Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Neuropsychological development in children with early and continuously treated phenylketonuria : association with biochemical markers

PKU is a genetically inherited inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. The failure of this enzyme causes incomplete metabolism of protein ingested in the diet, specifically the conversion of one amino acid, phenylalanine, to tyrosine, which is a precursor to the neurotransmitter dopamine. Rising levels of phenylalanine is toxic to the developing brain, disrupting the formation of white matter tracts. The impact of tyrosine deficiency is not as well understood, but is hypothesized to lead to a low dopamine environment for the developing brain. Detection in the newborn period and continuous treatment (a low protein phe-restricted diet supplemented with phenylalanine-free protein formulas) has resulted in children with early and continuously treated PKU now developing normal I.Q. However, deficits in executive function (EF) are common, leading to a rate of Attention Deficit Hyperactivity Disorder (ADHD) up to five times the norm. EF worsens with exposure to higher phenylalanine levels, however recent research has demonstrated that a high phenylalanine to tyrosine ratio (phenylalanine:tyrosine ratio), which is hypothesised to lead to poorer dopamine function, has a more negative impact on EF than phenylalanine levels alone. Research and treatment of PKU is currently phenylalanine-focused, with little investigation of the impact of tyrosine on neuropsychological development. There is no current consensus as to the veracity of tyrosine monitoring or treatment in this population. Further, the research agenda in this population has demonstrated a primary focus on EF impairment alone, even though there may be additional neuropsychological skills compromised (e.g., mood, visuospatial deficits). The aim of this PhD research was to identify residual neuropsychological deficits in a cohort of children with early and continuously treated phenylketonuria, at two time points in development (early childhood and early adolescence), separated by eight years. In addition, this research sought to determine which biochemical markers were associated with neuropsychological impairments. A clinical practice survey was also undertaken to ascertain the current level of monitoring/treatment of tyrosine in this population. Thirteen children with early and continuously treated PKU were tested at mean age 5.9 years and again at mean age 13.95 years on several neuropsychological measures. Four children with hyperphenylalaninemia (a milder version of PKU) were also tested at both time points and provide a comparison group in analyses. Associations between neuropsychological function and biochemical markers were analysed. A between groups analysis in adolescence was also conducted (children with PKU compared to their siblings) on parent report measures of EF and mood. Minor EF impairments were evident in the PKU group by age 6 years and these persisted into adolescence. Life-long exposure to high phenylalanine:tyrosine ratio and/or low tyrosine independent of phenylalanine were significantly associated with EF impairments at both time points. Over half the children with PKU showed severe impairment on a visuospatial task, and this was associated only with concurrent levels of tyrosine in adolescence. Children with PKU also showed a statistically significant decline in a language comprehension task from 6 years to adolescence (going from normal to subnormal), this deficit was associated with lifetime levels of phenylalanine. In comparison, the four children with hyperphenylalaninemia demonstrated normal function at both time points, across all measures. No statistically significant differences were detected between children with PKU and their siblings on the parent report of EF and mood. However, depressive symptoms were significantly correlated with: EF; long term high phe:tyr exposure; and low tyrosine levels independent of phenylalanine. The practice survey of metabolic clinics from 12 countries indicated a high level of variability in terms of monitoring/treatment of tyrosine in this population. Whilst over 80% of clinics surveyed routinely monitored tyrosine levels in their child patients, 25% reported treatment strategies to increase tyrosine (and thereby lower the phenylalanine:tyrosine ratio) under a variety of patient presentation conditions. Overall, these studies have shown that EF impairments associated with PKU provide support for the dopamine-deficiency model. A language comprehension task showed a different trajectory, serving a timely reminder that non-EF functions also remain vulnerable in this population; and that normal function in childhood does not guarantee normal function by adolescence. Mood impairments were associated with EF impairments as well as long term measures of phenylalanine:tyrosine and/or tyrosine. The implications of this research for enhanced clinical guidelines are discussed given varied current practice.

Synthesis of one-dimensional nanocomposites based on alumina nanofibres and their catalytic applications

