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To cut a short story long: development of full-length RNA-sequencing approaches to resolve transcript-level expression dynamics in Atlantic salmon
Get PDFAtlantic salmon is a finfish of significant cultural, ecological and commercial importance, representing the United Kingdom’s main aquaculture species. There is currently a great opportunity to apply genomics to improve the sustainability, efficiency and welfare of the aquaculture sector. This includes a current drive to perform functional annotation of genomes to identify genes and other elements that shape the traits of aquaculture species. The AQUA-FAANG consortium aimed to produce comprehensive functional annotations for six key aquaculture species, including Atlantic salmon. The work in this thesis was carried out under the AQUA-FAANG umbrella.
Long-read RNA-sequencing (RNA-seq) technologies are powerful tools for functional annotation of gene expression, with great scope to resolve complex transcript variants that cannot be accurately assessed using traditional short-read methods. However, long-read RNA-seq is yet to be applied and benchmarked in many aquaculture species. As such, my work aimed to develop a robust full-length RNA-seq method in Atlantic salmon using long-read technology to examine transcriptional diversity and conduct expression analyses resolved to individual transcript variants. My work focused on two distinct study systems where extensive transcriptional regulation is applied: 1) embryogenesis, the stage of ontogeny where the adult body plan is established, and 2) immune function in response to acute viral and bacterial stimulation, improving understanding of innate immune function.
I developed a full-length RNA-seq method using the Oxford Nanopore Technologies platform involving the optimisation of total RNA extraction and mRNA isolation protocols, as well as cDNA library generation and subsequent sequencing on the PromethION device. A custom transcriptome assembly pipeline was optimised to generate the first nanopore-based long-read transcriptome for Atlantic salmon, used as the reference for further analyses reported in this Thesis. The long-read transcriptome consisted of 266,222 transcripts and 35,480 genes, with a transcript-to-gene ratio of 7.50 in comparison with 2.65 in the current Ensembl reference annotation (Ssal_v3.1). Furthermore, 60% of transcript models were deemed to contain a novel splice site, indicating that my full-length RNA-seq method captured extensive novel transcript diversity not annotated in the current reference assembly.
To examine transcript expression dynamics in response to viral and bacterial infection, I developed a differential transcript expression and usage analysis workflow, adapting existing bioinformatic tools. My analysis captured complex dynamics of alternative transcript expression for antiviral and antibacterial genes involved in the interferon-JAK/STAT pathway and proinflammatory responses, respectively. A novel fusion transcript between pctk2 and an undescribed locus containing a FIP2-like coding sequence was identified to be upregulated in both viral and bacterial response.
A separate pipeline was developed to assess transcript expression during embryogenesis using a complex timecourse design that sampled embryos at six stages (from blastulation to the late-eyed stage). Using a dimensionality reduction technique called self-organising maps (SOM), twinned with a generalised linear model and quasi-likelihood F-test method, I optimised a differential transcript expression workflow and developed an approach to examine differential transcript usage across development stages. This resulted in a comprehensive description of transcript expression throughout early development and the discovery of alternative transcript usage events within individual genes including an exon-chaining event in the coding sequence of slc25a3b, (mitochondrial phosphate carrier PiC) causing expression of unique isoforms in blastulation and late-eyed stages of development, whilst a 5’ UTR difference in the tagl gene led to different isoforms being expressed in blastulation and somitogenesis.
The full-length sequencing method captured many mono-exonic, or intronless gene and transcript models not present in the reference annotation. Over a third of these models were found to contain a complete or partial ORF indicating they are protein-coding, whilst approximately 25% of mono-exonic transcripts were found to overlap repetitive regions. Additionally, I identified a previously undescribed retrogene family found to be widespread throughout the genome.
