A novel and rational approach towards designing aluminium chelators

Aluminium (Al) is known to be neurotoxic and has been associated with the aetiology of Alzheimer's Disease. To date, only desferrioxamine (DFO), a trihydroxamic acid siderophore has been used in the clinical environment for the removal of Al from the body. However, this drug is expensive, orally inactive and is associated with many side effects. These studies employed a theoretical approach, with the use of quantum mechanics (QM) via semi-empirical molecular orbital (MO) calculations, and a practical approach using U87-MG glioblastoma cells as a model for evaluating the influence of potential chelators on the passage of aluminium into cells. Preliminary studies involving the Cambridge Structural Database (CSD) identified that Al prefers binding to bidentate ligands in a 3:1 manner, whereby oxygen was the exclusive donating atom. Statistically significant differences in M-O bond lengths when compared to other trivalent metal ions such as Fe3+ were established and used as an acceptance criterion for subsequent MO calculations. Of the semi-empirical methods parameterised for Al, the PM3 Hamiltonian was found to give the most reliable final optimised geometries of simple 3:1 Al complexes. Consequently the PM3 Hamiltonian was used for evaluating the Hf of 3:1 complexes with more complicated ligands. No correlation exists between published stability constants and individual parameters calculated via PM3 optimisations, although investigation of the dicarboxylates reveals a correlation of 0.961 showing promise for affinity prediction of closely related ligands. A simple and inexpensive morin spectrofluorescence assay has been developed and optimised producing results comparable to atomic absorption spectroscopy methods for the quantitative analysis of Al. This assay was used in subsequent in vitro models, initially on E. coli, which indicated that Al inhibits the antimicrobial action of ciprofloxacin, a potent quinolone antibiotic. Ensuing studies using the second model, U87-MG cells, investigated the influence of chelators on the transmembrane transport of Al, identifying 1,2-diethylhydroxypyridin-4-one as a ligand showing greatest potential for chelating Al in the clinical situation. In conclusion, these studies have explored semi-empirical MO Hamiltonians and an in-vitro U87-MG cell line, both as possible methods for predicting effective chelators of Al.

From icon to naturalised icon:a linguistic analysis of media representations of the BP Deepwater Horizon crisis

This research explores how news media reports construct representations of a business crisis through language. In an innovative approach to dealing with the vast pool of potentially relevant texts, media texts concerning the BP Deepwater Horizon oil spill are gathered from three different time points: immediately after the explosion in 2010, one year later in 2011 and again in 2012. The three sets of 'BP texts' are investigated using discourse analysis and semi-quantitative methods within a semiotic framework that gives an account of language at the semiotic levels of sign, code, mythical meaning and ideology. The research finds in the texts three discourses of representation concerning the crisis that show a movement from the ostensibly representational to the symbolic and conventional: a discourse of 'objective factuality', a discourse of 'positioning' and a discourse of 'redeployment'. This progression can be shown to have useful parallels with Peirce's sign classes of Icon, Index and Symbol, with their implied movement from a clear motivation by the Object (in this case the disaster events), to an arbitrary, socially-agreed connection. However, the naturalisation of signs, whereby ideologies are encoded in ways of speaking and writing that present them as 'taken for granted' is at its most complete when it is least discernible. The findings suggest that media coverage is likely to move on from symbolic representation to a new kind of iconicity, through a fourth discourse of 'naturalisation'. Here the representation turns back towards ostensible factuality or iconicity, to become the 'naturalised icon'. This work adds to the study of media representation a heuristic for understanding how the meaning-making of a news story progresses. It offers a detailed account of what the stages of this progression 'look like' linguistically, and suggests scope for future research into both language characteristics of phases and different news-reported phenomena.

