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Neural mechanisms underlying behavioural choices in drosophila melanogaster
Get PDFAll animals are confronted with crucial behavioural choices on a daily basis, human and other- wise. These choices can range from the basic decision to feed or rest, to more complex decisions involving social interactions or finding a suitable mate. Behavioural choices are flexible and modulated by an animal’s physiological needs and external environment. Despite the importance of behavioural choices in animal survival, very little is known about the underlying neural mech- anisms that control them. How does the brain evaluate alternative options and determine the appropriate course of action? What influence do internal states, such as hunger or the health status of the animal, have on these pivotal decisions?
In my thesis, I aimed to uncover the neural basis of behavioural choices underlying various con- flicts using Drosophila melanogaster as a model system. Drosophila exhibits a diverse range of innate behaviours such as courtship, feeding and escape, each displaying remarkable stereotypy. Its relatively simple brain structure, coupled with an array of available genetic tools, makes it an ideal model organism to address this question.
In Chapter 2, I delved into the trade-off between reproduction and immunity. Using several bac- terial pathogens, I found that both infected male and female flies prioritised mating over survival suggesting that reproductive behaviours remain preserved despite the metabolic cost of infection.
Chapter 3 focused on the behavioural choice between feeding and courtship in male Drosophila. Starved males showed a preference for initiating feeding before courtship, while well-fed males prioritised courtship. Together with a master’s student in our lab, we identified the tyramine sig- nalling pathway as a key player in this decision-making process. Tyramine serves as a satiety sig- nal, activating courtship-promoting neurons while simultaneously inhibiting feeding-promoting neurons. Conversely, the perception of food inhibits courtship-promoting neurons and activates feeding-promoting neurons. This antagonistic regulation of important neuronal modules enables flies to prioritise one behaviour over the other in a state-dependent manner.
In Chapter 4, I explored the choice between feeding and escape behaviours in flies. I observed that males starved for 24 hours exhibited a preference for escape over feeding. However, this behavioural prioritisation was reversed by the severity of starvation in a sex-specific manner. Em- ploying techniques such as connectomics, neuroanatomy, and behavioural assays, I unravelled the neural mechanisms underlying this critical behavioural choice, specifically connecting sen- sory information to motor output.
These findings advance our understanding of how the brain resolves behavioural conflicts and incorporates the internal state of an animal to elicit the most appropriate behaviour. Through my research, I shed light on the neural mechanisms underlying behavioural choices in various contexts, using Drosophila melanogaster as a powerful model system
Development of asphalt pavement recycling method for road maintenance and construction in Ethiopia
Get PDFEthiopia is a landlocked country where the road network is of paramount importance as it carries over 90% of freight and people movement. Cognizant of this, the government launched a Road Sector Development Program (RSDP) in 1997 and spent over 525billion ETB (9.53 billion USD) for rehabilitation, upgrading and construction over 25 years. Seventy percent of the expenditure was on asphalt roads. Many of the roads constructed, upgraded or rehabilitated since the beginning of the RSDP are reaching the end of their design life and are creating a significant backlog in road maintenance works due to budget constraints and capacity limitations. Due to the lack of maintenance and increase in traffic, many roads need major rehabilitation. Conventional mill and overly may not be feasible considering the urgency of rehabilitating these roads and there is a need to reduce costs and conserve natural materials to improve sustainability and reduce environmental impact. It is considered that these benefits can be achieved by reusing old asphalt pavement. Accordingly, systematic review of the literature combined with suitability criteria was used to select the most appropriate recycling method. Using Analytical Hierarchy Process the criteria were evaluated and those related to cost effectiveness, Ease of application, environment, and energy conservation are more important in evaluating recycling methods. The result indicated that cold recycling methods are more favorable than hot recycling. It is also found out that as the Reclaimed Asphalt Pavement (RAP) amount used increases an average of 27%cost saving is obtained for RAP 20% to 90%used in HMA mix. The maximum amount of cost saving was 49% obtained for 90% RAP. Economic analysis indicated that saving on total transport cost does not vary for different climatic zones (Semi-arid, Sub-humid and Tropical-humid), however, they showed different pavement deterioration trends.