Overall, this thesis reports approaches for robust full-length RNA-seq analysis in a non-model species with a complex genome. This work has furthered our understanding of the transcript-level expression dynamics underpinning early development and immune function in Atlantic salmon, with possible applications in aquaculture research
Identification of repurposing opportunities for uric acid-lowering drugs using integrative multi-omics and machine learning analyses
No full textINTRODUCTION:
Previous epidemiological studies have identified that elevated uric acid (UA) levels were significantly associated with increased risk of disease outcomes other than gout, such as cardiovascular diseases (CVDs). However, whether uric acid-lowering therapies could be repurposed for the treatment of CVDs remains unclear. In addition, further investigation is needed to understand possible mechanisms through which uric acid-lowering drugs affect the progression of CVDs.
AIMS:
This project aims to estimate the effects of genetically proxied uric acid-lowering treatments on the risk of CVDs by using a candidate drug repurposing strategy. Furthermore, a drug-wide repurposing strategy is employed to provide more details regarding the underlying biological mechanisms by integrating multi-class data sources.
METHODS:
First, a systematic review on the methodologies in drug repurposing using human genomic data was conducted. Then, in the candidate drug repurposing strategy, I conducted both observational phenome wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to examine the links between uric acid levels and a broad spectrum of disease outcomes. For those disease outcomes identified as significant through both approaches, I conducted trajectory analysis to investigate patterns of disease progression following elevated uric acid levels. Meanwhile, with a multivariable logistic regression model, I performed drug repurposing analysis to assess potential therapeutic benefits of uric acid-lowering medications for the associated cardiovascular outcomes. Factorial Mendelian randomization (MR) was also
carried out to detect whether there exist potential interactions between uric acid-lowering and antihypertensive therapies. Finally, in the drug-wide repurposing strategy, meta-analysis of genome wide association studies (GWASs) on CVDs was conducted to identify associated genetic variants with greater statistical power and accuracy. Based on the combined summary statistics, transcriptome wide association study (TWAS) was performed to obtain differential expressed genes, which were subsequently included in the following Connectivity Map (CMap) analysis to identify potential repurposing candidates. Six machine learning approaches including linear discriminant analysis(LDA), classification and regression trees (CART), k-nearest neighbors (kNN), support vector machines (SVM), random forest (RF) and gradient boosted method (GBM), were applied to evaluate the validity of the identified repurposing opportunities. Additionally, proteome wide association study (PWAS) and MR analysis were carried out to prioritize compounds with high evidence. Drug and disease information for these candidates was also summarized to provide clinical validation.
RESULTS:
We searched MEDLINE and EMBASE databases to identify eligible studies up until 1 May 2023, with a total of 102 studies finally included after two-step parallel screening. Three drug repurposing strategies, including Mendelian randomization, multi-omic-based drug repurposing and network-based drug repurposing were summarized based on approaches and data sources used. Then, we integrated and categorized these methodologies into candidate drug repurposing and drug-wide repurposing strategies based on the objectives of the project. First, the candidate drug repurposing strategy observed a total of 41 overlapping disease outcomes with consistent effect directions across both Obs-PheWAS and PRS-PheWAS, including 17 circulatory diseases, 7 endocrine/metabolic diseases, 7 genitourinary diseases, 2 musculoskeletal diseases, 2 digestive diseases, 2 infectious diseases, 1 respiratory disease, 1 hematopoietic disease and 1 neoplasm. Then, trajectory analysis established 595 possible disease pairs for 35 unique health outcomes that were at an increased risk with elevated uric acid levels. As a result, one cluster mainly including diseases of cardiometabolic system was identified, where the disease tree thrived after the diagnoses of obesity, type 2 diabetes, hypercholesterolemia, essential hypertension, coronary atherosclerosis and myocardial infarction, followed by anemia, pneumonia, heart failure, renal failure, and finally ended up on death. Finally, drug repurposing analysis found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR=0.96, 95%CI: 0.93, 1.00, P=0.049), congestive heart failure (OR=0.64, 95%CI: 0.42, 0.99, P=0.043), occlusion of cerebral arteries (OR=0.93, 95%CI: 0.87, 1.00, P=0.044) and peripheral vascular disease (OR=0.60, 95%CI: 0.38, 0.94, P=0.025). Furthermore, the combination of uric acid-lowering therapy with antihypertensive treatment exerted additive effects and was associated with a 6%, 8%, 8% and 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively.
