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Diffusion-limited evaporation of polymer solutions
No full textIn many processes in nature and industry, water evaporates from polymer
solutions. When the evaporation is fast, a polymer layer can form at the water-air interface resulting in a diffusive mass transfer resistance inside the solution, in a process termed diffusion-limited evaporation (DLE). DLE has been observed in solutions containing lipids or microgels, that often have a specific structural complexity. To understand the generality of the physical mechanisms in DLE, it is highly relevant to study DLE of polymer solutions.
In this thesis, we study the evaporation of water from solutions containing
structurally simple polymers, with the aim of improving the fundamental
understanding of DLE. We first present experimental data, where a polymerwater solution evaporates unidirectionally from rectangular capillaries. The evaporation rate settles according to the predicted diffusive scaling m˙ (t) ∼ t−1/2, but surprisingly does not settle with m˙ (t) → 0 at late times, which would be expected at thermodynamic equilibrium with the environment. The steady state evaporation dynamics in our experiments is explained as resulting from the buildup of a tensile stress in a glassy polymer layer at the interface, resulting from the compression by the evaporation flux, that offsets the water activity at the interface ai from thermodynamic equilibrium with the environment. We furthermore show how DLE can result in evaporation from polymer solutions that is insensitive to the ambient humidity, which sets the driving force for
evaporation. Importantly, we find that for certain polymers evaporation is also humidity-insensitive at early times, without becoming diffusion-limited. This effect is caused by the rapid adsorption of polymers at the solution-air interface, with the interfacial polymer layer setting the early-times evaporation rate.
In the second part of this thesis we show DLE from polyelectrolyte solutions, that is similar to the neutral polymer at late times as a result of increased counterion condensation at high polyelectrolyte concentrations. The polymers we tested also approach a similar non-zero steady state evaporation rate m˙ (t), which suggests similar contributions from the mixing energy and mechanical response to the evaporative driving force.
The final part of this thesis presents a phase field model which allows us to
establish the ubiquitous nature of DLE, independent of polymer properties. For a one-dimensional geometry, results from the model clearly show how DLE with m˙ (t) ∼ t−1/2 occupies a large region in the evaporation phase space, which also includes pure solvent-like (m˙ (t) ∼ const.) and arrested (m˙ (t) ∼ 0) evaporative regions. Finally, we show how the model can be extended to more complicated systems, like droplets or materials with heterogeneous internal structuring, which is important to translating our results to many practical applications
Incomes and outcomes: preterm birth, socioeconomic status and neurodevelopment
Get PDFPreterm birth is a leading cause of atypical brain development, and is associated with long-term motor, cognitive, and behavioural outcomes, with effects across the life course. In the general population, low socioeconomic status (SES) is also associated with brain structure, cognition, education attainment, and behavioural and mental health diagnoses. However, the relative contributions of low SES and low birth gestational age (GA) to brain development from the neonatal period are unknown. Inflammation is associated with both preterm birth and SES independently and could be one mechanism through which they have effects on brain development.
This thesis aimed to investigate (1) the associations between SES and preterm birth with neonatal brain morphology; (2) the associations between white matter microstructure, SES, and preterm birth in the neonatal period and at five years of age; and (3) differences in the proteome associated with preterm birth and SES inferred from epigenetic scores (EpiScores), DNA methylation (DNAm)-based surrogates that have been developed for multiple circulating proteins.
These studies were undertaken with the Theirworld Edinburgh Birth Cohort (TEBC), a longitudinal cohort study of preterm and term infants. Several SES measures were gathered, and although these measures were correlated, the strength of correlation ranged from very weak to strong. This meant they were not sufficiently correlated to assume that one measure captures all dimensions of SES, so multiple measures of SES were examined in each study.
In the first study, 85 regional volumes across the brain were investigated at term-equivalent age, alongside whole-brain measures of cortical morphology; gyrification index (GI), sulcal depth, curvature, thickness, and surface area (SA). Six regional brain volumes associated with SES measures (standardised β 0.06-0.17), and there were interactions between birth GA and SES measures (standardised β -0.05-0.02), although there were more widespread associations with birth GA (standardised β -0.20-0.24). Family-level SES measures, such as maternal education and occupation, were associated with more regional volumes than neighbourhood-level SES measures, namely the Scottish Index of Multiple Deprivation (SIMD). For the cortical measurements, birth GA was associated with SA and GI (standardised β 0.10-0.16); there were no associations between cortical measurements and SES.