Key Words: Systematic review, Recycling, Asphalt, Pavement rehabilitation, RAP material
Investigation of the mechanisms driving endothelial dysfunction in patients with sepsis and COVID-19
Get PDFEndothelial cells play a crucial role in the active regulation of a quiescent anti-inflammatory and anti-thrombotic vascular surface. Controlled activation is also vital for mounting an appropriate immune response during inflammation. However, systemic endothelial activation can lead to an exaggerated immune response and thrombosis, independent of the original stimulus. We aimed to assess endothelial cell activation markers in the plasma of patients with sepsis and COVID-19 and to explore possible mechanisms driving endothelial dysfunction in patients. We also investigated the impact of two key damage-associated molecular patterns released during neutrophil extracellular trap formation, histone H4 and S100A8/A9, on endothelial cells under hyperglycaemic conditions and in the plasma of patients with sepsis. We showed that systemic endothelial cell activation is present in patients with both sepsis and COVID-19 as assessed by the increased levels of markers regulating immune recruitment, immunothrombosis and vascular permeability. Markers of NETosis were also observed in patients and these levels correlate with disease severity. Mechanistically, we show that hyperglycaemia alters the response of endothelial cells to histone 4 and increases its binding. Endothelial cell activation by histone 4 is significantly increased in the plasma of patients with sepsis, in particular patients who developed acute respiratory distress syndrome (ARDS) compared to healthy controls. In conclusion, endothelial activation in patients with sepsis and COVID-19 is a hallmark of disease severity. Immune cell activation, through the release of histone H4, increases endothelial cell activation and exacerbates immunothrombosis
A study of the Religious Society of Friends (Quakers) in Yorkshire during the later eighteenth and early nineteenth centuries, based on the notebooks of Joseph Wood, a Quaker minister
Get PDFThis thesis discusses the beliefs and lifestyle of the Religious Society of Friends (Quakers) in Northern England, particularly Yorkshire, during the eighteenth and early nineteenth centuries. This has been made possible by the transcription and publication of five volumes of Notebooks that had remained undisturbed for two centuries until made public in 2011.1 These were written by a travelling Quaker minister named Joseph Wood, who lived near Highflatts Meeting House in West Yorkshire. They are an invaluable source for the Quaker sect theologically, socially, politically and in every other secular way. Having the Notebooks to hand encouraged me to turn to another source on early Quakerism for more information about the purely spiritual side of a Meeting’s life. Carole Dale Spencer’s book ‘Holiness: The Soul of Quakerism’2 brings a modern understanding to many of the questions that puzzled Wood and to which he could only bring to bear the thinking of the 1700s.
It will quickly become obvious that Spencer appears to have been short-changed on space. She gets little more than a chapter while Wood has five. The reason for such inequality is that 18th century Quakerism takes a good deal of explaining as do each of Wood’s five volumes. By the time I get to the core of Spencer’s contribution the reader should be well versed in early modern Quakerism. The Notebooks provide evidence for some long-forgotten Quaker beliefs and practices. Foremost among these is the spiritual insight that gave life to the Society of Friends in the mid-17th century, the holy Inward Light of Christ. Related to this is the ‘Day of Visitation’ by which Wood’s generation set much store.
