1,721,077 research outputs found
A quantitative brain map of experimental cerebral malaria pathology.
Full text linkThe murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM
Discovering novel immunoregulatory molecules that can be manipulated for clinical advantage
No full textThe successful control of malaria parasites by an infected host requires complex and balanced interactions between pro-inflammatory and regulatory immune responses. An excessive, dysregulated pro-inflammatory response results in tissue damage and the subsequent development of severe pathologies, with the routinely fatal cerebral malaria among them. Conversely, uncontrolled immunoregulatory responses promoted by Plasmodium species serve to inhibit protective host immunity, contributing to the delay, or even failure, of parasite clearance. The most advanced anti-malarial vaccine candidate RTS,S exhibited only 30% efficacy in individuals suffering repeated exposure to malaria parasites from malaria-endemic settings. A major impediment to enhancing vaccine efficacy is malaria-induced immunoregulatory pathways that hamper the establishment of long-term anti-parasitic immunity. Thus, any viable therapeutic intervention must promote anti-parasitic immunity while concurrently minimizing pathology. CD4+ T cells respond to specific immunological and disease settings by differentiating into distinct subsets with corresponding effector functions. Key components in the response to parasitic disease, IFNγ-producing helper T (TH1) cells protect the host via the activation of phagocytic cells and subsequent clearance of intracellular parasites; while IL-21-producing follicular helper T (TfH) cells promote parasite-specific antibody generation via support of germinal centre B cell function. Alongside these protective CD4+ T cell subsets, Plasmodium spp. also induce a population of type I regulatory (TR1) cells that actively impair TH1-mediated protective immunity. To characterise, and thus better understand the development and function of, TH1 and TR1 cells during malaria, these CD4+ T cell subsets were isolated from human volunteers participating in studies of controlled human malaria infection (CHMI) with Plasmodium falciparum. RNA-sequencing was then employed to identify differentially expressed genes (DEGs) between these subsets. Among those identified, we determined that TMEM173, the gene encoding the DNA-sensing receptor stimulator of interferon genes (STING), was more highly expressed and phosphorylated in TR1 than TH1 cells. STING is an intracellular innate signalling receptor that recognises pathogen DNA and RNA. Required for effective host defence, STING is an essential signalling adaptor that functions primarily by initiating the production of type I interferons (IFNs). Extracellular self-DNA, cell-intrinsic mitochondrial DNA, or genomic DNA released by infected cells have all been demonstrated to activate the STING pathway. Emerging evidence further suggests that the STING signalling pathway shapes adaptive, in addition to innate, immune responses. STING activation in antigen-presenting cells (APCs) is associated with augmented inflammatory immune responses. In T cells, STING signalling has been shown to promote apoptosis and inhibit the proliferation. In the context of autoimmunity, gain-of-function mutation of STING corresponded to an auto-inflammatory syndrome, despite featuring T and B cell deficiencies. In malaria, Plasmodium falciparum genomic DNA delivered to monocytes can activate the STING-TBK1 pathway associated with type I IFN production. However, the role of STING in CD4+ T cell responses to Plasmodium infection remains unknown. To study the roles of STING in CD4+ T cells, we employed CRISPR-Cas9 to disrupt TMEM173 transcription in human primary CD4+ T cells. We determined that STING signalling promotes the production of cytokines IL-10, IFNγ, and type I IFN; and the development of TR1 (LAG3+CD49b+) cells in vitro. To further characterize the roles of STING during infection in vivo, we utilised an experimental model of malaria characterised by Plasmodium berghei ANKA (PbA) infection of C57BL/6J mice. Relevant parasite-specific responses were assessed using a T cell receptor (TCR)-transgenic mouse that features CD4+ T cells (PbTII) expressing a TCR specific for an antigen expressed by all rodent malaria parasites. We detected increased frequencies of PbTII∆Sting IL-10+ IFNγ+ TR1 and Tbet+ IFNγ+ TH1 cells compared to corresponding PbTIIWT cell subsets, suggesting that STING promoted the generation of TR1 cells and inhibited TH1 cells in vivo during experimental malaria. To explore the underlying mechanisms, we performed bulk RNA-sequencing on PbTIIWT and PbTII∆Sting cells isolated from C57BL/6J mice infected with PbA. Gene set enrichment analysis revealed downregulation of genes related to type I IFN signalling in PbTII∆Sting cells. Thus, we hypothesized that STING regulates CD4+ T cell subsets through type I IFN signalling. To address this, we treated TMEM173-disrupted CD4+ T cells with exogenous type I IFN (IFNβ1), and determined that STING-dependent regulation of TR1 cells occurred via type I IFN signalling. To investigate the role of type I IFN signalling in vivo during experimental malaria, we generated type I IFNα receptor knockout (Ifnar-/-) crossed with PbTII mice, featuring antigen-specific PbTII∆Ifnar cells deficient in type I IFN signalling. We subsequently performed an adoptive transfer of PbTII∆Ifnar (CD45.2+) combined with PbTIIWT (CD45.1+CD45.2+) cells into recipient wild-type (WT; CD45.1+) mice, and challenged with PbA. STING was found to promote the generation of TR1 cells through type I IFN signalling, and appeared to inhibit TH1 cell effector function through a STING-intrinsic, type I IFN-independent mechanism. To investigate the role of STING in human disease, we isolated PBMCs from volunteers participating in CHMI studies and stimulated them with uninfected red blood cells (uRBC) or parasitised RBCs (pRBCs) in the presence or absence of STING agonist cGAMP. We determined that parasite antigen has the potential to activate STING signalling in human CD4+ T cells within PBMC culture. Furthermore, exposure to Plasmodium antigen enhanced TR1 cell sensitivity to STING agonist, which then, in turn, promoted TR1 generation. Further experimentation revealed that a JAK1/JAK2 inhibitor ruxolitinib (Rux) inhibits the STING-dependent generation of TR1 cells in vitro, highlighting Rux as a promising drug candidate in the improvement of malaria control. Collectively, these results increase our understanding of how malaria parasites manipulate the immunoregulatory networks that shape anti-malarial immunity, and suggest that targeted inhibition of the STING pathway has the potential to improve anti-parasitic responses and subsequent parasite control.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Environment and ScScience, Environment, Engineering and TechnologyFull Tex
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
The induction of anti-disease and anti-parasitic immune responses in primary Plasmodium falciparum exposure
No full textDespite modern prevention and treatment therapies, malaria morbidity and mortality is on the rise. A major roadblock to malaria eradication is the failure of current vaccines to induce long-lasting disease protection in malaria-endemic children, who carry the highest burden of severe illness and mortality. Central to the slow acquisition of long-term anti-parasite immunity and low vaccine efficacy is the development of anti-disease regulatory immune cell responses. This thesis aims to investigate the global immune regulation of peripheral immune cells during blood-stage Plasmodium falciparum (Pf ) malaria and characterise the multi-functional activation of γδ T cell innate- and adaptive-like immune responses in malaria. To do this, we implemented a number of innovative strategies to characterise the transcriptional and protein profiles of peripheral immune cells in primary malaria infection models. [...]Thesis (PhD Doctorate)Doctor of PhilosophySchool of Environment and ScGriffith SciencesFull Tex
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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