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Anti-natalist ethics and their broader moral significance
Full text linkThis thesis explores key moral questions that are raised by anti-natalism. Collectively, thus far, most research on anti-natalism has focused on the arguments themselves, whether they are sound or unsound in demonstrating the moral impermissibility of reproducing. In this thesis, I explore how anti-natalism relates to our lives in other areas of moral significance, such as how anti-natalism relates to the value of death, the environment, food ethics (veganism), and extinction.
These explorations are important because, first, they can affect the viability of any anti-natalist theory. That is, even if we suppose that an anti-natalist theory is sound, how such a theory relates to, for example, the value of death or how one ought to value the environment can provide further reasons to accept or reject anti-natalism. Moreover, besides affecting the viability of such anti-natalist theories, these explorations connect areas of our moral lives that are prevalent and affect who we are, how we act, and what we value.
Moreover, the thesis does not focus on anti-natalism exclusively, and anti-natalism is not always the starting point in terms of argumentation. Instead, I also explore closely related concepts, such as death, in themselves and provide further context in terms of how such concepts can relate to anti-natalist theories. Thus, all things considered, I hope that this thesis provides original insights conducive to moral philosophy
Quantifying the uncertainty and generalisability of machine learning-based virtual staining for high-throughput screening
Full text linkHigh-throughput screening (HTS) [1] with fluorescence microscopy [2] enables different biological structures within cells to be simultaneously revealed, at scale, so that drug compound effects can be quantified. Fluorescence microscopy, however, is expensive, time-consuming [3] and can negatively impact cell samples [4]. While label-free microscopy [5, 6], is cost-effective and widely available, the biological information is not as easily accessible compared to when using fluorescence microscopy because of a lack of intrinsic optical contrast between cellular components. Virtual staining via image-to-image translation [4, 7–12] – a machine learning (ML) technique – aims to translate unstained label-free microscopy images into multiple fluorescent microscopy images to obtain the benefits of fluorescence staining without the associated costs.
Despite impressive qualitative results [4, 7–10], little is known about the feasibility of virtual staining with HTS due to the lack of quantitative, biologically meaningful evaluation metrics. HTS data is continuously being generated across different laboratory settings and new compound perturbations [1]. Despite this, existing virtual staining works [4, 7–12] have been trained and tested on images sampled from the same setting-specific training data distribution. What they have not done is evaluate the generalisability of virtual staining to never-before-seen data, sampled from a different laboratory or cell type. In light of this, we can not know whether virtual staining models trained on setting specific data can generalise to other experimental settings putting the scalability of virtual staining with HTS in doubt.
Virtual staining is an ill-posed problem; given access to a bright-field image, it is very challenging to define a single virtual staining solution. This uncertainty is expressed through the posterior distributions of possible virtual staining solutions and instance biological features given a bright-field image. Currently, very little understanding exists of how well virtual staining models can describe these posterior distributions. Furthermore, the challenge of comparing different predicted instance posterior distributions to a single target sample value from the true posterior distribution remains under-explored.
In the first part of this thesis, we introduce the motivations and core questions this work will address. We formally explore the use of HTS with conventional fluorescence microscopy and different virtual staining approaches. We then provide a background of the mathematical basis of some of the core approaches to virtual staining explored within this work and how they are connected. We provide a comprehensive review of the literature around different adaptations of the core approaches to virtual staining, approaches to evaluating virtual staining and generalisation within virtual staining.
In Chapter 4 we benchmark different virtual staining approaches and present the results of a newly developed evaluation pipeline that provides biologically meaningful results.
In Chapter 5 we further utilise this pipeline and provide an extensive analysis of the generalisation performance of virtual staining models for three common generalisation tasks within HTS.