Materials with one-dimensional (1D) nanostructure are important for catalysis. They are the preferred building blocks for catalytic nanoarchitecture, and can be used to fabricate designer catalysts. In this thesis, one such material, alumina nanofibre, was used as a precursor to prepare a range of nanocomposite catalysts. Utilising the specific properties of alumina nanofibres, a novel approach was developed to prepare macro-mesoporous nanocomposites, which consist of a stacked, fibrous nanocomposite with a core-shell structure. Two kinds of fibrous ZrO2/Al2O3 and TiO2/Al2O3 nanocomposites were successfully synthesised using boehmite nanofibers as a hard temperate and followed by a simple calcination. The alumina nanofibres provide the resultant nanocomposites with good thermal stability and mechanical stability. A series of one-dimensional (1D) zirconia/alumina nanocomposites were prepared by the deposition of zirconium species onto the 3D framework of boehmite nanofibres formed by dispersing boehmite nanofibres into a butanol solution, followed by calcination at 773 K. The materials were characterised by X-ray diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscope (TEM), N2 adsorption/desorption, Infrared Emission Spectroscopy (IES), and Fourier Transform Infrared spectroscopy (FT-IR). The results demonstrated that when the molar percentage, X, X=100*Zr/(Al+Zr), was > 30%, extremely long ZrO2/Al2O3 composite nanorods with evenly distributed ZrO2 nanocrystals formed on their surface. The stacking of such nanorods gave rise to a new kind of macroporous material without the use of any organic space filler\template or other specific drying techniques. The mechanism for the formation of these long ZrO2/Al2O3 composite nanorods is proposed in this work. A series of solid-superacid catalysts were synthesised from fibrous ZrO2/Al2O3 core and shell nanocomposites. In this series, the zirconium molar percentage was varied from 2 % to 50 %. The ZrO2/Al2O3 nanocomposites and their solid superacid counterparts were characterised by a variety of techniques including 27Al MAS-NMR, SEM, TEM, XPS, Nitrogen adsorption and Infrared Emission Spectroscopy. NMR results show that the interaction between zirconia species and alumina strongly correlates with pentacoordinated aluminium sites. This can also be detected by the change in binding energy of the 3d electrons of the zirconium. The acidity of the obtained superacids was tested by using them as catalysts for the benzolyation of toluene. It was found that a sample with a 50 % zirconium molar percentage possessed the highest surface acidity equalling that of pristine sulfated zirconia despite the reduced mass of zirconia. Preparation of hierarchically macro-mesoporous catalyst by loading nanocrystallites on the framework of alumina bundles can provide an alternative system to design advanced nanocomposite catalyst with enhanced performance. A series of macro-mesoporous TiO2/Al2O3 nanocomposites with different morphologies were synthesised. The materials were calcined at 723 K and were characterised by X-ray diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscope (TEM), N2 adsorption/desorption, Infrared Emission Spectroscopy (IES), and UV-visible spectroscopy (UV-visible). A modified approach was proposed for the synthesis of 1D (fibrous) nanocomposite with higher Ti/Al molar ratio (2:1) at lower temperature (<100oC), which makes it possible to synthesize such materials on industrial scale. The performances of a series of resultant TiO2/Al2O3 nanocomposites with different morphologies were evaluated as a photocatalyst for the phenol degradation under UV irradiation. The photocatalyst (Ti/Al =2) with fibrous morphology exhibits higher activity than that of the photocatalyst with microspherical morphology which indeed has the highest Ti to Al molar ratio (Ti/Al =3) in the series of as-synthesised hierarchical TiO2/Al2O3 nanocomposites. Furthermore, the photocatalytic performances, for the fibrous nanocomposites with Ti/Al=2, were optimized by calcination at elevated temperatures. The nanocomposite prepared by calcination at 750oC exhibits the highest catalytic activity, and its performance per TiO2 unit is very close to that of the gold standard, Degussa P 25. This work also emphasizes two advantages of the nanocomposites with fibrous morphology: (1) the resistance to sintering, and (2) good catalyst recovery.

1,1,3,3-Tetraethylisoindolin-2-ium chloride

In the structure of the title compound C16H26N+ Cl-, the salt of a precursor in the synthesis of an isoindolin-2-yloxyl free-radical trapping agent, the cations and anions form discrete centrosymetric cyclic dimers through N---H...Cl hydrogen-bonding associations [graph set R2/4(8)].

Mathematical modelling of the drying of sol gel microspheres

This thesis presents a mathematical model of the evaporation of colloidal sol droplets suspended within an atmosphere consisting of water vapour and air. The main purpose of this work is to investigate the causes of the morphologies arising within the powder collected from a spray dryer into which the precursor sol for Synroc™ is sprayed. The morphology is of significant importance for the application to storage of High Level Liquid Nuclear Waste. We begin by developing a model describing the evaporation of pure liquid droplets in order to establish a framework. This model is developed through the use of continuum mechanics and thermodynamic theory, and we focus on the specific case of pure water droplets. We establish a model considering a pure water vapour atmosphere, and then expand this model to account for the presence of an atmospheric gas such as air. We model colloidal particle-particle interactions and interactions between colloid and electrolyte using DLVO Theory and reaction kinetics, then incorporate these interactions into an expression for net interaction energy of a single particle with all other particles within the droplet. We account for the flow of material due to diffusion, advection, and interaction between species, and expand the pure liquid droplet models to account for the presence of these species. In addition, the process of colloidal agglomeration is modelled. To obtain solutions for our models, we develop a numerical algorithm based on the Control Volume method. To promote numerical stability, we formulate a new method of convergence acceleration. The results of a MATLAB™ code developed from this algorithm are compared with experimental data collected for the purposes of validation, and further analysis is done on the sensitivity of the solution to various controlling parameters.

