7,544 research outputs found

    A Design Science Research Approach to Smart and Collaborative Urban Supply Networks

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    Urban supply networks are facing increasing demands and challenges and thus constitute a relevant field for research and practical development. Supply chain management holds enormous potential and relevance for society and everyday life as the flow of goods and information are important economic functions. Being a heterogeneous field, the literature base of supply chain management research is difficult to manage and navigate. Disruptive digital technologies and the implementation of cross-network information analysis and sharing drive the need for new organisational and technological approaches. Practical issues are manifold and include mega trends such as digital transformation, urbanisation, and environmental awareness. A promising approach to solving these problems is the realisation of smart and collaborative supply networks. The growth of artificial intelligence applications in recent years has led to a wide range of applications in a variety of domains. However, the potential of artificial intelligence utilisation in supply chain management has not yet been fully exploited. Similarly, value creation increasingly takes place in networked value creation cycles that have become continuously more collaborative, complex, and dynamic as interactions in business processes involving information technologies have become more intense. Following a design science research approach this cumulative thesis comprises the development and discussion of four artefacts for the analysis and advancement of smart and collaborative urban supply networks. This thesis aims to highlight the potential of artificial intelligence-based supply networks, to advance data-driven inter-organisational collaboration, and to improve last mile supply network sustainability. Based on thorough machine learning and systematic literature reviews, reference and system dynamics modelling, simulation, and qualitative empirical research, the artefacts provide a valuable contribution to research and practice

    TOWARDS AN UNDERSTANDING OF EFFORTFUL FUNDRAISING EXPERIENCES: USING INTERPRETATIVE PHENOMENOLOGICAL ANALYSIS IN FUNDRAISING RESEARCH

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    Physical-activity oriented community fundraising has experienced an exponential growth in popularity over the past 15 years. The aim of this study was to explore the value of effortful fundraising experiences, from the point of view of participants, and explore the impact that these experiences have on people’s lives. This study used an IPA approach to interview 23 individuals, recognising the role of participants as proxy (nonprofessional) fundraisers for charitable organisations, and the unique organisation donor dynamic that this creates. It also bought together relevant psychological theory related to physical activity fundraising experiences (through a narrative literature review) and used primary interview data to substantiate these. Effortful fundraising experiences are examined in detail to understand their significance to participants, and how such experiences influence their connection with a charity or cause. This was done with an idiographic focus at first, before examining convergences and divergences across the sample. This study found that effortful fundraising experiences can have a profound positive impact upon community fundraisers in both the short and the long term. Additionally, it found that these experiences can be opportunities for charitable organisations to create lasting meaningful relationships with participants, and foster mutually beneficial lifetime relationships with them. Further research is needed to test specific psychological theory in this context, including self-esteem theory, self determination theory, and the martyrdom effect (among others)

