12 research outputs found
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
No full textThe majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class Ibinding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitopederived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecificIFN-c-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire
Exaptation, Degeneracy and Innovation
Get PDFIn innovation processes, exaptations are innovation-development processes through which an initial attribution of new functionality to existing artifacts leads to new artifacts and eventually new markets. In this article I focus on the theoretical foundations of these processes, proposing a theoretical framework to analyze them. The essay provides a contribution in the following two directions: • a discussion of the different levels of organization through which exaptations emerge in a market system; • an analysis of the complex links between exaptation and degeneracy (a many-tomany rather than one-to-one map between structure and function). Using this theoretical framework, I focus on the need for an analysis of the consequences of exaptations, arguing that exaptations may contribute to emerging degeneracy, which, in turn, may trigger further exaptations. In market systems one form of degeneracy is the coexistence of many structurally different artifacts providing at least in part the same functionality. I present historical examples that suggest that degeneracy increases the complexity of the system: the attribution of functionality previously provided by existing artifacts to new artifacts potentially able to provide them in a new way is a significant process giving raise to new artifacts and new marketsInnovation; Exaptation; Degeneracy; Adaptation;
Basel II compliant credit risk modelling: model development for imbalanced credit scoring data sets, loss given default (LGD) and exposure at default (EAD)
No full textThe purpose of this thesis is to determine and to better inform industry practitioners to the most appropriate classification and regression techniques for modelling the three key credit risk components of the Basel II minimum capital requirement; probability of default (PD), loss given default (LGD), and exposure at default (EAD). The Basel II accord regulates risk and capital management requirements to ensure that a bank holds enough capital proportional to the exposed risk of its lending practices. Under the advanced internal ratings based (IRB) approach Basel II allows banks to develop their own empirical models based on historical data for each of PD, LGD and EAD.In this thesis, first the issue of imbalanced credit scoring data sets, a special case of PD modelling where the number of defaulting observations in a data set is much lower than the number of observations that do not default, is identified, and the suitability of various classification techniques are analysed and presented. As well as using traditional classification techniques this thesis also explores the suitability of gradient boosting, least square support vector machines and random forests as a form of classification. The second part of this thesis focuses on the prediction of LGD, which measures the economic loss, expressed as a percentage of the exposure, in case of default. In this thesis, various state-of-the-art regression techniques to model LGD are considered. In the final part of this thesis we investigate models for predicting the exposure at default (EAD). For off-balance-sheet items (for example credit cards) to calculate the EAD one requires the committed but unused loan amount times a credit conversion factor (CCF). Ordinary least squares (OLS), logistic and cumulative logistic regression models are analysed, as well as an OLS with Beta transformation model, with the main aim of finding the most robust and comprehensible model for the prediction of the CCF. Also a direct estimation of EAD, using an OLS model, will be analysed. All the models built and presented in this thesis have been applied to real-life data sets from major global banking institutions
Characterisation of T cell defects in acute myeloid leukaemia
No full textPhDUnderstanding the immune system in patients with cancer and how it interacts with malignant cells is critical for the development of successful immunotherapeutic strategies at a time when novel cancer treatment approaches are required. Acute myeloid leukaemia (AML) results in widespread interaction between the malignant cells and T cells and as such, offers an opportunity to study these interactions. A flow cytometric analysis of T cells in the peripheral blood of patients presenting with AML illustrated that the absolute number of T cells is increased in AML compared with healthy controls. Furthermore, a large population of CD3+56+ cells was identified. These cells are not natural killer T cells but effector T cells that may represent a failing immunosurveillance mechanism. Two technical issues were explored: how to separate T cells from the peripheral blood of newly diagnosed AML patients and the impact of the method of immunomagnetic cell separation on the gene expression profile of healthy T cells. Gene expression profiling was subsequently performed on T cells from AML patients compared with healthy controls. Global differences in transcription were observed suggesting aberrant T cell activation patterns in AML. As differentially regulated genes involved in actin cytoskeletal formation were noted, a functional assessment of the ability of T cells from AML patients to form immunological synapses was performed. This illustrated that although T cells from AML patients can form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signalling molecules to that signalling interface is impaired. Taken together, these findings demonstrate that numerically T cells are plentiful in AML however they are abnormal in terms of the genes they are transcribing and in their interactions with tumour cells. Targeting immunological synapse formation may represent an important means of improving T cell recognition of tumour cells across a range of cancers
Gulf equity markets : a comparison of the structure and performance
Get PDFThe present study extends the literature available on the equity markets of
developing countries by describing the development, the structure and by
investigating the performance of the Gulf Equity markets in Kuwait, Saudi
Arabia, Bahrain and Oman.