Strolling through the (post)modern city: Modes of being a flaneur in picture books

The city and the urban condition, popular subjects of art, literature, and film, have been commonly represented as fragmented, isolating, violent, with silent crowds moving through the hustle and bustle of a noisy, polluted cityspace. Included in this diverse artistic field is children’s literature—an area of creative and critical inquiry that continues to play a central role in illuminating and shaping perceptions of the city, of city lifestyles, and of the people who traverse the urban landscape. Fiction’s textual representations of cities, its sites and sights, lifestyles and characters have drawn on traditions of realist, satirical, and fantastic writing to produce the protean urban story—utopian, dystopian, visionary, satirical—with the goal of offering an account or critique of the contemporary city and the urban condition. In writing about cities and urban life, children’s literature variously locates the child in relation to the social (urban) space. This dialogic relation between subject and social space has been at the heart of writings about/of the flâneur: a figure who experiences modes of being in the city as it transforms under the influences of modernism and postmodernism. Within this context of a changing urban ontology brought about by (post)modern styles and practices, this article examines five contemporary picture books: The Cows Are Going to Paris by David Kirby and Allen Woodman; Ooh-la-la (Max in love) by Maira Kalman; Mr Chicken Goes to Paris and Old Tom’s Holiday by Leigh Hobbs; and The Empty City by David Megarrity. I investigate the possibility of these texts reviving the act of flânerie, but in a way that enables different modes of being a flâneur, a neo-flâneur. I suggest that the neo-flâneur retains some of the characteristics of the original flâneur, but incorporates others that take account of the changes wrought by postmodernity and globalization, particularly tourism and consumption. The dual issue at the heart of the discussion is that tourism and consumption as agents of cultural globalization offer a different way of thinking about the phenomenon of flânerie. While the flâneur can be regarded as the precursor to the tourist, the discussion considers how different modes of flânerie, such as the tourist-flâneur, are an inevitable outcome of commodification of the activities that accompany strolling through the (post)modern urban space.

An empirical investigation of health information system failure in regional Sri Lanka

Public health decision making is critically dependant on accurate, timely and reliable information. There is a widespread belief that most of the national and sub-national health information systems fail in providing much needed information support for evidence based health planning and interventions. This situation is more acute in developing nations where resources are either stagnant or decreasing, coupled with the situations of demographic transition and double burden of diseases. Literature abounds with publications, which provide information on misguided health interventions in developing nations, leading to failure and waste of resources. Health information system failure is widely blamed for this situation. Nevertheless, there is a dearth of comprehensive evaluations of existing national or sub-national health information systems, especially in the region of South-East Asia. This study makes an attempt to bridge this knowledge gap by evaluating a regional health information system in Sri Lanka. It explores the strengths and weaknesses of the current health information system and related causative factors in a decentralised health system and then proposes strategic recommendations for reform measures. A mix methodological and phased approach was adopted to reach the objectives. An initial self administered questionnaire survey was conducted among health managers to study their perceptions in relation to the regional health information system and its management support. The survey findings were used to establish the presence of health information system failure in the region and also as a precursor to the more in-depth case study which was followed. The sources of data for the case study were literature review, document analysis and key stake holder interviews. Health information system resources, health indicators, data sources, data management, data quality, and information dissemination were the six major components investigated. The study findings reveal that accurate, timely and reliable health information is unavailable and therefore evidence based health planning is lacking in the studied health region. Strengths and weaknesses of the current health information system were identified and strategic recommendations were formulated accordingly. It is anticipated that this research will make a significant and multi-fold contribution for health information management in developing countries. First, it will attempt to bridge an existing knowledge gap by presenting the findings of a comprehensive case study to reveal the strengths and weaknesses of a decentralised health information system in a developing country. Second, it will enrich the literature by providing an assessment tool and a research method for the evaluation of regional health information systems. Third, it will make a rewarding practical contribution by presenting valuable guidelines for improving health information systems in regional Sri Lanka.