In Chapter 6 we explore the predicted instance posterior distributions of two generative modelling approaches and present a principled method for directly predicting these distributions from the bright-field image. We systematically compare the predicted instance posterior distributions of both generative modelling approaches using three newly proposed evaluation criteria and compare our findings to population metrics
Hiding in plain sight: an examination of the sexual and religious lives of bisexual 18 – 25 year olds within the Church of England, through critical document analysis of Church of England policies and reflective participant interviews
Full text linkThe relationship between bisexuality and Christianity presents a nuanced and frequently overlooked dynamic; the lived experiences of bisexual Christians are often skewed by societal misconceptions and are exacerbated by oversimplified views of sexuality. Whilst there is a growing body of research exploring the unique dynamics between bisexuality and Christianity that strives to explore the lives of those within this community, there remains a significant gap in understanding as to whether the language used in Christian policies and publications accurately reflects the realities faced by bisexual Christians. This research endeavour aims to address this gap by employing a triangulation approach of qualitative semi-structured interviews, document analysis, and a publications-focused reading task, to support understanding of lived experience. Through engaging with both the bisexual Christian community, and academics and clergy involved in the creation of Church policies and
publications, alongside an in-depth analysis of particular Church publications, both through literature-based analysis and the implementation of a reading task, it is anticipated that the findings will reveal the discrepancy between the language used in Church of England policy, and the lived experiences of bisexual individuals within Church communities.
It is hoped that this research will, whilst not presenting a definitive statement, lend support to the view that current bisexual discourse within the Church of England is outdated, and lacks an accurate representation of the contemporary experiences of this demographic. Through an analysis of the lived experience data, alongside critical discussion of the language that exists within Church policy, it is hoped that this research will shed a small yet powerful insight into feelings of wariness and a lack of affirmation, coupled with stereotypical misunderstandings and the privileges and downfalls of (in)visibility within the Church of England. Additionally, the study aims to shed light on the unique struggles of guilt and privilege encountered by bisexual individuals in relation to marriage discourse, where their voices are often marginalised and unheard. It is hoped that this study will provide a stronger voice for bisexual Christians within their communities, will offer detailed insights into the unique challenges that bisexuals face, and will ultimately encourage more effective change-making in policy and documentation, by focusing on the importance of lived experiences. This study wishes to narrow the disparity that exists between what is publicly ‘thought’, and what privately ‘is’ for the bisexual
community within the Church of England
Adhesion strength testing – An improved approach
Full text linkBackground:
Generally, the bonding of one material to another is important for function, and especially with so-called ‘adhesive dentistry’. A test with discriminatory power that mimics the clinical failure mode i.e., the failure of that bond in peel mode, has not emerged.
Objective: Develop and validate a test protocol based on 4-point bending that may be used to examine the bonding of various dental materials to a range of substrates, taking dentine, stainless steel and aluminium alloy as examples.
Methods:
An improved approach for static flexural strength of ‘adhesive’ bond to dentine based on 4-point bend was developed. Slices of coronal dentine from extracted molars (larger and more squared teeth) were prepared using a diamond blade. Bonded interface specimens were prepared by shaping the material within the respective manufacturers’ (3M ESPE, Shofu, Ivoclar Vivadent, GC Europe, DE Healthcare, Dentsply DeTrey, Septodont) stated working time using a stainless steel split mould. The support span-depth ratio for the beam was chosen to minimise shear effects and to enable failures to occur in the maximum tension surface due to bending moments only. The new method was used to measure quantitatively the adhesive bond potential of various systems, i.e., zinc phosphate cement, zinc polycarboxylate cement, glass ionomer cement, calcium silicate cement, total-etch resin systems, and a self-adhesive resin cement. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) were used to examine fracture surfaces, identify failure origins, and confirm failure mode.
Results:
Symmetrical 4-point bending was found to be a valid approach, compared with currently employed test methods, for the characterization of ‘adhesive’ and cohesive strengths. The test set up employed a relevant mode of loading with a subsequent failure pattern initiating at the tooth-restoration interface.
