442 research outputs found
The Life-Cycle Income Analysis Model (LIAM): a study of a flexible dynamic microsimulation modelling computing framework
Get PDFThis paper describes a flexible computing framework designed to create a dynamic microsimulation model, the Life-cycle Income Analysis Model (LIAM). The principle computing characteristics include the degree of modularisation, parameterisation, generalisation and robustness. The paper describes the decisions taken with regard to type of dynamic model used. The LIAM framework has been used to create a number of different microsimulation models, including an Irish dynamic cohort model, a spatial dynamic microsimulation model for Ireland, an indirect tax and consumption model for EU15 as part of EUROMOD and a prototype EU dynamic population microsimulation model for 5 EU countries. Particular consideration is given to issues of parameterisation, alignment and computational efficiency.flexible; modular; dynamic; alignment; parameterisation; computational efficiency
Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid
Get PDFFive new platinum(IV) derivatives of carboplatin each incorporating the histone deacetylase inhibitor 4-phenylbutyrate in axial position were synthesized and characterized by 1H and 195Pt NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis, namely cis,trans-[Pt(CBDCA)(NH3)2(PBA)(OH)] (1), cis,trans-[Pt(CBDCA)(NH3)2(PBA)2] (2), cis,trans-[Pt(CBDCA)(NH3)2(PBA)(bz)] (3), cis,trans-[Pt(CBDCA)(NH3)2(PBA)(suc)] (4) and cis,trans-[Pt(CBDCA)(NH3)2)(PBA)(ac)] (5) (PBA = 4-phenylbutyrate, CBDCA = 1,1-cyclobutane dicarboxylate, bz = benzoate, suc = succinate and ac = acetate). The reduction behavior in the presence of ascorbic acid was studied by high performance liquid chromatography. The cytotoxicity against a panel of human tumor cell lines, histone deacetylase (HDAC) inhibitory activity, cellular accumulation and the ability to induce apoptosis were evaluated. The most effective complex, compound 3, was found to be up to ten times more effective than carboplatin and to decrease cellular basal HDAC activity by approximately 18% in A431 human cervical cancer cells
Project Triton : A study into delivering targeted information to an individual based on implicit and explicit data.
No full textThe World Wide Web is frequently seen as a source of knowledge, however much of this remains undiscovered by its users. In recent times, recommender systems (e.g. Digg and Last.fm) have attempted to bridge this gap, alerting users to previously untapped knowledge. As more socially oriented services appear on the Web (e.g. Facebook and MySpace), it has never been easier to obtain information pertaining to an individual’s interests. At present, solutions for automated data recommendation tend to be highly topic specific (recommending only a certain topic such as news) and often only allow access to the system using monolithic interfaces. This report hopes to detail the stages from research to evaluation involved in creating an extensible framework, which will operate without the need for human intervention. The framework will feature several proof-of-concept plugins residing in a custom workflow, which target information that is useful to the user. Information will be retrieved automatically through plugins involved with data gathering (such as feed processing and page scraping), while users’ interests will be obtained implicitly (for example, using header information to derive location) or explicitly (taking advantage of Social Network APIs such as Facebook Connect). Finally, Third Parties will be able to integrate the framework into their own solutions using the customisable XML API (written in PHP), so that their products can provide custom user interfaces without style constraints
Validating a dynamic population microsimulation model: Recent experience in Australia
Get PDFAvailable published research on microsimulation tends to focus on the results of policy simulations rather than upon validation of the models and their outputs. Dynamic population microsimulation models, which age an entire population through time for some decades, create particular validation challenges. This article outlines some of the issues that arise when attempting to validate dynamic population models, including changing behaviour, the need to align results with other aggregate ‘official’ projections, data quality and useability. Drawing on recent experience with the construction of the new Australian Population and Policy Simulation Model (APPSIM), the article discusses the techniques being used to validate this new dynamic population microsimulation model.Dynamic microsimulation, validation, model output, usability
Cultural Mythology and Anxieties of Belonging: Reconstructing the "bi-cultural" subject in the fiction of Toni Morrison, Amy Tan and Annie Proulx
No full textPhDThe thesis considers the construction of cultural identity in the writings of Tom Morrison,
Annie Proulx, and Amy Tan. It consists of three chapters, one dedicated to each of the
writers. In the examination of these writers the focus is upon the construction of the "bicultural"
subject in the contemporary United States. The paradigm of analysis is
constructed through discourses of space, landscape and physical geography.
The first chapter is devoted to Toni Morrison and is divided into two sections
dealing with the novels Beloved and Jazz. The first section examines how spatial
discourses disrupt binaries that marginalise the black community. It concentrates upon
the location of the "porch" in the novel and parallels it with the "porch" as a black spatial
icon. The Jazz section examines the idealised space of the City. It focuses on the
material layout of American Cities and discusses its relationship to constructions of
American cultural identity. The debate is used to highlight how the geographical
marginalisation of communities parallels their cultural alienation.
