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What does it mean to experience paediatric depression?: the ethics of mental health diagnosis and treatment in children and adolescents
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Title: What does it mean to experience paediatric depression?: the ethics of mental health diagnosis and treatment in children and adolescents
Authors: Deacutis, Molly
Abstract: This thesis explores the ethics of mental health diagnosis and treatment in children and adolescents through a collection of different perspectives based on literature analysis and interviews with practising clinicians. Compared to other medical fields, paediatric psychiatry is considerably novel; it has only recently become a medical specialty and differs from other medicine by involving both biological and psychological aspects of care. Recently, human brain development has become better understood, but the effect of mental illness on the trajectory of development is only just beginning to be studied. Despite this limited understanding, children who may not have been diagnosed for psychiatric disorders in the past are increasingly receiving off-label prescription treatments. This trend may be due to improved sensitivity of diagnostic practices as well as the medicalisation of normal, classifying previously healthy borderline behaviours as pathological. What are the implications of increasing medicalisation? How are child-specific diagnoses and treatment plans determined? I focus on identity development in young people with mental disorders, specifically depression, and try to explain the effects of labelling and medication on that development. Also the physiological impact of psychopathology and psychotropic treatment on neurodevelopment is examined, as well as the lack of long-term clinical data for drug treatment in children. Though the key source material has been from literature in the US and UK, the thesis broadens to an international perspective with a global look at the relationship between culture and paediatric psychiatry practices. Finally, mental health care professionals were interviewed to provide a clinical perspective to supplement the literature analysis. By drawing historical, philosophical, psychological, biological, cultural, and professional perspectives together in this novel way, ethical considerations necessary in the psychiatric care of paediatric patients are given a more thorough understanding, and a framework for assessing these considerations is presented through a focused interdisciplinary lens.
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Structural studies of Vibrio cholerae quorum sensing proteins
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Title: Structural studies of Vibrio cholerae quorum sensing proteins
Authors: Jahan, Nasrin
Abstract: The spread of cholera is always associated with contaminated food or waterand this is the reason this disease has been endemic in developing countriesfor centuries due to their lack of proper sanitation facilities and poor or noinfrastructure for sewage systems. Cholera can spread quickly andsporadically after any natural disaster that destroys the sewage system orsafe drinking water supply of both developed and undeveloped countries. InSoutheast Asia in December 2004 and in Pakistan and Haiti 2010, choleraoutbreaks followed the natural disasters; with most of the cholera victimsbeing children. Although it is known that the best way to prevent choleraoutbreak is the development of the infrastructure, provision of a safe drinkingwater supply and proper sanitation, this is a very long-term process, and mostof the developing countries cannot afford such improvements. Thesesituations can be made worse by natural disasters. Therefore there is apressing need for the development of a cholera vaccine and there have beennumerous research projects working towards this end for several decades. Afew of them have been successful to date but because of the severe sideeffects and narrow range of protection, more effective and wider rangevaccine development is still ongoing.In this study, crystallographic and enzymatic studies have been carried out onseveral novel proteins involved in the control of the production of the factorsrequired for quorum sensing. Quorum sensing is a process in which bacterialcells communicate among themselves by the synthesis, release and detectionof small chemical compounds called autoinducers. In this work, structural analysis was carried out on proteins involved in the synthesis and detection ofthe major autoinducer of Vibrio cholerae, named CAI-1. The crystal structureof CqsA involved in CAI-1 synthesis has been successfully solved and itsenzymatic properties have been characterized. The structure of one domainof the cytoplasmic region of the CAI-1 receptor CqsS was also elucidated, andother domains were expressed. The crystal structure of another enzyme(VCA0859, an aldo-keto reductase) thought to have been involved in thesynthesis of CAI-1 was also determined. Another protein named VCA0939was also studied, due to its importance in biofilm development, and its abilityto control quorum-sensing in an alternative pathway in the mutated version ofpathogenic strains of V. cholerae that were responsible for the seventhcholera pandemic. The aim of this project was to understand the threedimensional structure of some proteins that are involved in quorum sensingand control of the expression of virulence genes for the pathogenesis of V.cholerae. Understanding the three dimensional structure of the proteins andthe mode of autoinducer binding to its specific receptor could be highlyvaluable in the development of a chemical compound that could lead to thediscovery of a novel drug with the ability to target cross species specification.
