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159 lines
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<title>03 April, 2024</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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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>Distal Protein-Protein Interactions Contribute to SARS-CoV-2 Main Protease Substrate Binding and Nirmatrelvir Resistance</strong> -
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SARS-CoV-2 main protease, Mpro, is responsible for the processing of the viral polyproteins into individual proteins, including the protease itself. Mpro is a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component of Paxlovid). Resistance mutants identified clinically and in viral passage assays contain a combination of active site mutations (e.g. E166V, E166A, L167F), which reduce inhibitor binding and enzymatic activity, and non-active site mutations (e.g. P252L, T21I, L50F), which restore the fitness of viral replication. Although the mechanism of resistance for the active site mutations is apparent, the role of the non-active site mutations in fitness rescue remains elusive. In this study, we use the model system of a Mpro triple mutant (L50F/E166A/L167F) that confers not only nirmatrelvir drug resistance but also a similar fitness of replication compared to the wild-type both in vitro and in vivo. By comparing peptide and full-length Mpro protein as substrates, we demonstrate that the binding of Mpro substrate involves more than residues in the active site. In particular, L50F and other non-active site mutations can enhance the Mpro dimer-dimer interactions and help place the nsp5-6 substrate at the enzyme catalytic center. The structural and enzymatic activity data of Mpro L50F, L50F/E166A/L167F, and others underscore the importance of considering the whole substrate protein in studying Mpro and substrate interactions, and offers important insights into Mpro function, resistance development, and inhibitor design.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.04.01.587566v1" target="_blank">Distal Protein-Protein Interactions Contribute to SARS-CoV-2 Main Protease Substrate Binding and Nirmatrelvir Resistance</a>
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<li><strong>Single-cell analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells</strong> -
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The ability of SARS-CoV-2 to evade antiviral immune signaling in the airway contributes to the severity of COVID-19 disease. Additionally, COVID-19 is influenced by age and has more severe presentations in older individuals. This raises questions about innate immune signaling as a function of lung development and age. Therefore, we investigated the transcriptome of different cell populations of the airway epithelium using pediatric and adult lung tissue samples from the LungMAP Human Tissue Core Biorepository. Specifically, lung lobes were digested and cultured into a biomimetic model of the airway epithelium on an air-liquid interface. Cells were then infected with SARS-CoV-2 and subjected to single-cell RNA sequencing. Transcriptional profiling and differential expression analysis were carried out using Seurat. The clustering analysis identified several cell populations: club cells, proliferating epithelial cells, multiciliated precursor cells, ionocytes, and two biologically distinct clusters of ciliated cells (FOXJ1high and FOXJ1low). Interestingly, the two ciliated cell clusters showed different infection rates and enrichment of processes involved in ciliary biogenesis and function; we observed a cell-type-specific suppression of innate immunity in infected cells from the FOXJ1low subset. We also identified a significant number of genes that were differentially expressed in lung cells derived from children as compared to adults, suggesting the differential pathogenesis of SARS-CoV-2 infection in children versus adults. We discuss how this work can be used to identify drug targets to modulate molecular signaling cascades that mediate an innate immune response and begin to understand differences in COVID-19 outcomes for pediatric vs. adult populations.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.04.02.587663v1" target="_blank">Single-cell analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells</a>
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<li><strong>Mapping immunodominant sites on the MERS-CoV spike glycoprotein targeted by infection-elicited antibodies in humans</strong> -
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Middle-East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012 and causes human infections in endemic regions. Most vaccines and therapeutics in development against MERS-CoV focus on the spike (S) glycoprotein to prevent viral entry into target cells. These efforts, however, are limited by a poor understanding of antibody responses elicited by infection along with their durability, fine specificity and contribution of distinct S antigenic sites to neutralization. To address this knowledge gap, we analyzed S-directed binding and neutralizing antibody titers in plasma collected from individuals infected with MERS-CoV in 2017-2019 (prior to the COVID-19 pandemic). We observed that binding and neutralizing antibodies peak 1 to 6 weeks after symptom onset/hospitalization, persist for at least 6 months, and broadly neutralize human and camel MERS-CoV strains. We show that the MERS-CoV S1 subunit is immunodominant and that antibodies targeting S1, particularly the RBD, account for most plasma neutralizing activity. Antigenic site mapping revealed that polyclonal plasma antibodies frequently target RBD epitopes, particularly a site exposed irrespective of the S trimer conformation, whereas targeting of S2 subunit epitopes is rare, similar to SARS-CoV-2. Our data reveal in unprecedented details the humoral immune responses elicited by MERS-CoV infection, which will guide vaccine and therapeutic design.