First, an attempt was made to evaluate these equity markets by briefly
examining the financial systems, providing a historical background to their
development and introducing their current structure.
Second, the thesis examines the performance of these markets by; (a)
conducting a survey interviews to find out the obstacles for growth and
investments in these markets; (b) investigating whether share returns are
independent (c) investigating whether successive share returns are random
(d) examining whether there is any pattern, for instance, day-of-the -week
effect on the share returns; (e) estimating their transaction costs (the
effective bid-ask spread).
To analyse the performance, the study employed the classical techniques of
Fama (1965), Errunza and Losoq (1985) and Dickinson and Muragu (1994)
to determine the independency and randomness of share returns. The
method of French (1980), Solnik and Bousquet (1990) and Insup Lee et al
(1990) is used to test for the day-of-the week effect. Roll (1984) and Hsia,
Fuller and Kao (1994) methods were used to estimate the transaction costs
(the effective bid-ask spread).
To summarise, the results show that the Gulf Equity Markets have a
dependency on their share returns for Kuwait, Saudi Arabia, Bahrain and a
lesser dependency for Oman Market. On the other hand, the share returns on
each of the four markets were shown to be non random. The day of the week
effect was not found in the market of Kuwait, Bahrain and Oman, whereas the
Saudi Market showed the day-of-the week effect in the two periods tested.
The spread as measured by the modified method of Hsia et al. is consistent
with the results given by the Roll method which found the highest average
spread in the Saudi Market followed by the Bahrain, Kuwait and Muscat
markets
Modernist Repositionings of Rousseau's Ideal Childhood: Place and Space in English Modernist Children's Literature and Its French Translations
Get PDFIt is a little-known fact that several modernists wrote for children: this project will focus on T.S. Eliot‘s Old Possum‟s Book of Practical Cats, James Joyce‘s The Cat and the Devil,
Gertrude Stein‘s The World is Round and Virginia Woolf‘s Nurse Lugton‟s Curtain. While not often thought of as a modernist, I contend that Walter de la Mare‘s short stories for children, especially The Lord Fish, take part in this corpus of modernist texts for children. These
children‘s stories, while scarcely represented in critical circles, have enjoyed a wide popular audience and have all been translated into French. Modernism is often considered an elitist
movement, but these texts can contribute to its reassessment, as they suggest an effort towards inclusivity of audience.
The translation of children‘s literature is a relatively new field of study, which builds
from descriptive translation studies with what is unique to children‘s literature: its relation to
pedagogy and consequent censorship or other tailoring to local knowledge; frequently, the
importance of images; the dual audience that many children‘s books have in relating to the
adults who will select, buy and potentially perform the texts; and what Puurtinen calls ‗readaloud-
ability‘ for many texts.
For these texts and their French translations, questions of children‘s relations to place
and space are emphasised, and how these are complicated in translation through
domestication, foreignisation and other cultural context adaptations. In particular, these
modernists actively write against Rousseau‘s notion of the ―innocent‖ boy delighting in the
countryside and learning from nature. I examine the international dialogue that takes place in
these ideas of childhood moving between France and England, and renegotiated over the span
of the twentieth and twenty-first centuries.