Conclusion:
With reproducibility, discriminatory power, economy with regard to substrates, and a straightforward robust process, the method is adaptable to many systems
Actinopterygian and chondrichthyan palaeocommunity responses to early Cenozoic global warming
Full text linkClimate change in the geological past can be a valuable tool for assessing the context of current and future global warming, with numerous warming events punctuating the early Paleogene (~48 to 66 Ma) greenhouse world considered partially analogous to today’s anthropogenic climate change. The Palaeocene-Eocene Thermal Maximum (PETM, ~56 Ma), Early Eocene Climate Optimum (EECO, ~49 to 53 Ma) and Middle Eocene Climate Optimum (MECO, ~40.1 to 40.5 Ma) are three key intervals of environmental change, during which atmospheric carbon dioxide peaked at levels akin to predictions by the Intergovernmental Panel on Climate Change for 2100 under worst-case emissions scenarios. Consequently, the interplay of the atmosphere and ocean in response to global warming and environmental change is important to understand the ecological and biological impacts, with inferences on how this may translate to the modern day and the future.
Palaeontology is invaluable for exploring biotic responses to such climate events as fossils can indicate the abundance and diversity of palaeocommunities through time. To understand the response of the marine realm to early Paleogene climate perturbations, actinopterygian (bony fish) and chondrichthyan (shark) fossils are important as they comprised over half of all marine vertebrate diversity at this time, and fish radiated due to expansion of ecological niches after the end-Cretaceous mass extinction. Whilst complete articulated body fossils of fish and sharks are relatively rare, microfossils from them are considerably more abundant, with the possibility to generate higher temporal and spatial resolution records. Important microfossils are otoliths (calcareous components in vertebrate inner ears), teeth and denticles (tooth-like scales external of cartilaginous sharks), collectively termed ichthyoliths, which enable reconstruction of fish and shark productivity and diversity.
Museum collections provide an important but often underutilised resource for palaeobiodiversity studies, partly due to poor data accessibility (particularly digitally) but also because the value of such collections in large-scale analyses is highly dependent upon the quality of the information associated with them. Here, the potential of the largest public early Eocene (~48 to 56 Ma) actinopterygian otolith collection in the United Kingdom (housed in the Natural History Museum, London) is evaluated to reconstruct the shallow marine bony fish palaeocommunity from southern England and test if there is a true radiation post-Cretaceous or if sampling and museum curatorial biases are impacting the signal.
Turning to the response of deeper marine fish and shark palaeocommunities to climate change, fish teeth and shark denticles extracted from Indian and South Atlantic Ocean cores are assessed to understand productivity and diversity responses to short-lived PETM warming, long-term EECO warming and intermediate MECO warming. Whilst fish productivity is often elevated during warming intervals, diversity responses fluctuate between these three climate events. Ultimately, the rate of environmental change over which the onset and termination of each event occurs is a major determinant of the ability of fish, in particular, to adapt to the ambient environmental perturbations. As such, fish turnover associated with the rapid onset of the PETM and termination of the MECO highlight the potential ‘short-term’ instability of fish communities responding to modern climate change, but the ‘longer-term’ ability to equilibrate for a thriving marine ecosystem in the future
Disorientalism: the counternarratives of Jim Crace
Full text linkThe primary objective of this study is to provide an analysis of selected prose fiction by Jim Crace and present the work as political commentary. The intention is to highlight this generally overlooked aspect of Crace’s first novels by investigating the development of his fabulist methodology. This interpretation is then employed to inform readings of further works with the additional layer of meaning as symbolic allegory. As a result, this investigation will refute criticisms of Crace’s work being removed from political discourse.
The study defines Crace’s individual mode of defamiliarization as disorientalism to emphasise the critical concept of Crace’s strategic mode. As this study illustrates, Crace initially developed his methodology to counter misrepresentation of African countries in literary fiction and subsequently applied the mode to critique the dominance of neoliberal ideology with counternarratives.
The study begins with a brief biographical overview and summary of literary characteristics within the context of contemporary British fiction, as well as providing definitions of key terms. This leads into the second chapter examining political inspiration and motivations for Crace’s transition from journalistic writing to a parabolic fabulism informed by magical realism, while the following section assesses Crace’s debut novel, Continent, as allegory rather than abstract invention. These first sections also provide a theoretical framework and literature review. Further chapters employ close readings to investigate the novels The Gift of Stones, Arcadia, and Quarantine as sociopolitical commentary of post-Thatcherite urban Britain and counternarrative to the cultural shift toward globalized neoliberalism. The next chapters continue this analysis with close readings of Crace’s more refined mode of critical mythopoeia for The Pesthouse and Harvest to frame these works as contemporary fables rather than dystopian and historical genre fictions respectively, as they are often presented and critiqued accordingly. A final reading of the more explicitly allegorical The Melody further illustrates the political credo informing Crace’s fabulism and explains the disorientalist method as a socially conscious form of symbolism.