The drug-wide repurposing strategy identified 270, 25, 33, 166, 30, 13 and 29 genomic loci for CVD, angina, coronary atherosclerosis, myocardial infarction (MI), valvular heart disease (VHD), venous thromboembolism (VTE) and heart failure (HF), respectively. Correspondingly, by integrating the joint effects of multiple variants within specific genes, TWAS detected 269, 32, 54, 215, 29, 17 and 40 signals representing strong evidence of shared causal variants influencing both gene expression and the cardiovascular outcomes. Based on the transcriptome files from both diseases and compounds, CMap analysis revealed 578, 78, 36 and 3 repurposing candidates for CVD, coronary atherosclerosis, MI and VHD, respectively. Machine learning methods exhibit high performance, with a receiver operating characteristic (ROC) value around 0.9, in distinguishing repurposed compounds from non-repurposed ones.
Finally, 16 compounds were prioritized based on their protein levels being significantly related to cardiovascular risk, and 7 of them have completed phase 4 clinical trials for CVDs.
CONCLUSIONS:
Our findings from candidate drug repurposing strategy support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment. Furthermore, drug-wide repurposing strategy also validated that uric acid-lowering drugs, particularly xanthine oxidase inhibitors (XOIs), are promising repurposing candidates for CVD treatment
Estimating costs and impacts of decarbonising heat in the public sector
No full textIn this report we provide evidence on the costs, opportunities and barriers of decarbonising heat in Scotland’s public sector buildings. We use modelling to estimate the capital cost of moving to clean heating systems in all public sector buildings in. We gather evidence on the opportunities offered by decarbonising Scotland’s public sector buildings as well as the barriers to doing so by assessing wider themes including practicalities and operational considerations
Indexing expectations of informativity
No full textPredictions about upcoming content are important to language processing and, among
other things, serve to facilitate communicative interactions. In studying how guesses
about upcoming content are generated, comprehenders have been found to rely on real
world knowledge, such that, for example, real-world typical content is associated with
processing ease. This preference for typical content has been found in both online and
offline tasks indexing people’s expectations about upcoming content. However, this does
not align with the production choices that speakers tend to make; speakers favour the
inclusion of non-typical, informative content and will often omit typical and thereby
easily inferable content where optional to do so.
This thesis attempts to reconcile this asymmetry between what comprehenders prefer
and what speakers do. Specifically, it posits that in addition to a comprehender’s
knowledge of the world, such as what situations and events are typical, comprehenders
also take into account speakers’ production preferences when they make guesses of
what someone will say next. To investigate this, I have developed a paradigm testing how
variations in the much-used sentence completion or Cloze task (Taylor 1953) can induce
variations in the kinds of responses participants provide. In this way, this thesis indexes
comprehenders’ expectations of the informativity of upcoming content and further
examines how fine-grained these informativity expectations are. Additionally, I posit a
method for measuring informativity that relies on five distinct measures, each of which is
intended to capture a different sense in which someone can be informative.
An expectation for upcoming content to be about real-world typical situations would
reflect an expectation in comprehenders for language use to be transparent; i.e. that
speakers tend to communicate about the world as it typically is. However, if
comprehenders are sensitive to the production preferences of speakers, they should
expect content that cooperative speakers are likely to mention, rather than simply
content that is likely to be the case in the real world; that is, they should expect filtered
language use.
Experiment I tests this prediction by manipulating the salience of the speaker across four
Cloze task conditions to see whether an increased emphasis on the speaker prompts
participants to estimate more informative content. Results show that the most speaker-salient
condition yielded the most informative sentence completions. I argue that this
reflects an increased awareness of speaker intentions and thereby speakers’ production
preference to be informative. Experiment I thus establishes that, despite the well-demonstrated
finding that comprehenders rely on real-world knowledge when
anticipating content, they also have expectations of informativity.