In the second study, tract-based spatial statistics (TBSS) were used to investigate differences in fractional anisotropy (FA) with birth GA and SES in the neonatal period and at five years of age. In the preterm subgroup in the neonatal period, FA positively associated with birth GA and maternal education, and there were associations with an interaction between birth GA and both maternal education and SIMD. In the preterm subgroup at five years of age, there were associations between FA and an interaction between birth GA and SIMD. The SES measure that best correlated with FA was maternal education in the neonatal period, but SIMD at five years of age. For the term cohort, in the neonatal period there were negative associations with maternal education and SIMD, but only a small region of positive association with SIMD at five years of age.
In the final study, inflammation was investigated as a possible mechanism for the correlations between preterm birth and SES with brain development. This used EpiScores, developed in large association studies of DNAm patterns with protein abundance, as these may provide a more accurate measure of chronic inflammation than phasic and maturation-dependent acute phase proteins. 43 EpiScores associated with low birth GA (standardised β |0.14 to 0.88|). Only three EpiScores associated with SES (standardised β |0.06 to 0.13|), and these did not remain significant after adjustment for perinatal pro-inflammatory co-exposures (HCA, sepsis, BPD, and NEC).
In conclusion, preterm birth and SES both associate with differences on brain MRI at term-equivalent age and at five years of age, with differences in volumetric and other structural measures, and in FA as a measure of white matter microstructure. From findings at different timepoints, it appears that family-level SES measures may be particularly important in the neonatal period, and neighbourhood-level SES measures at five years of age. A range of EpiScores associate with preterm birth, providing various proteins that warrant further study to understand their correlation with developmental outcomes. However, inflammation is unlikely to be the primary axis through which SES is embedded in the early development of preterm infants. There is time for interventions to reduce social disparities during the perinatal period, which could promote healthier brain development after preterm birth. The differences in SES measure associations at different ages suggests that the most beneficial socioeconomic interventions for brain development in this vulnerable population may change over time
A novel FLI1+ hybrid cell state in melanoma residual disease
No full textMelanoma, formed from the malignant transformation of the pigment producing melanocytes,
is the most aggressive form of skin cancer. In the UK, melanoma is the 5th most common
cancer and its incidence has more than doubled since the early 1990s. Despite recent
advances in treatment options, patients with metastatic melanoma typically have a poor
prognosis, due to low response rate to immune therapies (e.g., checkpoint inhibitors) and high
frequency of resistance to targeted therapies (e.g., BRAF inhibitors). Therefore, it is a
necessity to develop more effective and durable therapeutic options for patients with
metastatic melanoma.
Melanoma is comprised of diverse cell populations of highly plastic transcriptional cell states
which are considered key drivers of therapy resistance and disease progression. Previously,
we showed via fate mapping that the cells which survive during disease regression, known as
residual disease, directly contribute to tumour relapse (Travnickova et al., 2022). Thus,
emphasising the importance of identifying and functionally interrogating the transcriptional cell
states that arise and persist during disease regression and recurrence.
To interrogate this heterogeneity and plasticity in melanoma, I have used an adult zebrafish
model of cutaneous melanoma, in which I can follow tumour regression and recurrence, just
as we see in patients as a result of therapy resistance. The origin of my project came from
single cell RNA-sequencing of zebrafish melanomas completed by Travnickova et al., (2019),
which showed a tumour subpopulation in residual disease unexpectedly expressing fli1. FLI1,
an ETS transcription factor, is a key transcriptional regulator in development and homeostasis,
and is predominately expressed in hematopoietic and endothelial cells. However, the
functional significance of aberrant FLI1 expression in melanoma was unknown.