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.03.31.586409v1" target="_blank">Mapping immunodominant sites on the MERS-CoV spike glycoprotein targeted by infection-elicited antibodies in humans</a>
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<li><strong>Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process</strong> -
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The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas CD4_CTL precursors were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift- myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model, PHARE (https://xiazlab.org/phare/), which applies to both scRNA-seq and bulk RNA-seq data. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.04.01.587649v1" target="_blank">Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process</a>
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<li><strong>Host factor PLAC8 is required for pancreas infection by SARS-CoV-2</strong> -
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Background Although COVID-19 initially caused great concern about respiratory symptoms, mounting evidence shows that also the pancreas is productively infected by SARS-CoV-2. However, the severity of pancreatic SARS-CoV-2 infection and its pathophysiology are still under debate. Here we investigated the consequences of SARS-CoV-2 pancreatic infection and the role of the host factor Placenta-associated protein (PLAC8) Methods We analyzed plasma levels of pancreatic enzymes and inflammatory markers in a retrospective cohort study of 120 COVID-19 patients distributed in 3 severity-stratified groups. We studied the expression of SARS-CoV-2 and PLAC8 in the pancreas of deceased COVID-19 patients as well as in non-infected donors. We performed infection experiments in PLAC8 knock-out PDAC cell lines with full SARS-CoV-2 virus. Results We found that analysis of circulating pancreatic enzymes aided the stratification of patients according to COVID-19 severity and predict outcomes. Interestingly, we found an association between PLAC8 expression and SARS-CoV-2 infection in postmortem analysis of COVID-19 patients. Using full SARS-CoV-2 infectious virus inoculum from Wuhan-1 and BA.1 strains, we demonstrated that PLAC8 is necessary for productive infection of PDAC cell lines. Finally, we observed an overlap between PLAC8 and SARS47 CoV-2 immunoreactivities of the pancreas of deceased patients. Conclusion Our data indicate the human pancreas as a SARS-CoV-2 target with plausible signs of injury and demonstrate that the host factor PLAC8 is required for SARS-CoV-2 pancreatic infection, thus defining new target opportunities for COVID-19-associated pancreatic pathogenesis.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.18.553908v2" target="_blank">Host factor PLAC8 is required for pancreas infection by SARS-CoV-2</a>
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<li><strong>Large-scale statistical mapping of T-cell receptor β sequences to Human Leukocyte Antigens</strong> -
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Interactions between diverse sets of T-cell receptors (TCRs) and peptides presented by human leukocyte antigens (HLAs) are the foundation of the adaptive immune system but population-level analysis of TCR-HLA interactions is lacking. Here we use the TCR{beta} repertoire of 4,144 HLA-genotyped subjects to associate [~]10^6 public TCRs (i.e., TCRs observed in multiple subjects) with specific HLAs, providing a new window into the functional characteristics of HLAs. We find that the vast majority of these HLA-associated public TCRs are specific to unique HLA allotypes, not allelic groups, and to the paired -{beta} heterodimer of class II HLAs though we observe some exceptions and also that the breadth of the TCR response is proportional to HLA zygosity. Identification of public HLA-specific TCRs permits highly accurate imputation of 248 class I and II HLAs from the TCR{beta} repertoire alone. Notably, 45 HLA-DP and -DQ heterodimers cannot be imputed due to a lack of associated TCRs, despite high representation in our training set. Gene linkage analysis indicates these heterodimers primarily arise from trans-complementation resulting in non-functional -{beta} pairs. Cell sorting, clonal expansion, and comparisons between SARS-CoV-2-exposed and -naive populations suggest that public class I and class II HLA-associated TCRs we identify are primarily expressed on CD8+ and CD4+ memory T cells, respectively, which are responding to a mix of common antigens. Our results recapitulate fundamental immunology, provide critical new insights into the functionality of HLAs, and demonstrate the power and potential of population-level TCR repertoire sequencing.