The following two experiments ask how malleable comprehenders’ expectations for
informativity are by testing aspects of the context that may affect comprehenders’
content estimates. Experiment II tests properties of the speaker: Participants are
familiarised with two different speakers who vary in the informativity of their utterances.
When completing utterances from each of the two speakers, comprehenders provide
more informative completions for the HIGH-INFORMATIVITY speaker compared to the LOWINFORMATIVITY
speaker. This shows that comprehenders are able to adapt their
expectations of informativity to individual speakers’ communicative styles. Experiment
III tests the role of the addressee: As in Experiment I, participants complete utterances
from several different speakers, with the manipulation that the utterances are addressed
either to an adult or to a child. Although less clear-cut than in the preceding experiments,
results indicate that the identity of the addressee affects comprehenders’ guesses such
that they provide less informative, more typical completions in child-addressed
utterances.
Experiments I-III begin to model the informativity bias observed in adult comprehenders
by positing that (at least) two main factors underlie the process of generating guesses for
upcoming content: (Real-)world knowledge and sensitivity to speakers’ production
preferences. Experiment IV tests the robustness of this model by extending the paradigm
to children, a population in which one or both of these underlying factors may vary -
children’s knowledge of the world is different to adults’, and how attuned they are to
speakers’ productions may also be different. As such, Experiment I tests if speaker
saliency influences children’s guesses of what someone will say next by using a
simplified version of Experiment I. Overall, results indicate that children rely more on their
world knowledge when completing sentences than adults do, although there is some
indication that speaker salience plays a role in older children’s guesses. I discuss how
this finding informs our understanding of the interplay of world knowledge and
perspective-taking in (typical) development, as well as future directions of study which
could further illuminate this issue.
Overall, this thesis demonstrates that comprehenders are sensitive to speakers’
production preferences and have an expectation for informativity when they generate
guesses of what someone will say next. In other words, comprehenders seem to have a
bias towards filtered language when content is conveyed by a speaker. These findings
contribute to the wider field in three ways. Firstly, it demonstrates that sentence
completion tasks are not necessarily static measures of predictability and need precise
fine-tuning to answer the research questions one is interested in. Secondly, it proposes
a method for measuring informativity that attempts to capture several strategies that may
be used by a speaker intending to be informative and which the comprehender might take
into account when generating their guesses about upcoming content. And finally, this
thesis shows that our models of language processing need to include a role for
informativity-driven reasoning about the speaker to more accurately capture the
processes at play
Developing a click chemistry imaging platform using aromatic ynamines
Get PDFThe copper-catalysed azide alkyne cycloaddition (CuAAC) is a widely used bio-orthogonal
reaction. However, drawbacks include oxidative damage of biomolecules leading to
cytotoxicity which limits the in vivo applications of the CuAAC reaction. Strategies to temper
oxidative damage include the use of ligands and chelating azides, yet there has been little
development on the alkyne design. Aromatic ynamines are alkyne analogues displaying an
enhanced reactivity relative to conventional terminal alkynes. This enhanced reactivity
provides rapid kinetics for the CuAAC reaction, enabling low copper loadings without using
ligand or additives. However, the aromatic ynamine core – the benzimidazole heterocycle –
has yet to be systematically investigated. This work aims to investigate how the structure of
the ynamine influences the CuAAC reaction and solvent on reactivity. These findings will then
be applied to construct a probe for calcium imaging, in an attempt to utilise the unique
reactivity of the ynamine for addition of a fluorophore or an organelle targeting moiety.
