An Integrated Approach to the Discovery of Inhibitors of Protein-Protein Interactions

Protein-protein interactions present challenging targets for therapeutic intervention with enormous potential for modulating biological pathways, particularly in the field of oncology. Two α-helix mediated protein-protein interactions of interest, hypoxia inducible factor-1α (HIF-1α)/p300 and eukaryotic initiation factor 4E (eIF4E) /eIF4G are introduced and their known inhibitors discussed in Chapter 1. Initially, biophysical assays for both interactions were developed and the binding requirements between peptides derived from helix donor components (HIF-1α and eIF4G) to their protein counterparts (p300 and eIF4E respectively) were investigated. This information was used to develop competition assays capable of identifying inhibitors and provided important insight for the rational design of inhibitors. Subsequently, a computational approach, described in Chapter 3, to inhibitor discovery was applied to both targets, using both docking and pharmacophore modelling. Several series of compounds were purchased or prepared and screened as inhibitors. The development of a synthetic route to a novel scaffold is described providing a weak small molecule inhibitor. In parallel, a proteomimetic approach to inhibitor design was employed, using sequence based rational design, drawing on the knowledge gained in Chapter 2. By mimicking a key helical region of HIF-1α, the interaction with p300 can be disrupted, as discussed in Chapter 4. Additionally, new methods for the preparation of oligobenzamide helix mimetics were investigated allowing the preparation of challenging targets, late stage functionalization and the preparation of oligobenzamide/peptide hybrids. Overall, this thesis provides an introduction to two therapeutically relevant interactions, provides biophysical assays for the identification of inhibitors and discloses the first biophysically characterised inhibitors of the HIF-1α/p300 interaction

Edaphic Specialization in Tropical Trees: Physiological Correlates and Responses to Reciprocal Transplantation

Recent research has documented the importance of edaphic factors in determining the habitat associations of tree species in many tropical rain forests, but the underlying mechanisms for edaphic associations are unclear. At Sepilok Forest Reserve, Sabah, Malaysian Borneo, two main soil types derived from sandstone (ridges) and alluvium (valleys) differ in nutrient and water availability and are characterized by forests differing markedly in species composition, structure, and understory light availability. We use both survey and reciprocal transplants to examine physiological adaptations to differences in light, nutrient, and water availability between these soil types, and test for the importance of resource-use efficiency in determining edaphic specialization. Photosynthetic surveys for congeneric and confamilial pairs (one species per soil type) of edaphic specialists and for generalists common to both soil types show that species specializing on sandstone derived soil had lower stomatal conductance at a given assimilation rate than those occurring on alluvial soil and also had greater instantaneous and integrated water-use efficiencies. Foliar dark respiration rates per unit photosynthesis were higher for sandstone ridge than alluvial lowland specialists. We suggest that these higher respiration rates are likely due to increases in photosynthetic enzyme concentrations to compensate for lower internal CO2 concentrations resulting from increased stomatal closure. This is supported by lower photosynthetic nitrogen-use efficiencies in the sandstone ridge specialists. Generalist species had lower water-use efficiencies than sandstone ridge specialists when growing on the drier, sandy ridgetops, but their nitrogen-use efficiencies did not differ from the species specialized to the more resource-rich alluvial valleys. We varied light environment and soil nutrient availability in a reciprocal transplant experiment involving two specialist species from each soil type. Edaphic specialist species, when grown on the soil type for which they were not specialized, were not capable of acclimatory shifts to achieve similar resource-use efficiencies as species specialized to that soil type. We conclude that divergent water-use strategies are an important mechanism underlying differences in edaphic associations and thus contributing to maintenance of high local tree species diversity in Bornean rain forests

TRANSFORMING OUTCOMES TO INCREASE PARTICIPATION IN THE INDEPENDENT LIVING PROGRAM SPONSORED BY SUNRISE CHILDREN’S SERVICES