To investigate this fli1+ tumour cell state, I first generated a Tg(fli1:GFP, crestin:mCherry)
zebrafish line on the mutant melanoma background. Using IHC-IF, I was able to visualise fli1+
tumour cells in primary tumours, in persister cells at the residual disease site and in relapsed
melanomas. Importantly, I demonstrated that this cell state is relevant to human disease, as I
also detected FLI1+ melanoma cells in both patient biopsies and scRNA-sequencing data.
Next, I used the Tg(fli1:GFP, crestin:mCherry) zebrafish melanoma model to quantify the fli1+
melanoma subpopulation in primary and regressed tumours using flow cytometry. Excitingly,
these data showed that the fli1+ cell state is specifically enriched in residual disease, relative
to the progressing tumour. Importantly, preliminary results from ongoing in vitro experiments
generating BRAF inhibitor (Vemurafenib) resistant patient cell lines, indicate that FLI1 is also
upregulated in response to prolonged Vemurafenib treatment. This provides an important link
to the clinic, suggesting the enrichment observed in our genetic model of residual disease, is
also conserved in response to targeted therapy.
To further understand the dynamics of the fli1+ cell state, I successfully developed a tamoxifen
inducible dual marker lineage tracing strategy, which enables a fluorescent ‘switch’ of the fli1+
melanoma cells, allowing tracking of this cell state through disease stages. Using this system
in combination with IHC-IF and RNAscopeTM, to assess fli1 expression in fluorescently
‘switched’ cells, I demonstrated that the fli1+ tumour cells persist beyond residual disease and
contribute to tumour relapse. In addition, this strategy revealed the plasticity of the fli1+ cell
state, showing that fli1+ melanoma cells in residual disease can alter their transcriptional
identity and turn off fli1 expression during tumour relapse.
Next, to better understand the cellular identity of the fli1+ cell state, I isolated fli1+ tumour cells
from primary and regressed zebrafish melanomas and performed transcriptomic profiling.
Crucially, differential gene expression analysis showed that fli1 expression is more than simply
a single marker gene, rather representative of a transcriptionally distinct tumour cell state.
Furthermore, pathway analysis revealed that the fli1+ tumour cells are hybrid in nature,
maintaining melanoma gene expression, while also being enriched for mesenchymal gene
signatures. Moreover, a large proportion of the differentially expressed genes of the fli1+ cell
state are both targets of Fli1 and expressed in the neural crest lineage during early
development, suggesting that Fli1 may be driving a developmental mesenchymal programme,
which could prove critical for tumour cell survival during regression.
Therefore, to determine whether Fli1 is sufficient to drive the mesenchymal programme in
vivo, and assess the impact this has on response to treatment and tumour relapse, I generated
an inducible fli1 over-expression transgenic zebrafish line. Early validation experiments in
embryos are promising and indicate this line will be effective in driving fli1 over-expression in
melanoma tumours in adult zebrafish.
Together, this work identifying and characterising this novel fli1+ cell state will better inform
our understanding of tumour heterogeneity and plasticity in melanoma residual disease and
how to combat therapy resistance
Are anonymised datasets from clinical trials truly anonymous?
No full textBACKGROUND:
Funders, regulators and publishers are increasingly requesting that clinical trial researchers share their research data with others, once the primary analysis has been completed. Existing clinical trial data could significantly contribute to expanding medical and scientific knowledge by investigating questions beyond the original study scope, facilitating individual participant data (IPD) meta-analysis, verifying results, and exploring novel methodologies for data analysis. Anonymisation of IPD before sharing can offer a way to safeguard participants' privacy. While there are several recommendations and guidance available for attempting data anonymisation prior to sharing, completely anonymising data while keeping it usable remains challenging. Moreover, many anonymised datasets are already publicly available for secondary research. However, it remains unclear whether study participants could potentially be at risk of re-identification, and under what circumstances re-identification is more likely to occur.
