The hippocampus, in humans and rats, plays crucial roles in spatial tasks and nonspatial tasks involving episodic-type memory. This thesis presents a novel computational model of the hippocampus (CA1, CA3 and dentate gyrus) which creates a framework where spatial memory and episodic memory are explained together. This general model follows the approach where the memory function of the rodent hippocampus is seen as a “memory space” instead of a “spatial memory”. The innovations of this novel model are centred around the fact that it follows detailed hippocampal architecture constraints and uses spiking networks to represent all hippocampal subfields. This hippocampal model does not require stable attractor states to produce a robust memory system capable of pattern separation and pattern completion. In this hippocampal theory, information is represented and processed in the form of activity patterns. That is, instead of assuming firing-rate coding, this model assumes that information is coded in the activation of specific constellations of neurons. This coding mechanism, associated with the use of spiking neurons, raises many problems on how information is transferred, processed and stored in the different hippocampal subfields. This thesis explores which mechanisms are available in the hippocampus to achieve such control, and produces a detailed model which is biologically realistic and capable of explaining how several computational components can work together to produce the emergent functional properties of the hippocampus. In this hippocampal theory, precise explanations are given to why mossy fibres are important for storage but not recall, what is the functional role of the mossy cells (excitatory interneurons) in the dentate gyrus, why firing fields can be asymmetric with the firing peak closer to the end of the field, which features are used to produce “place fields”, among others. An important property of this hippocampal model is that the memory system provided by the CA3 is a palimpsest memory: after saturation, the number of patterns that can be recalled is independent of the number of patterns engraved in the recurrent network. In parallel with the development of the hippocampal computational model, a simulation environment was created. This simulation environment was tailored for the needs and assumptions of the hippocampal model and represents an important component of this thesis.

There is much interest in the study of midbrain dopaminergic (mDA) neurons as their functions include the regulation of motor function, emotion and reward pathways. Furthermore the dysfunction of these neurons is implicated in a number of human disorders such as Parkinson’s disease (PD), addiction and schizophrenia. PD is characterised by the degeneration of mDA neurons of the substantia nigra pars compacta (SNc), therefore, research into the specification and development of mDA neurons is of particular interest in relation to this disease. An understanding of the development of mDA neurons may lead to new methods of preventing their degeneration or potentially a human ES cell derived source of mDA neurons that could be used for transplantation in PD patients. Pitx3 is a bicoid-related homeodomain protein with an expression pattern restricted to the mDA neurons of the SNc and ventral tegmental area (VTA), within the central nervous system. To directly investigate a role for Pitx3 in mDA neuron development, I have analysed a line of transgenic mice with a green fluorescent protein (GFP) reporter under the control of the endogenous Pitx3 promoter. Use of the targeted GFP reporter as a midbrain dopaminergic lineage marker in the phenotypically normal heterozygous mice identified previously unrecognised ontogenetically distinct subpopulations of dopaminergic cells within the ventral midbrain. These subpopulations were detectable at E12.5 based on their temporal and topographical expression of Pitx3 and TH. Analysis of the Pitx3 null mice revealed that Pitx3 is required for the survival of a subset of nascent mDA neurons at the beginning of their terminal differentiation. The loss of mDA neurons via apoptosis continued throughout development resulting in a complete absence of SNc neurons whilst the VTA remained relatively intact in adult Pitx3 null mice. In addition, during embryonic development Pitx3 deficiency caused a loss of tyrosine hydroxylase (TH) expression specifically in the SNc dopaminergic neurons. Analysis of chimeric mice made with Pitx3 null and Pitx3 heterozygous ES cells revealed that Pitx3 acts in a cell autonomous manner. These findings point to two roles for Pitx3 in SNc mDA neurons, one in their survival and the other in regulation of TH expression. Taken together, these studies suggest that the ontogenetically distinct subpopulations may provide the molecular basis for the specific dependence of substantia nigra DA neurons on Pitx3. In addition, to establish whether the subpopulations identified at E12.5 do form the SNc and VTA, respectively, a strategy to track the fate of the earliest Pitx3- expressing cells has been initiated. In order to achieve this I have created transgenic mice in which a tamoxifen inducible form of Cre recombinase is under the control of the endogenous Pitx3 promoter. These mice can be crossed with existing mice which contain a ubiquitously expressed Cre-inducible reporter, such as LacZ or GFP, to give a temporally and spatially restricted reporter expression.