This study thus seeks to contribute to British modernist studies, the growing field of the translation of children‘s literature, and children‘s geographies
The Anadyomene Movement: metamorphics of figure-ground
No full text‘Figure-ground’ is about the production of meaning based on the perception of contrasts or binary oppositions and segregations. Viewers of my paintings, and of the kind of paintings that interest me, have the impression that the ‘figure’ subsides or slips or fades into ‘ground’, or that the ‘ground’ is more powerful or dominant than the ‘figure’, or that the ‘figure’ is insecurely attached, suggesting it is incapable, unwilling, too acquiescent or complicit to fully differentiate itself from the ‘ground’. I address flux, mutation, indistinctness and complementarity within the visual field of painting. I develop and extend the heuristic context for the interpretation of my studio practice and for work of a similar kind, and then feedback this new context into my practice in order to generate new works, also in the process shedding a new light on my interpretative models. Beyond this, I also make a more general argument for the re alignment of the relationship between art theory and practice - one that can better incorporate a sense of in between-ness, indistinctness or liminality. My approach is comparative: I look at East Asian art and ideas and, in particular, deploy the writings of the French Sinologist and philosopher François Jullien, in whose work there is the attempt to expand Western epistemology, ontology, semantics and aesthetics via a discussion of Chinese thought and aesthetics. Jullien proposes a paradigm that draws the ‘in-out’ respiratory rhythm or pulse within the perceptual field towards the centre of a theory of representation, a theory that seeks to account for consciousness from the ‘inside’ rather than the ‘outside’. The consequence of this relocation of agency is an interpretative framework that is firmly grounded in a nondualistic and holistic approach, foregrounding affect and empathetic relationships between artist and work, viewer and work, and self and the world. Traditional East Asian thought begins with similar premises to poststructuralism in the West: the ‘self’ is an illusion and the possibility of knowledge of reality independent of thought is dismissed as untenable because there is no objective reality accessible to us. Everything depends on the bias of the mind, rather than on anything we can identify as an innate attribute of reality itself, thus there is no escape from our lived experience, and we are profoundly limited by the interpretive knowledge of our mind; we are trapped within the ‘prison house of language’. But within the different recursive orientations that characterize ‘East’ and ‘West’ the interpretation and consequences of these insights are understood in quite different ways. I explore why this should be the case and what some of the consequences are, both theoretically through the written text and performatively through my studio work
Israel's worst king? : the story of Ahab in light of its relationship to the stories of Saul, David and Solomon
Get PDFIn the story of King Ahab (I Kgs 16.29-22.40), Ahab is declared to be the worst person in the Hebrew Bible(I Kgs 21.25)seemingly because he repeats the infamous crimes of King Saul, King David and King Solomon. Because of the similarities in the behaviour of Ahab with his three predecessors, however, the story is a story about these three kings as well. As a result of the associations, Ahab's evil status is challenged. Views of the character Ahab in other literary traditions lend credence to the suggestion that Ahab does not live up to his bad name, and a close reading of the text of the story supports the suggestion. Such a reading leads to seeing King Ahab as a character who
is a composite of Saul, David and Solomon at their worst. These correspondences between the four kings lead to several results. Without saying that Ahab is not wicked, the correspondences (relatively) normalise the moral character of Ahab (in that Saul, David and Solomon may be considered 'normal'), while they diminish the moral character of the three kings by their association with Ahab. As a result, Ahab is viewed in a different and better light than what he is declared to be, while Saul, David and Solomon are viewed
in a lesser light. The diminishing after-effect also leads to rereading the stories of Saul, David and Solomon in the light of the story of Ahab. Read from such a perspective, their stories become stained by the stigma of being associated with Ahab
Development and evaluation of DNA vaccines in chickens against a wild bird H6N2 avian influenza virus from Western Australia
Get PDFGenetic immunization, also known as DNA or polynucleotide immunisation, is well documented to induce broad-based immunity in various animal models of infectious and non-infectious diseases. However, the low potency of DNA vaccines has to date precluded the development of commercial vaccines. The aim of this study was to systematically investigate a number of parameters to improve the potency of DNA vaccines for use in chickens, using a low pathogenic avian influenza (LPAI) virus as a proof-of-concept for their ability to produce a humoral immune response.