A semi-oriented radial measure for measuring the efficiency of decision making units with negative data, using DEA

Data Envelopment Analysis (DEA) is a nonparametric method for measuring the efficiency of a set of decision making units such as firms or public sector agencies, first introduced into the operational research and management science literature by Charnes, Cooper, and Rhodes (CCR) [Charnes, A., Cooper, W.W., Rhodes, E., 1978. Measuring the efficiency of decision making units. European Journal of Operational Research 2, 429–444]. The original DEA models were applicable only to technologies characterized by positive inputs/outputs. In subsequent literature there have been various approaches to enable DEA to deal with negative data. In this paper, we propose a semi-oriented radial measure, which permits the presence of variables which can take both negative and positive values. The model is applied to data on a notional effluent processing system to compare the results with those yielded by two alternative methods for dealing with negative data in DEA: The modified slacks-based model suggested by Sharp et al. [Sharp, J.A., Liu, W.B., Meng, W., 2006. A modified slacks-based measure model for data envelopment analysis with ‘natural’ negative outputs and inputs. Journal of Operational Research Society 57 (11) 1–6] and the range directional model developed by Portela et al. [Portela, M.C.A.S., Thanassoulis, E., Simpson, G., 2004. A directional distance approach to deal with negative data in DEA: An application to bank branches. Journal of Operational Research Society 55 (10) 1111–1121]. A further example explores the advantages of using the new model.

The effective use of implicit parallelism through the use of an object-oriented programming language

This thesis explores translating well-written sequential programs in a subset of the Eiffel programming language - without syntactic or semantic extensions - into parallelised programs for execution on a distributed architecture. The main focus is on constructing two object-oriented models: a theoretical self-contained model of concurrency which enables a simplified second model for implementing the compiling process. There is a further presentation of principles that, if followed, maximise the potential levels of parallelism. Model of Concurrency. The concurrency model is designed to be a straightforward target for mapping sequential programs onto, thus making them parallel. It aids the compilation process by providing a high level of abstraction, including a useful model of parallel behaviour which enables easy incorporation of message interchange, locking, and synchronization of objects. Further, the model is sufficient such that a compiler can and has been practically built. Model of Compilation. The compilation-model's structure is based upon an object-oriented view of grammar descriptions and capitalises on both a recursive-descent style of processing and abstract syntax trees to perform the parsing. A composite-object view with an attribute grammar style of processing is used to extract sufficient semantic information for the parallelisation (i.e. code-generation) phase. Programming Principles. The set of principles presented are based upon information hiding, sharing and containment of objects and the dividing up of methods on the basis of a command/query division. When followed, the level of potential parallelism within the presented concurrency model is maximised. Further, these principles naturally arise from good programming practice. Summary. In summary this thesis shows that it is possible to compile well-written programs, written in a subset of Eiffel, into parallel programs without any syntactic additions or semantic alterations to Eiffel: i.e. no parallel primitives are added, and the parallel program is modelled to execute with equivalent semantics to the sequential version. If the programming principles are followed, a parallelised program achieves the maximum level of potential parallelisation within the concurrency model.

An investigation into the nature and consequences of teachers' implicit philosophies of science

The aims of this study were to investigate the beliefs concerning the philosophy of science held by practising science teachers and to relate those beliefs to their pupils' understanding of the philosophy of science. Three philosophies of science, differing in the way they relate experimental work to other parts of the scientific enterprise, are described. By the use of questionnaire techniques, teachers of four extreme types were identified. These are: the H type or hypothetico-deductivist teacher, who sees experiments as potential falsifiers of hypotheses or of logical deductions from them; the I type or inductivist teacher, who regards experiments mainly as a way of increasing the range of observations available for recording before patterns are noted and inductive generalisation is carried out; the V type or verificationist teacher, who expects experiments to provide proof and to demonstrate the truth or accuracy of scientific statements; and the 0 type, who has no discernible philosophical beliefs about the nature of science or its methodology. Following interviews of selected teachers to check their responses to the questionnaire and to determine their normal teaching methods, an experiment was organised in which parallel groups were given H, I and V type teaching in the normal school situation during most of one academic year. Using pre-test and post-test scores on a specially developed test of pupil understanding of the philosophy of science, it was shown that pupils were positively affected by their teacher's implied philosophy of science. There was also some indication that V type teaching improved marks obtained in school science examinations, but appeared to discourage the more able from continuing the study of science. Effects were also noted on vocabulary used by pupils to describe scientists and their activities.