    Modelling and Solving the Single-Airport Slot Allocation Problem

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    Currently, there are about 200 overly congested airports where airport capacity does not suffice to accommodate airline demand. These airports play a critical role in the global air transport system since they concern 40% of global passenger demand and act as a bottleneck for the entire air transport system. This imbalance between airport capacity and airline demand leads to excessive delays, as well as multi-billion economic, and huge environmental and societal costs. Concurrently, the implementation of airport capacity expansion projects requires time, space and is subject to significant resistance from local communities. As a short to medium-term response, Airport Slot Allocation (ASA) has been used as the main demand management mechanism. The main goal of this thesis is to improve ASA decision-making through the proposition of models and algorithms that provide enhanced ASA decision support. In doing so, this thesis is organised into three distinct chapters that shed light on the following questions (I–V), which remain untapped by the existing literature. In parentheses, we identify the chapters of this thesis that relate to each research question. I. How to improve the modelling of airline demand flexibility and the utility that each airline assigns to each available airport slot? (Chapters 2 and 4) II. How can one model the dynamic and endogenous adaptation of the airport’s landside and airside infrastructure to the characteristics of airline demand? (Chapter 2) III. How to consider operational delays in strategic ASA decision-making? (Chapter 3) IV. How to involve the pertinent stakeholders into the ASA decision-making process to select a commonly agreed schedule; and how can one reduce the inherent decision-complexity without compromising the quality and diversity of the schedules presented to the decision-makers? (Chapter 3) V. Given that the ASA process involves airlines (submitting requests for slots) and coordinators (assigning slots to requests based on a set of rules and priorities), how can one jointly consider the interactions between these two sides to improve ASA decision-making? (Chapter 4) With regards to research questions (I) and (II), the thesis proposes a Mixed Integer Programming (MIP) model that considers airlines’ timing flexibility (research question I) and constraints that enable the dynamic and endogenous allocation of the airport’s resources (research question II). The proposed modelling variant addresses several additional problem characteristics and policy rules, and considers multiple efficiency objectives, while integrating all constraints that may affect airport slot scheduling decisions, including the asynchronous use of the different airport resources (runway, aprons, passenger terminal) and the endogenous consideration of the capabilities of the airport’s infrastructure to adapt to the airline demand’s characteristics and the aircraft/flight type associated with each request. The proposed model is integrated into a two-stage solution approach that considers all primary and several secondary policy rules of ASA. New combinatorial results and valid tightening inequalities that facilitate the solution of the problem are proposed and implemented. An extension of the above MIP model that considers the trade-offs among schedule displacement, maximum displacement, and the number of displaced requests, is integrated into a multi-objective solution framework. The proposed framework holistically considers the preferences of all ASA stakeholder groups (research question IV) concerning multiple performance metrics and models the operational delays associated with each airport schedule (research question III). The delays of each schedule/solution are macroscopically estimated, and a subtractive clustering algorithm and a parameter tuning routine reduce the inherent decision complexity by pruning non-dominated solutions without compromising the representativeness of the alternatives offered to the decision-makers (research question IV). Following the determination of the representative set, the expected delay estimates of each schedule are further refined by considering the whole airfield’s operations, the landside, and the airside infrastructure. The representative schedules are ranked based on the preferences of all ASA stakeholder groups concerning each schedule’s displacement-related and operational-delay performance. Finally, in considering the interactions between airlines’ timing flexibility and utility, and the policy-based priorities assigned by the coordinator to each request (research question V), the thesis models the ASA problem as a two-sided matching game and provides guarantees on the stability of the proposed schedules. A Stable Airport Slot Allocation Model (SASAM) capitalises on the flexibility considerations introduced for addressing research question (I) through the exploitation of data submitted by the airlines during the ASA process and provides functions that proxy each request’s value considering both the airlines’ timing flexibility for each submitted request and the requests’ prioritisation by the coordinators when considering the policy rules defining the ASA process. The thesis argues on the compliance of the proposed functions with the primary regulatory requirements of the ASA process and demonstrates their applicability for different types of slot requests. SASAM guarantees stability through sets of inequalities that prune allocations blocking the formation of stable schedules. A multi-objective Deferred-Acceptance (DA) algorithm guaranteeing the stability of each generated schedule is developed. The algorithm can generate all stable non-dominated points by considering the trade-off between the spilled airline and passenger demand and maximum displacement. The work conducted in this thesis addresses several problem characteristics and sheds light on their implications for ASA decision-making, hence having the potential to