVID-19-convalescent donors to infer TCR repertoire features that were induced by SARS-CoV-2 exposure. The new batch effect correction method allowed us to use data from different batches together, as well as combine the analysis for data obtained using different protocols. Proper standardization of AIRR-seq batches, access to human leukocyte antigen (HLA) typing, and the use of both - and {beta}-chain sequences of TCRs resulted in a high-quality biomarker database and a robust and highly accurate classifier for COVID-19 exposure. This classifier is applicable to individual TCR repertoires obtained using different protocols, paving the way to AIRR-seq-based immune status assessment in large cohorts of donors.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.11.08.566227v2" target="_blank">Robust detection of SARS-CoV-2 exposure in population using T-cell repertoire profiling</a>
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</div></li>
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<li><strong>CNP blocks mitochondrial depolarization and inhibits SARS-CoV-2 replication in vitro and in vivo</strong> -
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<div>
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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 that CNP inhibits the generation of new SARS-CoV-2 virions, reducing intracellular titers without inhibiting viral structural protein translation. Additionally, we show that targeting of CNP to mitochondria is necessary for inhibition, blocking mitochondrial depolarization and implicating CNP’s proposed role as an inhibitor of the mitochondrial permeabilization transition pore (mPTP) as the mechanism of virion assembly inhibition. We also demonstrate that an adenovirus expressing virus expressing both human ACE2 and CNP inhibits SARS-CoV-2 titers to undetectable levels in lungs of mice. Collectively, this work shows the potential of CNP to be a new SARS-CoV-2 antiviral target.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.06.09.544327v2" target="_blank">CNP blocks mitochondrial depolarization and inhibits SARS-CoV-2 replication in vitro and in vivo</a>
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</div></li>
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<li><strong>Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies</strong> -
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<div>
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SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) {beta} sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). In donors exhibiting sustained anti-S antibody titers (designated as “sustainers”), S-reactive T cell clonotypes detected immediately after 2nd vaccination polarized to follicular helper T (Tfh)-like cells, which was less obvious in “decliners”. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic bacteria. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly-responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination contributes to the longevity of anti-S antibody titers.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.06.06.543529v2" target="_blank">Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies</a>
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</div></li>
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<li><strong>UVAE: Integration of Heterogeneous Unpaired Data with Imbalanced Classes</strong> -
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<div>
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We introduce the Unbiasing Variational Autoencoder (UVAE), a novel computational framework developed for the integration of unpaired biomedical data streams, with a particular focus on clinical flow cytometry. UVAE effectively addresses the challenges of batch effect correction and data alignment by training a semi-supervised model on partially labeled datasets. This approach enables the simultaneous normalisation and integration of diverse data within a shared latent space. The framework is implemented in Python with a descriptive interface for the specification and incorporation of multiple, partially overlapping data series. UVAE employs a probabilistic model for batch effect normalisation, with a generative capacity for unbiased data reconstruction and inference from heterogeneous samples. Its training process strategically balances class contents during various stages, ensuring accurate representation in statistical analyses. The model's convergence is achieved through a stable, non-adversarial training mechanism, complemented by an automated selection of hyper-parameters via Bayesian optimization. We quantitatively validate the performance of UVAE's constituent components and consequently apply it to the real problem of integrating heterogeneous clinical flow cytometry data collected from COVID-19 patients. We show that the alignment process enhances the statistical signal of cell types associated with severity and enables clustering of subpopulations without the impediment of batch effects. Finally, we demonstrate that homogeneous data generated by UVAE can be used to improve the performance of longitudinal regression for predicting peak disease severity from temporal patient samples.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.18.572157v1" target="_blank">UVAE: Integration of Heterogeneous Unpaired Data with Imbalanced Classes</a>
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</div></li>
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<li><strong>Quantification of biases in predictions of protein-protein binding affinity changes upon mutations</strong> -
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<div>