The second chapter is split into two sections, the first focuses upon The Joy Luck
Club, the second concerns The Kitchen God's Wife. Tan's work is discussed in relation
to cultural geographic debates about mythic geography. It deals with the different ways
in which Tan's texts try to palliate cultural anxieties about "belonging" by constructing a
culturally soothing mythic location. An idealised version of the Chinese-American
community is sustained through her constructions of both San Francisco and China,
which she employs and negotiates in different ways in the two texts.
The third chapter examines three Proulx texts, Postcards, Accordion Crimes, and
Close Range Wyoming Stories. The chapter explores the different ways these texts
negotiate cultural belonging in relation to geographic migration. Postcards is considered
in relation to the literary discourse of migration. In Accordion Crimes the employment of
similarly positivist conceptions of the construction of a "home" in North America is
examined. The final section examines the problematic nature of "location" as both
geographically and textually soothing.
The Epilogue suggests the possible extension of the thesis and foregrounds the
importance of the materiality of spatial construction to the cultural anxieties the thesis
examines
Investigating the pathogenesis of African trypanosome infection via the skin
Get PDFAfrican trypanosomes (Trypanosoma brucei sp.) are single-celled extracellular
protozoan parasites that are transmitted via the tsetse fly vector across sub-
Saharan Africa. T. brucei subspecies cause trypanosomiasis in both humans
and animals, inflicting substantial disease and economic strains in affected
regions. Mammalian infection begins when the tsetse fly takes a blood meal
and injects trypanosomes into the dermal layer of skin. The parasites then
invade the circulatory and lymphatic systems, reaching the draining lymph
nodes and disseminate systemically. Little is understood about the host-pathogen
interactions which influence the establishment of host infection at
the initial bite site in the skin. Most experimental transmissions of African
trypanosomiasis have studied the intraperitoneal or intravenous routes of
exposure. However, these by-pass the natural route of infection via the skin.
Therefore the aim of this thesis is to investigate the pathogenesis of African
trypanosome infection via the skin.
Chemokines play important roles in attracting leukocytes towards the
lymphatics and lymph nodes. To investigate how trypanosomes migrate from
the bite site to the draining lymph nodes, the hypothesis that chemokines may
act as chemoattractants for trypanosomes was tested. Chemokines can also
possess antimicrobial properties, including against the related protozoan
parasite Leishmania mexicana, therefore their potential cytotoxic effects
against T. brucei were tested. Data presented in this thesis shows that these
chemokines do not induce the chemotaxis of T. brucei. The motility
characteristics of the parasites were also not affected by chemokine exposure.
Nor did these chemokines exert any trypanostatic effects on trypanosomes.
These data suggest trypanosomes use alternative cues to reach the
lymphatics post-infection.
The skin is an overlooked area of research for African trypanosome infections.
Therefore work in this thesis sought to investigate the hypothesis that the
infection kinetics would be different in a host infected by the natural intradermal
route when compared with the routinely-researched intraperitoneal route.
Experiments in this thesis revealed clear differences in the infection kinetics
and disease progression in mice infected intradermally when compared with
those infected by the intraperitoneal route. These data imply that further
infection models should utilise intradermal injections and investigate the
overlooked skin stage of disease which occurs naturally in the wild.
Upon deposition in the skin the trypanosomes home towards the lymphatic
system before migrating systemically. Lymphotoxin-β-receptor signalling
(LTβR) is essential for lymphoid organogenesis and the maintenance of
secondary lymphoid tissue microarchitecture. For example, LTβ-/- mice lack
most lymph nodes and have grossly disturbed splenic microarchitecture. As a
consequence of these disturbances LTβ-/- mice have impaired antibody isotype
class-switching. Experiments in this thesis were performed to test the
hypothesis that deficiencies in lymph node development and antibody isotype
class-switching would influence disease pathogenesis. These data show that
disease susceptibility and pathogenesis were exacerbated in LTβ-/- mice,
which lacked class-switched antibody isotypes in their sera. This disease
profile was then reversed in LTβ-/- mice which received wild-type bone-marrow
transfers after their haematopoietic system was ablated through lethal
irradiation. These data could identify the importance of the class-switching
capability of the adaptive immune system to combat trypanosome infection.
Little is known of the early host-parasite interactions following injection of T.
brucei into the dermis of the skin. Macrophages are key players in the innate
immune response against African trypanosome infection, and manipulating
these cells during infection may help our understanding of the disease
pathogenesis. To address their potential role in disease susceptibility,
experiments were designed to manipulate the density and inflammatory status
of the macrophages in the skin prior to infection with T. brucei. These data
show, that manipulation of the inflammatory status of the skin reduced
susceptibility to infection with T. brucei via the skin. A greater understanding
of the macrophage-parasite interactions which occur during the early stages
of African trypanosome infection is important for understanding how the
immune system responds to infection and how we can boost immunity to
combat infection.