Research demonstrates the transition for aging-out foster youth evidences they are not equipped with the necessary tools to live a self-sufficient adult life. Many children who age-out of the foster system have encountered trauma at multiple levels. Sunrise Children’s Services is an agency in Kentucky committed to changing negative outcomes for this population of individuals. The optimum goal for children and youth is for them to grow up within their biological family where they receive guidance and support as they mature. For some individuals that is not an option, and the government along with agencies like Sunrise are focused on helping these individuals be successful and productive human beings once they reach adulthood. Turning 18 years old is tragically problematic for many adolescents because one’s chronological age does not automatically endow adulthood on an individual. Through this research, I sought to understand the proclivities of emerging emancipated youth who choose to participate in Sunrise’s Independent Living Program and to discover reasons why some of their peers choose not to participate. This understanding helped guide development of recruitment materials intended to inform and inspire aging out clients to receive benefits that include being a participant in Independent Living

The morphology and exine ornamentation of fresh pollen from four dipterocarp species in Sabah

Peer reviewedPublisher PD

Global rigidity of solvable group actions on S^1

In this paper we find all solvable subgroups of Diff^omega(S^1) and classify their actions. We also investigate the C^r local rigidity of actions of the solvable Baumslag-Solitar groups on the circle. The investigation leads to two novel phenomena in the study of infinite group actions on compact manifolds. We exhibit a finitely generated group Gamma and a manifold M such that: * Gamma has exactly countably infinitely many effective real-analytic actions on M, up to conjugacy in Diff^omega(M); * every effective, real analytic action of Gamma on M is C^r locally rigid, for some r>=3, and for every such r, there are infinitely many nonconjugate, effective real-analytic actions of Gamma on M that are C^r locally rigid, but not C^(r-1) locally rigid.Comment: Published by Geometry and Topology at http://www.maths.warwick.ac.uk/gt/GTVol8/paper23.abs.htm

Leaf venation networks of Bornean trees: images and hand-traced segmentations.

The data set contains images of leaf venation networks obtained from tree species in Malaysian Borneo. The data set contains 726 leaves from 295 species comprising 50 families, sampled from eight forest plots in Sabah. Image extents are approximately 1 × 1 cm, or 50 megapixels. All images contain a region of interest in which all veins have been hand traced. The complete data set includes over 30 billion pixels, of which more than 600 million have been validated by hand tracing. These images are suitable for morphological characterization of these species, as well as for training of machine-learning algorithms that segment biological networks from images. Data are made available under the Open Data Commons Attribution License. You are free to copy, distribute, and use the database; to produce works from the database; and to modify, transform, and build upon the database. You must attribute any public use of the database, or works produced from the database, in the manner specified in the license. For any use or redistribution of the database, or works produced from it, you must make clear to others the license of the database and keep intact any notices on the original database

\u3ci\u3eA peep into Toorkisthān\u3c/i\u3e

It is a record of a few weeks snatched from a soldier\u27s life in Afghanistan

Improving the usability of spatial point processes methodology : an interdisciplinary dialogue between statistics and ecology

The last few decades have seen an increasing interest and strong development in spatial point process methodology, and associated software that facilitates model fitting has become available. A lot of this progress has made these approaches more accessible to users, through freely available software. However, in the ecological user community the methodology has only been slowly picked up despite its obvious relevance to the field. This paper reflects on this development, highlighting mutual benefits of interdisciplinary dialogue for both statistics and ecology. We detail the contribution point process methodology has made to research on biodiversity theory as a result of this dialogue and reflect on reasons for the slow take-up of the methodology. This primarily concerns the current lack of consideration of the usability of the approaches, which we discuss in detail, presenting current discussions as well as indicating future directions.Publisher PDFPeer reviewe

Contrasting growth responses to aluminium addition among populations of the aluminium accumulator Melastoma malabathricum

Acknowledgements: The authors are grateful to Dr Weitz Hedda, Dr John Danku and Mr. David Hadwen for their help during this research. Sources of Funding: This research was funded by Ministry of Higher Education of Malaysia (MOHE) under SLAB/SLAI scheme and University of Aberdeen research grantPeer reviewedPublisher PD