-
An investigation of the ABAD-Aβ interaction as a potential therapeutic target for the treatment of Alzheimer’s disease
view abstract
|
access in Research@StAndrews:Full text
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.
Description: Electronic version does not contain associated previously published material
-
A comparative investigation of the cognitive and social factors underlying a capacity for cumulative culture
view abstract
|
access in Research@StAndrews:Full text
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.
-
Female mating decisions in the rose bitterling (Rhodeus ocellatus)
view abstract
|
access in Research@StAndrews:Full text
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.
-
The impact of microbial extracellular polymeric substances on sediment stability
view abstract
|
access in Research@StAndrews:Full text
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.
-
Range-wide analysis of the spatial distribution and genetic diversity of Delonix s.l. (Leguminosae) in Madagascar : enhancing herbarium-based conservation assessments
view abstract
|
access in Research@StAndrews:Full text
Title: Range-wide analysis of the spatial distribution and genetic diversity of Delonix s.l. (Leguminosae) in Madagascar : enhancing herbarium-based conservation assessments
Authors: Rivers, Malin C.
Abstract: Despite their ecological and economic importance, the majority of plant species andtheir conservation status are poorly known. Only 4% of plants have been assessedglobally and listed on the IUCN Red List of Threatened Species; and without plantconservation assessments, many plant species will not feature in conservationplanning.Herbarium collection information can significantly increase the number of plantconservation assessments. Thus, the aims of this thesis were: (1) to investigate howthe quality of herbarium-based conservation assessments can be optimised; (2) toassess the extent to which herbarium-based conservation assessments reflect thereality on the ground; and (3) to scientifically validate genetic and spatial underpinningof IUCN criteria.Preliminary range-based assessments of the Leguminosae of Madagascar achieved aresult consistent with the final conservation rating for over 95% of species when usingup to fifteen herbarium specimens. Bioclimatic modelling of range shifts based onfuture climate change predicted that, in the worst case scenario, up to one third ofendemic Leguminosae in Madagascar will be threatened with extinction over the next100 years. An analysis of the population structure of species of Delonix s.l.(Leguminosae) showed that combining spatial analysis with population genetic dataprovides a more complete picture of landscape-level population dynamics and theimpacts on conservation status.Moreover, range-wide genetic analysis of AFLP markers for four species of Delonixdemonstrated a genetic basis for IUCN categories distinguishing between threatenedand non-threatened species. Although genetic data are currently not oftenincorporated in conservation assessments, they are crucial in making accuratemanagement decisions and creating effective action plans for conservation. Only byusing all available scientific resources can informed conservation decisions be madeand the survival of plants and their associated ecosystems be ensured.
-
Studies on influenza A virus PB1-F2 protein
view abstract
|
access in Research@StAndrews:Full text
Title: Studies on influenza A virus PB1-F2 protein
Authors: Vater, Sandra
Abstract: The influenza A virus genome codes for up to 12 proteins. Segment 2 encodes three proteins, the polymerase subunit PB1, a small protein PB1-F2 and an N-terminally truncated version of PB1 called N40. Different functions have been reported for PB1-F2 such as induction of apoptosis, regulation of the viral polymerase activity, enhancement of secondary bacterial infections and modulation of the innate immune system. So far, no function has been ascribed to N40.To study PB1-F2 in more detail, its coding sequence was deleted from its original position and inserted downstream of the PB1 (segment 2), NA (segment 6) or M (segment 7) open reading frames (ORF) employing different strategies, including the use of an overlapping Stop-Start cassette, a duplicated promoter sequence and the self-cleaving 2A peptide derived from foot-and-mouth disease virus. Viruses with bicistronic segments were rescued and tested for their ability to express PB1-F2. Whereas no expression of PB1-F2 was detected from bicistronic segments 2 and 7, expression of PB1-F2 from segment 6 was observed in high levels. However, the phenotype of all these viruses was similar to that of viruses lacking PB1-F2 which made mutational analysis of PB1-F2 not worthwhile. Previously, the function of PB1-F2 was mainly studied using a virus deficient in PB1-F2 production but showing increased N40 expression. In the present study, recombinant WSN viruses lacking either PB1-F2 or N40, or both proteins were engineered and the effects of these mutations on the viral life cycle were examined. Viruses deficient for PB1-F2 that overexpressed N40 showed the most attenuated phenotype, whereas the loss of PB1-F2 alone did not obviously affect virus replication. Reduced viral polymerase activity was observed for viruses lacking N40, however attenuation in vivo was only seen in combination with the loss of PB1-F2. Neither the loss of PB1-F2 nor N40 alone had a great impact, but changes in the expression level of both proteins were disadvantageous for the virus. Increased levels of N40 shifted the polymerase activity towards replication, suggesting a new function for N40.Thus, it was shown that the segment 2 gene products and their expression level influence viral replication and pathogenicity, and a careful design of mutant recombinant viruses is vital for determining the experimental outcome.