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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/10.1101/2024.04.01.587617v1" target="_blank">Large-scale statistical mapping of T-cell receptor β sequences to Human Leukocyte Antigens</a>
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<li><strong>Robotic-inspired approach to multi-domain membrane receptor conformation space: theory and SARS-CoV-2 spike protein case study</strong> -
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The spike protein of SARS-CoV-2 is a highly flexible membrane receptor that triggers the translocation of the virus into cells by attaching to the human receptors. Like other type I membrane receptors, this protein has several extracellular domains connected by flexible hinges. The presence of these hinges results in high flexibility, which consequently results in challenges in defining the conformation of the protein. Here, We developed a new method to define the conformational space based on a few variables inspired by the robotic field's methods to determine a robotic arm's forward kinematics. Using newly performed atomistic molecular dynamics (MD) simulations and publicly available data, we found that the Denavit-Hartenberg (DH) parameters can reliably show the changes in the local conformation. Furthermore, the rotational and translational components of the homogenous transformation matrix constructed based on the DH parameters can identify the changes in the global conformation of the spike and also differentiate between the conformation with a similar position of the spike head, which other types of parameters, such as spherical coordinates, fail to distinguish between such conformations. Finally, the new method will be beneficial for looking at the conformational heterogeneity in all other type I membrane receptors.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.03.29.587391v1" target="_blank">Robotic-inspired approach to multi-domain membrane receptor conformation space: theory and SARS-CoV-2 spike protein case study</a>
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<li><strong>ViRNN: A Deep Learning Model for Viral Host Prediction</strong> -
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Viral outbreaks are on the rise in the world, with the current outbreak of COVID-19 being among one of the worst thus far. Many of these outbreaks were the result of zoonotic transfer between species, and thus understanding and predicting the host of a virus is very important. With the rise of sequencing technologies it is becoming increasingly easy to sequence the full genomes of viruses, databases of publicly available viral genomes are widely available. We utilize a convolutional and recurrent neural network architecture (ViRNN) to predict the hosts for the Coronaviridae family (Coronaviruses) amongst the eleven most common hosts of this family. Our architecture performed with an overall accuracy of 90.55% on our test dataset, with a micro-average AUC-PR of 0.97. Performance was variable per host. ViRNN outperformed previously published methods like k-nearest neighbors and support vector machines, as well as previously published deep learning based methods. Saliency maps based on integrated gradients revealed a number of proteins in the viral genome that may be important interactions determining viral infection in hosts. Overall, this method provides an adaptable classifier capable of predicting host species from viral genomic sequence with high accuracy.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.03.30.587436v1" target="_blank">ViRNN: A Deep Learning Model for Viral Host Prediction</a>
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<li><strong>Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2</strong> -
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The Covid-19 pandemic showcases a coevolutionary race between the human immune system and SARS-CoV-2, mirroring the Red Queen hypothesis of evolutionary biology. The immune system generates neutralizing antibodies targeting the SARS-CoV-2 spike protein's receptor binding domain (RBD), crucial for host cell invasion, while the virus evolves to evade antibody recognition. Here, we establish a synthetic coevolution system combining high-throughput screening of antibody and RBD variant libraries with protein mutagenesis, surface display, and deep sequencing. Additionally, we train a protein language machine learning model that predicts antibody escape to RBD variants. Synthetic coevolution reveals antagonistic and compensatory mutational trajectories of neutralizing antibodies and SARS-CoV-2 variants, enhancing the understanding of this evolutionary conflict.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.03.28.587189v1" target="_blank">Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2</a>
