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Transposition of ISAba13 in Acinetobacter baumannii AB5075
Get PDFAcinetobacter baumannii is a critical priority category pathogen for which new drug treatments are urgently required. A major cause of nosocomial infection, A. baumannii is able to colonise and persist for long periods of time in hospital environments. Here we have characterised a novel colony variant of the well-studied, highly virulent, and drug-resistant, model strain AB5075.
We determined the biological mechanism for formation of these rare colonies; insertion sequence ISAba13 disrupts gene gtr52 of the capsule synthesis locus. As a consequence, there are profound phenotypic effects. We also probed the effects of ISAba13 on transcription of adjacently located genes. This led to the discovery of the first bidirectional promoter within a bacterial insertion sequence.
Finally, we developed a method termed native Tn-Seq to map genome-wide natural insertions of ISAba13 across a population of AB5075. This highlighted a propensity for insertion into AT-rich DNA, and a pivotal role for the chromosome folding protein H-NS in directing transposition to these regions. We show that the ability of H-NS to bridge DNA is required for directing these transposition events. To our knowledge, this is the first example of a bacterium dictating its own downstream evolution by manipulating patterns of transposition
Explainability requirement in blockchain smart contracts: a human-centred approach
Get PDFBlockchain smart contracts have emerged as a transformative technology, enabling the automation and execution of contractual agreements. These self-executing software programs leverage blockchain’s distributed and immutable nature to eliminate the need for third-party intermediaries. However, this new paradigm of automation and authority introduces a complex environment with technical intricacies that users are expected to understand and trust. The irreversible nature of blockchain decisions exacerbates these issues, as any mistake or misuse cannot be rectified. Current smart contract designs often neglect human-centric approaches and the exploration of trustworthiness characteristics, such as explainability. Explainability, a renowned requirement in Explainable Artificial Intelligence (XAI) aimed at enhancing human understandability, transparency and trust, has yet to be thoroughly examined in the context of smart contracts. A noticeable gap exists in the literature concerning the early development of explainability requirements, including established methods and frameworks for addressing requirements analysis phases, design principles, evaluation of their necessity and trade-offs. Therefore, this thesis aims to advance the field of blockchain smart contract systems by introducing explainability as a design concern, fundamentally prompting requirements engineers and designers to cater to this concern during the early development phases. Specifically, we provide guidelines for explainability requirements analysis, addressing what, why, when and to whom to explain. We propose design principles for integrating explainability into the early stages of development. To tailor explainability further, we propose a human-centred framework for determining information requirements in smart contract explanations, utilising situational awareness theories to address the ‘what to explain’ aspect. Additionally, we present ‘explainability purposes’ as an integral resource in evaluating and designing explainability. Our approach includes a novel evaluation framework inspired by the metacognitive explanation-based theory of surprise, addressing the ‘why to explain’ aspect.
The proposed approaches have been evaluated through qualitative validations and expert feedback. We have illustrated the added value and constraints of explainability requirements in smart contracts by presenting case studies drawn from literature, industry scenarios and real-world projects. This study informs requirements engineers and designers regarding how to elicit, design and evaluate the need for explainability requirements, contributing to the advancement of the early development of smart contracts
Impact analysis of spatial-temporal resolution on high penetration of renewable energy
Get PDFThe power generation of variable renewable energy (VRE) is largely affected by natural environmental factors, such as wind speed and solar irradiance, which can cause great variability, fluctuation, and intermittency, and these characteristics will become more severe as renewable energy penetration increases. These power variations will bring operational challenges to the instantaneous balance, and will also increase in intraday trading frequency, and increase re-scheduling operation costs in the electricity market. Therefore, increasing penetration of VRE will cause fundamental and structural changes to traditional power system operation regimes. This doctoral study focuses on the investigation of increasing spatial-temporal resolution in high-penetration renewable energy systems and evaluates their impact on electricity market operations, hence providing scientific insights into the electricity market reform.
This thesis carries out a literature review and it is found: there is a lack of theoretical research on the impact of power fluctuation characteristics on the day-ahead power curve and the real-time power curve; there is a lack of quantitative scientific evaluation of the entire electricity market at different temporal granularity; Current research on increasing spatial granularity generally focuses on the regional and node electricity prices, but rarely mentions the increase of spatial network granularity, and lacks a scientific model for building spatial grid networks.