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Understanding the impact of mutations on protein-protein binding affinity is a key objective for a wide range of biotechnological applications and for shedding light on disease-causing mutations, which are often located at protein-protein interfaces. Over the past decade, many computational methods using physics-based and/or machine learning approaches have been developed to predict how protein binding affinity changes upon mutations. They all claim to achieve astonishing accuracy on both training and test sets, with performances on standard benchmarks such as SKEMPI 2.0 that seem overly optimistic. Here we benchmarked eight well-known and well-used predictors and identified their biases and dataset dependencies, using not only SKEMPI 2.0 as a test set but also deep mutagenesis data on the SARS-CoV-2 spike protein in complex with the human angiotensin-converting enzyme 2. We showed that, even though most of the tested methods reach a significant degree of robustness and accuracy, they suffer from limited generalizability properties and struggle to predict unseen mutations. Interestingly, the generalizability problems are more severe for pure machine learning approaches while physics-based methods are less affected by this issue. Moreover, undesirable prediction biases towards specific mutation properties, the most marked being towards destabilizing mutations, are also observed and should be carefully considered by method developers. We conclude from our analyses that there is room for improvement in the prediction models and suggest ways to check, assess and improve their generalizability and robustness.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.04.551687v2" target="_blank">Quantification of biases in predictions of protein-protein binding affinity changes upon mutations</a>
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<li><strong>Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance</strong> -
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<div>
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All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at air-liquid interface (ALI). HCoV-229E, HCoV-NL63 and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.18.571720v1" target="_blank">Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance</a>
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<li><strong>Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19</strong> -
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<div>
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The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble alpha-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) frequently experience hyposmia. We previously hypothesized that alpha-synuclein and tau misprocessing could occur following host responses to microbial triggers. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19+ patients (n=22), individuals with Lewy body disease (e.g., PD and dementia with Lewy bodies (DLB; n=6)), Alzheimer disease (AD; n=3), other non-synucleinopathy-linked degenerative diseases (e.g., progressive supranuclear palsy (PSP; n=2) and multisystem atrophy (MSA; n=1)). Further, we included neurologically healthy controls (HCO; n=9) and those with an inflammation-rich brain disorder as neurological controls (NCO; n=7). When probing for inflammatory changes focusing on anterior olfactory nuclei (AON) using anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, inflammation on average was not significantly altered in COVID19+ patients relative to controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-alpha-Syn and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes, when present, in the rostral, intracranial portion of the olfactory circuitry generally reflected neurodegenerative processes seen elsewhere in the brain. In general, inflammation correlated best with the degree of Alzheimer's-linked tauopathy and declined with progression of age in COVID19+ patients.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.18.572180v1" target="_blank">Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19</a>
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<li><strong>Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection</strong> -
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<div>
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The coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown that, except vaccination, few therapeutics options for its treatment or prevention are available. Among the pathways that can be targeted for COVID-19 treatment, the Keap1/Nrf2 pathway seems of high interest as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we use three potent activators of the Keap1/Nrf2 pathway and showed that Sulfodyne(R), a stabilized natural Sulforaphane preparation with optimal bioavailability, had the highest antiviral activity in pulmonary or colonic epithelial cell lines even when added late after SARS-CoV-2 infection. This antiviral activity was not dependent on NRF2 activity but associated with action on ER stress and mTOR signaling that are activated during SARS-CoV-2 infection. Sulfodyne(R) also decreased the inflammatory response of epithelial cell lines infected by SARS-CoV-2 independently of SARS-CoV-2 replication and reduced the activation of human monocytes that are recruited after infection of epithelial cells by SARS-CoV-2. Administration of Sulfodyne(R) had little effects on SARS-CoV-2 replication in mice and hamsters infected with SARS-CoV-2 but significantly reduced weight loss and disease severity. Altogether, these results pinpoint the natural compound Sulfodyne(R) as a potent therapeutic agent of COVID-19 symptomatology.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.18.572126v1" target="_blank">Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection</a>