The thesis also identifies some striking differences between Quakerism in the North and South of England which have been unrecognised until now. Richard Bauman in his book Let Your Words be Few says the Quakers ‘developed a distinctive, symbolically resonant’2 communicative style, one among many in ‘the Babelistic confusion of tongues’3 found in revolutionary England. We cannot assume that words and verbal constructions in Wood’s Notebooks meant to him what they mean to us. There are other aspects of Quakerism which figure large in the sect’s history but which are not developed here, the reason being that Joseph Wood makes little or no mention of them. The best example is slavery, seldom mentioned in Wood’s Notebooks but something to which he was passionately opposed. There are two more areas where originality in this thesis has been possible because of Wood’s Notebooks. Twentieth-century Quaker academic Lewis Benson believed eighteenth century Friends increasingly lost the initial understanding of the Inward Light. Over time, this changed the nature of Quakerism as it had been understood in the first generation. The Notebooks, and Spencer, show that a century later some still considered themselves to be led by the Inward Light, although the prevailing Quaker theology was by then based on Gospel Order (a system of mutual accountability that George Fox had introduced to control Friends’ behaviour and lifestyle). Although Wood was out of step with some aspects of the Quakerism of his day, the Notebooks show him to have remained an obedient Friend. He maintained both the Inward Light and ‘Plainness’ in his own life. Plainness, or simplicity in clothing, speech and possessions, was an essential part of Gospel Order Quakerism, and this is another theme explored here. The second area is women ministers. I make no claims for originality in this subject, but simply point out that women ministers came to outnumber men in Yorkshire and other Northern counties. Spencer will be of use in both these areas as well as helping to clarify the theology of the first Friends
Burial variation and funerary rituals in early iron age Greece: a comparative study of Athens, the Euboean Gulf regions and connected islands
Get PDFThis thesis investigates burial practices and contingent rituals during the Early Iron Age in Greece, with a specific focus on Athens, the Euboean Gulf, and associated Islands. The core of this research lies in six gazetteer chapters, each dedicated to a distinct geographical location 1) Athens, 2) Euboea, 3) Boeotia, 4) Magnesia, 5) Phthiotis-East Locris-Phokis, and 6) Pithekoussai-Naxos-Paros-Skyros-Skiathos. In the analysis of burial sites I examine the social dynamics underpinning regional burial customs. A comparative analysis of the data for all the applicable areas is then used to identify mortuary variability, highlighting identify trends and differences. The intricacies of the funerary process and related rituals provide contextual insight into the web of beliefs and practices. In the conclusion, I offer a nuanced perspective of the complexities inherent in Early Iron Age burials and rituals in central Greece. By placing the results within a multidimensional framework, my research contributes to our broader understanding of archaeology of the period and of the social and cultural factors that shaped this Greek society in the pre-Archaic perio
Knowledge transfer in dynamic multi-objective optimization
Get PDFDynamic multi-objective optimization problems (DMOPs) are optimization problems possessing multiple conflicting objectives varying with time. This type of problems widely exists in the real world, such as planning, resource allocation and scheduling problems. Knowledge transfer, a methodology inspired by the machine learning community, has been recently used for solving DMOPs, since it can transfer useful information from solving one problem instance to solve another related problem instance, potentially speeding up the optimization process for the new instance. This thesis contributes to the study of knowledge transfer in dynamic multi-objective optimization as follows:
1. Intuitively, it is doubtful that knowledge transfer approaches would always be beneficial for improving optimization when solving DMOPs with changing position and/or shape of Pareto sets (PSs) and/or Pareto fronts (PFs), since transferring knowledge from an unrelated problem would be harmful to the optimization of the target problem. Therefore, an investigation is made to determine in which cases transfer works and fails. We find that knowledge transfer indeed does not always work and show that it fails on problems with fixed PS and when environmental changes are small. Moreover, we show that using a linear kernel function to transfer results in better quality of transferred solutions than using a Gaussian one.
2. Given that knowledge transfer contributes to improving optimization quality but introduces an overhead in the optimization process, a series of computational studies are carried out to comprehensively understand the efficiency and effectiveness of knowledge transfer when solving DMOPs with changing position and/or shape of PFs/PSs. Specifically, we computationally find that the 'inner' optimization method introduced by transfer learning is very time-consuming. We also find that spending the time optimizing instead of transferring knowledge would lead to better results, which defeats the purpose of knowledge transfer. Then, we propose to use two alternatives to replace the existing `inner' optimization method and find that the transfer algorithm with one alternative achieves better transfer efficiency and solutions quality.
3. Different from most other DMOPs where dynamic changes lead to changing position and/or shape of PSs and/or PFs, DMOPs with a changing number of objectives usually result in expansion or contraction of the PF or PS manifold when the number of objectives increases or reduces, respectively. Therefore, to improve the optimization process when there is a change in the number of objectives, it is intuitive to determine the expansion and contraction directions. These directions could then be used to generate transferred solutions for the new environment and further expand or contract the PSs. Therefore, we firstly propose a heuristic way to determine PS expansion and contraction directions. Then, a novel knowledge transfer algorithm is proposed via PS expansion and contraction based on the found directions for solving DMOPs with a changing number of objectives. The algorithm is able to achieve transferred solutions with good diversity after changes, improving optimization especially in fast changing environments.