The importance of spiritual care by nurses for health and recovery has become increasingly topical in the last decade. However, there is little research into why nurses should give spiritual care. Whilst bodily caring has always been associated with nurses and nursing, spiritual care has been seen as the concern of religious ministers. The steady decline of people belonging to conventional religions in secular British society is paralleled by an upsurge of interest in spiritualities. But why nurses should give spiritual care is unclear. This qualitative, interdisciplinary study aims to explore why nurses are asked to give spiritual care to patients by considering whether there is something amiss with nursing care that would be remedied by the addition of spiritual care. To investigate this, spiritualities and bodily caring are considered in tension with each other. By using feminist standpoint epistemological approaches I propose to: a) allow the everyday experiences of nurses in giving nursing care to be expressed; b) demonstrate that themes of nursing care as comforting, compassionate caring challenge claims that the addition of spiritual care is necessary; c) show that nurses conform to the perverse body/spirit dualisms of dominant patriarchal institutions and cultural norms in describing bodily nursing care as spiritual and d) present living models of nurses and nursing care as meaningful materialist world views. Material for the study was obtained in semi-structured, one-to-one conversational interviews with eighteen experienced practising nurses. Stories of nursing care were interpreted and analysed within nursing theories of spiritual care as either imperative or integral to nursing care. Body/spirit critiques in feminist informed theologies provided a further theoretical framework for analysis. The thesis describes the everyday distress that nurses experience. The feminist design created a vehicle for fresh constructs of care by nurses not previously identified in studies of spiritual care by nurses. The findings provide an evidence base for practising nurses to validate their own skills; for managers and policy makers in planning support for nurses to give nursing care, as well as for chaplains and others to listen and respond to care matters.

Book designers and manuscript artists have inserted illustrations into narrative works for centuries now. This practice is an intelligent behaviour that requires specialised knowledge of the text and the external parameters affecting the selection and placement criteria. This thesis offers a model for automation of illustration insertion into a narrative discourse. The model presented here is a significant improvement to the crudest method of dividing the text into equal parts and inserting one illustration into each part. This study starts from the position that narratives are expressions of mental representations of a sequence of events in various modes of discourse. Here, this mental representation is referred to as ‘the story’. When coupled with a mode of discourse, the story becomes a narrative. Thus, a story can be expressed as oral, written, pictorial, or film narratives. If they all express the same sequence of events, they are telling the same story. In an illustrated narrative, while the written discourse expresses the event sequence in the form of sentences, illustrations depict them using pictorial elements. The insertion of illustration into written narrative is analogous to collating two texts into one, based on their event content. In this process, sentential representation of events are collated against the pictorial expressions of the same events. Thus, for the purposes of automation, this study claims that an investigation into the locations of events can lead to potential locations for illustration insertions. However, the list of potential illustration locations can be improved further through eliminating the events that are not depictable. This model is also able to further improve on the insertion policy by incorporating event constraints as parameters for event priorities. If a set of event types is given preference in the illustration policy, the model is able to prioritise the list accordingly. Furthermore, the model is able to allow the samedegree of customisation for preferred characters, locations, or time in the story. The prioritisation can be applied to the entire narrative, or smaller chunks of the narrative text such as chapters or sections. The model is developed via the study of the verb roots of sentences – denoting the event types – in the discourse of Mohl’s critical edition of the Shāhnāma, the Persian epic composed by Abu al Qāsium Firdausī in 400/1010. A collection of 109 illustrated manuscripts of the Shāhnāma was considered in this study. These manuscripts come from various traditions of Persian paintings and cover a long period from the early 14th century to the late 19th century. A population of nearly 6,000 Shāhnāma illustrations were annotated. Each illustration is linked to a sentence in the narrative. The bottom-up approach to the study of verb distribution in the written discourse against the illustration location distribution indicates that illustration distribution follows the same trend as that of the depictable event distribution in the discourse. Particular event tokens displayed a high rate of illustration rendering them as all time favourite events. In summary, this study claims that investigation into the distribution of events in a narrative discourse provides a model for the insertion of illustrations into a narrative work.

