This thesis presents a novel distributed control method which allows a collection of independently mobile robotic units, with two or three dimensional movement, to self-assemble into self-repairing hierarchical structures. The proposed method utilises a simple model of the cellular adhesion mechanisms observed in biological cells, allowing the robotic units to form virtually bonded aggregates which behave as predicted by Steinberg’s differential adhesion hypothesis. Simulated robotic units based on the design of the subaquatic HYDRON module are introduced as a possible platform on which the model can be implemented. The units are used to carry out a detailed investigation of the model behaviour and parameter space focusing on the two main tasks of rounding and sorting in both two and three dimensions. These tasks assess the model’s ability to reach a thermodynamically stable configuration when the aggregates consist of either a single population of units or multiple populations of units with differing adhesive properties. The results are analysed in detail with particular attention given to the role of random movements in determining the overall performance, and demonstrate that this model provides a very robust solution to these complex tasks. Finally, a possible extension of this work is presented in which the original model is combined with a genetic regulatory network controller. The performance of this composite is evaluated, and the benefits of this hybrid approach, in which a powerful control system manipulates a robust self-organising behaviour, are discussed.

The task of developing a framework for which agents can communicate reliably and flexibly in open systems is not trivial. This thesis addresses the dichotomy between reliable communication and facilitation of the autonomy of agents to create more flexible and emergent interactions. By the introduction of adaptations to a distributed protocol language, agents benefit from the ability to communicate interaction protocols to elucidate the social norms (thus creating more reliable communication). Yet, this approach also provides the functionality for the agent to unilaterally introduce new paths for the conversation to explore unforeseen opportunities and options (thus restoring more autonomy than possible with static protocols). The foundation of this work is Lightweight Coordination Calculus (LCC). LCC is a distributed protocol language and framework in which agents coordinate their own interactions by their message passing activities. In order to ensure that adaptations to the protocols are done in a reasonable way, we examine the use of two models of communication to guide any transformations to the protocols. We describe the use of FIPA's ACL and ultimately its unsuitability for this approach as well as the more fecund task of implementing dialogue games, an model of argumentation, as dynamic protocols. The existing attempts to develop a model that can encompass the gulf between reliability and autonomy in communication have had varying degrees of success. It is the purpose and the result of the research described in this thesis to develop an alloy of the various models, by the introduction of dynamic and distributed protocols, to develop a framework stronger than its constituents. Though this is successful, the derivations of the protocols can be dificult to reconstruct. To this end, this thesis also describes a method of protocol synthesis inspired by models of human communication that can express the dialogues created by the previous approaches but also have a fully accountable path of construction. Not only does this thesis explore a unique and novel approach to agent communication, it is tested through a practical implementation.

This thesis reports on my narratively-framed PhD study in which I explored doctoral supervision using a small cultures approach (Holliday, 1999); thus, I viewed the doctoral supervision in question as dynamic emerging small cultures developing within a wider set of shaping influences. Specifically, the study sought to understand the experiences of doctoral supervision as narrated to me by some recently completed doctoral students and experienced supervisors from a public university in Malaysia, namely the International Islamic University Malaysia (hereafter known as the IIUM). My motivation for this study originated in my professional curiosity - as set against the IIUM strategic ambitions regarding internationalisation of higher education and Islamisation of Knowledge - about the development of doctoral supervision at the IIUM where I have been a member of academic staff for more than ten years and where, upon the completion of my doctoral education, I will be assuming a supervisory role. As stimulated through face-to-face, one-to-one encounters, in English and/or Bahasa Malaysia, I generated narratives of supervisory experiences from six recent graduates and three experienced supervisors. These narratives were then restoried in English and analysed using holistic-content approach (Lieblich et al., 1998) to reveal the global impression and key themes of supervisory experiences of the individual participants. Findings from the narrative analysis were first interpreted through the small cultures lens (Holliday, 1999). From the interpretation, I proposed that the emerging small cultures of doctoral supervision are characterised by the following features: the students' learning process; the supervisory styles; the supervisory roles; the supervisory relationships; and the expectation of students and supervisors. I then interpreted the narrative findings using a host culture complex model (Holliday, 1994) and identified eight cultural influences that may shape the construction of the emerging small cultures of doctoral supervision, namely: the student culture; the supervisor culture; the host university culture; the postgraduate culture; the wider learning community culture; the national host culture; the internationalisation of higher education culture; and the Islamisation of Knowledge culture. My study makes a number of contributions. In terms of cultures of supervision, it provides a detailed exploration of the emergent aspects of supervision as it develops amid a wider complex of shaping influences, and these emergent aspects and shaping influences extend the current literature regarding supervision. There are implications in these insights for supervisors and their students but also for university managers. Conceptually, the extension of the small cultures approach and host culture complex heuristic, from internationally - oriented English language education to internationally - oriented doctoral supervision, demonstrates the usefulness of this approach for practitioners in their particular contexts of practice as informed by a deeper understanding of the complexities involved rather than relying on large culture a priori characterisation. Methodologically, my study also demonstrates the feasibility and value of coupling narrative (rather than ethnographic) methods to the small cultures approach. Whilst not focused directly on internationalisation of higher education and Islamisation of Knowledge, the study does add to debates in this area with regard to the shaping influences these interlinked strategic objectives may have on doctoral supervision. Finally, my study adds a Malaysian non-Western perspective to the often Western-oriented literature on doctoral supervision.