Computer methods for the heat conduction equation

The merits of various numerical methods for the solution of the one and two dimensional heat conduction equation with a radiation boundary condition have been examined from a practical standpoint in order to determine accuracies and efficiencies. It is found that the use of five increments to approximate the space derivatives gives sufficiently accurate results provided the time step is not too large; further, the implicit backward difference method of Liebmann (27) is found to be the most accurate method. On this basis, a new implicit method is proposed for the solution of the three-dimensional heat conduction equation with radiation boundary conditions. The accuracies of the integral and analogue computer methods are also investigated.

Sustainable agricultural production:an investigation in Brazilian semi-arid livestock farms

This paper investigates the environmental sustainability and competitiveness perceptions of small farmers in a region in northern Brazil. The main data collection instruments included a survey questionnaire and an analysis of the region's strategic plan. In total, ninety-nine goat and sheep breeding farmers were surveyed. Data analysis methods included descriptive statistics, cluster analysis, and chi-squared tests. The main results relate to the impact of education, land size, and location on the farmers' perceptions of competitiveness and environmental issues. Farmers with longer periods of education have higher perception scores about business competitiveness and environmental sustainability than those with less formal education. Farmers who are working larger land areas also have higher scores than those with smaller farms. Lastly, location can yield factors that impact on farmers' perceptions. In our study, farmers located in Angicos and Lajes had higher perception scores than Pedro Avelino and Afonso Bezerra, despite the geographical proximity of these municipalities. On the other hand, three other profile variables did not impact on farmers' perceptions, namely: family income, dairy production volume, and associative condition. The authors believe the results and insights can be extended to livestock farming in other developing countries and contribute generally to fostering effective sustainable development policies, mainly in the agribusiness sector. © 2013 Elsevier Ltd. All rights reserved.

Selective in vitro glycosylation of recombinant proteins:semi-synthesis of novel homogeneous glycoforms of human erythropoietin

Background: A natural glycoprotein usually exists as a spectrum of glycosylated forms, where each protein molecule may be associated with an array of oligosaccharide structures. The overall range of glycoforms can have a variety of different biophysical and biochemical properties, although details of structure–function relationships are poorly understood, because of the microheterogeneity of biological samples. Hence, there is clearly a need for synthetic methods that give access to natural and unnatural homogeneously glycosylated proteins. The synthesis of novel glycoproteins through the selective reaction of glycosyl iodoacetamides with the thiol groups of cysteine residues, placed by site-directed mutagenesis at desired glycosylation sites has been developed. This provides a general method for the synthesis of homogeneously glycosylated proteins that carry saccharide side chains at natural or unnatural glycosylation sites. Here, we have shown that the approach can be applied to the glycoprotein hormone erythropoietin, an important therapeutic glycoprotein with three sites of N-glycosylation that are essential for in vivo biological activity. Results: Wild-type recombinant erythropoietin and three mutants in which glycosylation site asparagine residues had been changed to cysteines (His10-WThEPO, His10-Asn24Cys, His10-Asn38Cys, His10-Asn83CyshEPO) were overexpressed and purified in yields of 13 mg l−1 from Escherichia coli. Chemical glycosylation with glycosyl-β-N-iodoacetamides could be monitored by electrospray MS. Both in the wild-type and in the mutant proteins, the potential side reaction of the other four cysteine residues (all involved in disulfide bonds) were not observed. Yield of glycosylation was generally about 50% and purification of glycosylated protein from non-glycosylated protein was readily carried out using lectin affinity chromatography. Dynamic light scattering analysis of the purified glycoproteins suggested that the glycoforms produced were monomeric and folded identically to the wild-type protein. Conclusions: Erythropoietin expressed in E. coli bearing specific Asn→Cys mutations at natural glycosylation sites can be glycosylated using β-N-glycosyl iodoacetamides even in the presence of two disulfide bonds. The findings provide the basis for further elaboration of the glycan structures and development of this general methodology for the synthesis of semi-synthetic glycoproteins. Results: Wild-type recombinant erythropoietin and three mutants in which glycosylation site asparagine residues had been changed to cysteines (His10-WThEPO, His10-Asn24Cys, His10-Asn38Cys, His10-Asn83CyshEPO) were overexpressed and purified in yields of 13 mg l−1 from Escherichia coli. Chemical glycosylation with glycosyl-β-N-iodoacetamides could be monitored by electrospray MS. Both in the wild-type and in the mutant proteins, the potential side reaction of the other four cysteine residues (all involved in disulfide bonds) were not observed. Yield of glycosylation was generally about 50% and purification of glycosylated protein from non-glycosylated protein was readily carried out using lectin affinity chromatography. Dynamic light scattering analysis of the purified glycoproteins suggested that the glycoforms produced were monomeric and folded identically to the wild-type protein. Conclusions: Erythropoietin expressed in E. coli bearing specific Asn→Cys mutations at natural glycosylation sites can be glycosylated using β-N-glycosyl iodoacetamides even in the presence of two disulfide bonds. The findings provide the basis for further elaboration of the glycan structures and development of this general methodology for the synthesis of semi-synthetic glycoproteins