Abstraction concepts based on process groups have largely dominated the design and implementation of communication patterns in message passing systems. Although such an approach seems pragmatic—given that participating processes form a ‘group’—in this dissertation, we discuss subtle issues that affect the qualitative and quantitative aspects of this approach. To address these issues, we introduce the concept of a ‘communication structure,’ which defines a communication pattern as an implicit runtime composition of localised patterns, known as ‘roles.’ During application development, communication structures are derived from the algorithm being implemented. These are then translated to an executable form by defining process specific data structures, known as ‘branching channels.’ The qualitative advantages of the communication structure approach are that the resulting programming model is non-ambiguous, uniform, expressive, and extensible. To use a pattern is to access the corresponding branching channels; to define a new pattern is simply to combine appropriate roles. The communication structure approach therefore allows immediate implementation of ad hoc patterns. Furthermore, it is guaranteed that every newly added role interfaces correctly with all of the existing roles, therefore scaling the benefit of every new addition. Quantitatively, branching channels improve performance by automatically overlapping computations and communications. The runtime system uses a receiver initiated communication protocol that allows senders to continue immediately without waiting for the receivers to respond. The advantage is that, unlike split-phase asynchronous communications, senders need not check whether the send operations were successful. Another property of branching channels is that they allow communications to be grouped, identified, and referenced. Communication structure specific parameters, such as message buffering, can therefore be specified immediately. Furthermore, a ‘commit’ based interface optimisation for send-and-forget type communications—where senders do not reuse sent data—is presented. This uses the referencing property of branching channels, allowing message buffering without incurring performance degradation due to intermediate memory copy.

We present an investigation into the design of an evolutionary mechanism for multiagent protocol constraint optimisation. Starting with a review of common population based mechanisms we discuss the properties of the mechanisms used by these search methods. We derive a novel algorithm for optimisation of vectors of real numbers and empirically validate the efficacy of the design by comparing against well known results from the literature. We discuss the application of an optimiser to a novel problem and remark upon the relevance of the no free lunch theorem. We show the relative performance of the optimiser is strong and publish details of a new best result for the Keane optimisation problem. We apply the final algorithm to the multi-agent protocol optimisation problem and show the design process was successful.

Direct fitness is measured as the number of surviving offspring. Thus adult males may try to produce as many offspring as possible or to increase the survival of their offspring. Recent findings have shown the many potential benefits of fathers’ presence and support on infants’ development and survival. However, little is known about the influence of socio-ecological factors on male-infant interactions. The main aim of this thesis was therefore to investigate male-infant interactions in wild crested macaques (Macaca nigra). In particular, we aimed to examine the affiliative and agonistic interactions taking place in this species, along with the factors influencing these interactions and offspring survival. Data collection for this thesis took place in the Tangkoko-Duasudara Reserve in Sulawesi, Indonesia, on 3 wild groups of crested macaques. For the first study, data were collected on migrations, births, disappearances, and encounters between groups over 5 years. We analyzed the influence of socio-ecological factors (e.g. rainfall, alpha-male position takeover, and male hierarchy stability) on pre- and post-natal loss. The results showed that high infant mortality was mainly associated to male alpha-position takeover, which suggests that infanticide may indeed occur in this species. In addition, we found that female within-group competition for food sources and between-group resource defense influenced fetal and infant loss. Based on these findings, we were interested to see whether fathers protected their own offspring against male attacks. Thus, in the second study, we investigated the social determinants and characteristics of male-infant affiliations. Our results indicate that adult males and infants form preferential association, and that infants initiate the majority of male-infant affiliations. Infants initiated affiliations mainly towards a high ranking male or a male in a close relationship with their mother. In addition, infants affiliated mainly with adult males in the absence of their mother, while males affiliated mostly with infants when the infants‘ mother was present in proximity. Furthermore, males initiated affiliations towards an infant when they held a high rank or when they had a strong bond with the infant‘s mother. Interestingly, paternity did not affect male-infant affiliations. In conclusion, these studies provide insights in the specifics of both infant survival strategies and male reproductive strategies. In addition, we show that infants are active agents in establishing and maintaining preferential relationships with males. This thesis, thus, confirm that male-infant interactions, although rare, have a strong influence both on males’ and infants’ direct fitness.