In terms of power fluctuation, this thesis proposes metrics including power incremental statistics, coefficient of variation, and peak power duration to characterize the power variability characteristics. Based on these metrics, the mathematical relationship between these variations and net-load power curves, and real-time power imbalance curves are analysed. It is found that power variability will directly affect net-load power curves and the power gradient will affect the real-time power imbalance. For example, the solar power variability characteristics will cause the net-load power curve to look like a duck curve, while real-time power imbalance to look like a butterfly curve.
In terms of increasing temporal resolution reform in electricity markets, this thesis proposes an evaluation method for the electricity market at different time granularity, including ex-ante real-time power deviation prediction; real-time power scheduling operation and clearing; and ex-post power deviation settlement. Based on this evaluation model proposed, this thesis provides strong evidence that the higher the time granularity, the power step changes and the real-time power deviation quantities are smaller, and vice versa. Increasing the time granularity from 30 to 5 minutes will reduce the balancing cost by nearly half and reduce the power step amplitude standard deviation by nearly 80%.
In regarding the increasing spatial resolution for electricity market reform, including the space granularity of renewable generation units and the space granularity of the subnetworks, the thesis proposes the stochastic energy network theory to characterize the supply-demand adaptation balance index (SDABI) and further proposes a subnetwork networking method to evaluate the impact of increasing space granularity on reducing power system operation costs, power flow losses, and power transmission network congestion.
In summary, this doctoral thesis for the first time provides scientific evidence to support the worldwide power market reform of the increasing spatial-temporal resolution with massive renewable energy integration systems
Exploring educational psychologists’ experiences of culturally competent consultation
Get PDFProfessional bodies for educational psychology emphasise that educational psychologists and trainee educational psychologists consider culture within their practice and be anti-oppressive. Consultation is often used by educational psychologists as a conversational tool to gather information, problem solve and collaborate with consultees to create the next steps (Nolan and Moreland 2014). This research uses an exploratory case study design to investigate educational psychologists’ experiences of culturally competent practice during consultation, within the West Midlands. Semi-structured individual interviews were used to collect data, the data was analysed using reflective thematic analysis (Braun & Clarke 2019).
The results of the research suggest that participants understand the importance of considering culture within consultation; however, require support to develop their confidence and skill level to demonstrate culturally competent consultation. Participants shared that further input during training exploring models and theories while also, making culturally competent consultation a service priority would develop culturally competent consultation within educational psychology practice. Barriers to culturally competent consultation were also identified including fear of offending, being perceived as “racist,” and not knowing how to approach culturally competent consultation. A key learning point from the research was the need to broaden the way educational psychologists consider culture, as ethnicity and other observable markers dominated discussions
B Cells selection in the Germinal Centre
Get PDFVaccination triggers the long-term production of high-affinity antibodies. Germinal centers (GCs) are sites within lymphoid tissues where B cells undergo clonal expansion and affinity maturation during T cell-dependent antibody responses. However, the regulation of affinity�matured B cell selection within GCs remains poorly understood. In this study, we examined the roles of antibody secretion and feedback in GC regulation using various mouse models: those incapable of secreting IgM or undergoing class-switching (IgMi), those unable to undergo affinity maturation or class-switching (AIDKO), and those restricted to producing and secreting IgG1 antibodies (IgG1M). Following immunisation with a T cell-dependent (TD) antigen, IgMi and AIDKO mice exhibited an increased percentage of GC B cells. In contrast, the percentage of GC B cells in IgG1M mice was reduced compared to wild-type mice. Introducing antibody feedback by injecting antigen-specific IgM into IgMi or AIDKO mice slightly reduced the proportion of GC B cells. It was shown that more stringent antibody feedback strongly inhibits B-Tfh cell interactions. The Nr4a3-Tocky reporter system is unstable fluorescent protein that changes fluorescence from blue to red and can record the timing of TCR signalling. It was utilized to track interactions between GC B cells and Tfh cells in mice with altered B cell receptors (IgMg1 and IgG1M mice) or absence of affinity maturation (AIDKO mice). IgMg1 enhances interaction with and activation of Tfh cells, also reflected by higher Tfh frequencies. Additionally, testing expression of Nr4a3-blue and red forms of the reporter reveals an increase in newly activated Tfh cells in IgMg1 and IgG1M versus wildtype mice after immunisation. There was no change in Nr4a3-reporter expression in Tfh cells of AID-deficient mice, indicating unaffected Tfh cell activation in AID-deficient GCs. This work gives insight, by using mouse models with altered antibody feedback, into how IgM and IgG1 antibody secretion shapes GC developments and how altering BCR isotypes and signalling regulates Tfh cell activity through antigen presentation within the GC
Multiscale topological analysis for mapping molecular environments and dynamics