A palette of benzimidazole and imidazole ynamine substrates containing various electrondonating
and electron-withdrawing groups were synthesised. First, hydrogen deuterium
exchange (HDE) was utilised to probe how substituents affect the alkyne proton lability. It
was found that the substituent changes on benzimidazole influenced the HDE, with EDGs
increasing the rate of HDE and EWGs reducing the rate. Imidazole substituents were slower
to exchange than the benzimidazole equivalents, and a larger difference was observed between
substituents. Then HPLC analysis was used to investigate the influence of the modification on
the CuAAC reaction. The experiments showed how reaction kinetics are strongly affected by
varying the heterocycle and the substituents in the aromatic moiety, with a 5,6-dimethoxy
benzimidazole displaying fast reaction kinetics in MeCN with 5,6-difluoro benzimidazole
significantly slower. When these groups were substituted on imidazole ynamine scaffolds, the
fluorine substituent gave faster reaction rates. Additionally, reaction rates and side product
formation are highly dependent on solvents and copper-catalyst loading, with the catalyst
percentage able to be lowered to 0.15 mol% for a benzimidazole ynamine containing two
methoxy groups on the scaffold. The changes in reaction rates in solvents are substrate
dependent, however, it was consistently observed that using HFIP/water resulted in no side
product formation, but solubility issues were common.
In addition, these results uncovered fundamental differences between imidazole and
benzimidazole ynamines. This points to potential changes in rate determining step of the
imidazole ynamine CuAAC.
The use of the ynamine in bioconjugation applications was explored through the use of calcium
probes. Synthesis of calcium probes containing varying functional groups was attempted, with
the aim of conjugation an ynamine, to allow for modular click modification with fluorophores.
Research initially began with the conjugation of fluorophore to ynamine to determine
precedent, and research on the BAPTA focused on the synthesis of probes with a range of
linkers.
The findings in this thesis underpin the potential of aromatic ynamines for bioconjugation.
Specifically, future ynamine probes should utilise benzimidazole substituents to avoid
solubility issues and use a 5,6 methoxy group in MeCN to maximise reactivity, however, all
factors need to be taken into consideration before deciding on a system. Additionally, the lack
of dependence on the copper concentration of imidazoles highlights their potential for
bioconjugation/imaging which has not been explored yet
Tagging proteins for live-cell super-resolution imaging
Get PDFThe advent of super-resolution microscopy has opened new frontiers in biological imaging, making it possible to observe structures at the nanometre scale. However, translating this capability to live mammalian cells remains a persistent challenge. This study aimed to develop and optimise peptide-based targeting methods for PAINT-style super-resolution microscopy in live cells. First, a method termed direct-LIVE-PAINT was established, using a single binding peptide to transiently and directly label protein targets. Specifically, the LifeAct-14 peptide fused to EGFP enabled successful super-resolution imaging of F-actin across various mammalian cell models. Next, the existing LIVE-PAINT method, originally developed for yeast, was adapted for mammalian cells. Utilising the 101A/101B coiled-coil pair and the mNeonGreen fluorescent protein, this approach allowed imaging of mitochondrial and nuclear proteins in the SH-SY5Y human neuroblastoma cell line. To further enhance performance, a new method called LIVE-res-PAINT was developed in yeast. This technique employed the photoconvertible fluorescent protein mEos, providing multiple improvements over traditional LIVE-PAINT, including more stable localisation rates, simplified imaging workflows, and compatibility with transient transfections, eliminating the need for stable cell lines. Collectively, these methods advance the toolkit for live-cell super-resolution imaging. The results demonstrate that LIVE-PAINT and its derivatives can fill a critical gap in the field for high-resolution visualisation of proteins inside live mammalian cells
An epidemiological assessment of schistosomiasis: hotspots, morbidity, and transmission
No full textThere are currently over 250 million humans infected with schistosomiasis, over
90% of which reside within sub-Saharan Africa. The World Health Organization
(WHO) aims to eliminate schistosomiasis as a public health problem (EPHP) in all 78
currently endemic countries, and achieve interruption of transmission (IoT) in
selected African regions, by 2030. Achieving these targets requires targeted
research to refine intervention strategies. My thesis evaluates several aspects of the
WHO guidelines, critically assessing definitions and thresholds, transmission
dynamics and exploring alternative methodologies.
Chapter one includes a general introduction into schistosomiasis, WHO goals and
targets, highlighting knowledge gaps and setting the scene for all the different
aspects of the thesis.