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<li><strong>Emotional distress and affective knowledge representation one year after the Covid-19 outbreak</strong> -
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This study examines whether the detrimental effects of the COVID-19 pandemic on the affectivity of the population extend one year after the outbreak. In an online-mobile session, participants completed surveys (i.e. demographic characteristics, positive-negative affectivity, interoceptive awareness) and a similarity judgment task of triplets of emotional concepts, from which we derived 2D maps of their affective knowledge representation. Compared with pre-pandemic data derived from a comparable population, we report three main findings. First, we observed enhanced negative affectivity during the pandemic, but no changes in positive affectivity levels. Second, increased self-reported interoceptive awareness compared to pre-pandemic data, with greater attention to bodily sensations and adaptive aspects of interoceptive sensitivity. Furthermore, female participants reported higher scores than males on the questionnaire subscales of Emotional Awareness and Attention Regulation. Third, the effect of pandemic-related conditions is also apparent in the mental organization of emotional concepts, especially for female participants (i.e., reduced coherence in the organization of the concepts along the arousal dimension and more misclassification of concepts based on arousal) and participants who did not perform physical activity (a collapse of the arousal dimension). Some of the effects of the pandemic, thus, persist about a year after the outbreak. These results advise providing programs of psychological and emotional assistance throughout the pandemic beyond the outbreak, and that age-dependent gender differences should be accounted for to define tailored interventions. Physical activity might relieve pandemic-related stressors, so it should be promoted during particularly stressful periods for the population.
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🖺 Full Text HTML: <a href="https://osf.io/gmazn/" target="_blank">Emotional distress and affective knowledge representation one year after the Covid-19 outbreak</a>
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<li><strong>Nanoscale cellular organization of viral RNA and proteins in SARS-CoV-2 replication organelles</strong> -
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The SARS-CoV-2 viral infection transforms host cells and produces special organelles in many ways, and we focus on the replication organelle where the replication of viral genomic RNA (vgRNA) occurs. To date, the precise cellular localization of key RNA molecules and replication intermediates has been elusive in electron microscopy studies. We use super-resolution fluorescence microscopy and specific labeling to reveal the nanoscopic organization of replication organelles that contain vgRNA clusters along with viral double-stranded RNA (dsRNA) clusters and the replication enzyme, encapsulated by membranes derived from the host endoplasmic reticulum (ER). We show that the replication organelles are organized differently at early and late stages of infection. Surprisingly, vgRNA accumulates into distinct globular clusters in the cytoplasmic perinuclear region, which grow and accommodate more vgRNA molecules as infection time increases. The localization of ER labels and nsp3 (a component of the double-membrane vesicle, DMV) at the periphery of the vgRNA clusters suggests that replication organelles are enclosed by DMVs at early infection stages which then merge into vesicle packets as infection progresses. Precise co-imaging of the nanoscale cellular organization of vgRNA, dsRNA, and viral proteins in replication organelles of SARS-CoV-2 may inform therapeutic approaches that target viral replication and associated processes.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.11.07.566110v3" target="_blank">Nanoscale cellular organization of viral RNA and proteins in SARS-CoV-2 replication organelles</a>
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<li><strong>A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival</strong> -