Pulmonary fibrosis is a common consequence of lung inflammation, leading to organ dysfunction and significant morbidity and mortality. Macrophages, through their diverse functions associated with polarisation status, play a role in lung homeostasis and alternatively activated (M2) macrophages have been associated with lung fibrosis. Prolyl hydroxylases (PHDs) are the main oxygen sensors and regulators of hypoxia inducible factors (HIFs). The PHD/HIF pathway is known to play a role in tissue inflammation and fibrosis, but their role in macrophage polarisation is not fully understood. Aim To study the role of the PHD/HIF pathway in macrophage polarisation and lung fibrosis, and specifically in Idiopathic Pulmonary Fibrosis (IPF). Hypothesis It was hypothesised that pan hydroxylase inhibition alters macrophage polarisation and modulates lung inflammation and fibrosis. Methods A combination of pharmacological (pan hydroxylase inhibitors DMOG and FG41) and genetic (HIF and PHD-null) tools were used to manipulate the PHD/HIF pathway. The bleomycin induced lung fibrosis model was used to define the effect of pan hydroxylase inhibition during the early, inflammatory or the late, fibrotic phase of this model. Murine bone marrow derived macrophages (BMDM), human monocyte derived macrophages and alveolar macrophages obtained from patients with lung fibrosis were used to study the effect of pan hydroxylase inhibition on macrophage polarisation. Bronchoalveolar lavage fluid (BALF) from patients was used to define the association between lung CCL18, an M2 associated chemokine, and disease progression in IPF. Results DMOG therapy during the early phase of the bleomycin model significantly reduced lung fibrosis at day 24. In contrast, late phase pan hydroxylase inhibition enhanced lung fibrosis at day 24. In both instances there was evidence of enhanced alveolar macrophage M2-like polarisation following pan hydroxylase inhibition. Reduced fibrosis after early pan hydroxylase inhibition was not a consequence of reduced acute lung inflammation or direct inhibition of collagen synthesis. In BMDM, pan hydroxylase inhibition resulted in an ‘augmented M2-like’ macrophage. Using LysM-Cre HIF-1α, HIF-2α and PHD-3 KO mice as well as chetomin, a potent inhibitor of HIF-1α and HIF-2α mediated gene expression, the HIF-dependent and HIF-independent polarisation markers were defined. PHD-3 deficiency was not sufficient to enhance M2 skewing. In contrast to murine BMDM, in human monocyte derived macrophages and alveolar macrophages from healthy volunteers and patients with interstitial lung disease including IPF, pan hydroxylase inhibition did not augment M2 polarisation and indeed significantly inhibited macrophage CCL18 expression. CCL18 studies in clinical BALF samples confirmed that CCL18 was elevated in the lungs of patients with IPF and other ILDs compared to controls. However, baseline BALF CCL18 concentrations did not correlate with disease severity or with disease progression, suggesting this is not a useful biomarker in IPF. Further, a unique study of serial BAL in IPF patients showed no association between 12-month change in CCL18 and disease progression over the same period. Indeed CCL18 concentrations mostly fell over 12 months in patients that did progress, strongly suggesting that CCL18 does not play a major pathogenic role in IPF. Concluding, it was shown that in both BMDM and murine lung pan hydroxylase inhibition promoted an ‘augmented M2-like’ polarisation. Pharmacological pan hydroxylase inhibition during the late fibrotic phase of injury enhanced fibrosis but it is not known if there was a causal association between M2 macrophages and lung fibrosis. Similarly, the functional relevance of finding enhanced M2 polarisation observed during early DMOG therapy, which subsequently resulted in attenuated fibrosis, is not known. In human macrophages, pan hydroxylase inhibition unexpectedly attenuated CCL18 production, a chemokine associated with an M2-like phenotype in man whilst other M2 markers were unchanged. However, there was no evidence to support a pathogenic role for CCL18 in IPF, and therefore there is little potential for using pan hydroxylase inhibition to target CCL18 and treat IPF.