In chapter two, I evaluated the validity of the WHO’s heavy infection intensity
threshold (≥400 eggs per gram [EPG]) as a morbidity indicator for S. mansoni and
the reliance on infection intensity as a proxy for morbidity. I examined infection
intensity and morbidity in individuals from Bugoto, Uganda, using egg-based Kato-
Katz and point-of-care circulating cathodic antigen (POC-CCA) tests for diagnosis,
and ultrasound (Niamey protocol) for morbidity quantification. While school-aged
children (SAC) had the highest infection intensities, pre-SAC had a significantly
higher proportion of positive portal vein dilation (PVD), left parasternal line (PSL)
enlargement, and anaemia compared to all other age groups. Infection intensity
only predicted fibrosis and anaemia at burdens far above the WHO’s threshold, and
malaria was strongly associated with PVD and anaemia. These findings suggest that
the current WHO standard of simply using the prevalence of individuals with heavy
infection intensities within a community is an unreliable morbidity proxy,
highlighting the need for refined metrics that account for broader health impacts,
age differences and co-infections.
In chapter three, I examined the operational designation of persistent hotspots, as
introduced in the WHO’s most recent Roadmap for Neglected Tropical Diseases.
The definition identifies areas where transmission persists above the 10% baseline
prevalence despite ongoing control or elimination interventions, a distinction that
has implications for determining which communities receive biannual treatment.
Using a systematic-style review methodology, I outlined the historical use of the
term hotspot and observed a substantial increase in its use after 2016, with the
Schistosomiasis Consortium for Operational Research and Evaluation being most
influential in the use of the term. Next, using studies that had identified hotspots, I
assessed the four criteria outlined in the WHO draft definition. The most restrictive
criteria for designation of a hotspots by WHO definition was achieving ≥75%
coverage alongside a 1/3 reduction in prevalence. Using these results, in
combination with novel data obtained from interviews with key stakeholders and
program managers, I proposed a revised framework for defining persistent
hotspots, advocating for greater regional flexibility in prevalence reduction
thresholds and distinguishing between biological and operational hotspots which
may not meet coverage targets.
In chapter four, I examined the relationship between human mobility and S.
mansoni transmission, focusing on the impact of habitual travel to and from a
persistently hyper-endemic region and one that has reached elimination thresholds.
Understanding these dynamics is critical for achieving and maintaining WHO
elimination targets, particularly in low-prevalence regions where overlooked
transmission drivers and surveillance gaps may hinder progress to control. Using
parasite diagnostics and travel questionnaires from individuals living ~5 km from
Lake Victoria, Uganda, I developed a causal model of infection, constructing a
directed acyclic graph (DAG) to identify key confounders, determinants, and
mediators. Bayesian linear models estimated infection probability as a function of
travel frequency, water exposure, and duration in water. Results showed that
frequent travellers had a higher infection risk and that the activity that they did
when at the Lake was also an important driver of infection. In settings approaching
elimination thresholds, such mobility may undermine control efforts if not
adequately captured by existing surveillance systems.
In chapter five, I evaluated the potential of Nanopore adaptive sampling to
selectively enrich S. mansoni DNA from miracidia preserved on Whatman FTA® cards
for whole-genome sequencing (WGS). While unwashed miracidia on FTA cards are
generally suitable for targeted gene amplification or microsatellite analyses, WGS
typically requires additional pre-washing to reduce contamination, particularly from
faecal material. This study aimed to determine whether adaptive sampling could
minimise the need for labour-intensive pre-washing while maximising DNA recovery
from long-term archived samples. Using Nanopore sequencing, I compared washed
and unwashed miracidia samples, assessing contamination levels with Kraken2 and
sequencing depth through read mapping. While washed samples contained more S.
mansoni DNA, adaptive sampling failed to generate sufficient reads for effective
WGS, likely due to high genomic repeat content causing the rejecEon of valid S.
mansoni reads. These findings suggest that while washing improves purity, adaptive
sampling alone is insufficient, and further optimisation or alternative enrichment
strategies will be necessary to improve sequencing efficiency and data quality.