The index virus used in the study was avian influenza virus A/coot/WA/2727/79 (H6N2), isolated from an apparently healthy Eurasian coot in 1979. Prior to any DNA experiments the virus was rigorously characterized. The virus strain was shown to be an H6 subtype by haemaglutination inhibition (HI) testing and as an N2 subtype by gene sequence analysis. The isolate was shown to be able to grow on MDCK cells in the absence of exogenous trypsin. It was further biologically characterized as LPAI with an intravenous pathogenicity index (IVPI) of 0.15 and a motif of 321PQAETRG328 at the cleavage site of the haemagglutinin (HA) protein. It was capable of infecting domestic chickens under experimental conditions with a low level of virus excretion via the cloaca and oropharynx following intravenous or oral and oculonasal inoculation.
The full-length HA and nucleoprotein (NP) genes of this H6N2 virus were subsequently cloned into the eukaryotic expression vector VR1012 to generate VR-HA and VR-NP constructs. Six-week-old Hy-Line chickens were intramuscularly injected with either the VR-HA or VR-NP vaccine at different dose rates, with or without lipofectin as adjuvant. Minimal or no detectable antibody was produced, as measured by HI, ELISA and Western blotting-based assay, but high titres of H6-specific HI antibodies appeared 10 days after homologous virus challenge. In contrast to the empty vector controls, there was a significant difference in HI antibody titre between pre- and post-challenge in vaccinated birds, indicating some evidence for the priming effect of the DNA vaccines. Using the frequency of virus shedding as an indicator of protection, lower doses (50 or 100 ¦Ìg per chicken) of either adjuvanted VR-HA or VR-NP vaccine significantly reduced virus shedding in oropharyngeal and cloacal swabs compared to higher doses (300 or 500 ¦Ìg per chicken ) or empty vector control chickens. Although two vaccinations with naked VR-HA alone were not sufficient to induce an effective immune response against a homologous virus challenge, further repeat vaccinations and incorporation of adjuvant did lead to the generation of low to moderate HI antibody titres in some chickens and resulted in no or reduced virus shedding after challenge.
Next, to examine the effect of expression vector, three different DNA vectors, pCI, pCI-neo and pVAX1 were used to clone the same HA gene and generate three DNA vaccine constructs. Once again, direct intramuscular injection of the three DNA constructs did not elicit measurable H6-specific HA antibody response in Hy-Line chickens but the 100 µg pCI-HA lipofectin adjuvanted vaccine group showed a significant increase in post-challenge HI titres from the naive control group, indicating that an anamnestic antibody response had been induced by the pCI-HA DNA vaccination. Compared with the controls, the three DNA constructs showed significantly reduced virus shedding in cloacal swabs post virus challenge, suggesting that the three DNA vaccines induced some level of immune response in vaccinated chickens. As with the VR-HA construct, the lower dose groups for each vaccine (50 or 100 g) were more effective at reducing virus shedding from the cloaca than the higher dose group (300 g).
To further investigate why the DNA vaccines did not elicit a measurable antibody response, the HA gene incorporating a Kozak enhancer sequence was cloned into an alternative expression vector, pCAGGS, to produce the pCAG-HAk construct. Three-week-old SPF chickens were immunized with this construct either by the intramuscular route (IM) or electroporation (EP). H6 HI antibodies were present in some chickens by 3 weeks after the first IM vaccination and 75% of the chickens vaccinated with 10, 100 or 300 µg pCAG-HAk were antibody positive by 2 weeks after the second IM vaccination. For EP immunization, 87.5% of vaccinated birds seroconverted after the first vaccination and 100% seroconverted after the second vaccination and the H6 HI antibody titres were significantly higher than for chickens vaccinated by IM inoculation. Another group was given a single dose IM vaccination with 100 µg of the pCAG-HAk construct and showed a maximum sero-conversion rate of 53.3% with a peak H6 HI titre of 27 at 5 weeks post-vaccination. This demonstrated that optimization of the expression vector and insertion of a Kozak sequence could synergistically enhance expression of the H6 HA gene and result in a measurable H6 antibody response in SPF chickens. EP was also compared with IM inoculation with the 100 g pCI-HA construct in SPF chickens, resulting in a 50% sero-conversion rate and mean HI titre of 21.3 at 2 weeks after the second vaccination by EP. By comparison, only 25% chickens had trace HI titres by IM inoculation. This indicated that EP was more efficient than IM delivery for both constructs.