Mass spectrometry-based methods for identifying oxidized proteins in disease:advances and challenges

Many inflammatory diseases have an oxidative aetiology, which leads to oxidative damage to biomolecules, including proteins. It is now increasingly recognized that oxidative post-translational modifications (oxPTMs) of proteins affect cell signalling and behaviour, and can contribute to pathology. Moreover, oxidized proteins have potential as biomarkers for inflammatory diseases. Although many assays for generic protein oxidation and breakdown products of protein oxidation are available, only advanced tandem mass spectrometry approaches have the power to localize specific oxPTMs in identified proteins. While much work has been carried out using untargeted or discovery mass spectrometry approaches, identification of oxPTMs in disease has benefitted from the development of sophisticated targeted or semi-targeted scanning routines, combined with chemical labeling and enrichment approaches. Nevertheless, many potential pitfalls exist which can result in incorrect identifications. This review explains the limitations, advantages and challenges of all of these approaches to detecting oxidatively modified proteins, and provides an update on recent literature in which they have been used to detect and quantify protein oxidation in disease.

Comparison of subjective and objective methods to determine the retinal arterio-venous ratio using fundus photography

Purpose: To assess the inter and intra observer variability of subjective grading of the retinal arterio-venous ratio (AVR) using a visual grading and to compare the subjectively derived grades to an objective method using a semi-automated computer program. Methods: Following intraocular pressure and blood pressure measurements all subjects underwent dilated fundus photography. 86 monochromatic retinal images with the optic nerve head centred (52 healthy volunteers) were obtained using a Zeiss FF450+ fundus camera. Arterio-venous ratios (AVR), central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) were calculated on three separate occasions by one single observer semi-automatically using the software VesselMap (ImedosSystems, Jena, Germany). Following the automated grading, three examiners graded the AVR visually on three separate occasions in order to assess their agreement. Results: Reproducibility of the semi-automatic parameters was excellent (ICCs: 0.97 (CRAE); 0.985 (CRVE) and 0.952 (AVR)). However, visual grading of AVR showed inter grader differences as well as discrepancies between subjectively derived and objectively calculated AVR (all p < 0.000001). Conclusion: Grader education and experience leads to inter-grader differences but more importantly, subjective grading is not capable to pick up subtle differences across healthy individuals and does not represent true AVR when compared with an objective assessment method. Technology advancements mean we no longer rely on opthalmoscopic evaluation but can capture and store fundus images with retinal cameras, enabling us to measure vessel calibre more accurately compared to visual estimation; hence it should be integrated in optometric practise for improved accuracy and reliability of clinical assessments of retinal vessel calibres. © 2014 Spanish General Council of Optometry.