In chapter six, my general discussion, I addressed the common themes and topics of
interest from within and across each of the chapters and outlined ideas for further
research. Through a series of studies, I questioned the reliability of egg burden as a
morbidity proxy, assessed the effectiveness of the persistent hotspot designation,
explored the role of human mobility in sustaining transmission, and evaluated the
potential of adaptive sampling for parasite genotyping. These findings provide
evidence which can contribute to recommendations to refine intervention strategies
and improve surveillance accuracy for Schistosoma spp. research, supporting more
effective disease control and elimination efforts to ultimately improve health
outcomes for affected populations
Maximianus and Boethius: reading Latin love elegy in Late Antiquity
Get PDFMaximianus’ Elegies and Boethius’ Consolation of Philosophy, two works from sixth-century Italy, share a striking similarity in their reception of Augustan love elegy. Both engage with the genre not only through verbal allusions typical of late antique literature, but in a sustained dialogue with its programme and poetics. In the first full-length study of its kind, I examine the connection between these two authors and their shared reception of Latin love elegy. Through close analyses of key passages, I argue that Maximianus’ poems are best understood as a humorous, yet politically motivated, tribute to the recently executed philosopher, and as a send-up of anti-intellectualism in Italy under the Ostrogoths
Understanding understanding: paediatric fMRI investigations of theory of mind development
No full textTheory of Mind (ToM) is the ability to reason about others’ mental states. Our current understanding
of ToM development, particularly regarding domain-specificity and susceptibility to experiential
variation, largely stems from behavioural research. Behavioural tasks are highly valuable tools in
developmental research, allowing direct measurement and quantification of individual differences
with high ecological validity, thereby enabling us to map out typical development. Yet, performance
on behavioural ToM tasks almost always reflects the measured ability interwoven with other cognitive
capacities, like language abilities or executive functioning – this can be an obstacle, especially in non-typically developing populations. While statistically controlling for such covariates is a good first step
in trying to separate the contributions of these different abilities, assessing development in the brain
regions recruited for ToM reasoning offers a more direct measure of domain-specific development.
This thesis investigates domain-specific ToM development and how it is impacted by two experiential
factors: preterm birth, an example an experience that can lead to differences in development across
several domains, with high heterogeneity across individuals, and the number of children’s siblings, a
more typical example of experiential variation with similar potential for distributed impacts on
development. Both studies use a combination of behavioural assessment and neuroimaging –
specifically, a comprehensive behavioural measure assessing a range of earlier and later developing
ToM concepts along with naturalistic movie-viewing functional magnetic resonance imaging (fMRI).
Naturalistic movie-viewing fMRI offers several advantages: compared to traditional neuroimaging
tasks, it increases accessibility for younger children and non-typically developing populations, and the
data are very rich, allowing for the extraction of multiple neural metrics of ToM development.
The study investigating ToM development following preterm birth in a well-characterised, longitudinal
cohort enriched for preterm birth, found that children born early show reduced performance on
behavioural ToM tasks, even when statistically controlling for language abilities (which were also
reduced among children born preterm). The neuroimaging results indicated subtle domain-specific
differences as a function of gestational age, however, on most measures, functional responses in ToM
brain regions were similar across children born preterm and at term. The second study, which
opportunistically investigated the effect of children’s number of siblings on domain-specific ToM
development in an open dataset, found subtle effects of the number of siblings on domain-specific
ToM development. Children with more siblings had more functionally mature responses in ToM brain
regions.
Overall, the results from these two studies demonstrate that early life experiences can shape domain-specific ToM development to varying degree. These results also encourage the further use of
naturalistic movie-viewing fMRI for this line of research, to help build our understanding of individual
differences in domain-specific ToM development and how it is affected by experiential factors
throughout early and middle childhood.Theory of Mind (ToM) is the ability to reason about others’ mental states. Our current understanding of ToM development, particularly regarding domain-specificity and susceptibility to experiential variation, largely stems from behavioural research. Behavioural tasks are highly valuable tools in developmental research, allowing direct measurement and quantification of individual differences with high ecological validity, thereby enabling us to map out typical development. Yet, performance on behavioural ToM tasks almost always reflects the measured ability interwoven with other cognitive capacities, like language abilities or executive functioning – this can be an obstacle, especially in non-typically developing populations. While statistically controlling for such covariates is a good first step in trying to separate the contributions of these different abilities, assessing development in the brain regions recruited for ToM reasoning offers a more direct measure of domain-specific development.