Get PDFModern fluorescence microscopy techniques can visualise biological samples from micro- to nano-scale resolutions. Conventional microscopy produces images of cellular structures, while single molecule localisation microscopy (SMLM) localises individual molecules, which are represented as spatial or marked point pattern data. Depending on the imaging target and modality, the data arising from fluorescence microscopy can vary in architecture and present features with irregular or unpredictable geometries, which can be challenging to quantify. Topological data analysis is invariant of geometry and lends itself well to this form of feature extraction, but is yet to see widespread adaptation in quantifying biophysical properties of cellular structures. The cell plasma membrane is of particular interest, as the dynamic reorganisation of transmembrane proteins plays a crucial role in regulating cell signalling. Dysfunction in this process is associated with several human disorders,
such as autoimmune diseases and cancer. Further, it is hypothesised that this reorganisation is influenced by the biophysical properties of the membrane, such as lipid composition. As such, this thesis concerns the development of novel topological data analysis techniques for feature extraction in image and point pattern data, with an emphasis on investigating membrane properties across acquisition scales. For conventional fluorescence microscopy, we present a topological image analysis tool (TOBLERONE) for cell and organelle segmentation. Then, we produce a framework for agent-based modelling of molecular aggregation on the plasma membrane (ASMODEUS), which simulates transmembrane protein dynamics. Furthermore, we introduce a software package (PLASMA) for partitioning marked point patterns and identify nano-scale lipid heterogeneity in RAMA27 SMLM data. These techniques may yield a promising avenue for mapping multiscale membrane properties
Low mood in rare genetic syndromes associated with intellectual disability
Get PDFThis thesis contains four chapters. The first chapter is a literature review that discusses a systematic review and meta-analysis on the prevalence of depression in genetic syndromes associated with intellectual disability. The pooled prevalence estimates of depression are reported in four genetic syndromes where there were five or more studies that reported the depression prevalence. The pooled prevalence rates ranged from 9% in Williams syndrome to 13% in 22q11.2 deletion syndrome. The methodological quality of studies is reported and the need for further research reporting the prevalence of depression in genetic syndromes is highlighted.
The second chapter describes an empirical research project on correlates and predictors of low mood in three genetic syndromes associated with intellectual disability: Cornelia de Lange syndrome; fragile X syndrome; and Rubinstein-Taybi syndrome. The study found differences in the correlates and predictors of low mood in each syndrome group, suggesting there might be syndrome specific pathways to low mood. The clinical implications of understanding correlates of low mood in people with genetic syndromes are discussed.
The third and fourth chapters are two press releases and provide a summary of the literature review and the empirical research paper, respectively
Dita goes to Disneyland: aesthetics of power and play in contemporary pin-up culture
Get PDFVisual depictions of the human body engaging in beauty and glamour praxis serve as commentary on social mores, gender roles, and even political and economic power. This thesis is concerned with how beauty and glamour praxis interrogate, destabilise, and renegotiate assumptions about feminine bodies in popular culture across a variety of settings. My methodological approach comprises Michel Foucault’s Technologies of the Self, Johan Huizinga’s Characteristics of Play, and my own criteria for evaluating the effects of beauty praxis which I have termed Vectors of Glamour. This framework is used to evaluate contemporary pin-up culture as exemplified by Dita Von Teese, social media as a vehicle for the production and consumption of women’s aesthetic labour, and the role of Disney parks as loci of beauty praxis. Dita Von Teese’s corpus of work is characterised by normative femininity and the promotion of a glamourous, beauty-centred lifestyle. Her public persona reflects hegemonic ideals of feminine beauty. The use of social media to showcase pin-up imagery alongside other forms of women’s aesthetic labour relies upon the false promise of affective empowerment. The pursuit of affective empowerment exploits women’s labour in social media by perpetuating patriarchal economic and social systems. Disney parks are liminal zones that occupy a space between the magical and the mundane. The semiotics of luxury are embedded in the Disney parks experience and visitors engage in various forms of beauty and glamour praxis inside these liminal zones. The three case studies are further linked by nostalgia as a capitalist tool. Broadly, these case studies are situated within the discursive contexts of feminist thought, media studies, and critical tourism
Exploring mycobacterium tuberculosis cell envelope: studying proteins and lipids using styrene maleic acid polymer
Get PDFIn 2022, tuberculosis TB caused 1.3 million deaths with nearly 10 million new cases reported, emphasizing the urgent need for new drugs targeting different pathways. The cell envelope of Mycobacterium tuberculosis is an excellent target for novel therapeutics due to its complex architecture, vital for pathogenicity, virulence, and drug resistance. Precise knowledge of molecular interactions on the M. tuberculosis envelope surface is key to identifying crucial components. Current analytical methods involve harsh organic solvents that don't selectively extract outer envelope components. Polymer nano-encapsulation techniques offer promise in studying membrane proteins. Amphipathic polymers like Styrene Maleic Acid (SMA) have been extensively used to directly solubilize proteins and lipids from the cytoplasmic membrane via SMA Lipid Particles (SMALPs).