improve ASA decision-making. Our findings suggest that the consideration of airlines’ timing flexibility (research question I) results in improved capacity utilisation and scheduling efficiency. The endogenous consideration of the ability of the airport’s infrastructure to adapt to the characteristics of airline demand (research question II) enables a more efficient representation of airport declared capacity that results in the scheduling of additional requests. The concurrent consideration of airlines’ timing flexibility and the endogenous adaptation of airport resources to airline demand achieves an improved alignment between the airport infrastructure and the characteristics of airline demand, ergo proposing schedules of improved efficiency. The modelling and evaluation of the peak operational delays associated with the different airport schedules (research question III) provides allows the study of the implications of strategic ASA decision-making for operations and quantifies the impact of the airport’s declared capacity on each schedule’s operational performance. In considering the preferences of the relevant ASA stakeholders (airlines, coordinators, airport, and air traffic authorities) concerning multiple operational and strategic ASA efficiency metrics (research question IV) the thesis assesses the impact of alternative preference considerations and indicates a commonly preferred schedule that balances the stakeholders’ preferences. The proposition of representative subsets of alternative schedules reduces decision-complexity without significantly compromising the quality of the alternatives offered to the decision-making process (research question IV). The modelling of the ASA as a two-sided matching game (research question V), results in stable schedules consisting of request-to-slot assignments that provide no incentive to airlines and coordinators to reject or alter the proposed timings. Furthermore, the proposition of stable schedules results in more intensive use of airport capacity, while simultaneously improving scheduling efficiency. The models and algorithms developed as part of this thesis are tested using airline requests and airport capacity data from coordinated airports. Computational results that are relevant to the context of the considered airport instances provide evidence on the potential improvements for the current ASA process and facilitate data-driven policy and decision-making. In particular, with regards to the alignment of airline demand with the capabilities of the airport’s infrastructure (questions I and II), computational results report improved slot allocation efficiency and airport capacity utilisation, which for the considered airport instance translate to improvements ranging between 5-24% for various schedule performance metrics. In reducing the difficulty associated with the assessment of multiple ASA solutions by the stakeholders (question IV), instance-specific results suggest reductions to the number of alternative schedules by 87%, while maintaining the quality of the solutions presented to the stakeholders above 70% (expressed in relation to the initially considered set of schedules). Meanwhile, computational results suggest that the concurrent consideration of ASA stakeholders’ preferences (research question IV) with regards to both operational (research question III) and strategic performance metrics leads to alternative airport slot scheduling solutions that inform on the trade-offs between the schedules’ operational and strategic performance and the stakeholders’ preferences. Concerning research question (V), the application of SASAM and the DA algorithm suggest improvements to the number of unaccommodated flights and passengers (13 and 40% improvements) at the expense of requests concerning fewer passengers and days of operations (increasing the number of rejected requests by 1.2% in relation to the total number of submitted requests). The research conducted in this thesis aids in the identification of limitations that should be addressed by future studies to further improve ASA decision-making. First, the thesis focuses on exact solution approaches that consider the landside and airside infrastructure of the airport and generate multiple schedules. The proposition of pre-processing techniques that identify the bottleneck of the airport’s capacity, i.e., landside and/or airside, can be used to reduce the size of the proposed formulations and improve the required computational times. Meanwhile, the development of multi-objective heuristic algorithms that consider several problem characteristics and generate multiple efficient schedules in reasonable computational times, could extend the capabilities of the models propositioned in this thesis and provide decision support for some of the world’s most congested airports. Furthermore, the thesis models and evaluates the operational implications of strategic airport slot scheduling decisions. The explicit consideration of operational delays as an objective in ASA optimisation models and algorithms is an issue that merits investigation since it may further improve the operational performance of the generated schedules. In accordance with current practice, the models proposed in this work have considered deterministic capacity parameters. Perhaps, future research could propose formulations that consider stochastic representations of airport declared capacity and improve strategic ASA decision-making through the anticipation of operational uncertainty and weather-induced capacity reductions. Finally, in modelling airlines’ utility for each submitted request and available time slot the thesis proposes time-dependent functions that utilise available data to approximate airlines’ scheduling preferences. Future studies wishing to improve the accuracy of the proposed functions could utilise commercial data sources that provide route-specific information; or in cases that such data is unavailable, employ data mining and machine learning methodologies to extract airlines’ time-dependent utility and preferences