These readings seek to address issues of literary misrepresentation and cultural appropriation prominent in contemporary discourse by championing a single author’s personal strategy for ethically addressing global themes of exploitation, inequality, and dehumanisation beyond his own ethnic and social background
Regulation of CD4 T cell Il10 transcription and TCR signal strength in tolerance and cancer
Full text linkT cells secrete IFNγ, which has a key role in activating macrophages and enhancing antigen presentation through increasing MHC class I and II expression. The inflammatory response is counteracted by negative regulators of the immune system, which limit damage to self by excessive immune responses, including via FOXP3 CD4 Tregs and Type 1 Regulatory CD4 T cells (Tr1 cells). These induce negative regulation through PD-1, CTLA-4 and TIGIT, for example, but also through expression of immunosuppressive cytokines such as interleukin-10.
Previously published data showed that immunisation with modified myelin basic protein ([4Y]-MBP) peptide to transgenic Tg4 T cell Receptor (TCR) mice that specifically and uniquely recognise MBP led to rapid induction of transcription in a CD4 T cell subset. Here we sought to define and modulate T cell early development.
We found that a high dose of [4Y]-MBP peptide rapidly induced a Tr1-like phenotype in expressing CD4 T cells, and that emergence of Tr1-like cells was preceded by Ifng transcription. Via APCs, anti-IFNγ strongly reduced CD4 Il10 transcription, strong TCR signalling, and Tr1-like markers, an effect that was additive with anti-IL-27. In complementary experiments, we explored the role of IFNγ in modulating T cell transcription during an anti-tumour immune response. Anti-IFNγ increased tumour burden in mice, reducing their survival, which was associated with reduced CD4 T cell transcription and TCR signalling strength. Changes in Treg transcription through IFNγ neutralisation correlated with reduced activation of tumour associated macrophages. These data reveal a regulatory feedback role for IFNγ and TCR signalling strength in modulating Il10 transcription in two distinct subsets of regulatory T cells under a variety of immune environments
A qualitative exploration of the use and implementation of the ATTEND Framework within schools.
Full text linkThe prevalence and recent increase in absenteeism is widely discussed in the literature. The ATTEND Framework (Tobias, 2021) is a tool that has been developed to support with identifying barriers to attendance that links with recommended strategies to support. This thesis investigates the usefulness of the ATTEND Framework from the perspectives of those that have completed it. Adopting a
multiple case study design, the parents and school staff across three case studies were included in this research. Through the use of qualitative methods, semi�structured interviews were used to gain an understanding of the experiences of each individual both during and after the completion of the framework. Each case study adopted a slightly different approach to completion and each reported varying degrees of success. The findings of this research indicate that the ATTEND Framework is a useful tool for identifying barriers to attendance and developing suitable strategies to support. However, the need for this to be underpinned by good relationships and a collaborative approach is highlighted as being essential for its success. In addition, early use of the framework was also highlighted as a factor for the success of its implementation
Catherine Osler and the development of the political and social role of women in Birmingham 1868 to 1924
Full text linkThis thesis explores the development of women’s political and civic role in Birmingham in the last quarter of the nineteenth century and the first two decades of the twentieth through a study of the life of Catherine Courtauld Osler (1854-1924). Osler was an affluent middle-class woman from a radical Liberal Unitarian background who became both the President of the Women’s Section of the Birmingham Liberal Association and the President of the Birmingham Women’s Suffrage Society. She came to Birmingham in 1868 and lived in the city for the rest of her life. In 1873, she married Alfred Osler, a prominent Liberal activist and businessman. Her family connections in London enabled her to meet eminent and influential Liberal thinkers and activists including John Stuart Mill. As the mother of five children, Osler also led an active private life in addition to her public activities and engaged in extensive philanthropic work. This thesis will consider how her domestic life evidenced changes in women’s role as wives and mothers during the period. She campaigned for women’s emancipation for some fifty years and lived to witness