This study presents a protocol for solubilizing and purifying three complexes of an ATP-binding protein ABC transporter from Mycobacterium tuberculosis, predicted to be involved in drug transport as an efflux system. Additionally, this study demonstrates that SMALPs selectively extract peripheral molecules from the cell envelope of mycobacteria. Using [14 C]-uniformly labelled lipids, we show that SMA can extract complex molecules like glycolipids (trehalose monomycolate, trehalose dimycolate, and glucose monomycolate), phospholipids (phosphatidyl inositol mannosides), lipoglycans (lipomannan and lipoarabinomannan), and surface-exposed proteins from the envelopes of Mycobacterium smegmatis without causing cell rupture
A home away from home: heritage, memory and identity in Latin American migrant communities of Santiago de Chile
Get PDFThis dissertation constitutes a qualitative study that delves into the identities of migrants from a micro perspective, specifically focusing on working-class Latin Americans (originating from Venezuela, Haiti, Peru, Colombia, and Argentina) who have migrated to Chile over the last two decades. Through in-depth ethnographic interviews at home, participant observation, and unstructured interviews in the neighbourhoods of Santiago Centro and Estación Central, this research captures the intimate experience of identity, memory, and heritage construction among migrants. The findings of this project highlight the advantage of entering migrant homes and, simultaneously, connecting them with surrounding public spaces in order to understand how heritage, identity and memory are intertwined with their material culture. The study involves a comprehensive examination of migrant material culture as an expression of the constant ongoing process of creating and recreating individual and collective identity in the context of migration, revealing how memory and intangible heritage related to home and neighbourhood both differ and overlap, reflecting the identity of these groups. The results indicate that the ways in which migrants perceive themselves and their community are closely connected to movement, a phenomenon that transforms their identity before and during travel, setting it apart from that of their past home-country and of Chileans’. This transformation, influenced by movement, imbues migrant objects with new meanings while coexisting with the sense of permanence suggested by nostalgic memories of their geographical and historical past. Objects and rituals within the migrant home and neighbourhood unveil systems of value and identity amongst the migrants, contributing to the formation of their cultural heritage. This materiality also reveals the gender dimension that particularly affects migrant women, who experience high levels of sexualization in Chile, revealing specific exercises of memory and identity unique to the female migrant experience. Ultimately, the material culture of migrants within the neighbourhood and home—how it is shaped, the role it plays, and how it is mapped in a city like Santiago—provides insight into the negotiation of their identity and memory.
In parallel, this study also sheds light on the negotiation of Chilean identity. Chileans confront migrant materiality with nineteenth century narratives about whiteness, exoticizing and sexualizing new migrant arrivals in recent decades. Challenging these perspectives and foregrounding the practices and experiences of the migrants themselves, this thesis successfully elucidates specific rituals, objects and settings, such as the Noche de las velitas for the Colombian community, the consumption of coffee for Venezuelans, and role of the Los Paisas supermarket for migrants in general, as elements that serve as both the result and witness of the negotiation of memory and identity. By emphasising such points of convergence in migrant constructions of identity, the study likewise challenges conventional notions of memory confined to fixed locations and underscoring how memory serves as a consistent thread amid periods of change. The manner in which migrants navigate the intricate and frequently challenging dynamics of movement and border crossing significantly shapes their integration and overall welfare within the host society. The escalation of tensions between migrants and locals, due to a rise in criminality and cultural difference in discourses on the use of public space, gives rise to novel formulations of identity, impacting recollections of national narratives and community histories. Concurrently, this transformative process alters the local landscape, prompting a demand for rethinking social policies. This study emphasises the need for a profound comprehension of these identification processes, heritage construction, and memory in order for Chile to achieve a harmonious intercultural coexistence among its inhabitants
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