    How to Be a God

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    When it comes to questions concerning the nature of Reality, Philosophers and Theologians have the answers. Philosophers have the answers that can’t be proven right. Theologians have the answers that can’t be proven wrong. Today’s designers of Massively-Multiplayer Online Role-Playing Games create realities for a living. They can’t spend centuries mulling over the issues: they have to face them head-on. Their practical experiences can indicate which theoretical proposals actually work in practice. That’s today’s designers. Tomorrow’s will have a whole new set of questions to answer. The designers of virtual worlds are the literal gods of those realities. Suppose Artificial Intelligence comes through and allows us to create non-player characters as smart as us. What are our responsibilities as gods? How should we, as gods, conduct ourselves? How should we be gods

    Radionuclide and heavy metal sorption on to functionalised magnetic nanoparticles for environmental remediation

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    The presence of radionuclides and heavy metal ions in aqueous waste streams from industrial processes, especially in the nuclear waste industry, are a major concern. Many other processes are inherent producers of hazardous aqueous waste streams that require treatment for further disposal. These wastes quite often contain many contaminants, from harmful to very toxic. Contact with the environment, through groundwater or rivers, with such contaminants needs to be avoided. The ability to selectively sequester and remove contaminants from aqueous wastes with high loading capacities is of paramount importance to achieve full removal of the contaminants produced in many industries. The recent development of phosphate functionalised superparamagnetic magnetite ((PO)x-Fe3O4) nanoparticles have been shown to have ultra-high loading capacities and a high degree of selectivity towards uranium (U(VI)). The ability to manipulate these NPs with an external magnetic field gives these nanomaterials an advantage over many other conventional technologies in the field. These low-cost, non-toxic, and easily prepared magnetic NPs are highly biocompatible and have already been widely applied in the biotechnology and biomedical industries. The addition of specific functionalities allows for the fine tuning of the selectivity towards certain elements, therefore allowing full control over the selective removal of a wide range of contaminants. This study addresses the optimisation of the NPs manufacturing process that allows for the use of these NPs in a wider range of environments. Many of these waste streams are extreme environments, where they can be highly acidic or highly basic conditions. Therefore the feasibility of coating the Fe3O4 with silica (SiO2) was addressed, to provide an acid resistant layer and substrate for further functionalisation. Both the silica coating, and the applied surface functionality, were found to be stable against dissolution or chemical changes under acidic conditions from pH 1-4. Once acid resistance was established, the ability to extract a wide range of contaminant ions was also investigated. Sorption experiments with a wide range of contaminant ions were conducted to determine the selectivity and loading capacities of both (PO)x-Fe3O4 and (PO)x-SiO2@Fe3O4 NPs, at acidic (pH 3), neutral (pH 7), and basic (pH 11) conditions. Providing a basis for the manufacture of a state-of-the-art, novel extraction tool for both heavy metals and radionuclides. Inductively Coupled Plasma - Optical Emission Spectrometry (ICP-OES), Transmission Electron Microscopy (TEM), and Scanning Transmission Electron Microscopy - Energy Dispersive X-Ray (STEM-EDX) were used to achieve full characterisation of the NP complexes and supernatants to determine the successful extraction and presence of the contaminant metal ions used in this study. Determining the uptake kinetics, loading capacities for Cs(I), K(I), Na(I), Ca(II), Cd(II), Co(II), Cu(II), Mg(II), Mn(II), Mo(II), Ni(II), Pb(II), Sr(II), Al(III), Ce(III), Cr(III), Eu(III), Fe(III) and La(III) on to (PO)x-Fe3O4 and (PO)x-SiO2@Fe3O4 NPs. Implications of the use of these NPs in the extraction of radionuclides and heavy metals have been discussed in each case along with the potential for developing a broad-spectrum adsorbent. In conclusion, this PhD has shown the potential of these novel as-synthesised phosphate functionalised NP complexes to be utilised for heavy metal and radionuclide extraction, of a range of contaminants, from aqueous solutions, in acidic, neutral, and basic conditions. The production of these cost-effective and selective nanomaterials which exhibit rapid kinetics has the potential to be an important asset to the water treatment industry. Overall, these NP-complexes have been effective in fully removing a wide range of heavy metal contaminants and, therefore, have shown great promise to become a broad-spectrum adsorbent tool, which ultimately will aid in the clean-up of many new and legacy waste environments.Open Acces

    The applied psychology of addictive orientations : studies in a 12-step treatment context.