4. Moreover, it may also be possible to learn the expansion and contraction directions, so that determining them does not rely entirely on heuristics, potentially leading to more effective transfer of knowledge. Therefore, a novel learning method for determining the expansion and contraction directions is proposed based on principal component analysis, further expanding and contracting the PSs. Specifically, principal component analysis is firstly conducted on the PS of the previous environment to get the candidates of the expansion and contraction directions. Then, the most promising directions for the expansion and contraction are selected according to dominance relationship between existing solutions and those generated along the candidate directions. This approach is able to improve solution quality, not only right after changes but also after optimization of different generations
Reclaiming the domestic: exploring the significance of 'home' for women who have experienced domestic violence and abuse
Get PDFDomestic violence and abuse (DVA) is a pervasive phenomenon that disproportionately affects women (ONS, 2021). While existing DVA research often addresses the physical, emotional, sexual, and financial manifestations of abuse experienced by women, as well as coercive control, the spatial realities of DVA are rarely explored in the same way.
It is argued that societal sexism enables and excuses domestic abuse (Women’s Aid, 2022), and as sociological and feminist explanations of the prevalence of DVA have developed, there has been a move towards making ‘public’ a problem that was once thought ‘private’. Although welcome, this shift in how we approach DVA – along with the rejection of traditional male-female, public-private binaries – has displaced debate about the relationship between women and the home.
This research argues the case for reclaiming the ‘domestic’ in DVA following an exploration of how home changes for victim-survivors of DVA, what the idea of home represents, and how re-building home can aid women in their recovery. Following 15 in-depth, qualitative interviews and the application of Interpretative Phenomenological Analysis (IPA), this research has found that there is a unique spatial quality to DVA; that DVA has spatial consequences that move with victim-survivors; that the home is an important site of reclamation for victim-survivors; and that feeling 'at home' matters in the context of DVA.
This research proposes that by recognising what the home symbolises to victim-survivors, a greater understanding of how DVA is experienced and how its long-term implications may manifest is available. This research also offers possible indicators of DVA in relation to space, as well as practical recommendations for agencies and organisations who re-house women, whether in permanent or emergency accommodation
Investigation of the phases present in Al-7Si-0.3Mg alloy with the addition of transition metals
Get PDFThis research aimed to investigate the effects of the addition of the transition metals molybdenum, tungsten, and vanadium to Al-7Si-0.3Mg (2L99) and the mechanism by which their addition can improve the tensile properties of 2L99. Although the addition of certain transition metals is thought to enhance the properties of Al alloys, research has been limited on this subject.
It is known that the presence of entrapped double oxide film defects (bifilms) in the aluminium alloy has a detrimental effect on its mechanical and corrosion resistance properties. As part of this study, various alloys of 2L99 + 0.4 wt.% Mo, W and V were made using the sand-casting method. It was observed that the addition of Mo and W improved the Ultimate Tensile Strength (UTS), %Elongation and yield strength of 2L99, whilst the addition of V showed a negligible increase in these parameters. Statistical analysis showed a significant increase in the Weibull moduli of the measured tensile properties of the alloys due to the addition of all three transition metals.
Subsequent to tensile testing, SEM and EDX analyses were carried out on various alloys to study the phases of oxides, nitrides and intermetallics on each alloy's polished and fractured surfaces. Characterisation of the fractured surfaces of 2L99 alloy in as-cast condition discovered for the first time AlN patches with a different "nodular” morphology of approximately
15 μm length, which were considered to be impermeable. This discovery reinforces Nyahumwa's hypothesis on the utilisation of internal gases, indicating that the presence of AlN is likely a result of increased consumption of entrapped air within the bifilms. This process begins with converting oxygen into spinel, followed by nitrogen transformation into AlN. Furthermore, impermeable nodular AlN morphologies observed in this study are considered to prevent hydrogen diffusion into the bifilms and prevent their expansion, ultimately leading to the reduction in bifilms’ size.
Sedimentation testing was carried out on 2L99 and 2L99 + Mo, W and V alloys by holding the melt at 800°C for 1 hour, followed by air cooling of the samples. The results showed that the addition of transition metals to 2L99 encouraged the settlement of a large portion of the intermetallics and bifilms to the base of the melt. This is thought to be due to the suitability of bifilms as a potent substrate for the nucleation of most intermetallics and the higher density of the intermetallics compared to liquid Al.