Using fiber Bragg grating in geothermal monitoring

Earthquake precursor monitoring is the foundation of earthquake prediction and geothermal monitoring is one of the basic methods of earthquake precursor monitoring. High temperature well contains more information and therefore its monitoring is more important. However, electric sensors are hard to meet the monitoring requirements of high sensitivity and long lifetime. For a better observation of the earthquake precursor, a high sensitive fiber Bragg grating (FBG) temperature sensor is designed to monitoring a well at 87.5±1◦C. The performance of the FBG sensor demonstrates that it’s quite possible that applying FBG to high-sensitivity temperature-monitoring fields, such as geothermal monitoring. As far as we known, it is the first time that trying a high sensitive FBG temperature sensor in a practical application, let alone in the field of geothermal monitoring.

Engineering of vascularized adipose constructs

Adipose tissue engineering offers a promising alternative to the current surgical techniques for the treatment of soft tissue defects. It is a challenge to find the appropriate scaffold that not only represents a suitable environment for cells but also allows fabrication of customized tissue constructs, particularly in breast surgery. We investigated two different scaffolds for their potential use in adipose tissue regeneration. Sponge-like polyurethane scaffolds were prepared by mold casting with methylal as foaming agent, whereas polycaprolactone scaffolds with highly regular stacked-fiber architecture were fabricated with fused deposition modeling. Both scaffold types were seeded with human adipose tissuederived precursor cells, cultured and implanted in nude mice using a femoral arteriovenous flow-through vessel loop for angiogenesis. In vitro, cells attached to both scaffolds and differentiated into adipocytes. In vivo, angiogenesis and adipose tissue formation were observed throughout both constructs after 2 and 4 weeks, with angiogenesis being comparable in seeded and unseeded constructs. Fibrous tissue formation and adipogenesis were more pronounced on polyurethane foam scaffolds than on polycaprolactone prototyped scaffolds. In conclusion, both scaffold designs can be effectively used for adipose tissue engineering.

Ozone-initiated particle formation, particle aging, and precursors in a laser printer

An increasing number of researchers have hypothesized that ozone may be involved in the particle formation processes that occur during printing, however no studies have investigated this further. In the current study, this hypothesis was tested in a chamber study by adding supplemental ozone to the chamber after a print job without measurable ozone emissions. Subsequent particle number concentration and size distribution measurements showed that new particles were formed minutes after the addition of ozone. The results demonstrated that ozone did react with printer-generated volatile organic compounds (VOCs) to form secondary organic aerosols (SOAs). The hypothesis was further confirmed by the observation of correlations among VOCs, ozone, and particles concentrations during a print job with measurable ozone emissions. The potential particle precursors were identified by a number of furnace tests, which suggested that squalene and styrene were the most likely SOA precursors with respect to ozone. Overall, this study significantly improved scientific understanding of the formation mechanisms of printer-generated particles, and highlighted the possible SOA formation potential of unsaturated nonterpene organic compounds by ozone-initiated reactions in the indoor environment. © 2011 American Chemical Society.

The performance and politics of practice for New Graduate Nurses

The change from nursing student to Registered Nurse (RNs) is both a desirable and anticipated event for New Graduate Nurses (NGNs). Having completed their formal education, most NGNs approach the threshold of their professional career with mixed emotions. While excited about the future and eagerly awaiting the commencement of employment, many are aware that this change also signifies a time of personal upheaval, professional insecurity and further personal learning. In the nursing professions’ enthusiasm to facilitate a smooth passage for NGNs a vast literature now addresses preparation-for-practice degrees, as well as the perceived workplace deficits and support needs of NGNs. However, the importance this change from working as a student to working as a NGN is not well conceptualised, theorised or understood as this largely instrumental literature essentially reduces the problematisation of the NGN transition experience to the problematisation of the individual by identifying NGNs as ‘the’ problem. Subsequently it fails to expose or challenge the normative assumptions underpinning processes that have formerly been considered solutions, or, the impact of such processes in a workplace that frames itself as “supportive”. Conspicuously absent is an exploration of how the NGN role is performed by former students, now beginning RNs undergoing the very personal transition of “becoming registered nurses”. Using Goffman’s (1956) theorisation of performance in everyday life exploring how process and meaning in mundane interactions present themselves in the “regular” lives of people at large, and Margaret Archer’s (2000) work emphasising the significance of the inner dialogue for managing the emotions that emerge out of situations that confront us, this paper draws upon data collected during a study of NGNs’ experience of transition to practice (Malouf 2010). It focuses on an emergent understanding of the need to differentiate the performance of ‘student’ from that of ‘NGN’ role. Further, it explores how these roles have become conflated into a conceptual continuum and viewed as a slide from student to NGN performance, rather than a significant moment of change involving roles that need to be distinctly defined as a necessary precursor to enhancing and supporting the professional and personal development of beginning practitioners.