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    The clinical data for the studies was collected at The PROMIS Recovery Centre, a Minnesota Model treatmentc entre for addictions,w hich encouragesth e membership and use of the 12 step Anonymous Fellowships, and is abstinence based. The area of addiction is contextualised in a review chapter which focuses on research relating to the phenomenon of cross addiction. A study examining the concept of "addictive orientations" in male and female addicts is described, which develops a study conductedb y StephensonM, aggi, Lefever, & Morojele (1995). This presents study found a four factor solution which appeared to be subdivisions of the previously found Hedonism and Nurturance factors. Self orientated nurturance (both food dimensions, shopping and caffeine), Other orientated nurturance (both compulsive helping dimensions and work), Sensation seeking hedonism (Drugs, prescription drugs, nicotine and marginally alcohol), and Power related hedonism (Both relationship dimensions, sex and gambling. This concept of "addictive orientations" is further explored in a non-clinical population, where again a four factor solution was found, very similar to that in the clinical population. This was thought to indicate that in terms of addictive orientation a pattern already exists in this non-clinical population and that consideration should be given to why this is the case. These orientations are examined in terms of gender differences. It is suggested that the differences between genders reflect power-related role relationships between the sexes. In order to further elaborate the significance and meaning behind these orientations, the next two chapters look at the contribution of personality variables and how addictive orientations relate to psychiatric symptomatology. Personality variables were differentially, and to a considerable extent predictably involved with the four factors for both males and females.Conscientiousness as positively associated with "Other orientated Nurturance" and negatively associated with "Sensation seeking hedonism" (particularly for men). Neuroticism had a particularly strong association with the "Self orientated Nurturance" factor in the female population. More than twice the symptomatology variance was explained by the factor scores for females than it was for males. The most important factorial predictors for psychiatric symptomatology were the "Power related hedonism" factor for males, and "Self oriented nurturance" for females. The results are discussed from theoretical and treatment perspectives