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<li><strong>Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates</strong> -
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Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.18.572191v1" target="_blank">Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates</a>
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<li><strong>Direct comparison of SARS-CoV-2 variant specific neutralizing antibodies in human and hamster sera</strong> -
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Antigenic characterization of newly emerging SARS-CoV-2 variants is important to assess their immune escape and judge the need for future vaccine updates. As exposure histories for human sera become more and more complex, animal sera may provide an alternative for antigenic characterization of new variants. To bridge data obtained from animal sera with human sera, we here analyzed neutralizing antibody titers in human and hamster first infection sera in a highly controlled setting using the same live-virus neutralization assay performed in one laboratory. Using a Bayesian framework, we found that titer fold changes in hamster sera corresponded well to human sera and that hamster sera generally exhibited higher reactivity. Our results indicate that sera from infected hamsters are a good surrogate for the antigenic characterization of new variants.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.19.572347v1" target="_blank">Direct comparison of SARS-CoV-2 variant specific neutralizing antibodies in human and hamster sera</a>
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<li><strong>Comparison of mitochondrial response to SARS-CoV-2 spike protein receptor binding domain in human lung microvascular, coronary artery endothelial and bronchial epithelial cells</strong> -
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Recent evidence indicate that SARS-CoV-2 spike protein affects mitochondria with a cell type-dependent outcome. We elucidate the effect of SARS-CoV-2 receptor binding domain (RBD) on the mitochondrial network and cristae morphology, oxygen consumption, mitoROS produc-tion, and inflammatory cytokine expression in cultured human lung microvascular (HLMVEC) and coronary artery endothelial (HCAEC) and bronchial epithelial cells (HBEC). Live Mito Orange staining, STED microscopy and Fiji MiNa analysis were used for mitochondrial cristae and net-work morphometry, Agilent XFp analyser for mitochondrial/glycolytic activity, MitoSOX fluo-rescence for mitochondrial ROS, and qRT-PCR plus Luminex for cytokines. In HLMVEC, SARS-CoV-2 RBD fragmented the mitochondrial network, decreased cristae density, mitochondrial oxygen consumption and glycolysis and induced mitoROS-mediated GM-CSF and IL-1{beta} expression in all three investigated cell types and IL-8 - in both endothelial cell types. Mito-chondrial ROS control SARS-CoV-2 RBD-induced inflammation in HLMVEC, HCAEC and HBEC, with the mitochondria of HLMVEC being more sensitive to SARS-CoV-2 RBD.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.19.572363v1" target="_blank">Comparison of mitochondrial response to SARS-CoV-2 spike protein receptor binding domain in human lung microvascular, coronary artery endothelial and bronchial epithelial cells</a>
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<li><strong>Are we done with Hydroxychloroquine for COVID-19? Studies with ethical, legal, and methodological concerns must now be retracted</strong> -
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On October 30th, a new study from the Institut Hospitalo-Universitaire Méditerranée Infection (IHU-MI) was published in the journal “New Microbes and New Infections” [1]. This is the latest publication in a long series that is controversial both scientifically and legally. Indeed, several other articles had been published by this team on the topic of Covid-19. The first one [2], has been adjudicated to be fraudulent by the former President of the board of this institute [3]. Further COVID-19 research has had significant ethical concerns arise, regarding the conduct of the studies [4,5,6,7,8] due to their purported retrospective nature despite the trial description appearing to be a prospective trial. These trials are also prima facie problematic because, from May the 11th 2020 and the removal of a special decree authorizing it temporarily, the use of hydroxychloroquine was forbidden outside of clinical trials in France, and these were not conducted as clinical trials. Similarly, off-label prescription was not possible in that case because this process is subject to a strict law regulation in France and can be proposed to patients only if: i) there is no alternative labeled therapy, ii) it is used case by case and not systematically for all patients as was the case at the IHU and iii) the available scientific data ensures efficacy and safety of the drug in the dedicated indication (see Code de la Santé Publique, Article L5121-12-1-2), which was clearly not the case for hydroxychloroquine in COVID-19 treatment. Consequently, since hydroxychloroquine is considered in this indication as an experimental drug in France, a retrospective design likely contravenes French law on biomedical research (see Code de la santé publique, Article L1121-1) [9]. Despite all scientific and ethics arguments having been brought to the attention of the editor, and the publisher themselves declaring that the study has no scientific merit and is “fully irresponsible” [10] even prior to the fraud being uncovered, the initial publication has still not been retracted [11].