Observation of new particle formation in subtropical urban environment

The aim of this study was to characterise the new particle formation events in a subtropical urban environment in the southern hemisphere. The study measured the number concentration of particles and its size distribution in Brisbane, Australia during 2009. The variation of particle number concentration and nucleation burst events were characterised as well as the particle growth rate which was first reported in urban environment of Australia. The annual average NUFP, NAitken and NNuc were 9.3 x 103, 3.7 x 103 and 5.6 x 103 cm-3, respectively. Weak seasonal variation in number concentration was observed. Local traffic exhaust emissions were a major contributor of the pollution (NUFP) observed in morning which was dominated by the Aitken mode particles, while particles formed by secondary formation processes contributed to the particle number concentration during afternoon. Overall, 65 nucleation burst events were identified during the study period. Nucleation burst events were classified into two groups, with and without particles growth after the burst of nucleation mode particles observed. The average particle growth rate of the nucleation events was 4.6 nm hr-1 (ranged from 1.79 – 7.78 nm hr-1). Case studies of the nucleation burst events were characterised including i) the nucleation burst with particle growth which is associated with the particle precursor emitted from local traffic exhaust emission, ii) the nucleation burst without particle growth which is due to the transport of industrial emissions from the coast to Brisbane city or other possible sources with unfavourable conditions which suppressed particle growth and iii) interplay between the above two cases which demonstrated the impact of the vehicle and industrial emissions on the variation of particle number concentration and its size distribution during the same day.

Bone tissue engineering

Currently, well-established clinical therapeutic approaches for bone reconstruction are restricted to the transplantation of autografts and allografts, and the implantation of metal devices or ceramic-based implants to assist bone regeneration. These standard techniques face significant disadvantages. As a result, research has focused on the development of alternative therapeutic concepts aiming to design and engineer unparalleled structural and functional bone grafts. Substantial academic and commercial interest has been sparked in bone engineering methods to stimulate, control and eventually replicate key events of bone regeneration ex vivo. Over the years, this interest has further increased and bone tissue engineering has now become a well-recognized research discipline in the area of regenerative medicine. The following chapter gives an overview of bone tissue engineering principles. It focuses on research related to the combination of scaffolds with multipotent precursor cells, such as bone marrow-derived mesenchymal stem cells or human umbilical cord perivascular cells, and the clinical applications of these tissue engineered bone constructs.

Neural differentiation of mouse embryonic stem cells on conductive nanofiber scaffolds

Nerve tissue engineering requires suitable precursor cells as well as the necessary biochemical and physical cues to guide neurite extension and tissue development. An ideal scaffold for neural regeneration would be both fibrous and electrically conductive. We have contrasted the growth and neural differentiation of mouse embryonic stem cells on three different aligned nanofiber scaffolds composed of poly L: -lactic acid supplemented with either single- or multi-walled carbon-nanotubes. The addition of the nanotubes conferred conductivity to the nanofibers and promoted mESC neural differentiation as evidenced by an increased mature neuronal markers expression. We propose that the conductive scaffold could be a useful tool for the generation of neural tissue mimics in vitro and potentially as a scaffold for the repair of neural defects in vivo.

The Development of Competency Standards for Specialist Critical Care Nurses

In defining the contemporary role of the specialist nurse it is necessary to challenge the concept of nursing as merely a combination of skills and knowledge. Nursing must be demonstrated and defined in the context of client care and include the broader notions of professional development and competence. This qualitative study sought to identify the competency standards for nurse specialists in critical care and to articulate the differences between entry-to-practice standards and the advanced practice of specialist nurses. Over 800 hours of specialist critical care nursing practice were observed and grouped into 'domains' or major themes of specialist practice using a constant comparison qualitative technique. These domains were further refined to describe attributes of the registered nurses which resulted in effective and/or superior performance (competency standards) and to provide examples of performance (performance criteria) which met the defined standard. Constant comparison of the emerging domains, competency standards and performance criteria to observations of specialist critical care practice, ensured the results provided a true reflection of the specialist nursing role. Data analysis resulted in 20 competency standards grouped into six domains: professional practice, reflective practice, enabling, clinical problem solving, teamwork, and leadership. Each of these domains is comprised of between two and seven competency standards. Each standard is further divided into component parts or 'elements' and the elements are illustrated with performance criteria. The competency standards are currently being used in several Australian critical care educational programmes and are the foundation for an emerging critical care credentialling process. They have been viewed with interest by a variety of non-critical care specialty groups and may form a common precursor from which further specialist nursing practice assessment will evolve.