    Towards thinking classrooms: foundation stage possibilities in Northern Ireland

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    The integration of thinking skills programmes into primary and secondary school curricula has gained increasing prominence in global educational policy over the past two decades. This research investigated the factors that influence how a particular approach to the development of thinking skills adopted in the Northern Ireland (NI) context is interpreted and implemented by teachers in early years classrooms. The Thinking Skills and Personal Capabilities Framework (TSPC) was introduced as a statutory component of the revised NI curriculum in 2007 and this study explores its enactment through the perceptions of key groups that interface with the policy from a range of different contexts: teachers and Head Teachers, Curriculum Advisory and Support staff, university academics and Initial Teacher Education staff. The study adopted an interpretive approach, utilising interviews with members of these key groups to explore their perceptions of the factors that influence the effective and consistent implementation of the TSPC and to explain possible reasons why it has embedded effectively in some NI primary schools and not in others. In addition to interviews, policy analysis of key texts that shape teachers’ approaches to the TSPC was undertaken using a framework based on Fairclough’s three-dimensional approach to critical discourse analysis. The purpose of this analysis was to explore the connection between the discourses used in these texts, and the extent to which the ideological cues that underpin them exert an influence on how teachers interpret and implement thinking skills in their practice. The study also explored how human capital theory, and an ecological approach to the enactment of the TSPC based on Bronfenbrenner’s Ecological Systems Model (1979), provide different frameworks for understanding how the TSPC is interpreted and implemented in practice, with particular reference to Northern Ireland. The findings suggest that there are a number of significant factors that both enable and constrain the effective implementation of the TSPC across schools. The region’s political, social and historical context was viewed by participants as playing a key role in how policy reforms are interpreted and implemented. School leaders can play a central role in mediating the impact of these reforms to ensure that they are implemented in ways that take account of diverse and specific school contexts. From the perspective of participants, Head Teachers and school leaders also play a pivotal role in nurturing teachers’ professional learning, skill, and motivation in the teaching of thinking skills. Consistent opportunities for professional development, including collaborative working, and sharing of practice, both in and beyond the school, was viewed as the primary means of ensuring the development of a shared vision and language about thinking skills, and participants agreed that this is central to its consistent implementation across all schools. Analysis of the participants’ understandings of the purpose of teaching thinking skills, and the aims of education more broadly, highlighted a tension between approaches to education that focus on children’s holistic development, and policy discourses, especially those related to Human Capital Theory that view education as a mechanism for achieving economic goals. The influence of these discourses across a range of public policy areas, as well as the disconnect between what participants and policy-makers viewed as the purpose of thinking, was highlighted in the analysis. For participants, the integration of thinking skills into the curriculum was about developing autonomy, criticality, and independence in children’s thinking, whereas policy-makers viewed it from a human capital perspective and strongly linked it to discourses of ‘lifelong learning’, ‘employability’ and ‘skill’. From the perspective of participants, the findings indicate that for policy makers in Northern Ireland to better understand how to embed the TSPC as a core component of the curriculum in all schools a number of cross-system actions need to be undertaken. These include a baseline review of the impact of the TSPC in the ten years since its inception as part of the comprehensive review of education announced by the Minister for Education in January 2021. The data suggests that this review should ensure that teachers and school leaders are central to its design and approach and that it is fully inclusive of all schools in Northern Ireland that sit within its scope. A return to more localised support and advice services with a coordinated approach to the development of the TSPC in all schools was also viewed by participants as essential to its development and embedding in all schools. A more coordinated, multi-disciplinary approach to implementation would, it was argued, ensure that ongoing professional learning in thinking skills was accessible, including the establishment of more strategic, collaborative partnerships with higher education, ITE and Inspection Services. This changed focus, I conclude, requires a move away from human capital and sector specific approaches to the consistent development of thinking skills programmes in all Northern Ireland schools. Recommendations also centre on future policy reforms that are inclusive and that give teachers their professional place as the primary implementers for the development of thinking skills programmes in schools

    The Digital Continent:Placing Africa in Planetary Networks of Work

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    Only ten years ago, there were more internet users in countries like France or Germany than in all of Africa put together. But much has changed in a decade. The year 2018 marks the first year in human history in which a majority of the world’s population are now connected to the internet. This mass connectivity means that we have an internet that no longer connects only the world’s wealthy. Workers from Lagos to Johannesburg to Nairobi and everywhere in between can now apply for and carry out jobs coming from clients who themselves can be located anywhere in the world. Digital outsourcing firms can now also set up operations in the most unlikely of places in order to tap into hitherto disconnected labour forces. With CEOs in the Global North proclaiming that ‘location is a thing of the past’ (Upwork, 2018), and governments and civil society in Africa promising to create millions of jobs on the continent, the book asks what this ‘new world of digital work’ means to the lives of African workers. It draws from a year-long fieldwork in South Africa, Kenya, Nigeria, Ghana, and Uganda, with over 200 interviews with participants including gig workers, call and contact centre workers, self-employed freelancers, small-business owners, government officials, labour union officials, and industry experts. Focusing on both platform-based remote work and call and contact centre work, the book examines the job quality implications of digital work for the lives and livelihoods of African workers

    Breaking Ub with Leishmania mexicana: a ubiquitin activating enzyme as a novel therapeutic target for leishmaniasis