Nitrogen growth test was carried out on CP-AL, 2L99, 2L99 + 0.6 wt.% Mo and 0.2 wt.% W alloys. Alloy melts were held at 850°C in a nitrogen atmosphere for various holding times. The test showed the presence of different aluminium nitride morphologies such as rod, whisker, nodular, and feather-shaped.
Phase analysis also indicated that the reduction in the amount of bifilms resulted in the improvement of tensile properties of the 2L99 alloy, likely due to a combination of the following factors: (i) Substantial settling of double oxide films to the base of the melt due to nucleation of intermetallics on bifilms, (ii) The presence of more frequent AlN patches and morphologies suggesting an increase in the rate of consumption of the internal gases inside the bifilms and subsequent reduction of their size, and (iii) Alteration of the β- Al5FeSi morphology or its type to an α-compound intermetallic phase in 2L99, which is considered less detrimental to mechanical properties of the alloy due to its differing morphology and/or size.
The findings of this research contribute to understanding the mechanism by which the mechanical properties of 2L99 alloy are improved by the addition of Mo, W and V. Furthermore; it upholds previous research undertaken by Nyahumwa for the consumption of gases within double oxide films and the existence of nitride in the process, as well as providing evidence of different AlN morphologies in Al-Si-Mg alloys
Immunotherapeutic opportunities in oesophageal adenocarcinoma
Get PDFIntegration of immunotherapy into the treatment pathways for many solid cancers has led to important improvements in survival outcomes. Until recently there was no evidence to confirm that immunotherapy could improve survival over and above current gold standards in treatment for patients with potentially curative oesophageal cancer. Checkmate 577 has demonstrated that adjuvant PD-1 inhibition improves disease free survival for patients who have undergone neoadjuvant chemoradiotherapy and oesophagectomy. Oesophageal adenocarcinoma (OAC) is potentially susceptible to immunotherapy however little is known about the tumour microenvironment (TME). This thesis explores the immunophenotypic landscape of oesophageal adenocarcinoma to identify new mechanisms for immunotherapy.
A combination of proteomic and transcriptomic studies have identified that the OAC TME is dominated by immune and stromal populations. T cells are the majority immune population, and a range of effector and regulatory subsets were identified. OAC is broadly immunogenic and CD39+ T cells, generally regarded as correlates of a tumour-specific cytotoxic cellular response, are observed in both CD4+ and CD8+ T cell subsets. T cells within the TME often express an exhausted phenotype with high levels of checkpoint expression (PD-1, Tigit, TIM-3, LAG-3). A highly proliferative population of T cells has been identified that exhibit features of tumour specificity but in addition feature similar rates of checkpoint expression. Neoadjuvant chemotherapy decreases immunosuppressive Tregs and can potentially decrease exhaustion in effector phenotypes.
These findings have significant implications in the development of novel immunotherapy which is already starting to show promise in improving survival for this challenging cancer
Characterisation of IN718 fasteners for aero-engine applications
Get PDFStandard IN718 fasteners are widely employed in aeroengine applications owing to their exceptional mechanical properties, including tensile, fatigue and creep strength at temperatures up to 650°C. Notably, IN718 is a cost-effective choice compared with other alloys [1]. However, the flexibility allowed by the industrial manufacturing specification in the choice of raw material and determining the solution treatment temperature range introduces variations in microstructure of bolt and consequently mechanical performance of the bolts [2].
This project focused on examining the microstructure and mechanical properties in the threaded section of IN718 bolts. Bending tests were carried out on the split bolts at 650°C to evaluate the influence of possible microstructural variation and associated failure mechanism. Further investigations into fatigue and creep behaviours were accomplished using the ½” IN718 large bolts through the axial-tension dwell fatigue and stress relaxation tests. These tests also verified the microstructural evolution at the threads under the long-term thermal exposure. As a result, cold rolling in the threaded section demonstrated a clear enhancement in fatigue mechanism at the investigated temperature. In addition to the shank properties, the IN718 test pieces with simulated microstructures were tested, revealing a profound influence of annealing temperature on dwell fatigue life and a noticeable change in failure mechanism. Microstructural characterisation and fractographic examination were conducted
throughout to aid understanding. A manufacturing route of IN718 aero-engine bolts was proposed in the end to better control the microstructure, subsequently the performance of the final products
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