-
Virus and interferon : a fight for supremacy : comparison of the mechanisms of influenza A viruses and parainfluenza virus 5 in combatting a pre-existing IFN-induced antiviral state
view abstract
|
access in Research@StAndrews:Full text
Title: Virus and interferon : a fight for supremacy : comparison of the mechanisms of influenza A viruses and parainfluenza virus 5 in combatting a pre-existing IFN-induced antiviral state
Authors: Xiao, Han
Abstract: The Interferon (IFN) family of cytokines are produced in direct response to virus infection and they constitute the first line of defence against virus infection by inducing hundreds of interferon stimulated genes (ISGs) which act in concert to establish the so-called “antiviral state”. Influenza A viruses and parainfluenza virus type 5 (PIV5) are both small negative strand RNA viruses that must circumvent their hosts’ interferon (IFN) response for replication. However, the ways in which these viruses interact with the IFN system are very different. Although PIV5 replication is initially severely impaired in cells in a pre-existing IFN-induced antiviral state, it manages to overcome the antiviral state by targeting an essential component of type I IFN signalling, STAT1, for degradation. Thus the cells cannot maintain the antiviral state indefinitely without continuous signalling. Consequently, the virus resumes its normal replication pattern after 24-48 hours post-infection. In clear contrast, influenza virus fails to establish its replication in the majority of infected cells (90-95%) with a pre-existing IFN-induced antiviral state, although a few cells are still able to produce viral antigens. To further investigate how influenza virus interacts with cells in a pre-existing IFN-induced antiviral state, I have used in situ hybridization to follow the fate of input and progeny genomes in cells that have, or have not, been treated with IFN prior to infection. Here I show for the first time that IFN pre-treatment blocks the nuclear import of influenza A virus genome, which prevents the establishment of virus replication, but this can be overcome by increasing multiplicities of infection. Of those IFN-induced antiviral molecules, human MxA is an essential component of the IFN-induced antiviral state in blocking influenza virus genome import, as this block can be abolished by lentivirus-mediated knockdown of MxA. I also show that in cells constitutively expressing MxA the viral genome still manages to be transported into the nucleus, indicating that MxA might require an unidentified IFN-induced factor to block nuclear import of the influenza virus genome. These results reveal that IFN exerts its action at an early stage of virus infection by inducing MxA to interfere with the transport of viral genome into the nucleus, which is the factory for viral RNA production.
-
Geographic and species variation in bottlenose dolphin (Tursiops spp.) signature whistle types
view abstract
|
access in Research@StAndrews:Full text
Title: Geographic and species variation in bottlenose dolphin (Tursiops spp.) signature whistle types
Authors: Gridley, Teresa
Abstract: Geographic variation in the whistle vocalisations of dolphins has previously been reported. However, moststudies have focused on the whole whistle repertoire, with little attempt to classify sounds into biologicallyrelevant categories. Common bottlenose dolphins (Tursiops truncatus) use individually distinctive signaturewhistles which are thought to help maintain contact between conspecifics at sea. These whistles may show adifferent kind of variation between populations than non-signature whistles. Here I investigate signaturewhistle use and variation in the two recognised species of bottlenose dolphins (T. truncatus and T. aduncus)from populations inhabiting the coastal waters of the North America, Scotland, South Africa, Tanzania,Japan, Australia and New Zealand, and one captive colony. I identified likely signature whistles (signaturewhistles types, SWTs) from acoustic recordings by combining two novel techniques: automated contourcategorisation in ARTwarp (Deecke and Janik, 2006) and a specific bout analysis based on the timing ofsignature whistle production in T. truncatus termed SIGID (Janik et al. in press). Three ways of categorisingthe contours were tested and between 87 and 111 SWTs were identified in total. Repeated emissions ofstereotyped contours were apparent in the repertoire of all T. aduncus populations using both automated andhuman observer categorisation, providing good evidence for signature whistle use in this species. There wassignificant inter-specific variation in the frequency parameters, looping patterns and duration of SWTs.Inflection points, duration and measures of SWT complexity showed high variation within populations,suggesting inter- and intra-individual modification of these parameters, perhaps to enhance identity encodingor convey motivational information. Using 328 bases of the mtDNA control region, I found high levels ofpopulation differentiation (FST and φST) within the genus Tursiops. These data do not support a link betweenmtDNA population differentiation and variability in call type. Instead, morphological variations at thespecies level, and learned differences at the population level, better explain the variation found.