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Functional design and use of acoustic signals produced by killer whales (Orcinus orca)
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Title: Functional design and use of acoustic signals produced by killer whales (Orcinus orca)
Authors: Samarra, Filipa Isabel Pereira
Abstract: This study aimed to investigate possible functions of the sounds produced byherring-eating killer whales in the Northeast Atlantic.In this study, I investigated the whistle repertoire of killer whales, which hadpreviously only been studied in British Columbia, where it appeared to be restricted tothe audible range. However, I show that high frequency whistles (> 17 kHz) weredetected in Northeast Atlantic populations but not in Northeast Pacific populations.These results indicated substantial intraspecific variation in whistle production inkiller whales. Little variation was observed in high frequency whistles recorded fromthree different sites in the Northeast Atlantic, suggesting this signal has a similarfunction across locations.The estimated active space of high frequency whistles and burst-pulse callssuggested that these are short-range signals used for within-group communication.Source levels of burst-pulse calls were lower than what was previously described inBritish Columbia, which possibly reflected the fact that these sounds do not need topropagate far because distances between group members are generally short. Calls,high frequency whistles and herding calls produced at different depths did not appearto suffer effects due to increased pressure, such as changing frequency or durationcharacteristics.Feeding appeared to take place below 10 m of depth, as suggested by thelocalisation of depth of production of feeding-related sounds. These depths wereconsistent with those at which tailslaps were produced in Dtags attached to individualwhales. Feeding periods were characterised by deep diving, increased soundproduction and highly non-directional movement. These findings suggested that killerwhales in a herring spawning ground use a feeding strategy different from carouselfeeding used in herring overwintering grounds.These findings showed that Northeast Atlantic killer whales have a different soundrepertoire to other populations, and suggested that they may employ different feedingstrategies depending on prey behaviour.
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Ants as flower visitors : floral ant-repellence and the impact of ant scent-marks on pollinator behaviour
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Title: Ants as flower visitors : floral ant-repellence and the impact of ant scent-marks on pollinator behaviour
Authors: Ballantyne, Gavin
Abstract: As flower visitors, ants rarely benefit a plant, commonly disrupting pollination by deterring other flowervisitors, or stealing nectar. This thesis examines three aspects of ant-flower interactions, focusing onthe occurrence of floral traits that prevent disruption of pollination and a novel means by which antsmay influence pollinator behaviour.To assess which types of plant species possess ant-repelling floral traits I carried out a surveyof 49 Neotropical plant species. Around a third of these species were repellent to the commongeneralist ant Camponotus novograndensis (Formicinae). This repellence was positively correlatedwith large nectar volumes within individual flowers. It appears that there has been selection for floralant-repellence as a defence against ant thieves in plant species that invest in large volumes of nectar.In some cases these repellent traits were effective against a wide range of ant species. However, in noplant species were predacious ants particularly repelled, indicating that there may be little selectivepressure on non-ant-plants to defend potential pollinators from aggressive ants.To investigate the importance of coevolution in determining the effectiveness of ant-repellents,a small but diverse range of Mediterranean plant species were tested with the invasive nectar thievingant Linepithema humile (Dolichoderinae) and the native but non-nectar thieving ant Messor bouvieri(Myrmecinae). Responses of both ant species to floral traits were very similar. The ability of someplants to restrict access to ant species with which they have no evolutionary history may help toreduce the impact invasive species, as nectar thieves, have on plant-pollinator interactions.It is reported that flowers recently visited by bees and hoverflies may be rejected for a periodof time by subsequent bee visitors through the detection of scent-marks. Nectar-thieving ants couldpotentially influence the foraging decisions of bees in a similar way if they come to associate ant trailpheromones or footprint hydrocarbons with poor reward levels. However, my empirical work found nodifferences were found in bee visitation behaviour between flowers of Digitalis pupurea(Plantaginaceae), Bupleurum fruticosum (Apiaceae) or Brassica juncea (Brassicaceae) that had beenin contact with ants and control flowers. Ant-attendance at flowers of these species may not reduce reward levels sufficiently to make it worthwhile for bees to incorporate ant scent-marks into foragingdecisions.Investigations like these into the interactions between ants, flowers and other flower visitorsare essential if we hope to understand the part ants play in pollination ecology, and determine howants have helped shape floral evolution.
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Willin as a novel 4.1 ezrin radixin moesin (FERM) domain protein in the mammalian hippo signalling pathway
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Title: Willin as a novel 4.1 ezrin radixin moesin (FERM) domain protein in the mammalian hippo signalling pathway
Authors: Angus, Liselotte
Abstract: The Salvador/Warts/Hippo (Hippo) pathway defines a novel signalling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The Hippo pathway was initially utilised in D. melanogaster, where the Expanded protein acts in the Hippo signalling cascade to control organ size. Willin is the proposed human orthologue of Expanded and the aim of this thesis is to investigate whether willin can activate the mammalian Hippo signalling pathway. Ectopic willin expression causes an increase in phosphorylation of the core Hippo signalling pathway components MST1/2, LATS1 and YAP, an effect which can be antagonised by ezrin. In MCF10A cells, willin over-expression antagonises a YAP-induced epithelial-to-mesenchymal transition via the N- terminal FERM (Four-point-one Ezrin Radixin Moesin) domain of willin. Preliminary results show that willin is expressed within the sciatic nerve of rat and mice, and within the neuromast cells in the zebrafish; suggesting that willin and the Hippo pathway may play a vital role in the developmental regulation within the peripheral nervous system. To conclude, willin influences Hippo signalling activity by activating the core Hippo pathway kinase cassette in mammalian cells.