the granting of partial suffrage for women in 1918. Her adopted city honoured her achievements by the commission of her portrait for the Museum and Art Gallery and by the conferral of an Honorary MA degree by the University of Birmingham. Although Osler is now a little-remembered figure, a primary aim of this study is to re-establish her as a major figure in the history of the city. In the course of this research, the first academic study of Osler, it became evident that the existing historiography relating to activist women in Birmingham is sparse. Concentrated exploration of Osler’s life enables an assessment of the extent of her individual success in overcoming male prejudice for the benefit of her sex. The thesis also questions the extent to which Liberal politicians in the city assisted women in their quest for political and civic recognition, particularly after the split in the Liberal Party in 1888 following the defeat of the Irish Home Rule Bill. It explores the nature of Birmingham politics and society, particularly Osler’s relationship with Unionist politicians such as Joseph Chamberlain whom Osler opposed over women’s suffrage, Irish Home Rule, the Boer War and Colonialism. This thesis also examines Osler’s success as a suffragist in attracting support for her cause in the twentieth century against the competition of the more militant suffragettes. By following Osler’s activities this thesis enables the extent of the change in the public position of women during the period to be better evaluated and understood.
The writing of this study has been made possible through the provision by Osler’s descendants of much original source material in the form of her memories and journals - documents that have not previously been accessible for historical consideration. Reviewed in tandem with newspaper reports and with archive material relating to the organisations with which Osler was associated, these sources have thrown fresh light on her activities and interactions with other family members and activists, both male and female. Aside from issues relating to women’s rights, the new material provided by Osler’s family has enabled a deeper and more nuanced understanding of her interest in both the Boer and First World Wars, her growing anti-war stance in general, her pacifist leanings and her opposition to censorship. Taken together with all other material presented, this study breaks new ground in the study of Osler in Birmingham during a period of great political and social change
Mechanisms of platelet activation in vaccine-induced thrombotic thrombocytopenia and heparin-induced thrombocytopenia
Full text linkVaccine-induced immune thrombocytopenia with thrombosis (VITT) and heparin-induced thrombocytopenia (HIT) are disorders mediated by antibodies against platelet factor 4 (PF4), an abundant, positively charged, platelet-derived chemokine. In VITT, immune complexes consisting of PF4 and anti-PF4 antibodies form and activate platelets through the low-affinity immune receptor FcγRIIA whereas in HIT, the immune complexes also contain the anticoagulant heparin. Both heparin and PF4 are known to activate platelets independently. Heparin acts through platelet endothelial aggregation receptor 1 (PEAR1) but the mechanism of activation by PF4 is unknown.
The aims of this thesis were therefore to firstly ascertain the mechanism of platelet activation by PF4 and then to investigate whether PF4 and heparin play a role in directly activating platelets in VITT and HIT. A third, separate aim was to investigate endothelial activation in VITT and HIT to elucidate any differences that may contribute to the common occurrence of cerebral venous sinus thrombosis in VITT but not in HIT.
Herein, PF4 is shown to lead to platelet aggregation, α-granule release, and spreading in a dose-dependent manner starting at 10 μg/mL (1.28 μM). This occurs through binding to the thrombopoietin receptor c-Mpl and signalling through Janus kinase 2 (JAK2), a process that can be blocked by the JAK2 inhibitor, ruxolitinib, and a c-Mpl blocking antibody. Next, it was shown that blockade of the PF4-c-Mpl interaction and downstream signalling could reduce platelet aggregation to sera and isolated immunoglobulin G from patients with VITT. There was no such clear effect with HIT sera and antibodies. However, blockade of the heparin-PEAR1 interaction with an inhibitory anti-PEAR1 nanobody did lead to reduction in platelet aggregation and α-granule release to HIT sera and antibodies. These findings may have therapeutic relevance when developing targeted therapies for use in these disorders. Endothelial cell work showed no direct induction of endothelial activation by VITT or HIT sera or antibodies, nor did they lead to platelet recruitment
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