1,721,116 research outputs found
Drivers of quasispecies development in SARS-CoV-2 and implications for emergent variants and COVID-19
No full text: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, significant research has focused on SARS-CoV-2 evolution and transmission. Most transmission studies rely on RT-qPCR and consensus sequencing for SARS-CoV-2 characterization, often overlooking the collection of viable genetically linked genomes characterized by one or more intra-host single nucleotide variants (iSNVs) within the same sample, defined as "quasispecies" (QS), which could influence disease outcomes. QS are highly variable in genomic position and frequency and have been proven to impact viral evolution substantially. Several de novo mutations were detected in QS before becoming lineage defining in variants of concern (VOCs). These mutations can also result from errors during replication and transcription leading to the development of defective viral genomes (DVGs) that are incapable of replicating, but important for propagating viral diversity during infection. In a continuously changing landscape of dominating VOCs and anti-SARS-CoV-2 therapy and vaccination strategies, this scoping review aims to summarize the current state-of-the-art and identify knowledge gaps in understanding QS development and their impact on intra-host SARS-CoV-2 evolution, virulence, and intra-host immunity. Finally, we explore the potential of studying inter-host transmission in households as a mirror for community transmission and evolution
Biomarkers and molecular immunopathology of pneumonia
No full textAbstract: Pneumonia remains worldwide the single largest infectious cause of death both in children and adults, as well as in hospitalised patients. One of the most important bacterial causes of hospital-related mortality is Pseudomonas aeruginosa (PA), which is high on the WHO priority list of pathogenic organisms. This is because of PA\u2019s substantial ability to rapidly gain resistance against antibiotics, partly because of protective biofilm formation, and cause mortality in immunocompromised patients including patients on mechanical ventilation (MV). We studied the effect of MV on innate immune factors such as cytokines and its relation to development of ventilator-associated pneumonia (VAP). We showed both in a rat VAP model as well as in VAP patients that the pro-inflammatory Th17-related cytokines are substantially dampened. We concluded that this form of immune modulation caused by MV can be an important cause of VAP. We further elucidated how inducing dispersal of bacteria from a biofilm causes an increased in vivo dissemination and mortality in mice, thereby suggesting that biofilm dispersion as a potential anti-PA therapy should be treaded carefully. While performing these studies, we also identified a knowledge gap regarding temporal evolution of immune responses in animal infection models. We showed distinct temporal expression profiles of cytokines and, importantly, demonstrated that serum levels are representative of the local lung immune response in mice. We believe that these studies will have an important impact on pre-clinical research utilizing these rodent pneumonia models. With the emergence of SARS-CoV-2, the focus of this thesis shifted on COVID-19 pneumonia. In the search for biomarkers of disease severity, we first developed a model based on the cytokine, chemokine, and growth factors (CCG) to predict development of acute respiratory distress syndrome already at the time of hospital admission. This research also elucidated a significant role of TGF-\u3b2 in COVID-19 whose function is linked both with normal healing, as with fibrosis seen in COVID-19 patients. Lastly, we showed in a SARS-CoV-2 exposed cancer population long-term alterations in levels of inflammatory CCGs, some of which are also tumour-promoting factors. These data prompt for increased vigilance in SARS-CoV-2-exposed cancer patients and long-COVID management. The work performed in this thesis has provided useful insights in our understanding of the molecular pathology of pneumonia and will form the basis for future translational research in development of early diagnostic tools as well as for new therapies directed towards the immune system targeting bacterial and viral pneumonia
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Immunological biomarkers of COVID-19 : response to vaccination and monoclonal antibody treatments in immunocompromised patients