In this work, two projects were pursued. In the first project, I investigated two different subtypes of opioid receptors, which play a key role as target for analgesia. A set of subtype specific fluorescent ligands for μ opioid receptor (MOR) and δ opioid receptor (DOR) was characterised and used to gain insights into the diffusion behaviour of those receptors. It was shown that the novel ligands hold photophysical and pharmacological properties making them suitable for single-molecule microscopy. Applying them to wild-type receptors expressed in living cells revealed that both sub-types possess a heterogeneous diffusion behaviour. Further- more, the fluorescent ligands for the MOR were used to investigate homodomerisation, a highly debated topic. The results reveal that only ≈ 5 % of the receptors are present as homodimers, and thus the majority is monomeric. G-protein coupled receptors (GPCRs) play a major role as drug targets. Accordingly, understanding the activation process is very important. For a long time GPCRs have been believed to be either active or inactive. In recent years several studies have shown, that the reality is more complex, involving more substates. [1, 2, 3, 4] In this work the α 2A AR was chosen to investigate the activation process on a single-molecule level, thus being able to distinguish also rare or short-lived events that are hidden in ensemble mea- surements. With this aim, the receptor was labelled intracellular with two fluorophores using supported membranes. Thus it was possible to acquire movies showing qualita- tively smFRET events. Unfortunately, the functionality of the used construct could not be demonstrated. To recover the functionality the CLIP-tag in the third intracellular loop was replaced successfully with an amber codon. This stop codon was used to insert an unnatural amino acid. Five different mutants were created and tested and the most promising candidate could be identified. First ensemble FRET measurements indicated that the functionality might be recovered but further improvements would be needed. Overall, I could show that single-molecule microscopy is a versatile tool to investigate the behaviour of typical class A GPCRs. I was able to show that MOR are mostly monomeric under physiological expression levels. Furthermore, I could establish intra- cellular labelling with supported membranes and acquire qualitative smFRET events. / In dieser Arbeit wurden zwei Projekte verfolgt. Im ersten Projekt wurden zwei Subtypen der Opioidrezeptoren untersucht, die eine wichtige Rolle für die Wirksamkeit von Analgetika spielen. Ein Set von subtypspezifischen fluoreszierenden Liganden für den MOR und den DOR wurde charakterisiert und eingesetzt, um Einblicke in das Diffuionsverhalten der Rezeptoren zu gewinnen. Es konnte gezeigt werden, dass die neuartigen Liganden sowohl photophysikalische als auch pharmakologische Eigenschaften besitzen, die sie für die Einzelmolekülmikroskopie interessant machen. Versuche mit Opioidrezeptoren, die in lebenden Zellen exprimiert werden, zeigten, dass beide Subtypen heterogenes Diffuionsverhalten aufweisen. Des Weiteren wurden die fluoreszierenden Liganden für den MOR genutzt um Homodimerisierung zu untersuchen, da dies ein kontrovers diskutiertes Thema ist. Die Ergebnisse zeigen, dass lediglich ≈ 5% der Rezeptoren als Homodimere vorliegen und der Großteil monomerisch ist. GPCRs sind besonderem Interesse, weil sie Angriffspunkt vieler Medikamente sind. Deshalb ist es wichtig ihren Aktivierungsmechanismus besser zu verstehen. Lange Zeit wurde angenommen, dass GPCRs entweder aktiv oder inaktiv sind. Neuere Studien zeigten jedoch, dass die Realität komplexer ist und der Prozess Zwischenschritte involviert. [1, 2, 3, 4] In dieser Arbeit wurde der α 2A Adrenorezeptor als prototypischer Klasse A GPCR gewählt, um den Aktivierungsprozess auf Einzelmoleküllevel zu untersuchen. Durch die Betrachtung einzelner Rezeptoren ist es möglich auch seltene oder sehr kurzlebige Ereignisse zu unterscheiden, die in Kollektivmessungen untergehen. Um dies zu erreichen wurde der Rezeptor erfolgreich intrazellulär mit zwei Fluorophoren markiert. Dies gelang durch die Herstellung von „supported membranes", also Zellmembranen die auf einem Objektträger fixiert wurden. Dadurch war es möglich Videos aufzunehmen, die Einzelmolekül-FRET-Ereignisse zeigen. Jedoch gelang es nicht zu zeigen, dass der Rezeptor als Ganzes noch funktional war. Um einen funktionalen Rezeptor zu erhalten, wurde das CLIP-Tag in der dritten intrazellulären Schleife erfolgreich durch ein Stopcodon ersetzt, welches für eine nicht kanonische Aminosäure kodierte. Fünf verschiedene Mutanten wurden kloniert und getestet, wobei der vielversprechendste Mutant identifiziert werden konnte. Erste FRET-Kollektivmessungen deuten darauf hin, dass dieser Mutant funktional sein könnte. Jedoch sind weitere Verbesserungen nötig. Insgesamt konnte ich zeigen, dass Einzelmolekülmikroskopie vielseitige Möglichkeiten bietet um das Verhalten von GPCRs zu untersuchen. Ich konnte nachweisen, dass MOR unter physiologischen Bedingungen hauptsächlich als Monomere vorliegen. Des Weiteren konnte ich Dank supported membranes die Markierung durch Farbstoffe im Intrazellularbereich etablieren und qualitative smFRET Ereignisse aufnehmen.