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Lysosomal damage poses a significant threat to cell survival. Our previous work has reported that lysosomal damage induces stress granule (SG) formation. However, the importance of SG formation in determining cell fate and the precise mechanisms through which lysosomal damage triggers SG formation remains unclear. Here, we show that SG formation is initiated via a novel calcium-dependent pathway and plays a protective role in promoting cell survival in response to lysosomal damage. Mechanistically, we demonstrate that during lysosomal damage, ALIX, a calcium-activated protein, transduces lysosomal damage signals by sensing calcium leakage to induce SG formation by controlling the phosphorylation of eIF2. ALIX modulates eIF2 phosphorylation by regulating the association between PKR and its activator PACT, with galectin-3 exerting a negative effect on this process. We also found this regulatory event of SG formation occur on damaged lysosomes. Collectively, these investigations reveal novel insights into the precise regulation of SG formation triggered by lysosomal damage, and shed light on the interaction between damaged lysosomes and SGs. Importantly, SG formation is significant for promoting cell survival in the physiological context of lysosomal damage inflicted by SARS-CoV-2 ORF3a, adenovirus infection, Malaria hemozoin, proteopathic tau as well as environmental hazard silica.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.03.29.587368v1" target="_blank">A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival</a>
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<li><strong>Aversive personality and COVID-19: A first review and meta-analysis</strong> -
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The Coronavirus Disease 2019 (COVID-19) has strongly affected individuals and societies worldwide. In this review and meta-analysis, we investigated how aversive personality traits—i.e., relatively stable antisocial personality characteristics—related to how individuals perceived, evaluated, and responded to the COVID-19 pandemic. Across 34 studies with overall 26,780 participants, we found that people with higher scores in aversive personality traits were less likely to perceive guidelines and restrictions to curb the spread of the virus as protective (p̂ = -.11), to engage in health behaviors related to COVID-19 (p̂ = -.16), and to engage in non-health related prosocial behavior related to COVID-19 (p̂ = -.14). We found no consistent relation between aversive personality and negative affect regarding the pandemic. The results thus indicate the importance of aversive personality traits in understanding individual differences with regard to COVID-19.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/psyarxiv/vg465/" target="_blank">Aversive personality and COVID-19: A first review and meta-analysis</a>
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<li><strong>Information about herd immunity through vaccination and empathy promote COVID-19 vaccination intentions</strong> -
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Objective: An effective vaccine against COVID-19 is a desired solution to curb the spread of the disease. However, vaccine hesitancy might hinder high uptake rates and thus undermine efforts to eliminate COVID-19 once an effective vaccine became available. The present contribution addresses this issue by examining two ways of increasing the intention to get vaccinated against COVID-19. Methods: Two pre-registered online studies were conducted (N = 2,315 participants from the UK) in which knowledge about and beliefs in herd immunity through vaccination, as well as empathy for those most vulnerable to the virus, were either measured (Study 1) or manipulated (Study 2). As a dependent variable, individuals’ self-reported vaccination intention once a vaccine against COVID-19 became available was assessed. Results: In Study 1 (N = 310), the intention to get vaccinated against COVID-19 was correlated with knowledge about and belief in herd immunity (r = .58, p < .001), as well as with empathy for those most vulnerable to the virus (r = .26, p < .001). In Study 2 (N = 2,005), information about herd immunity (Cohen’s d = 0.13, p = .003) and empathy (Cohen’s d = 0.22, p < .001) independently promoted vaccination intention. Conclusions: The motivation to get vaccinated against COVID-19 was related to and could be causally promoted by both mere information about herd immunity and by empathy. As such, the present research provides a better understanding of the intention to get vaccinated against COVID-19.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/psyarxiv/wzu6k/" target="_blank">Information about herd immunity through vaccination and empathy promote COVID-19 vaccination intentions</a>
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<li><strong>The emotional path to action: Empathy promotes physical distancing and wearing of face masks during the COVID-19 pandemic</strong> -