From art for arts sake to art as means of knowing:a rationale for advancing arts-based methods in research, practice and pedagogy

This paper advances a philosophically informed rationale for the broader, reflexive and practical application of arts-based methods to benefit research, practice and pedagogy. It addresses the complexity and diversity of learning and knowing, foregrounding a cohabitative position and recognition of a plurality of research approaches, tailored and responsive to context. Appreciation of art and aesthetic experience is situated in the everyday, underpinned by multi-layered exemplars of pragmatic visual-arts narrative inquiry undertaken in the third, creative and communications sectors. Discussion considers semi-guided use of arts-based methods as a conduit for topic engagement, reflection and intersubjective agreement; alongside observation and interpretation of organically employed approaches used by participants within daily norms. Techniques span handcrafted (drawing), digital (photography), hybrid (cartooning), performance dimensions (improvised installations) and music (metaphor and structure). The process of creation, the artefact/outcome produced and experiences of consummation are all significant, with specific reflexivity impacts. Exploring methodology and epistemology, both the "doing" and its interpretation are explicated to inform method selection, replication, utility, evaluation and development of cross-media skills literacy. Approaches are found engaging, accessible and empowering, with nuanced capabilities to alter relationships with phenomena, experiences and people. By building a discursive space that reduces barriers; emancipation, interaction, polyphony, letting-go and the progressive unfolding of thoughts are supported, benefiting ways of knowing, narrative (re)construction, sensory perception and capacities to act. This can also present underexplored researcher risks in respect to emotion work, self-disclosure, identity and agenda. The paper therefore elucidates complex, intricate relationships between form and content, the represented and the representation or performance, researcher and participant, and the self and other. This benefits understanding of phenomena including personal experience, sensitive issues, empowerment, identity, transition and liminality. Observations are relevant to qualitative and mixed methods researchers and a multidisciplinary audience, with explicit identification of challenges, opportunities and implications.

When is an image a health claim? A false-recollection method to detect implicit inferences about products' health benefits

Objective: Images on food and dietary supplement packaging might lead people to infer (appropriately or inappropriately) certain health benefits of those products. Research on this issue largely involves direct questions, which could (a) elicit inferences that would not be made unprompted, and (b) fail to capture inferences made implicitly. Using a novel memory-based method, in the present research, we explored whether packaging imagery elicits health inferences without prompting, and the extent to which these inferences are made implicitly. Method: In 3 experiments, participants saw fictional product packages accompanied by written claims. Some packages contained an image that implied a health-related function (e.g., a brain), and some contained no image. Participants studied these packages and claims, and subsequently their memory for seen and unseen claims were tested. Results: When a health image was featured on a package, participants often subsequently recognized health claims that—despite being implied by the image—were not truly presented. In Experiment 2, these recognition errors persisted despite an explicit warning against treating the images as informative. In Experiment 3, these findings were replicated in a large consumer sample from 5 European countries, and with a cued-recall test. Conclusion: These findings confirm that images can act as health claims, by leading people to infer health benefits without prompting. These inferences appear often to be implicit, and could therefore be highly pervasive. The data underscore the importance of regulating imagery on product packaging; memory-based methods represent innovative ways to measure how leading (or misleading) specific images can be. (PsycINFO Database Record (c) 2016 APA, all rights reserved)

Recent advances in explaining hedge fund returns:implicit factors and exposures

We survey articles covering how hedge fund returns are explained, using largely non-linear multifactor models that examine the non-linear pay-offs and exposures of hedge funds. We provide an integrated view of the implicit factor and statistical factor models that are largely able to explain the hedge fund return-generating process. We present their evolution through time by discussing pioneering studies that made a significant contribution to knowledge, and also recent innovative studies that examine hedge fund exposures using advanced econometric methods. This is the first review that analyzes very recent studies that explain a large part of hedge fund variation. We conclude by presenting some gaps for future research.