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The desaturase gene family : an evolutionary study of putative speciation genes in 12 species of Drosophila
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Title: The desaturase gene family : an evolutionary study of putative speciation genes in 12 species of Drosophila
Authors: Keays, Maria C.
Abstract: The formation and persistence of species are the subject of much debate among biologists. Many species of Drosophila are behaviourally isolated, meaning that heterospecific individuals are not attracted to one another and do not interbreed. Often, this behavioural isolation is at least in part due to differences in pheromonal preference. Drosophila pheromones are long-chain cuticular hydrocarbons (CHCs). Desaturases are enzymes that are important for the production of CHCs. This thesis investigates the evolution of the gene family across 12 species of Drosophila. Desaturase genes were located in all species. Some genes, those that have previously been shown to have important roles in pheromonal communication, have experienced duplication and loss in several species. Two previously undiscovered duplicates were identified. Generally the desaturase gene family is governed by purifying selection, although following duplication these constraints are relaxed and in some cases duplicated genes show compelling evidence of positive selection. One of the loci under positive selection, the novel duplicate desat1b of the obscura group, was found to have a sex-biased expression pattern and alternative splicing in its 5′ UTR. In RNAi knock-down experiments of desaturase gene function in D. melanogaster, several desaturases were shown to affect CHC profiles of males and females, including some that were previously unlinked to CHC production.
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An investigation of the ABAD-Aβ interaction as a potential therapeutic target for the treatment of Alzheimer’s disease
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Title: An investigation of the ABAD-Aβ interaction as a potential therapeutic target for the treatment of Alzheimer’s disease
Authors: Muirhead, Kirsty E.A.
Abstract: Alzheimer’s disease (AD) is the leading cause of dementia but despite beingidentified over a century ago, current treatments remain limited. To date, no disease-modifying therapies are available.Soluble, intracellular forms of β-amyloid (Aβ), a protein associated with AD, havebeen identified and intracellular targets of Aβ are being investigated as potentialtargets for new drugs. Amyloid binding alcohol dehydrogenase (ABAD) waspreviously identified as a mitochondrial target of Aβ and is known to be up-regulatedin AD. This interaction results in production of reactive oxygen species and cell death. Using a small peptide, known as the “decoy peptide”, disruption of thisinteraction has been shown to reverse biochemical and behavioural symptoms in anAD mouse model.The work reported in this thesis describes the approaches taken to develop methodsfor in vitro and ex vivo study of the interaction between ABAD and Aβ. Afluorogenic assay for measuring the intracellular activity of ABAD in living cells was developed and using this technique, the intracellular inhibition of ABAD by Aβ was observed for the first time. Surface plasmon resonance was used to measurebinding between ABAD and Aβ and also showed the first quantitative analysis of direct binding of the decoy peptide to Aβ42. In order to synthesise small molecule inhibitors of ABAD activity with the aim of developing a molecular probe of theenzyme’s activity, compounds were identified by screening a fragment-based library.Subsequent optimisation of the compound structure led to a 10-fold improvement inthe IC50 and has resulted in a lead compound for future development. A similar screening strategy was employed to identify potential small molecule inhibitors of the ABAD-Aβ interaction.This research has resulted in a range of tools and methods for studying ABAD activity and interactions, which will greatly benefit future work on developing compounds that inhibit the ABAD-Aβ interaction to provide a novel method for treating Alzheimer’s disease.
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A comparative investigation of the cognitive and social factors underlying a capacity for cumulative culture
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Title: A comparative investigation of the cognitive and social factors underlying a capacity for cumulative culture
Authors: Dean, Lewis G
Abstract: Human culture has been proposed to uniquely exhibit a ‘ratchet effect’, with beneficial modifications being made to cultural traits over many generations. This is widely thought to have allowed an accumulation of technology and knowledge over time, and to be of central importance to the remarkable ecological and demographic success of humans. Whilst many researchers argue that the roots of human culture lie in social learning, a process widespread in nature, the exact cognitive capacities that set humans apart are not known.To provide a comparative assessment of nine separate hypotheses regarding different social and cognitive factors that may underlie a capacity for cumulative culture, in this thesis a cumulative puzzlebox was presented to three species. Groups of capuchins, chimpanzees and children were provided with the opportunity to solve the puzzlebox to three sequential levels to retrieve rewards of increasing desirability. Higher level solutions spread only in the children. Evidence was found for the occurrence of teaching, imitation, complex communication and prosociality in groups of children, but not in groups of capuchins and chimpanzees. Furthermore, these processes were positively correlated with the performance of individuals within the groups of children which was the only species to show evidence of cumulative cultural learning. Five further hypotheses focussed on alternative social and cognitive factors were not supported by the evidence from this experiment.