A thorough identification of the mechanisms involved in establishing African
trypanosome infections in the skin and their systemic dissemination will aid the
development of novel approaches to block disease transmission
Investigating oxidative stress responses in Trypanosoma brucei and Trypanosoma congolense bloodstream forms
No full textAfrican trypanosomes are parasites spread by tsetse flies that cause severe diseases in humans and animals. The clinically relevant species include Trypanosoma brucei, upon which the majority of our biological understanding is based, and T. congolense, which is less understood. These parasites are extracellular in all stages of their complex life cycle, as a result, they are continuously exposed to harsh environments in their mammalian and insect hosts. In the mammalian host, the immune system is characterised by key innate immune cells such as macrophages, which release reactive oxygen and nitrogen species, imposing oxidative stress. The parasite response to oxidative stress, as well as redox balance maintenance, have been studied to some degree in T. brucei, but not in T. congolense, which is known to exhibit divergence at the genome, transcriptome and metabolome levels. Understanding these responses and how they differ between closely related species is crucial for uncovering parasite survival strategies and developing therapeutic interventions.
This thesis investigates the hypothesis that oxidative stress responses and redox balance mechanisms differ between bloodstream forms (BSFs) of T. brucei and T. congolense, and that these differences underlie phenotypes such as differential sensitivity to oxidative stress and interactions with macrophages. Specifically, it examines the oxidative stress responses, redox balance mechanisms, and interactions with macrophages in these two species to determine their differential parasite sensitivity. Techniques including metabolomics and transcriptomics were used to compare genes and pathways involved in these processes between the two species that may explain any observed phenotypic differences and similarities. Finally, the thesis also explored a gene linked to oxidative stress resistance previously studied in the parasite Leishmania, but not yet explored in African trypanosomes.
To facilitate the study of the two trypanosome species under comparable conditions, a novel lipid-rich medium, Morrison’s Universal Medium (MUM) was developed and optimised. This medium enabled the direct comparison of redox balance and oxidative stress response pathways between T. brucei and T. congolense. Experiments were carried out to find suitable candidates for inducing oxidative stress under in vitro conditions, which led to the identification of the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) as a viable candidate. Subsequently, experiments with SNAP showed that T. congolense was more sensitive to nitrosative stress compared to T. brucei. In vitro studies on trypanosome-macrophage interaction further supported these findings, as T. congolense viability was reduced to a greater extent in the presence of macrophages.
To investigate potential underlying metabolic differences that could explain the differences in SNAP sensitivity, a comparative analysis of intracellular and extracellular metabolites of T. brucei and T. congolense was carried out using cells derived from the same medium. It was found that both species showed a similar capacity for glucose consumption, in contrast to previous data showing that T. congolense had reduced capacity. Metabolomics data further showed that T. brucei excreted high levels of pyruvate while T. congolense consumed this metabolite, indicating a species-specific difference in pyruvate utilisation. T. brucei culture supernatants consistently showed elevated acetate levels, which was not consistent with previous literature. Taken together, these results are indicative of metabolic adaptation to MUM. T. brucei supernatants also exhibited higher levels of immunomodulatory aromatic ketoacids such as indolepyruvate, hydroxyphenylpyruvate and phenylpyruvate. Conversely, T. congolense exhibited higher levels of antioxidant metabolites, such as glutathione, oxidised glutathione, and ornithine, which help protect cells from damage.
Metabolomics data were integrated with previously generated transcriptomics data, highlighting that T. congolense exhibited a higher expression of genes associated with the trypanothione cycle and polyamine biosynthesis – pathways that play a role in handling oxidative stress. Moreover, T. congolense displayed a higher transcript abundance of genes linked to the oxidative branch of the Pentose Phosphate Pathway (PPP), which produces antioxidant components. In contrast, T. brucei showed higher activity of genes from the non-oxidative branch of the PPP, which are involved in energy production. Combined, the data indicated that T. congolense has more activity in oxidative stress response pathways compared to T. brucei, even under steady-state conditions.