METHODS:
In the first phase of this PhD research, a systematic scoping review was conducted to gather publications that reported recommendations on anonymisation for enabling data sharing from clinical trials, to understand what guidance was available to researchers and how publicly available anonymised datasets from clinical trials might have been compiled. Two reviewers, Aryelly Rodriguez with Chris Tuck or Alastair Murray independently assessed titles, abstracts, and full texts for eligibility. One reviewer extracted data from selected papers using thematic synthesis, which was then reviewed by a second reviewer for accuracy. Results were summarised through narrative analysis. Moving on to the second phase, I collected a broad selection of publicly available anonymised datasets that have been made available for research purposes extending beyond their original scope, to explore the characteristics of these anonymised datasets, assess the feasibility of applying re-identification risk scores to them, and determine how these scores could be useful. I estimated their re-identification risk scores with three equations designed for calculation of such scores based on the information in the entire dataset. These equations are commonly applied to routinely collected health records and only generate numerical values ranging from 0 (lowest risk) to 1 (maximum risk), without attempting to re-identify individuals within the datasets. Subsequently, I calculated the re-identification risk scores for each dataset, using the three equations. This analysis explored the characteristics of the datasets associated with increased or decreased risk scores, and compared the risk scores to evaluate their practicality for implementation. In the third and final phase of this PhD research, I used an online exploratory cross-sectional descriptive survey that consisted of both open-ended and closed questions to gather the UK researchers’ views regarding their experiences with the de-identification, anonymisation, release methods and re-identification risk estimation for clinical trials datasets.
RESULTS:
The systematic scoping review identified 59 eligible articles (from 43 studies) for inclusion. From these articles, three distinct themes emerged: anonymisation, de-identification and pseudonymisation. The articles also showed that the most commonly recommended anonymisation techniques are removal of direct participant identifiers, and the careful evaluation and modification of indirect identifiers to minimise the risk of identification. Anonymisation of datasets in conjunction with controlled access was the most recommended method for data sharing.
For the next phase, I contacted data holders and followed their local procedures to access the anonymised datasets. I identified 86 potentially eligible datasets from 18 repositories and successfully secured 76 of them. After full evaluation, 70 datasets met the inclusion criteria and were included in the analysis, representing 14 out of the 18 repositories. Thirty-one datasets were shared with minimal restrictions (open access), while 39 were shared with varying levels of restrictions before access was granted (controlled access). Datasets had, on average, four identifiers and mean risk scores ranging from 0.47 to 0.91. The most common pieces of information present in the datasets that, when combined, may indirectly identify a participant were sex (80%) and age (72.9%). For the final phase, the exploratory survey had 38 responses to invitation from June 2022 to October 2022. Thirty-five participants (92%) used internal documentation, institutional standard operating procedures and/or published guidance to de-identify/anonymise clinical trials datasets. De-identification followed by anonymisation and then fulfilling data holders’ requirements before access was granted (controlled access) was the most common process for releasing the datasets as reported by 18 (47%) participants. Eleven participants (29%) had previous knowledge of re-identification risk estimation but had not used this. Experiences in the process of de-identifying/anonymising the datasets and maintaining such datasets were mostly negative, the main reported issues were lack of resources, guidance, and training.
CONCLUSIONS:
There is no single standardised set of recommendations on how to anonymise clinical trial datasets for sharing. However, the systematic scoping review showed a developing consensus on techniques used to achieve anonymisation. Researchers in clinical trials still consider that anonymisation techniques by themselves are insufficient to protect participant privacy, and they need to be paired with controlled access. The second phase of this research confirmed that clinical trial datasets are very rich in personal details and using re-identification risk scores as a measure of this richness is feasible. These scores could inform the anonymisation process of clinical trials datasets to release them for secondary research. We proposed a strategy for incorporating these scores into the decision-making process for releasing clinical trials datasets. Finally, the majority of responders to the survey reported using documented processes for de-identification and anonymisation. However, our survey results clearly indicate that there are still gaps in the areas of guidance, resources and training to fulfil sharing requests of de-identified/anonymised datasets, and that re-identification risk estimation is an underdeveloped area. This work will be of interest to the clinical trials research community, funders and publishers seeking to improve the process of anonymisation and foster data sharing
A co-transcriptional mechanism for tightly controlling RNA homeostasis in yeast
Get PDFTranscription termination by the Nrd1-Nab3-Sen1 (NNS) complex plays a
pivotal role in repressing pervasive transcription in Saccharomyces cerevisiae.
