1,721,027 research outputs found
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
The immunopathogenesis of group A streptococcal skin disease
No full textGroup A Streptococcus (GAS, Streptococcus pyogenes) is a Gram-‐positive bacterial pathogen exhibiting human host exclusivity. GAS is responsible for a wide array of non-‐ invasive suppurative infections of the throat and skin, such as pharyngitis and pyoderma respectively. GAS is also capable of causing severe invasive diseases and post-‐streptococcal complications, each with high rates of morbidity and mortality. Epidemiological studies have demonstrated a high prevalence of pyoderma in tropical regions such as in northern Australia. Streptococcal skin infections are thought to be a significant risk factor for the development of rheumatic fever in Indigenous Australians within these tropical regions. The skin is also a common portal of entry for invasive GAS disease. The ability of GAS to cause these invasive diseases relies upon the timely expression of specific virulence factors enabling the bacteria to evade host immune responses. Several important virulence factors are under the transcriptional control of the CovR/S operon. GAS strains possessing a mutation within their CovR/S regulatory system are particularly adept at evading host immunity resulting in hypervirulence and an increased capacity for invasive disease. CovR/S wild-‐type (WT) and mutant (MT) GAS pairs were identified from a panel of clinical and laboratory isolates. Each CovR/S MT assessed possessed a different mutation within their CovR or CovS gene. It was observed that mice immunised with the M protein-‐derived vaccine candidate J8-‐DT/Alum were protected from local and systemic infections by the CovR/S WT strains; however, protection was significantly compromised for all mice infected with the CovR/S MT strains. Analysis of gene expression via RT-‐PCR revealed that each of the CovR/S MT isolates were up-‐regulating specific virulence factors, namely streptolysin O (SLO), SpyCEP, and the hyaluronic acid capsule, that enhanced their immune evasion capabilities. The increased gene expression by CovR/S MT strains observed using in vitro assays with increased red blood cell lysis, increased IL-‐8 chemokine degradation, and a greater production of hyaluronic acid. The virulence of these CovR/S mutant strains was then tested in the context of the redesigned J8-‐DT vaccine (J8-‐DT combined with an inactive 20-‐mer fragment from SpyCEP, ‘S2’). The J8 CombiVax (comprising J8 and S2 with four lysine residues, ‘K4S2’) afforded significantly better protection compared to J8-‐DT, as each of the CovR/S MT strains were unable to cause a systemic infection in a murine model of pyoderma in the immunised cohorts. The combination of two minimal epitopes provided a synergistic effect through the opsonic J8-‐specific antibodies and the S2-‐ specific antibodies neutralizing SpyCEP, and thus preserving IL-‐8-‐mediated neutrophil chemotaxis. Further investigation into the altered virulence profile of CovR/S mutants underscored SLO as an essential virulence factor for the pathogenesis of these hypervirulent strains. Utilising the CovR/S mutant 5448 (5448 MT) as a representative M1T1 GAS isolate, we generated several additional CovR/S mutants lacking SLO (ΔSLO) to investigate the contribution of this toxin to GAS virulence. The up-‐regulation of SLO by 5448 MT resulted in increased SLO-‐mediated hemolysis, decreased dendritic cell (DC) viability post-‐infection, and an increased production of pro-‐inflammatory cytokines TNF and MCP-‐1 under in vitro conditions. Further to this, it was observed that when SLO was absent from the isolate, the viability of infected DCs improved whilst inflammatory cytokine production decreased. This was despite the observation that infecting isolates still exhibited the characteristic CovR/S mutant virulence factor up-‐regulation of SpyCEP and the hyaluronic acid capsule. Moreover, histological analyses showed that DC presence was restored in murine skin post-‐infection with 5448 MT if SLO was absent from the strain. The presence of SLO correlated with systemic infection and severe pathology at the site of infection in a murine model of pyoderma. Conversely, the absence of SLO significantly attenuated the virulence of 5448 MT in vivo. J8 CombiVax immunisation was effective against all CovR/S mutant infections and provided significant systemic protection. Neutrophils have been shown to be critical in controlling GAS infection, and also for the protective efficacy of J8 CombiVax. Therefore, we sought to investigate the main cellular source of CXCL2, the primary murine neutrophil chemoattractant (a homologue of human IL-‐8) and target of SpyCEP-‐mediated proteolysis. We used a clinical isolate (NS88.2 MT) sourced from the Northern Territory of Australia that possessed a natural CovS mutation, in parallel with the genetically repaired isogenic CovR/S wild-‐type strain (NS88.2 Rep). Following cutaneous infection in a murine model, we observed hypervirulence of the NS88.2 MT strain and differential interactions with neutrophils between the NS88.2 MT and NS88.2 Rep strains. The NS88.2 Rep strain was observed via immunofluorescence analysis interacting with neutrophils in skin sections in vivo and also being killed by human neutrophils in vitro. Conversely, NS88.2 MT appeared to inhibit neutrophil