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🖺 Full Text HTML: <a href="https://osf.io/vhr7s/" target="_blank">Are we done with Hydroxychloroquine for COVID-19? Studies with ethical, legal, and methodological concerns must now be retracted</a>
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<li><strong>Should we publish every correlation during the COVID-19 pandemic?</strong> -
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Recently, Sun et al. published an article in Scientific Reports entitled: “Increased emergency cardiovascular events among under-40 population in Israel during vaccine rollout and third COVID-19 wave” [2]. In this paper, the authors highlighted correlations between the Israeli vaccine campaign and an increased number of severe cardiovascular event calls to Emergency Management Services in the under-40 population. Even if the correlation seemed statistically significant, it is, to our opinion, clinically irrelevant.
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🖺 Full Text HTML: <a href="https://osf.io/zj4xr/" target="_blank">Should we publish every correlation during the COVID-19 pandemic?</a>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluate the Efficacy and Safety of “Formosa 1-Breath Free (NRICM101)” in Subjects With the Symptoms of COVID-19 or Influenza-like Disease</strong> - <b>Conditions</b>: Influenza Viral Infections; COVID-19 <br/><b>Interventions</b>: Drug: Formosa 1-Breath Free (NRICM101); Drug: Placebo control drug <br/><b>Sponsors</b>: China Medical University Hospital; Tian-I Pharmaceutical,. Co. Ltd.; China Medical University, China; Qualitix Clinical Research Co., Ltd. <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>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).</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Biological: Recombinant COVID-19 (XBB) Trimer Protein Vaccine (Sf9 Cell) (WSK-V102D); Biological: Recombinant COVID-19 Variant Vaccine (Sf9 Cell) (WSK-V102); Biological: Placebo <br/><b>Sponsors</b>: WestVac Biopharma Co., Ltd.; WestVac Biopharma (Guangzhou) Co., Ltd. <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Restoring Energy With Sub-symptom Threshold Optimized Rehabilitation Exercise for Long COVID</strong> - <b>Conditions</b>: Long Covid19; Exercise Intolerance, Riboflavin-Responsive <br/><b>Interventions</b>: Behavioral: Restoring Energy with Sub-symptom Threshold Aerobic Rehabilitation Exercise; Behavioral: Light Stretching/Breathing Exercises <br/><b>Sponsors</b>: Columbia University; New York University <br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Pilot Study of Liraglutide (A Weight Loss Drug) in High Risk Obese Participants With Cognitive and Memory Issues</strong> - <b>Conditions</b>: Multiple Sclerosis; Long COVID; Long Covid19; Obese; Obesity; Obesity, Morbid; Acute Leukemia in Remission <br/><b>Interventions</b>: Drug: Liraglutide Pen Injector [Saxenda]; Other: Medication Diary <br/><b>Sponsors</b>: University of Chicago <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Phase 1 Trial of Recombinant COVID-19 Trivalent Protein Vaccine （CHO Cell）LYB002V14 in Booster Vaccination</strong> - <b>Conditions</b>: SARS-CoV-2; COVID-19 Vaccine <br/><b>Interventions</b>: Biological: 30μg dose of LYB002V14; Biological: 60μg dose of LYB002V14; Biological: placebo <br/><b>Sponsors</b>: Guangzhou Patronus Biotech Co., Ltd.; Yantai Patronus Biotech Co., Ltd. <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>COVID-19 Vaccine Effectiveness Against Recurrent Infection Among Lung Cancer Patients and Biomarker Research</strong> - <b>Conditions</b>: COVID-19 Recurrent; Lung Cancer; Vaccination; Antibody; Chemotherapy; Immune Checkpoint Inhibitor <br/><b>Interventions</b>: Biological: Any Chinese government-recommended COVID-19 booster vaccine <br/><b>Sponsors</b>: Peking Union Medical College Hospital <br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>EXERCISE TRAINING USING AN APP ON PHYSICAL CARDIOVASCULAR FUNCTION INDIVIDUALS WITH POST-COVID-19 SYNDROME</strong> - <b>Conditions</b>: Post-Acute COVID-19 Syndrome <br/><b>Interventions</b>: Behavioral: Exercise; Behavioral: Control <br/><b>Sponsors</b>: University of Nove de Julho <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>IMMUNERECOV CONTRIBUTES TO IMPROVEMENT OF RESPIRATORY AND IMMUNOLOGICAL RESPONSE IN POST-COVID-19 PATIENTS.