Intriguingly, many upregulated protein-coding RNAs are also increasingly bound by the
NNS complex during starvation. This implies that a subset of mRNAs encoding stressresponsive
proteins are targeted for degradation shortly after transcription initiation.
However, the biological significance of this observation has hitherto remained unclear.
Premature termination of stress-responsive mRNAs has been proposed as a putative
beneficial cellular mechanism to keep the expression of such genes low and tightly
regulated during nutrient deprivation. To test this, I focused on the effect that NNS
regulation exerted on one of its stress-specific targets, PIC2, which encodes a
mitochondrial phosphate and copper importer.
Using strains lacking Nab3 and Nrd1 RNA-binding sites in PIC2 RNA, I have
demonstrated that this NNS-mediated attenuation is important for fine-tuning the
expression of an evolutionarily conserved mitochondrial transporter, Pic2, when cells
rely on respiration to produce ATP. Remarkably, single-cell microfluidic analyses
showed that NNS regulation of PIC2 not only reduced Pic2 protein levels but also
decreased cell-to-cell variability in Pic2 expression, revealing a novel role for NNS as
a transcriptional noise suppressor. Using GFP reporters, I show that this attenuation
mechanism is generally applicable.
To investigate whether impairing NNS regulation of PIC2 affected cellular
physiology, I characterised the mutants and compared their phenotype to that of the
parental strain. My results prove that specifically disrupting Nab3 binding to PIC2
disturbs energy homeostasis, decreases cell fitness and leads to severe cell size
increases and cell cycle delays. To determine whether these phenotypes solely
emerged from the increase in activity of Pic2, I generated and inspected a PIC2
overexpression mutant, which only exhibited defective growth and energy
homeostasis. Despite proving that maintaining an optimal expression of PIC2 is critical
to enhancing microbial fitness during adaptation, this evidence also illustrated that
larger levels of Pic2 did not underlie all the observed anomalies.
Combining multi-omics profiling and transcriptome-wide NNS-RNA binding
footprinting, I demonstrate that disrupting Nab3 binding to PIC2 leads to redistribution
of Nrd1 among its targets and changes levels of many other NNS-regulated transcripts.
Given that depleting Nab3 from the nucleus causes an enlargement of cell size and a
prolongation of the cell cycle, I posit that alterations in Nrd1 transcriptome occupancy
underlie the cell volume and cycle anomalies observed upon abrogation of Nab3
binding to PIC2. Collectively, my findings illustrate that even subtle changes in how
RNA-binding proteins interact with their RNA substrates can drive significant systemwide
defects and emphasise the crucial role of the NNS complex in preserving
microbial fitness during stress
A review of effective public engagement on climate and implications for Scotland
No full textThis report reviews the state of play of public body climate adaptation planning in Scotland, compares different approaches across the public sector to adaptation planning and delves into available cost-benefit information for investing in resilience
Novel applications of fluorine-18 labelled radiotracers in cardiovascular disease
Get PDFINTRODUCTION:
Coronary artery, aortic valve and myocardial disease are important manifestations of cardiovascular disease responsible for a leading cause in cardiovascular morbidity and mortality in the UK and worldwide. In recent years the advent of non-invasive hybrid imaging through the amalgamation of positron emission tomography (PET) with computed tomography (CT) and magnetic resonance (MR) imaging has allowed for the identification of physiological abnormalities which, in addition to established anatomical features, permit more accurate identification of high-risk coronary plaques, aortic valve disease and myocardial disease. To address the increasing burden of these conditions, improved diagnostic accuracy may enhance our ability to deliver more precise existing and novel therapies to target these disease processes.
The objective of this thesis was to investigate the ability of novel advanced non-invasive imaging technologies to identify high-risk coronary plaque, coronary atherothrombosis, and aortic valve and myocardial disease.