ingress in vivo and proliferated in the presence of human neutrophils in vitro. RT-‐PCR revealed that NS88.2 MT significantly up-‐regulated its SpyCEP expression compared to NS88.2 Rep providing a likely causative factor for the observed differential neutrophil interactions. To specifically target the up-‐regulated expression of SpyCEP, mice were immunised with K4S2-‐DT/Alum. Whilst there was no significant protection against NS88.2 Rep or MT infection with K4S2 alone, spleen samples of immunised mice showed evidence of germinal centre formation post-‐infection, particularly in the context of NS88.2 MT, which was consistent with immunological boosting of K4S2-‐specific B cells by MT infection. Investigation into the cellular response of infection using intracellular staining (ICS) revealed that neutrophils were the primary source of CXCL2 in the skin. This in turn, enabled further recruitment of neutrophils to the site of the infection. This was highlighted by the significant increase in neutrophil abundance in K4S2-‐immunised cohorts compared to the non-‐immunised cohorts, suggesting that protection against SpyCEP-‐mediated cleavage through K4S2 antibodies in vivo contributes to the adaptive immune response against GAS skin infections. ICS also revealed that CXCL2+ve neutrophils were more abundant in the skin of CovR/S WT-‐infected mice compared to the skin of mice infected with the CovR/S MT NS88.2. Similarly, significantly higher levels of CXCL2 protein were found in the skin of mice infected with the CovR/S WT compared to those infected with the CovR/S MT by day 3 post-‐infection. The degradation of CXCL2 in vitro by NS88.2 Rep or NS88.2 MT supernatant was effectively inhibited by the addition of K4S2 anti-‐sera. Overall, the studies within this thesis highlight the hypervirulent nature of CovR/S mutant GAS and some of the mechanisms by which each strain can evade the host immune system. Gaining a greater understanding of host-‐pathogen interactions during GAS infections has enabled improved vaccine design strategies, such as the generation of vaccine candidate J8 CombiVax from J8-‐DT/Alum. J8, being a highly conserved cryptic epitope, in synergy with a 20-‐mer epitope from SpyCEP, provides protective coverage against GAS by neutralizing two of their most important virulence factors.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Institute for GlycomicsScience, Environment, Engineering and TechnologyFull Tex
Modelling natural immunity to streptococcal mucosal infections and novel approaches to vaccine delivery
No full textStreptococcus pyogenes causes significant global morbidity and mortally through a range of pathologies. The most common sites of infection are the upper respiratory tract and the skin, resulting in pharyngitis and impetigo respectively. Non-invasive infections are usually self-limiting; however, they have the potential to progress to life threatening invasive diseases such as toxic-shock syndrome and necrotizing fasciitis with a high rate of mortality. Furthermore, S. pyogenes infections can give rise to auto-immune sequelae of ARF/RHD and ASPGN that result in approximately 500 000 deaths each year. Despite global efforts that span decades, no human vaccine is approved for use. The major hurdles in vaccine development are the broad serotypic and antigenic diversity of S. pyogenes, the risk for potential auto-immune disease due to the molecular mimicry of the S. pyogenes M-protein (a prime vaccine target) and human cardiac myosin, and the ability of S. pyogenes to infect different body sites that require different protective immune mechanisms.
Previous research has shown that exposure to S. pyogenes can result in protective antibodies, though immunity is slow to develop and its role in preventing subsequent infections is poorly understood. In addition, there is a need to understand the mechanism of cross-compartment immunity to aid in guiding vaccine development to protect from multiple serotypes and also at various infection sites. To understand the mechanisms involved in site-specific and cross-compartment immunity, repeated mucosal exposures to S. pyogenes non-lethal infections in mice were performed to mimic endemic settings. Repeated homologous mucosal infections resulted in significant site-specific protection that endured for at least 9 weeks. Mice developed type-specific serum antibodies and antibody secreting cells (ASCs) that increased with increasing number of infections. These data indicate that the longevity of the antibody response is governed by the number of prior mucosal infections; however, no direct correlation with protection was established. Mucosal protection indicated a role for cell-mediated immunity. Repeated acute mucosal infections resulted in significant neutrophil recruitment to the local site of inflammation that correlated with protection.
Cytokine analysis suggested a role for IL-17A in mucosal protection, particularly for enduring protection. To assess the importance of IL-17, IL-17 knockout (IL-17-/-) mice were given repeated homologous mucosal infections. Unlike wild type BALB/c mice, IL-17-/- mice failed to generate mucosal protection with repeated exposures. Furthermore, IL-17-/- mice had significantly reduced M-protein type-specific salivary IgG, IgG and IgA-secreting cells in bone marrow, and neutrophil influx to the lung, correlating with lack of protection.