Little is known about the experiences of doctoral students who are active duty military or veterans seeking a degree in counselor education and supervision (CES). The purpose of this research was to positively impact the counseling profession by ensuring adequate representation of military-competent counselors through an exploration of the academic journey of military students. This research sought to highlight military students' perceptions of barriers and contributors to degree completion. Selection criteria for participants involved any United States military personnel classified as active or inactive. These military personnel had to have earned within the past 12 months or were currently enrolled in a counselor education and supervision PhD program at an institution accredited by the Council for Accreditation of Counseling and Related Educational Programs. This research adopted a phenomenological hermeneutic theoretical approach to explore the lived experiences of 6 military students on their journey to degree completion in a CES doctoral program. The central research question focused on the lived experiences of military CES students related to their journey towards degree completion. Key results emerged in the form of themes that contributed to degree completion such as helping other veterans/giving back and programmatic fit. Themes that showed prevalent barriers to degree completion included professional identity development, military students and degree completion, environmental factors, and access to military counselors. The implications of this study for social change include supporting academic institutions in reducing the attrition rates of military CES students.

The plant homeodomain (PHD) is a protein domain of ~45�100 residues characterised by a Cys4-His-Cys3 zinc-binding motif. When we commenced our study of the PHD in 2000, it was clear that the domain was commonly found in proteins involved in transcription. Sequence alignments indicate that while the cysteines, histidine and a few other key residues are strictly conserved, the rest of the domain varies greatly in terms of both amino acid composition and length. However, no structural information was available on the PHD and little was known about its function. We were therefore interested in determining the structure of a PHD in the hope that this might shed some light on its function and molecular mechanism of action. Our work began with the structure determination of a representative PHD, Mi2b-P2, and this work is presented in Chapter 3. Through comparison of this structure with the two other PHD structures that were determined during the course of our work, it became clear that PHDs adopt a well-defined globular fold with a superimposable core region. In addition, PHDs contain two loop regions (termed L1 and L3) that display increased flexibility and overlay less well between the three PHD structures available. These L1 and L3 regions correspond to variable regions identified earlier in PHD sequence alignments, indicating that L1 and L3 are probably not crucial for the PHD fold, but are instead likely to be responsible for imparting function(s) to the PHD. Indeed, numerous recent functional studies of PHDs from different proteins have since demonstrated their ability in binding a range of other proteins. In order to ascertain whether or not L1 and L3 were in fact dispensable for folding, we made extensive mutations (including both insertions and substitutions) in the loop regions of Mi2b-P2 and showed that the structure was maintained. We then went on to illustrate that a new function could be imparted to Mi2b-P2 by inserting a five-residue CtBP-binding motif into the L1 region and showed this chimera could fold and bind CtBP. Having established that the PHD could adopt a new binding function, we next sought to use combinatorial methods to introduce other novel functions into the PHD scaffold. Phage display was selected for this purpose, because it is a well-established technique and has been used successfully to engineer zinc-binding domains by other researchers. However, in order to establish this technique in our laboratory, we first chose a control system in which two partner proteins were already known to interact in vitro. We chose the protein complex formed between the transcriptional regulators LMO2 and ldb1 as a test case. We have examined this interaction in detail in our laboratory, and determined its three-dimensional structure. Furthermore, inappropriate formation of this complex is implicated in the onset of T-cell acute lymphoblastic leukemia. We therefore sought to use phage display to engineer ldb1 mimics that could potentially compete against wild-type ldb1 for LMO2, and this work is described in Chapter 4. Using a phage library containing ~3 x 10 7 variants of the LMO2-binding region of ldb1, we isolated mutants that were able to interact with LMO2 with higher affinity and specificity than wild-type ldb1. These ldb1 mutants represent a first step towards finding potential therapeutics for treating LMO-associated diseases. Having established phage display in our laboratory, we went on to search for PHD mutants that could bind selected target proteins. This work is described in Chapter 5. We created three PHD libraries with eight randomized residues in each of L1, L3 or in both loops of the PHD. These PHD libraries were then screened against four target proteins. After four rounds of selection, we were able to isolate a PHD mutant (dubbed L13-FH6) that could bind our test protein Fli-ets. This result demonstrates that a novel function can be imparted to the PHD using combinatorial methods and opens the way for further work in applying the PHD scaffold to other protein design work. In summary, the work detailed in Chapters 3 and 5 demonstrates that the PHD possesses many of the properties that are desirable for a protein scaffold for molecular recognition, including small size, stability, and a well-characterised structure. Moreover, the PHD motif possesses two loops (L1 and L3) of substantial size that can be remodeled for target binding. This may lead to an enhancement of binding affinities and specificities over other small scaffolds that have only one variable loop. In light of the fact that PHDs are mainly found in nuclear proteins, it is reasonable to expect that engineered PHDs could be expressed and function in an intracellular environment, unlike many other scaffolds that can only function in an oxidizing environment. Therefore, our results together with other currently available genomic and functional information indicate PHD is an excellent candidate for a scaffold that could be used to modify cellular processes. Appendices 1 and 2 describe completed bodies of work on unrelated projects that I have carried out during the course of my PhD candidature. The first comprises the invention and application of DNA sequences that contain all N-base sequences in the minimum possible length. This work is presented as a reprint of our recently published paper in Nucleic Acids Research. The second Appendix describes our structural analysis of an antifreeze protein from the shorthorn sculpin, a fish that lives in the Arctic and Antarctic oceans. This work is presented as a manuscript that is currently under review at the Journal of the American Chemical Society.