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The COVID-19 pandemic presents a major challenge to societies all over the globe. To curb the spread of the disease, two measures implemented in many countries are minimizing close contact between people (“physical distancing”) and wearing face masks. In the present research, we tested the idea that physical distancing and wearing face masks can be the result of a genuine prosocial emotion—empathy for those most vulnerable to the virus. In four pre-registered studies (total N = 3,718, Western population), we show that (i) empathy is indeed a basic motivation for physical distancing and wearing face masks, and (ii) inducing empathy for those most vulnerable to the virus promotes the motivation to adhere to these measures (whereas providing mere information about its importance is not). In sum, the present research provides a better understanding of the promoting factors underlying the willingness to follow two important measures during the COVID-19 pandemic.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/psyarxiv/y2cg5/" target="_blank">The emotional path to action: Empathy promotes physical distancing and wearing of face masks 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>Evaluation of the Impact of Rehabilitation Strategies and Early Discharge After Respiratory Failure</strong> - <b>Conditions</b>: Acute Respiratory Failure <br/><b>Interventions</b>: Behavioral: Standard of Care; Behavioral: Rehabilitation <br/><b>Sponsors</b>: Hospital Israelita Albert Einstein <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>Diaphragmatic Breathing Exercises for Post-COVID-19 Diaphragmatic Dysfunction (DD)</strong> - <b>Conditions</b>: Post-Acute Sequelae of COVID-19 <br/><b>Interventions</b>: Other: Usual care of traditional treatment; Other: Specific DB program/Diaphragmatic manipulation program <br/><b>Sponsors</b>: University of Minnesota <br/><b>Recruiting</b></p></li>
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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>Why have SGLT2 Inhibitors Failed to Achieve the Desired Success in COVID-19?</strong> - The SARS-CoV-2 virus emerged towards the end of 2019 and caused a major worldwide pandemic lasting at least 2 years, causing a disease called COVID-19. SARS-CoV-2 caused a severe infection with direct cellular toxicity, stimulation of cytokine release, increased oxidative stress, disruption of endothelial structure, and thromboinflammation, as well as angiotensin-converting enzyme 2 (ACE2) down-regulation-mediated renin-angiotensin system (RAS) activation. In addition to glucosuria and…</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>The death domain-associated protein suppresses porcine epidemic diarrhea virus replication by interacting with signal transducer and activator of transcription 1 and inducing downstream ISG15 expression</strong> - Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus that causes acute enteric disease in piglets and severely threatens the pig industry all over the world. Death domain-associated protein (DAXX) is a classical chaperone protein involved in multiple biological processes, such as cell apoptosis, transcriptional regulation, DNA damage repair, and host innate immunity. However, whether DAXX functions in the anti-PEDV innate immune responses remains unclear. In this study, we found that…</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>Quantitating SARS-CoV-2 Neutralizing Antibodies from Human Dried Blood Spots</strong> - CONCLUSION: SARS-CoV-2 neutralizing titers can be derived with confidence from DBS eluates, thereby opening the door to the use of these biospecimens for the analysis of vulnerable populations and normally hard to reach communities.</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>Lipid Nanoparticle-Based Inhibitors for SARS-CoV-2 Host Cell Infection</strong> - CONCLUSION: Both LNP-Trap and LNP-Trim formulations were able to safely and effectively inhibit SARS-CoV-2 pseudoviral infection in airway epithelial cells. These studies provide proof-of-principle for a localized treatment approach for SARS-CoV-2 in the upper airway.</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>Transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus</strong> - Tinnitus is a disturbing condition defined as the occurrence of acoustic hallucinations with no actual sound. Although the mechanisms underlying tinnitus have been explored extensively, the pathophysiology of the disease is not completely understood. Moreover, genes and potential treatment targets related to auditory hallucinations remain unknown. In this study, we examined transcriptional-profile changes in the medial geniculate body after noise-induced tinnitus in rats by performing RNA…</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>Acceptance, safety, and immunogenicity of a booster dose of inactivated SARS-CoV-2 vaccine in patients with primary biliary cholangitis</strong> - Inactivated coronavirus disease 2019 (COVID-19) vaccines showed impaired immunogenicity in some autoimmune diseases, but it remains unclear in primary biliary cholangitis (PBC). This study aimed to explore the antibody response to the inactivated COVID-19 vaccine in individuals with PBC, as well as to evaluate coverage, safety, and attitudes toward the COVID-19 vaccine among them. Two cohorts of patients with PBC were enrolled in this study. One cohort was arranged to evaluate the