METHODS AND RESULTS:
Cardiovascular ¹⁸F-fluoride positron emission tomography-magnetic resonance imaging: a comparison study:
Eighteen patients with aortic stenosis or recent myocardial infarction underwent ¹⁸F-fluoride PET/CT followed immediately by PET/MR. Valve and coronary 18F-fluoride uptake were evaluated independently. Both standard (Dixon) and novel (radial GRE) MR attenuation correction (AC) maps were validated against PET/CT with results expressed as target-to-background ratios (TBRs).
Visually, aortic valve 18F-fluoride uptake was similar on PET/CT and PET/MR. TBRMAX values were comparable with radial GRE AC (PET/CT 1.55±0.33 vs. PET/MR 1.58±0.34, p=0.66; 95% limits of agreement -27 to +25%) but performed less well with Dixon AC (1.38±0.44, p=0.06; bias (-)14%; 95% limits of agreement -25 to +53%). In native coronaries, 18F-fluoride uptake was similar on PET/MR to PET/CT regardless of AC approach. PET/MR identified 28/29 plaques identified on PET/CT however stents caused artefact on PET/MR making assessment of ¹⁸F-fluoride uptake challenging.
¹⁸F-Fluoride PET/MR in cardiac amyloid: a comparison study with aortic stenosis and age and sex-matched control subjects:
In this prospective multi-centre study, patients were recruited in Edinburgh and New York and underwent ¹⁸F-fluoride PET/MR imaging. Standardised volumes of interest were drawn in the septum and areas of late gadolinium enhancement to derive myocardial standardised uptake values (SUV) and tissue to background ratio (TBRMEAN) after correction for blood pool activity in the right atrium.
Fifty-three patients were scanned: 18 with cardiac amyloid (10 ATTR and 8 AL), 13 control subjects and 22 patients with aortic stenosis. No differences in myocardial TBR values were observed between participants scanned in Edinburgh and New York. Mean myocardial TBRMEAN values in patients with ATTR amyloid (1.13±0.16) were higher than control subjects (0.84±0.11, p=0.0006), those with aortic stenosis (0.73±0.12, p1.14 in areas of LGE demonstrated 100% sensitivity (95% confidence interval 72.25 to 100%) and 100% specificity (95% confidence interval 67.56 to 100%) for ATTR compared to AL amyloid (AUC 1, p=0.0004).
Non-invasive in vivo imaging of acute thrombosis: development of a novel Factor XIIIa radiotracer
Optical and positron emitting ENC2015 probes were assessed ex vivo using blood drawn from human volunteers and passed through perfusion chambers containing denuded porcine aorta as a model of arterial injury. Specificity of ENC2015 was established with co-infusion of a Factor XIIIa inhibitor. In vivo ¹⁸F-ENC2015 biodistribution, kinetics, radiometabolism and thrombus binding were characterised in rats. Both Cy5 and fluorine-18 labelled ENC2015 rapidly and specifically bound to thrombi. Thrombus uptake was inhibited by a factor XIIIa inhibitor. ¹⁸F-ENC2015 remained unmetabolized over 8 hours when incubated in ex vivo human blood. In vivo, 42% of parent radiotracer remained in blood 60 min post-administration. Biodistribution studies demonstrated rapid clearance from tissues with elimination via the urinary system. In vivo, ¹⁸F-ENC2015 uptake was markedly increased in the thrombosed carotid artery compared to the contralateral patent artery (mean standard uptake value ratio of 2.40 versus 0.74, p<0.0001).
Whole body distribution and dosimetry estimates of two novel factor XIIIa targeted thrombus tracers: ENC2015 and ENC2018
Whole-body positron emission tomography (PET) images were acquired over 240 min after intravenous bolus injection of Al¹⁸F-ENC2015 (n=3) or Al¹⁸F-ENC2018 (n=3) in adult rodents. Different models were investigated for quantification of radiation absorbed and effective doses using OLINDA/EXM 1.0 software. The main elimination route of both Al¹⁸F-ENC2015 and Al¹⁸F-ENC2018 was the urinary bladder and kidneys. Despite chemical restructuring in an attempt to reduce resident time in the critical organs, Al¹⁸F-ENC2018 performed less favorably than Al¹⁸F-ENC2015. Normalisation of rodent organs and whole-body masses to human equivalent reduced the calculated dosimetry values. The mean total body effective dose was 2.55 x 10-2 mSv/MBq for Al¹⁸F-ENC2015 and 2.83 x 10-2 mSv/MBq for Al¹⁸F-ENC2018.