Studies in the related kinetoplastid parasite Leishmania spp. showed that overexpressing the gene aconitase (ACO) increases resistance to nitrosative stress. The role of this gene in nitric oxide resistance has not been investigated in African trypanosomes. I, therefore, investigated the impact of ACO overexpression in T. brucei and T. congolense BSFs on SNAP sensitivity. Overexpressing ACO in T. congolense caused BSF parasites to differentiate into a form resembling the insect stage procyclic forms (PCFs), suggesting a role for ACO in parasite differentiation. In contrast, overexpressing ACO in the monomorphic T. brucei Lister 427 led to significant mortality without any morphological change, likely because this strain is incapable of differentiation. Analyses, including adaptation to PCF culture media, flow cytometry, and microscopy, confirmed that ACO overexpression caused T. congolense to differentiate into a form closely resembling PCFs. I was unable to evaluate the role of ACO in oxidative stress management across both species, which warrants further investigation. In addition, further work is required to determine the mechanisms by which ACO overexpression is linked to differentiation.
In summary, this thesis presents the development of a universal medium enabling the culture of multiple African trypanosome species. This system revealed T. congolense’s increased sensitivity to oxidative stress compared to T. brucei and highlighted metabolic similarities and differences between species. Additionally, this thesis describes the potential role of ACO in promoting differentiation in trypanosomes. These findings offer valuable insights into the adaptive mechanisms of African trypanosomes, and further support a growing body of literature evidencing biological divergence between two closely related species of clinically relevant protozoan parasites
Prevalence, species identification and genotyping Cryptosporidium from livestock and deer in a catchment in the Cairngorms with a history of a contaminated public water supply
Get PDFBackground:
The apicomplexan parasite Cryptosporidium represents a threat to water quality and public health. An important zoonotic species involved in human cryptosporidiosis from contaminated water is Cryptosporidium parvum (C. parvum), the main reservoirs of which are known to be farm livestock particularly neonatal calves, although adult cattle, sheep, lambs and wildlife are also known to contribute to catchment loading of C. parvum. This study aimed to establish Cryptosporidium prevalence, species and genotype in livestock, deer and water in a catchment with a history of Cryptosporidium contamination in the public water supply.
Methods:
A novel method of processing adult ruminant faecal sample was used to concentrate oocysts, followed by a nested species specific multiplex (nssm) PCR, targeting the 18S rRNA gene, to speciate Cryptosporidium. A multilocus fragment typing (MLFT) tool was used, in addition to GP60 sequencing, to genotype C. parvum positive samples.
Results:
A very high prevalence of Cryptosporidium was detected, with speciation identifying a predominance of C. parvum in livestock, deer and water samples. Four GP60 subtypes were detected within C. parvum with the majority IIaA15G2R1 which was detected in all host species and on all farms. Multilocus fragment typing further differentiated these into 6 highly related multilocus genotypes.
Conclusion:
The high prevalence of Cryptosporidium detected was possibly due to a combination of the newly developed sample processing technique used and a reflection of the high rates of the parasite present in this catchment. The predominance of C. parvum in livestock and deer sampled in this study suggested that they represented a significant risk to water quality and public health. Genotyping results suggested that the parasite is being transmitted locally within the study area, possibly via free-roaming sheep and deer. Further studies are needed to verify particular host associations with subtypes/MLGs. Land and livestock management solutions to reduce Cryptosporidium on farm and in the catchment are planned with the aim to improve animal health and production as well as water quality and public health
Cymbospondylus Leidy 1868
No full textCymbospondylus Leidy, 1868 (14) Type species Cymbospondylus piscosus Leidy, 1868 (14) Referred species Cymbospondylus petrinus Leidy, 1868 (14); Cymbospondylus buchseri (15); Cymbospondylus nichollsi (16); *Corresponding author. Email: [email protected] (P.M.S.); [email protected] (E.M.G.); [email protected] (L.S.) Cymbospondylus duelferi (17); Cymbospondylus youngorum sp. nov. Genus diagnosis For a recent detailed diagnosis of the genus, see (17). In addition, the results of the phylogenetic analysis in this study offer an apomorphy-based diagnosis.Published as part of Sander, P. Martin, Griebeler, Eva Maria, Klein, Nicole, Juarbe, Jorge Velez, Wintrich, Tanja, Revell, Liam J. & Schmitz, Lars, 2021, Early giant reveals faster evolution of large body size in ichthyosaurs than in cetaceans, pp. 1-15 in Science (New York, N. Y.) (New York, N. Y.) 374 (6575) on pages 1-2, DOI: 10.1126/science.abf5787, http://zenodo.org/record/580532
This is still breaking people: update on human rights violations at Australia’s asylum seeker processing centre on Manus Island, Papua New Guinea
Get PDFAbstract: There appears to have been little or no effort by the Australian and Papua New Guinean governments to address the recommendations in Amnesty International’s December 2013 report, This is Breaking People. The primary concerns around arbitrary and indefinite detention and lack of clear plans for processing and resettlement of asylum seekers remain unaddressed and are fuelling widespread anxiety and despair among detainees. Amnesty International remains concerned about overcrowding. Furthermore, not a single refugee assessment has been made in more than 18 months since the centre was first opened
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