immunogenicity…</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>Vgamma9Vdelta2 T-cells are potent inhibitors of SARS-CoV-2 replication and represent effector phenotypes in COVID-19 patients</strong> - Vγ9Vδ2 T-cells play a key role in the innate immune response to viral infections through butyrophilin (BTN)-3A. Here, we reported that blood Vγ9Vδ2 T-cells decreased in clinically mild COVID-19 compared to healthy volunteers (HV), and was maintained up to 28-days and in the recovery period. Terminally differentiated Vγ9Vδ2 T-cells tend to be enriched on the day of diagnosis, 28-days after and during the recovery period. These cells showed cytotoxic and inflammatory activities following…</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>Isolation, characterization and SARS-CoV-2 3CL protease inhibitory activity of a new methylsulfinyl-butanyl derivative from Raphani Semen</strong> - A new compound named raphanised A (1), along with two known methylsulfinyl -butanyl derivatives (2-3) and seven known indole derivatives (4-10), were isolated from the Raphani Semen. Among the indole derivatives, 5 was identified as a new natural product, and 4, 6, 7, 8, 9, 10 were isolated from the genus of Raphanus for the first time. Their structures were elucidated based on the NMR and HR-EI-MS analysis. Additionally, the inhibitory activity of methylsulfinyl-butanyl derivatives 1-3 on SARS…</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>CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation</strong> - CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells…</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>Comparative evaluation of tocilizumab and itolizumab for treatment of severe COVID-19 in India: a retrospective cohort study</strong> - CONCLUSIONS: The CI with itolizumab is similar to tocilizumab. Better oxygenation can be achieved with itolizumab and it can be a substitute for tocilizumab in managing severe 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>Synthesis and pharmacodynamic evaluation of Dihydropteridone derivatives against PDCoV in vivo and in vitro</strong> - Porcine Delta Coronavirus (PDCoV) infection can induce serious dehydration, diarrhea and even death of piglets, which has caused huge losses to the breeding industry. PDCoV has been reported to have the potential for cross species transmission, and even reports of infecting humans have emerged. At present, there are still no effective prevention and control measures for PDCoV. In this study, we have designed and synthesized a series of unreported Dihydropteridone derivatives. All of these…</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>New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses</strong> - The spread of COVID-19 continues due to genetic variation in SARS-CoV-2. Highly mutated variants of SARS-CoV-2 have an increased transmissibility and immune evasion. Due to the emergence of various new variants of the virus, there is an urgent need to develop broadly effective specific drugs for therapeutic strategies for the prevention and treatment of COVID-19. Molnupiravir (EIDD-2801, MK-4482), is an orally bioavailable ribonucleoside analogue of β-D-N4-hydroxycytidine (NHC), has demonstrated…</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>Biological responses in Danio rerio by the disinfectant SDBS in SARS-CoV-2 pandemic</strong> - The use of disinfectants, such as Sodium Dodecylbenzene Sulfonic acid salt (SDBS), has grown since the SARS-CoV-2 pandemic, with environmentally unknown consequences. The present study analyzed SDBS effects in the fish species Danio rerio, using a combination of biomarkers. Our data reported that larvae had their total locomotor activity increased when exposed to 1mg/L of SDBS, but this parameter was decreased in fish exposed to 5mg/L. A significant increment of erratic movements was reported in…</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>Preclinical evaluation of the SARS-CoV-2 M(pro) inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir</strong> - Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (M^(pro)), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower…</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 new DNA aptamer which binds to SARS-CoV-2 spike protein and reduces pro-inflammatory response</strong> - COVID-19 caused by SARS-CoV-2 spread rapidly around the world, endangering the health of people globally. The SARS-CoV-2 spike protein initiates entry into target cells by binding to human angiotensin-converting enzyme 2 (ACE2). In this study, we developed DNA aptamers that specifically bind to the SARS-CoV-2 spike protein, thereby inhibiting its binding to ACE2. DNA aptamers are small nucleic acid fragments with random structures that selectively bind to various target molecules. We identified…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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