Le filtrage multiobjet est une technique de résolution du problème de détection et/ou suivi dans un contexte multicible. Cette thèse s'intéresse au filtre PHD (Probability Hypothesis Density), une célèbre approximation du filtre RFS (Random Finite Set) adaptée au cas où les observations sont le fruit d'un seul capteur. La première partie propose une construction rigoureuse du filtre PHD multicapteur exact et son expression simplifiée, sans approximation, grâce à un partitionnement joint de l'espace d'état des cibles et des capteurs. Avec cette nouvelle méthode, la solution exacte du filtre PHD multicapteur peut être propagée dans des scénarios de surveillance simples. La deuxième partie aborde le problème de gestion des capteurs dans le cadre du PHD. A chaque itération, le BET (Balanced Explorer and Tracker) construit une prédiction du PHD multicapteur a posteriori grâce au PIMS (Predicted Ideal Measurement Set) et définit un contrôle multicapteur en respectant quelques critères opérationnels simples adaptés aux missions de surveillance.

Le p300/CBP acétyltransférase est un co-activateur transcriptionnel très important qui est impliqué dans la régulation d'un grand nombre de processus biologiques, comme la transcription d'ADN, le développement et l'immunité innée. Jusqu'à présent, le rôle de p300/CBP dans la régulation de l'expression des gènes a été largement étudiée, mais les mécanismes qui régulent son activité enzymatique sont encore peu connus. Des études ont montré que le dysfonctionnement de p300/CBP est associé à plusieurs formes de cancer et de maladies neurodégénératives. Dés lors, chaque progrès concernant les mécanismes de régulation de p300/CBP est devenu primordial pour le développement de nouvelles thérapies. Le 'noyau' de p300/CBP contient deux domaines pour la reconnaissance des modifications post-traductionnelles (MPTs), un bromodomaine et un PHD finger (le module BP), adjacent à un domaine HAT (ou domaine histone acétyltransférase). Plusieurs enzymes, modifiant la chromatine, contiennent des domaines de reconnaissance des MPTs. Fréquemment des groupements particuliers de ces domaines sont très conservés et liés, au sein de la même protéine ou du même complexe protéique, suggérant qu'ils réalisent des fonctions coordonnées. Ces domaines adjacents peuvent agir en concertation dans la reconnaissance simultanée de différents MPTs ou peuvent exercer des fonctions différentes de celles qui sont effectuées par ces deux domaines particuliers, tels que les fonctions de régulation enzymatique. Plusieurs études suggèrent que les cycles acétylation/désacétylation dans la boucle d'auto-inhibition, à l'intérieur du domaine HAT, jouent un rôle important dans la régulation de l'activité enzymatique de p300/CBP. La proximité du module BP et du domaine HAT suggère que la spécificité de liaison, appartenant au module BP, peut être intrinsèquement liée à la régulation de l'activité du domaine HAT. L'objectif de ma thèse est de déterminer le rôle du module BP dans la régulation de l'activité du domaine HAT. Je propose que le module BP soit impliqué dans la régulation de p300/CBP de deux façons. La première consiste à établir un lien avec le domaine HAT qui stabilise la conformation auto-inhibée de l'enzyme. La deuxième exige que le module BP joue un rôle dans le choix des substrats de p300/CBP. J'ai été en mesure de montrer que BP peut se lier au domaine HAT et à la chromatine modifiée et qu'il peut reconnaître les modifications effectuées par p300/CBP lui-même. Les données obtenues indiquent que le module BP peut être impliqué dans la régulation de l'activité de p300/CBP et dans son ciblage à la chromatine.