Mice required only one prior mucosal infection to develop significant and long-lasting protection against a homologous mucosal challenge. However, when cross-compartment protection at the skin was assessed, mice required a minimum of four repeated mucosal infections to generate significant protection. These data suggest that developing a protective immune response by repeated exposures is unlikely in a real-world setting. The literature indicates that multiple different S. pyogenes types move through communities, and people rarely encounter the same strain again within a short period of time. Realising these constraints in developing naturally acquired immunity to S. pyogenes, the next question was then asked: ‘could vaccine mediated immunity be boosted and broadened via natural exposures to S. pyogenes?’
Vaccine candidates based on the conserved C-terminal region of S. pyogenes M-protein (p145) have made considerable progress. The C-terminal region of the M protein is conserved across the majority of S. pyogenes strains, therefore forgoing the issue of serotype diversity. Two vaccine epitopes at the forefront of development, J8 and p*17, when conjugated to the carrier protein, diphtheria toxoid (DT), create J8-DT and p*17-DT.
p*17-DT delivered intramuscularly with the adjuvant, alum, (p*17-DT/Alum) has shown promising immunogenicity and protection against several S. pyogenes isolates; however, it does not protect mice against intranasal challenge with a hypervirulent covR/S mutant strain. To test the hypothesis that infection will boost vaccine-mediated immunity, mice received two vaccinations with p*17-DT/Alum, followed by repeated mucosal infections every three weeks with heterologous isolates. Mice that received vaccinations followed by sequential infections showed increasing protection against NALT (nasal associated lymphoid tissue) bacterial load with each subsequent infection when compared to naïve mice. Bacterial load in the NALT was significantly reduced in these mice following a covR/S mutant challenge. Antigen-specific ASCs were assessed as a determinant of humoral immunity. Although no increase in serum antibody levels or antibody avidity were observed between mice that received vaccination alone or when followed by repeated infections, the mice that received vaccination and sequential infections had significantly increased IgG secreting cells in the spleen. The ASCs, in combination with lung specific CD4+ T-cell responses may be contributing to increased protection seen in mice that were boosted with repeated heterologous infections. Although promising, the results were scattered, which may be attributed to the differences in sequence homology of p145 as well as characteristics of different isolates. These data suggest that vaccine-mediated immunity has the potential to be boosted with repeated exposures to S. pyogenes. However, it was demonstrated that there is room for improvement in vaccination strategy and alternative approaches should be explored. Therefore, the next aim was to assess if new delivery methods could be used to increase vaccine-mediated immunogenicity and protection.
Different methods of vaccine delivery can invoke varied immune responses. Skin-based immunisation routes have gained attention due to targeting of the epidermis and dermis layers rich in immune cells. Several advantages are associated with cutaneous routes, particularly when using high density/micro array patches (MAPs and HD-MAPs). These include dose sparing, enhanced thermostability, ease of administration, reduced generation of sharp-waste and risk of needle-stick injuries, good tolerability and enhanced acceptability in patients. HD-MAPs, developed by Vaxxas Pty Ltd, are at an advanced stage of development and have shown promising clinical trials results. The aim of his final study was to determine if the M-protein-based vaccine candidate J8-DT would have comparable immunogenicity and protection if delivered on the adjuvant free HD-MAP in comparison to intramuscular delivery.
The effect of dose sparing and the number of vaccinations on the antibody response profile of vaccinated mice were assessed. A reduction in the number of vaccinations (from three to two) with J8-DT/HD-MAP induced comparable antibody responses to three vaccinations with intramuscular J8-DT/Alum. J8-DT/HD-MAP vaccination led to a significant reduction in the number of S. pyogenes colony forming units in skin (92.9%) and blood (100%) compared to intramuscular vaccination with unadjuvanted J8-DT when assessed following skin challenge. J8-DT/HD-MAP induced a shift in the antibody isotype profile, with a bias towards Th1-related isotypes, compared to J8-DT/Alum (Th2 bias). Based on the results of this study, the use of J8-DT/HD-MAP should be considered in future clinical development and control programs against S. pyogenes.
The studies in this thesis demonstrate the constraints in developing naturally acquired immunity and highlight the importance for developing an effective vaccine against S. pyogenes.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Institute for GlycomicsScience, Environment, Engineering and TechnologyFull Tex
Design and evaluation of novel liposome-based peptide vaccines for improved efficacy against group A streptococcal infections of the mucosa and skin
No full textStreptococcus pyogenes (group A streptococcus, GAS) is an important human pathogen that is responsible for a range of diseases. Non-invasive diseases include pharyngitis, scarlet fever and pyoderma/impetigo. GAS is also capable of causing invasive diseases such as streptococcal toxic shock syndrome and necrotizing fasciitis. There is a high chance of mortality associated with GAS invasive diseases, with approximately 8-23% of patients dying within 7 days of infection. Consecutive GAS infections may give rise to auto-immune complications, including acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Approximately 2-3% of patients who acquire streptococcal pharyngitis develop ARF. Skin-associated GAS strains have also been linked to cases of ARF. A vaccine that can stop the progression of disease from the primary sites of infection (URT and skin) is desperately needed.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)Institute for GlycomicsScience, Environment, Engineering and TechnologyFull Tex
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