No full textAbstract: COVID-19 has caused almost 7 million deaths worldwide with 768 million documented cases of SARS-CoV-2 infections. However, the burden of the pandemic could have been even higher without the development of effective COVID-19 treatments and vaccines in record time. The overarching goal of this thesis was to expend the knowledge about immune responses to COVID-19 and COVID-19 vaccination with the focus on understanding how host immune responses, especially the ones driven by cytokines, chemokines, and growth factors, pre-determine or affect the course of the disease and vaccination. As part of my doctoral thesis, I studied multiple cohorts of immunocompromised patients with COVID-19, or at high risk of developing COVID-19, with the overall aim to build immune-related signatures to predict either development of vaccination responses or responses to treatments, such as those with anti-SARS-CoV-2 monoclonal antibodies (mAb). Specifically, I explored post-vaccine immune responses in solid organ transplant (SOT) recipients and patients with solid and haematological malignancies and identified clinical and molecular signatures predictive of insufficient immune responses. Given the inability of some of these patients to develop sufficient antibody responses to COVID-19 vaccines, I assessed currently available treatment and prophylaxis options. Specifically, I evaluated the effect of mAb treatments and of host immune factors on Spike mutation development. Additionally, I studied neutralizing capacity of bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab or tixagevimab/cilgavimab against SARS-CoV-2-CoV-2 variants of concern (VOCs). In conclusion, much like an orchestra, where the contributions of each instrument may seem minimal and indistinguishable among others, the influence of cytokines, chemokines and growth factors on COVID-19 is also subtle and may not be overtly noticeable, however, they play a crucial role in co-ordinating and orchestrating various immune responses important in COVID-19 disease and its prevention and treatment. Research findings described in this thesis utilise these variables to understand the molecular pathology of COVID-19 and hopefully would provide a lasting impact on ongoing efforts to combat this global health crisis and its aftermath
COVID-19 and SARS-CoV-2 vaccination related T-cell immune response in diverse populations
No full textAbstract: Immune dysregulation has been established as a key feature of COVID-19. Both vaccination against COVID-19 and infection by SARS-CoV-2 induce adaptive immune responses. However, much of the focus in vaccine development and immunity surveillance has been on the role of serology and neutralizing antibodies, with less emphasis on understanding the role of T cells, especially in immunocompromised hosts. Mounting evidence suggests T cell contributions to the host immune response are required for early, broad, and durable protection from the SARS-CoV-2 virus, especially in the setting of new variants of concern (VOCs). The main objective of this thesis was to expand our understanding of cellular immune responses against SARS-CoV-2 and COVID-19 vaccinations with a focus on CD4+ and CD8+ compartments in diverse populations. In the first chapters, I describe the current literature on key immunocompromised groups \u2013 concentrating on people living with human immunodeficiency virus (PLWH), solid organ transplant (SOT) recipients, and patients with solid and haematological malignancies \u2013 and the unique T cell phenotypes observed in different fragile hosts in response to SARS-CoV-2 antigens. After describing the framework of the T cell analysis in Chapter 2, I focus on investigating longitudinal T cell responses among PLWH after BNT162b2 vaccination in Chapter 3. Our results suggest that the durable serological and CD4+ T-cell responses developing in vaccinated PLWH are associated with IL-2-mediated CD4+ T-cell activation that likely compensates for CD4+ T-cell depletion in PLWH. In Chapter 4 I assess monoclonal antibody (mAb) therapy for the treatment of COVID-19 and the effect of host immune factors on Spike mutation development. We hypothesise that the de novo mutations identified in the SARS-CoV-2 spike protein are escape mutants that evade mAb neutralisation and facilitate a more natural progression of disease, thereby resulting in a more robust T cell immune response. We further demonstrate that host-driven immune and non-immune responses are essential for the development of mutant SARS-CoV-2 and support informed decision-making in reducing the risk of mAb treatment failure. Finally, in Chapter 5, I discuss the overall results with a focus on future considerations for our workgroup and the direction towards which this research can be expanded. This thesis forms the basis for future research in the development of effective vaccination strategies and provides advice for developing best practice policies in terms of COVID-19 therapeutics
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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