1,720,958 research outputs found
Engineering glycosylation in HIV-1 vaccine design
No full textThe development of a protective HIV-1 vaccine remains a major challenge to the scientific community. The nature of the virus necessitates an immune response that is able to overcome the significant genetic diversity of HIV-1. The elicitation of broadly neutralizing antibodies offer a route to overcome this diversity. As the only viral antigen expressed on the virion surface, all bnAbs target the HIV-1 Envelope spike, and as such all candidate immunogens are based around this protein. The envelope glycoprotein is one of the most densely glycosylated proteins in nature and this dense glycan shield provides protection to conserved regions of the protein from the immune system and this is reflected by the conservation of key glycan attachment sequons despite a background of formidable sequence diversity. Broadly neutralizing antibodies exploit this conservation to allow for their broad recognition through recognizing both the protein and the glycans of Env. As of yet, recombinant immunogens have been unable to elicit bnAbs in animal models and humans. This is due to two main facets. One is that the pathway of somatic hypermutations that are reuqired to generate bnAbs are rare, and in order to guide a glycan-binding antibody to maturation there are self-reactivity controls that need to be overcome which particularly hinder glycan-binding bnAb development. Also, off-target responses distract the immune system and result from key differences in Env glycosylation between the virus and recombinant proteins. Engineering the glycosylation of Env, therefore, represents a potential mechanism to improve recombinant immunogens towards eliciting bnAbs. There are numerous intrinsic and extrinsic properties that influence Env glycosylation, including structural constraints and enzymatic availability, that can be harnessed to alter Env glycosylation. In this thesis, multiple approaches are investigated with the goal of editing the Env glycan shield towards one that is favourable for the elicitation of bnAbs. Due to the heterogeneity of glycosylation, bespoke workflows are needed to analyse glycosylation, which is required to validate the effectiveness of different engineering approaches. To achieve this, a methodology based around liquid chromatography-mass spectrometry (LC-MS) was used to comprehensively determine the site-specific glycosylation of Env. First, the impact of glycan additions and deletions on the overall processing of the glycan shield was determined. Such additions and deletions are commonplace in immunogens aimed at eliciting bnAbs. This revealed that additions/deletions are well tolerated but their induction influences the processing of neighbouring glycan sites. These observations were consistent across multiple Env strains and immunogen platforms. Next, the impact of altering the availability of glycan processing enzymes on Env glycosylation was explored, demonstrating that co-expressing key enzymes in the pathway was successful in engineering the glycan shield, but these effects were unpredictable. Both of these approaches resulted in widespread alterations in the glycan shield. To limit glycan engineering to specific epitopes, the targeted epitopes of bnAbs were exploited to control glycosylation by co-transfecting Env with bnAbs, which in turn alter the availability of Env to glycan processing enzymes during glycosylation in the ER/Golgi. Finally, to alter the glycosylation of Env towards a more viral-like configuration, the gene codon usage of recombinant Env was altered to that of the native virus, which contrasted the codon optimized variants typically in use. This resulted in a decreased rate of translation, which, in turn, altered the glycan shield of recombinant Env to a more viral like state. This thesis demonstrates the wide arsenal of approaches that can be used to change Env immunogen glycosylation, however it is difficult to predict the outcomes of such engineering without comprehensively studying the resultant immunogens. By investigating a broad range of approaches and reporting their successes and caveats it is possible for these methods to be integrated into immunogen design approaches with specific epitopes in mind. These tools may prove valuable in the design of an effective HIV-1 vaccine with an appropriate glycan profile
Dataset supporting the University of Southampton Doctoral Thesis " Engineering glycosylation in HIV-1 vaccine design"
No full textDataset supporting the University of Southampton Doctoral Thesis " Engineering glycosylation in HIV-1 vaccine design". Data comprises excel spreadsheets for site-specific glycan analysis contained within the thesis.
Zipped folder containing excel files contianing data pertaining to chapters:
- Chapter 3 data.xlsx: All data associated with Chapter 3
- chapter 4 data.xlsx: All data associated with Chapter 4
- Chapter 5 data.xlsx: All data associated with Chapter 5
- Chapter 6 data.xlsx: All data associated with Chapter 6
Publications associated with these datasets include:
-G. E.Seabright et al “Networks of HIV-1 Envelope Glycans Maintain Antibody Epitopes in the Face of Glycan Additions and Deletions” Structure(2020).issn:18784186.doi:10.1016/j.str.2020.04.022.
-E. T Crooks et al “Engineering well-expressed, V2-immunofocusing HIV-1 envelope glycoprotein membrane trimers for use in heterologous prime-boost vaccine
regimens”, PLOS Pathogens(2021). doi:10.1371/journal.ppat.1009807
-T. Tong et al ”Impact of stabilizing mutations on the antigenic profile and glycosylation of membrane-expressed HIV-1 envelope glycoprotein”, PLOS Pathogens(2023). doi:10.1371/journal.ppat.1011452
This project has received funding from the European Union's Horizon 2020 Research and Innovation program under grant agreement no. 681137, the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (OPP1084519 and OPP1115782)
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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
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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