In this master thesis, the problem of tracking groups using an image sequence dataset is examined. Target tracking can be defined as the problem of estimating a target's state given prior knowledge about its motion and some sensor measurements related to the target's state. A popular method for target tracking is e.g. the Kalman filter. However, the Kalman filter is insufficient when there are multiple targets in the scene. Consequently, alternative multitarget tracking methods must be applied along with methods for estimating the number of targets in the scene. Multitarget tracking can however be difficult when there are many unresolved targets, e.g. associating observations with targets in dense crowds. A viable simplification is group target tracking, keeping track of groups rather than individual targets. Furthermore, group target tracking is preferred when the user wants to know the motion and extension of a group in e.g. evacuation scenarios. To solve the problem of group target tracking in video surveillance, a combination of GM-PHD filtering and mean shift clustering is proposed. The GM-PHD filter is an approximation of Bayes multitarget filter. Pedestrian detections converted into flat world coordinates from the image dataset are used as input to the filter. The output of the GM-PHD filter consists of Gaussian mixture components with corresponding mean state vectors. The components are divided into groups by using mean shift clustering. An estimate of the number of members and group shape is presented for each group. The method is evaluated using both single camera measurements and two cameras partly surveilling the same area. The results are promising and present a nice visual representation of the groups' characteristics. However, using two cameras gives no improvement in performance, probably due to differences in detections between the two cameras, e.g. a single pedestrian can be observed being at two positions several meters apart making it difficult to determine if it is a single pedestrian or multiple pedestrians.

Abstract Organic semiconductors (OSCs) and graphene are two classes of conjugated materials that hold promise to create flexible electronic displays, high speed transistors, and low-cost solar cells. Crucial to understanding the behavior of these materials is understanding the effects metallic contacts have on the local charge environment. Additionally, characterizing the charge carrier transport behavior within these materials sheds light on the physical mechanisms behind transport. The first part of this thesis examines the origin of the low-temperature, high electric field transport behavior of OSCs. Two chemically distinct OSCs are used, poly-3(hexylthiophene) (P3HT) and 6,13- bis(triisopropyl-silylethynyl) (TIPS) pentacene. Several models explaining the low-temperature behavior are presented, with one using the Tomonaga-Luttinger liquid (TLL) insulator-to-metal transition model and one using a field-emission hopping model. While the TLL model is only valid for 1-dimensional systems, it is shown to work for both P3HT (1D) and TIPS-pentacene (2D), suggesting the TLL model is not an appropriate description of these systems. Instead, a cross-over from thermally-activated hopping to field-emission hopping is shown to explain the data well. The second part of this thesis focuses on the interaction between gold and platinum contacts and graphene using suspended graphene over sub-100 nanometer channels. Contacts to graphene can strongly dominate charge transport and mobility as well as significantly modify the charge environment local to the contacts. Platinum electrodes are discovered to be strong dopants to graphene at short length scales while gold electrodes do not have the same effect. By increasing the separation distance between the electrodes, this discrepancy is shown to disappear, suggesting an upper limit on charge diffusion from the contacts. Finally, this thesis will discuss a novel technique to observe the high-frequency behavior in OSCs using two microwave sources and an organic transistor as a mixer. A theoretical model motivating this technique is presented which suggests the possibility of retrieving gigahertz charge transport phenomena at kilohertz detection frequencies. The current state of the project is presented and discrepancies between devices made with gold and platinum electrodes measured in the GHz regime are discussed.