-
Local development planning and bats in the UK : “an impenetrable fog” ?
view abstract
|
access in Research@StAndrews:Full text
Title: Local development planning and bats in the UK : “an impenetrable fog” ?
Authors: Cohen, Keith
Abstract: Despite national and international protection, and the focus of conservation biology research, UK bat populations remain under threat from development. Cumulative impacts from development threaten bat populations with the “death of a thousand cuts”: direct mortality; loss of roost spaces; increasing road traffic and wind turbines killing more bats; disturbance,fragmentation and degradation of habitat may increase mortality by reducing fitness. It istimely to investigate the efficacy of conservation measures targeted at protecting bats in local development planning (“development management”), in particular the process of screening planning applications for potential impacts upon bats, acting in resolution of this Human-Wildlife Conflict.Examination of published guidance was combined with review of practitioner experience through Local Planning Authority (LPA) development management staff and bat survey consultants, with the aim of determining weaknesses in principles, mechanisms and resources.Key issues were the lack of political and managerial support, poor enforcement, a lack of expert natural heritage skills, inconsistent interpretation and application of guidelines, and significant gaps in guidance. For one LPA, 22% of sampled planning applications showed a highrisk of potential impacts upon bats, yet only 1% had a bat survey undertaken; and 32% of known roost sites had been subject to one or more planning applications in 10 years. Only a few LPAs enjoy excellent access to expert natural heritage skills, biological data and advice from SNCOs.I present a multi-disciplinary synthesis to derive recommendations for process enhancement including seven good design principles, and seven key resources. The foundation to comprehensive adoption and enforcement is clear nationally consistent political support; thus engendering good practice e.g. all UK development applications should declare howbiodiversity issues are addressed; research should address bat population dynamics, andresponses to development impacts.
Description: This study was supported by RPS Group plc (Planning & Development)
-
An investigation of factors related to the bycatch of small cetaceans in fishing gear
view abstract
|
access in Research@StAndrews:Full text
Title: An investigation of factors related to the bycatch of small cetaceans in fishing gear
Authors: Mackay, Alice I.
Abstract: The bycatch of cetaceans in fishing gear is considered to be one of the biggest conservation threats to these species. Gear modifications have the potential to reduce these bycatches in global fisheries but there is little available information on how such modifications may change the fishing performance of gear, or indeed the behavior of cetaceans interacting with fishing gear.Generalized linear models (GLMs) were used to identify factors related to cetacean bycatches in UK bottom set gillnets. Rigged net height had a significant positive relationship with harbour porpoise (Phocoena phocoena) bycatch in ICES Area VII suggesting that lowering the profile of gillnets may have the potential to reduce bycatch rates. Modifications to gillnets, such as changing the amount of floatation or increasing the density of the meshes, were found to have significant effects on the active fishing heights of these nets. However, results from a bycatch mitigation trial in Argentina showed that the reduced fishing profile of one experimental net did not result in a concurrent reduction in the bycatch rate of Franciscana dolphins (Pontoporia blainvillei). While there was no significant difference in the rate, length or intensity of harbour porpoise encounters in the presence or absence of gillnets, the proportion of fast echolocation click trains were significantly higher when a net was present, indicating that porpoises either increased acoustic inspection of the net or foraging in the vicinity of the net.An analysis of underwater video footage collected inside trawl nets in an Australia fishery showed that bottlenose dolphins (Tursiops sp.) were present inside nets more frequently than they were caught and were actively foraging inside these nets. The orientation of dolphins inside these nets indicates that the current design of excluder devices used in this fishery could be improved to further reduce bycatch rates.