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Female mating decisions in the rose bitterling (Rhodeus ocellatus)
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Title: Female mating decisions in the rose bitterling (Rhodeus ocellatus)
Authors: Agbali, Muna
Abstract: The aim of this study was to obtain an understanding of the basis to female mating decisions in the Chinese rose bitterling (Rhodeus ocellatus). Bitterling have a resource-based mating system that involves the female laying her eggs inside the gills of a freshwater mussel. Male bitterling perform elaborate courtship behaviour and are territorial and aggressively guard mussels in their territory from other territory holders and non-territorial males. Using a series of laboratory experiments it was shown in this study that females were choosy over the males they mated with, but females were not congruent in their preferences. Female mate preferences correlated positively with offspring growth rates and survival during early development. Female mate choice did not correspond with male dominance, and there may be an intersexual conflict between female mate preferences and male dominance as a result. Females tended to prefer males with functionally dissimilar MHC alleles. MHC alleles may influence male odour cues, and females showed a preference for mussels in which the sperm of multiple males had been released, possibly indicating that females use odour cues associated with sperm release in mating decisions. Bitterling show an innate preference for the colour red in a foraging context and there may be a receiver bias for red nuptial colouration in female mating preferences. Despite a significant role for mate preferences, direct (oviposition) mating preferences were shown to be more important in the mating system. Choice of oviposition sites has both immediate (survival) consequences for offspring, as well as longer-term fitness effects.
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The impact of microbial extracellular polymeric substances on sediment stability
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Title: The impact of microbial extracellular polymeric substances on sediment stability
Authors: Lubarsky, Helen V.
Abstract: The main objective of this thesis is to investigate the impact of microbial extracellularpolymeric substances (EPS) on sediment stability and the related factors which influence“biogenic stabilisation” as a basis to the prediction of sediment erosion and transport.The ability to make direct and sensitive measurements of the physical properties of thebiofilm is a critical demand to further understanding of the overall biostabilisationprocesses.Therefore, attention has been focused on developing a new technique, MagneticParticle Induction (MagPI) for measuring the adhesive properties of the biofilm. MagPIdetermines the relative adhesive properties or “stickiness” of the test surface, whether abiofilm, a sediment or other submerged material. The technique may have futureapplications in physical, environmental and biomedical research.Newly developed Magnetic Particle Induction(MagPI) and traditional techniques CohesiveStrength Meter (CSM) for the determination of the adhesion/cohesion of the substratumwere used to assess the biostabilisation capacity of aquatic microorganisms. Whilst thesedevices determine slightly different surface properties of the bed, they were found tocomplement each other, increasing the range of measurements that could be made andpresented a strong correlation in the overlapping portion of the data.It is recognized that microorganisms inhabiting natural sediments significantly mediate theerosive response of the bed (“ecosystem engineers”) through the secretion of naturallyadhesive organic material (EPS: extracellular polymeric substances). Interactions betweenmain biofilm consortia microalgae, cyanobacteria and bacteria in terms of their individualcontribution to the EPS pool and their relative functional contribution to substratumstabilisation were investigated.The overall stabilisation potential of the various assemblages was impressive, as comparedto controls. The substratum stabilisation by estuarine microbial assemblages was due to thesecreted EPS matrix, and both EPS quality (carbohydrates and proteins) and quantity(concentration) were important in determining stabilisation. Stabilisation was significantlyhigher for the bacterial assemblages than for axenic microalgal assemblages. The peak ofengineering effect was significantly greater in the mixed assemblage as compared to thebacterial and axenic diatom culture. This work confirmed the important role ofheterotrophic bacteria in “biostabilisation” and highlighted the interactions betweenautotrophic and heterotrophic biofilm components of the consortia.An additional approach, to investigate the impact of toxins on biostabilisation capacity ofaquatic organism was performed on cultured bacterial and natural freshwater biofilm.Thedata suggest a different mode of triclosan (TCS) action ranging from suppressingmetabolisms to bactericidal effects depending on the TCS concentration. The inhibitoryeffect of triclosanon bacterial and freshwater biofilms was confirmed.This information contributes to the conceptual understanding of the microbial sedimentengineering that represents an important ecosystem function and service in aquatichabitats.