A codon-optimized complete HA gene from A/coot/WA/2727/79 (H6N2) was then chemically synthesized and cloned into a pCAGGS vector to generate the pCAG-optiHAk construct. SPF chickens immunized twice with either 10 µg or 100 µg of pCAG-optHA showed 37.5% and 87.5% sero-conversion rates respectively, with a mean H6 HI tire of 21.4 and 22.6 at 3 weeks after the second immunization, but the differences were not statistically significant. There were also no significant differences in either the sero-conversion rate or the H6 HI titre between the pCAG-HAk and pCAG-optiHAk groups, suggesting that a codon-optimized HA DNA vaccine did not achieve significantly better immunogenicity than the pCAG-HAk vaccine.
In vitro expression of the developed DNA constructs in chicken-, hamster-, monkey- and human-origin cells, as measured by Western blotting and immunofluorescence testing (IFT), showed the strength of H6 HA expression in the following descending order - pCAG-optiHAk/pCAG-HAk, pCI-HAk, VR-HA, pCI-HA, pCIneo-HA and pVAX-HA. The in vivo chicken vaccinations also showed that the pCI-HA construct was more effective than the pCI-neo-HA, and that the pCAG-optiHA or pCAG-HAk constructs were better than pCI-HAk in term of reduction in virus shedding after H6N2 virus challenge. Thus, in vitro HA gene expression directly correlated with the generation of immune responses in vivo, indicating that in vitro studies can be used for pre-selection of expression plasmids prior to development of avian influenza DNA vaccines.
Lipofectin as a chemical adjuvant was shown to enhance the DNA-induced immune response but is prohibitively expensive for routine use in poultry vaccines. Thus, an experimental adjuvant for poultry DNA vaccines (Essai) and a new nanoparticle (Phema) adjuvant used for the first time in poultry were compared with conventional aluminum salts (alum) adjuvant in the present study. No HI antibody was detected in any adjuvant-vaccinated Hy-Line chickens following two immunizations. However, in comparison with the naive control group, the alum- and Phema adjuvanted pCAG-HAk groups significantly reduced the frequency of virus shedding in oropharyngeal swabs, but Essai adjuvant was not effective in augmenting the pCAG-HAk vaccine efficacy. This pilot study also emphasised that the traditional aluminum hydroxide adjuvant, either DNA binding or non-binding, may be useful as an adjuvant for enhancing DNA-induced immune responses in chickens owing to its low price and safety record.
Overall, DNA immunization with various HA-expressing constructs was shown to be variably effective in inducing immune responses in chickens. The efficacy of DNA vaccines could be synergistically improved by taking appropriate approaches. With continuing research DNA vaccines have the potential to become an important tool for disease prevention and control
Social support, marriage and psychobiological pathways to adjustment after Acute Coronary Syndrome
No full textThe key aims of this thesis were to investigate the role of social support and marriage in adjustment and recovery in coronary heart disease (CHD). Declining death rates in CHD due to medical and surgical advances combined with increasing prevalence rates have contributed to a large and steadily growing population of chronic CHD patients, many of whom have suffered an acute cardiac event. In the context of this population, there is considerable need to determine factors that improve both adjustment and prognosis. Aspects of social support and marriage have been robustly associated with morbidity and mortality in CHD. Exploration of the potential psychological and biological pathways that link these factors forms the core of this thesis. Data from two separate studies are presented with the majority of analyses originating from data gathered in the Tracking Recovery after Acute Coronary Events (TRACE) study, a longitudinal study exploring diverse correlates of adjustment and recovery in 298 ACS patients. Associations between social support, marital satisfaction, distress, quality of life and HRV among ACS patients followed up from hospital admission to 12 months following discharge are presented. Data were also derived from a second study which explored psychobiological factors in a sample of 88 suspected coronary artery disease (CAD) patients and the analysis focused on marital influence on HRV. The overall thesis objective was to identify significant relationships between social and marital support, and various psychobiological factors that may contribute to adjustment and, ultimately, influence CHD prognosis