This thesis investigates domain-specific ToM development and how it is impacted by two experiential factors: preterm birth, an example an experience that can lead to differences in development across several domains, with high heterogeneity across individuals, and the number of children’s siblings, a more typical example of experiential variation with similar potential for distributed impacts on development. Both studies use a combination of behavioural assessment and neuroimaging – specifically, a comprehensive behavioural measure assessing a range of earlier and later developing ToM concepts along with naturalistic movie-viewing functional magnetic resonance imaging (fMRI). Naturalistic movie-viewing fMRI offers several advantages: compared to traditional neuroimaging tasks, it increases accessibility for younger children and non-typically developing populations, and the data are very rich, allowing for the extraction of multiple neural metrics of ToM development.
The study investigating ToM development following preterm birth in a well-characterised, longitudinal cohort enriched for preterm birth, found that children born early show reduced performance on behavioural ToM tasks, even when statistically controlling for language abilities (which were also reduced among children born preterm). The neuroimaging results indicated subtle domain-specific differences as a function of gestational age, however, on most measures, functional responses in ToM brain regions were similar across children born preterm and at term. The second study, which opportunistically investigated the effect of children’s number of siblings on domain-specific ToM development in an open dataset, found subtle effects of the number of siblings on domain-specific ToM development. Children with more siblings had more functionally mature responses in ToM brain regions.
Overall, the results from these two studies demonstrate that early life experiences can shape domain-specific ToM development to varying degree. These results also encourage the further use of naturalistic movie-viewing fMRI for this line of research, to help build our understanding of individual differences in domain-specific ToM development and how it is affected by experiential factors throughout early and middle childhood
Neoliberal beliefs about romantic relationships: scale development and novel barrier to collective action for gender equality
Get PDFNeoliberalism emphasizes individual solutions over collective action when seeking to resolve social problems. We argue that it plays a role in romantic relationships, encouraging women to mitigate relationship problems through personal effort, while ignoring structural gender inequality that puts women at a disadvantage, thus presenting a barrier for women to engage in collective action for gender equality. This thesis presents six studies (N = 1,808) that aimed to (1) develop and validate a new measure of neoliberal beliefs about romantic relationships, (2) examine whether women’s greater endorsement of neoliberal beliefs about romantic relationships is related to less collective action and lower support for gender equality, and (3) investigate whether exposing women to neoliberal beliefs about romantic relationships undermines their collective action and support for gender equality. In Studies 1–3, we developed and validated the 20-item Neoliberal Beliefs About Relationships Questionnaire (NBARQ) among women. We found that women’s greater endorsement of the NBARQ was associated with significantly lower collective action intentions, lower support for gender equality (Studies 2 and 3), lower probability of choosing to sign a petition against sexism, and lower number of people that they were willing to share the petition with (Study 3). Exploration of underlying mechanisms for these associations revealed that lower feminist identification and lower perceived injustice about gender inequality in parallel significantly mediated the associations between greater endorsement of the NBARQ and lower collective action intentions, as well as lower support for gender equality (Study 3). To further examine causality, we developed and tested manipulations of exposure to neoliberal beliefs about romantic relationships in two pilot studies (Studies 4a and 4b). The manipulation in Study 4b was successful, but when used in Study 5, we did not find a significant effect of women’s exposure to neoliberal beliefs about romantic relationships on their collective action intentions or support for gender equality. This thesis contributes to the social psychological literature by developing a new measure of neoliberal beliefs about romantic relationships and testing their role as a novel barrier to women’s engagement in collective action for gender equality. It provides guidance for achieving greater gender equality, especially in the private sphere, by demonstrating the limitations of trying to resolve relationship problems rooted in gender inequality through personal effort and highlighting the importance of facilitating collective action to challenge gender inequality
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