1,721,073 research outputs found
Functional and biochemical characterization of novel genetic variants in IRAK4 and IRF4 causing human inborn errors of immunity
No full textHuman inborn errors of immunity (IEIs) are a group of genetic disorders in which specific components of the human immune system are missing, dysfunctional, or poorly regulated. IEIs negatively impact the protective functions of the immune system, increasing susceptibility to infections, autoimmunity, inflammation, and malignancy. The investigation of monogenic IEIs enables the diagnosis and treatment of the affected individuals and provides unique opportunities to understand the role of the immune system and the functional roles of its constituents.
Toll-like receptor (TLR) signaling is a key aspect of the innate immune response, and interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade which enables the production of protective inflammatory cytokines. Human IRAK4-deficiency is an autosomal recessive IEI which presents with a blunted inflammatory response to infection and susceptibility to certain bacteria. We demonstrate that the novel IRAK4 (c.1049delG, p.(Gly350Glufs*15)) variant abrogates IRAK4 protein expression and abolishes TLR signaling, expanding the knowledge of pathogenic variants causing human IRAK4-deficiency.
We have also identified 3 unrelated individuals with a phenotype of combined immunodeficiency (agammaglobulinemia and infectious susceptibility) who carry a novel heterozygous de novo missense variant in Interferon Regulatory Factor 4 (IRF4) gene (c.284C>G, p.T95R). IRF4 is a transcription factor expressed in immune cells which plays a critical role in the differentiation of various immune cells. We demonstrate adaptive immune cell differentiation defects in proband primary cells, as well as decreased effector cytokine production in T cells. We also demonstrate that the IRF4 T95R variant is able to bind the canonical GAAA binding site as well as a novel GATA binding site. Therefore, we propose that the IRF4 T95R variant is defined as a neomorphic variant, as it has gained novel DNA-binding functions. This increase in DNA-binding sequence promiscuity may result in a dominant negative redistribution of the wild-type IRF4 and the combined immunodeficiency phenotype in the proband. We have characterized a novel neomorphic variant in the IRF4 gene and defined a novel human IEI which highlights the potential of IRF4 as an immunomodulatory therapeutic target.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat
Defining the functional impact of three new human primary immune regulatory disorders caused by defects in genes NFATC2, STAT6 and OSMR
No full textThe full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Medicine, Faculty ofMedicine, Department ofGraduat
Characterizing the molecular and clinical impact of two novel human inborn errors of immunity caused by defects in IKZF2 and ZBTB7B
No full textInborn errors of immunity (IEIs) are a diverse group of genetic disorders that adversely affect the function and/or development of the immune system, resulting in increased susceptibility to infections, autoimmunity, allergy, and malignancies. Primary immune regulatory disorders and primary atopic disorders are two subcategories of IEIs. While IEIs are commonly associated with frequent, severe, and unconventional infections, primary immune regulatory disorders mainly present with immune dysregulation, and primary atopic disorders with severe, early-onset allergies. These manifestations can occur with or without the typical infectious symptoms expected with IEIs. Given the recently acknowledged diversity of symptoms associated with IEIs, there is a pressing need to sequence and investigate individuals presenting with unconventional and newly identified manifestations of IEIs. The overarching goal of this thesis was to use an established pipeline of studying single patients to discover and characterize novel monogenic causes of primary immune regulatory disorders and primary atopic disorders. The discovery of these novel classes of IEIs significantly enriches our understanding of fundamental human biology, presenting new pathways for therapeutic development and repurposing, which promise substantial enhancements in patient care. By employing a comprehensive approach that included the collection of phenotypic information from patients and the use of advanced genomic sequencing and bioinformatics analyses, we identified two novel diseases caused by germline variants in IKZF2 and ZBTB7B, which encode critical transcription factors – Helios and ThPOK – that regulate broad-ranging biological processes in the human body. The first study delineates the consequences of two dominant-negative variants in Helios, revealing an association with a complex syndrome in humans characterized by immune dysregulation and developmental anomalies, thus broadening our understanding of Helios’s role in human physiology and development. The second study describes the discovery of a multimorphic variant in ThPOK, outlining its critical involvement in CD4 T cell development and its unexpected association with tissue fibrosis in humans. These findings not only demonstrate the profound impact of transcriptional regulation on immune function and disease, but also expand the diagnostic and therapeutic approaches of IEIs, enriching the future landscape of IEI management.Medicine, Faculty ofMedicine, Department ofGraduat
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
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