</strong> - <b>Conditions</b>: Long Covid19; Dietary Supplements; Respiratory Tract Infections; Inflammation <br/><b>Interventions</b>: Dietary Supplement: Nutritional blend (ImmuneRecov). <br/><b>Sponsors</b>: Federal University of São Paulo <br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Physical Activity Coaching in Patients With Post-COVID-19</strong> - <b>Conditions</b>: Post-COVID-19 Syndrome <br/><b>Interventions</b>: 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 <br/><b>Sponsors</b>: University of Alcala; Colegio Profesional de Fisioterapeutas de la Comunidad de Madrid <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study on Post-Acute COVID-19 Syndrome in Improvement of COVID-19 Rehabilitated Patients by Respiratory Training</strong> - <b>Conditions</b>: COVID-19, Post-Acute COVID-19 Syndrome, Dyspnea, Incentive Spirometer <br/><b>Interventions</b>: Device: breathing training <br/><b>Sponsors</b>: Tri-Service General Hospital <br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ensitrelvir for Viral Persistence and Inflammation in People Experiencing Long COVID</strong> - <b>Conditions</b>: Long COVID; Post Acute Sequelae of COVID-19; Post-Acute COVID-19 <br/><b>Interventions</b>: Drug: Ensitrelvir; Other: Placebo <br/><b>Sponsors</b>: Timothy Henrich; Shionogi Inc. <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Low-intensity Aerobic Training Associated With Global Muscle Strengthening in Post-COVID-19</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Procedure: muscle strengthening <br/><b>Sponsors</b>: Centro Universitário Augusto Motta <br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Intravenous Immunoglobulin Replacement Therapy for Persistent COVID-19 in Patients With B-cell Impairment</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Drug: Immunoglobulins <br/><b>Sponsors</b>: Jaehoon Ko <br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of Inhaled Hydroxy Gas on Long COVID Symptoms</strong> - <b>Conditions</b>: Post-Acute COVID-19 Syndrome <br/><b>Interventions</b>: Device: Hydroxy gas <br/><b>Sponsors</b>: Oxford Brookes University <br/><b>Recruiting</b></p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>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</strong> - 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…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Integrated metabolomics and transcriptomics analyses reveal metabolic responses to TGEV infection in porcine intestinal epithelial cells</strong> - 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…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>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</strong> - 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…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses</strong> - 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),…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition</strong> - 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…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Unraveling viral drug targets: a deep learning-based approach for the identification of potential binding sites</strong> - 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…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Inhibition of SARS-CoV-2 NSP-15 by Uridine-5’-Monophosphate Analogues Using QSAR Modelling, Molecular Dynamics Simulations, and Free Energy Landscape</strong> - 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…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Human super antibody to viral RNA-dependent RNA polymerase produced by a modified Sortase self-cleave-bacteria surface display system</strong> - CONCLUSION: The functionalized super antibody to RNA virus RdRp was successfully produced by using combined Sortase self-cleave and bacterial surface display systems with modification. The display system is suitable for downstream processing in a large-scale production of the super antibody. It is applicable also for production of other recombinant proteins in soluble free-folding form.