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    Leishmaniasis is a neglected tropical disease, which inflicts a variety of gruesome pathologies on humans. The number of individuals afflicted with leishmaniasis is thought to vary between 0.7 and 1.2 million annually, of whom it is estimated that 20 to 40 thousand die. This problem is exemplary of inequality in healthcare – current leishmaniasis treatments are inadequate due to toxicity, cost, and ineffectiveness, so there is an urgent need for improved chemotherapies. Ubiquitination is a biochemical pathway that has received attention in cancer research. It is the process of adding the ubiquitin protein as a post-translational modification to substrate proteins, using an enzymatic cascade comprised of enzymes termed E1s, E2s, and E3s. Ubiquitination can lead to degradation of substrate proteins, or otherwise modulate their function. As the name suggests, this modification can be found across eukaryotic cell biology. As such, interfering with ubiquitination may interfere with essential biological processes, which means ubiquitination may present a new therapeutic target for leishmaniasis. Before ubiquitination inhibitors can be designed, components of the ubiquitination system must be identified. To this end, a bioinformatic screening campaign employed BLASTs and hidden Markov models, using characterised orthologs from model organisms as bait, to screen publicly-available Leishmania mexicana genome sequence databases, searching for genes encoding putative E1s, E2s, and E3s. To confirm some of these identifications on a protein level, activity-based probes, protein pulldowns, and mass spectrometry were used. Using an activity-based probe that emulates the structure of adenylated ubiquitin, E1s were identified, and their relative abundance quantified. A chemical crosslinker extended the reach of this probe, allowing the identification of an E2 (LmxM.33.0900). It is noted that L. mexicana has two E1s – unusual for a single celled organism. Of these E1s, LmxM.34.3060 was considerably more abundant than LmxM.23.0550 in both major life cycle stages of the in vitro Leishmania cultures. It is important to describe the wider context of these enzymes – what is their interactome, what are their substrates? To study this, CRISPR was used to fuse a proximity-based labelling system, BioID, on genes of interest – LmxM.34.3060 and LmxM.33.0900. The E2 (LmxM.33.0900) was shown to interact with the E1 (LmxM.34.3060), validating the results from the activity-based probe and crosslinker experiments. Due to sequence homology with characterised orthologs, the E2 was hypothesised to function in the endoplasmic reticulum degradation pathway. Immunoprecipitations of a ubiquitin motif, diglycine, were conducted with a view to gathering information on the substrates of ubiquitin. Anti-diglycine peptides included some of those identified by BioID. Experiments examining ubiquitin’s role in the DNA damage response were also initiated, as were improvements to the proximity-based labelling system, however these were not followed to completion due to a lack of time and resources. To examine the possibility of finding novel drug targets in the ubiquitination cascade, recombinant proteins were expressed. LmxM.34.3060 was expressed in a functional form, while a putative SUMO E2 (LmxM.02.0390) was functional after refolding. Expressed LmxM.33.0900 was not functional and could not be refolded into a functional form. Drug assays were conducted on LmxM.34.3060, which found an inhibitor of the human ortholog, TAK-243, to be 20-fold less effective against the Leishmania enzyme. Additional assays found an inhibitor that was 50-fold more effective at inhibiting the Leishmania enzyme as opposed to its human equivalent - 5'O-sulfamoyl adenosine. Furthermore, a new mechanism of action, inhibiting the E1, for was identified for drugs previously characterised to inhibit protein synthesis. LmxM.34.3060 underwent biophysical characterisation, with structural information obtained using SAXS and protein crystallography. A crystal structure was solved to 3.1 Å, with the in-solution SAXS structure complementary to this. TAK-243 was modelled into the LmxM.34.3060 structure and clashes were predicted, concurring with TAK-243’s reduced efficacy against the Leishmania enzyme in the drug assays. This project aimed to characterise the potential of an understudied biochemical system to provide novel therapeutic targets for a neglected tropical pathogen. To achieve this aim it presents the identifications of two E1s, an interactome, a structure, and a potent, selective inhibitor of a Leishmania ubiquitin activating enzyme
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