This document describes an experimental investigation into dense collections of hard spherical particles just large enough to be studied using a light microscope. These particles display colloidal properties, but also some similarities with granular materials. We improve the quantitative analysis of confocal micrographs of dense colloidal systems, which allows us to show that methods from simulations of granular materials are useful (but not sufficient) in analysing colloidal systems, in particular colloidal glasses and sediments. Collections of spheres are fascinating in their own right, but also make convincing models for real systems. Colloidal systems undergo an entropy-driven fluid-solid transition for hard spheres and a liquid-gas transition for suitable inter-particle attraction. Furthermore, experimental colloidal systems display a so far not well-understood glass transition at high densities, so that the equilibrium state is not achieved. This may be due to limited experimental timescales, but experiments under reduced gravity (both using the Space Shuttle and densitymatching solvents) suggest that it is not. Most colloidal studies have used scattering (i.e. non-microscopical) techniques, which provide no local information. Microscopy (particularly confocal) allows individual particles and their motion to be followed. However, quantitative microscopy of densely-packed, solidlyfluorescent particles, such as colloidal glasses, is challenging. We report, to our knowledge for the first time, a quantitative measure of confidence in individual particle locations and use this measure in an iterative best-fit procedure. This method was crucial for the investigation of the colloidal samples reported in this thesis. One of the disadvantages of microscopy is that it requires particles too large to be truly colloidal; gravity is no longer negligible. The particles used here rapidly sediment to form solid ”plugs”, which are supposedly ”random close packed” (RCP). At least in some cases, this is not the case, since some particles remain free to move. This observation, as well as some literature results, suggest that gravity has some influence on the structure of the sediment. In this document we consider some ideas from literature not normally considered in colloidal studies. Firstly, we discuss the RCP state, and the preferred Maximally Random Jammed state. Secondly, we borrow a technique designed to identify structures known as bridges in simulations of granular materials. Finding bridges, i.e. structures stable against gravity, in colloidal samples is the primary aim of this thesis. Gravity is important in colloidal sphere packings both in sediments and in glasses; its effect is not known but the best available candidate is bridging. The basic results of this analysis, the bridge size distributions, are close to those for granular systems, but differ little for samples of different volume fractions. We identify important stages of the analysis which require more investigation. Whilst questioning the usefulness of the bridge properties, we identify some related packing properties which show interesting trends. No theoretical predictions exist for these quantities. We investigated initially a non-density-matched system, but compare our results with a nearly density-matched system. The results from both systems are similar, despite the particles apparently acquiring a charge in the latter case. This thesis shows that reliable confocal microscopy of very dense systems of solidly-fluorescent particles is possible, and provides a range of unreported properties of dense sedimenting and sedimented nearly-Brownian sphere packings. It provides several suggestions for further analysis of these experimental systems, as well as some to be performed by those who simulate granular matter.

This thesis uses insights from a modern theory of communication, Relevance Theory, to examine the function of certain particles - in particular the conjunction hina - in Koine Greek. This particle has been regarded from the time of Classical Greek as an introducer of purpose clauses and so has been thought to have the lexical meaning of ‘in order that.’ More recently, however, scholars have recognised that in the New Testament at least, no more than 60% of the uses of hina merit such a translation, with a considerable number of independent clauses being introduced by this particle also. Apart from the New Testament it is the case that pagan writers of Koine used this particle to introduce a wider range of clauses than merely those with a telic relationship to the main clause of the sentence. This is particularly noticeable in the Discourses of Epictetus, a philosopher who taught in the latter half of the first century of the Christian era. In addition, Dionysius of Halicarnassus, a notable critic of literary style and the historian Polybius, both writing within the Koine period used hina to introduce indirect commands and noun clauses as well as purpose clauses. The frequency of such uses (approximately 10% of all the instances of this particle) in their writings is considerably less than that of Epictetus, but those uses are nevertheless present in their works. Since iota-nu-alpha was used for this wider range of clauses by pagan, non-Jewish authors, some of whom spoke Greek as their first language, it seems extremely implausible to attribute such use to the incompetence of the implied authors of the New Testament, or ‘Semitic interference’. Since the many instances of non-telic hina in the New Testament are identified with reference to the context in which they occur, the telic instances should also be deduced from such context. I claim that the function of this particle is not to introduce a purpose clause nor does it have a fixed lexical meaning of ‘in order that’, but rather that it alerts the reader to expect an interpretation of the thought of the speaker or implied author. Of course in many instances a clause introduced by hina will be a purpose clause, but this is inferred from context rather than solely from the presence of this particle. This thesis proposes a unified account of the function of hina which fits the developing pattern of the language and relates it to the particle 'hina', and provides a theoretical basis for its use as an indicator of speaker or subject’s thought, thus enabling a reader to re-examine biblical texts whose interpretation has been problematic to date.