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Contemporary Public Health Finance: Varied Definitions, Patterns, and Implications</strong> - The financing of public health systems and services relies on a complex and fragmented web of partners and funding priorities. Both underfunding and “dys-funding” contribute to preventable mortality, increases in disease frequency and severity, and hindered social and economic growth. These issues were both illuminated and magnified by the COVID-19 pandemic and associated responses. Further complicating issues is the difficulty in constructing adequate estimates of current public health…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Investigation of the mutated antimicrobial peptides to inhibit ACE2, TMPRSS2 and GRP78 receptors of SARS-CoV-2 and angiotensin II type 1 receptor (AT1R) as well as controlling COVID-19 disease</strong> - SARS-CoV-2 is a global problem nowadays. Based on studies, some human receptors are involved in binding to SARS-CoV-2. Thus, the inhibition of these receptors can be effective in the treatment of Covid-19. Because of the proven benefits of antimicrobial peptides (AMPs) and the side effects of chemical drugs, they can be known as an alternative to recent medicines. RCSB PDB to obtain PDB id, StraPep and PhytAMP to acquire Bio-AMPs information and 3-D structure, and AlgPred, Toxinpred,…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Decoy peptides effectively inhibit the binding of SARS-CoV-2 to ACE2 on oral epithelial cells</strong> - The entry of SARS-CoV-2 into host cells involves the interaction between the viral spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor. Given that the spike protein evolves rapidly to evade host immunity, therapeutics that block ACE2 accessibility, such as spike decoys, could serve as an alternative strategy for attenuating viral infection. Here, we constructed a drug screening platform based on oral epithelial cells to rapidly identify peptides or compounds capable of…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy and safety of zapnometinib in hospitalised adult patients with COVID-19 (RESPIRE): a randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial</strong> - BACKGROUND: Zapnometinib is an oral, non-ATP-competitive, small-molecule inhibitor of MEK1/MEK2 with immunomodulatory and antiviral properties. We aimed to investigate the safety and efficacy of zapnometinib in patients with COVID-19.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Design, synthesis and biological evaluation of betulinic acid derivatives as potential inhibitors of 3CL-protease of SARS-CoV-2</strong> - During the coronavirus reproduction process, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are accountable for the fragmentation of two polyprotein precursors (pp1a/pp1ab) into substructural proteins. These two proteins are vital for the replication and transcription of the viral genome. Therefore, 3CLpro is a key protein and target for the design of coronavirus inhibitors. In previous studies, we found that betulinic acid has an inhibitory effect on 3CLpro, with 51.5 %…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Chlorogenic acid inhibits porcine deltacoronavirus release by targeting apoptosis</strong> - Porcine deltacoronavirus (PDCoV), belonging to family Coronaviridae, genus Deltacoronavirus, can cause acute diarrhea in piglets, and also possesses cross-species transmission potential, leading to severe economic losses and threatening public health. However, no approved drug against PDCoV infection is available. Here, we investigated the antiviral effect of chlorogenic acid (CGA), the main active component of Lonicerae Japonicae Flos, against PDCoV infection. The results showed that CGA…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Protective Efficacy of Novel Engineered Human ACE2-Fc Fusion Protein Against Pan-SARS-CoV-2 Infection In Vitro and in Vivo</strong> - Enduring occurrence of severe COVID-19 for unvaccinated, aged, or immunocompromised individuals remains an urgent need. Soluble human angiotensin-converting enzyme 2 (ACE2) has been used as a decoy receptor to inhibit SARS-CoV-2 infection, which is limited by moderate affinity. We describe an engineered, high-affinity ACE2 that is consistently effective in tissue cultures in neutralizing all strains tested, including Delta and Omicron. We also found that treatment of AC70 hACE2 transgenic mice…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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