CONCLUSION:
Cardiovascular PET/MR demonstrates good visual and quantitative agreement with PET/CT. However, PET/MR is hampered by stent-related artefacts currently limiting clinical application. Quantitative ¹⁸F-fluoride PET/MR imaging can distinguish ATTR amyloid from other similar phenotypes and holds promise in improving the diagnosis of this condition and helping to tailor appropriate treatments to those most likely to benefit. ENC2015 rapidly and selectively binds to acute thrombus in both an ex vivo human translational model and an in vivo rodent model of arterial thrombosis. The dosimetry estimates obtained indicate that radiation doses from both Al¹⁸F-ENC2015 and Al¹⁸F-ENC2018 are unfavorable with regards to guidelines recommended by key regulatory authorities that govern the translation of radiotracers to the clinic. Whilst this probe holds promise for the non-invasive identification of thrombus formation in cardiovascular disease, it is not ready for human translation in its current form
Planning and operations of water and energy networks
No full textThis thesis focuses on the optimal planning and operations of water and energy networks,
aiming to enhance efficiency, reduce costs, and address challenges associated with
large and high-altitude water supply systems. The first chapter introduces a binary expansion
approach to solve the water pump scheduling problem, characterised by high power
consumption and complex dynamics, which results in a nonlinear mixed-integer optimisation
model. By employing a binary expansion approach, the method reduces computational
complexity while maintaining high precision, as demonstrated through extensive
testing on various network topologies, including a real-world copper mine water network.
The second part extends this problem by incorporating demand response and addressing
uncertainties in electricity spot prices and water demand. A two-step stochastic optimisation
model integrates a robust water profile optimisation with a stochastic power profile
optimisation, effectively balancing the nonlinearities and uncertainties to optimise water
pump schedules and provide demand response ancillary services to the power network on
the capacity market. Case studies highlight the impact of different seasons and energy
policies on total costs and demand response provision, offering insights for energy policymakers. The third chapter explores long-term generation and transmission expansion
planning by integrating desalination flexibility within the Chilean electricity system. It underscores the significant role of reverse osmosis desalination in addressing water scarcity
and influencing power system dynamics. By co-optimising desalination operations with
energy generation and transmission planning, the model enhances system performance and
reveals synergies between solar, battery energy storage, and desalinated water systems.
These findings guide investment decisions, decarbonisation policies, and the sustainable
integration of water-energy systems. Finally, these studies contribute to a comprehensive
understanding of optimising water and energy networks, enabling the maximisation of
mutual benefits while minimising overall costs. Practical and effective solutions for enhancing
the efficiency of both networks are proposed, and operational and energy policies are recommended for future implementation, thus ensuring the achievement of energy and
sustainability goals by 2050
Accounting for morphosyntactic variation in the nominal domain: a quantitative and experimental investigation of nominal classification and related phenomena in Kîîtharaka
No full textThis dissertation investigates the morphosyntactic variation in the nominal domain in
Kîîtharaka language (Bantu, E54). The main focus is the variation in agreement classes
and gender, as (typically) influenced by dynamic gender assignment rules. However, the
dissertation also touches on related phenomena including representations of gender
and number morphology and nominal word order. There is a rich tradition of research
on the nominal domain in linguistics, from theories of abstract hierarchical structure to
experiments on the acquisition of noun classes and agreement. In the latter case, it has
been shown that nominal agreement often relies on an intricate interaction between two main factors–meaning (semantics), and the form (morphophonology) of the noun. One of the main goals of this dissertation is to establish how gender/noun classes vary as a function of the gender assignment rules in Kîîtharaka, with the goal of achieving a
more empirically grounded characterization of the nominal classification system in this
language. The first three chapters seek to answer three questions: (i) which semantic
and morphophonological features or cues might we predict to be productive for gender
assignment in Kîîtharaka based on corpus data, (ii) do Kîîtharaka speakers indeed consistently use these cues to classify novel nouns, and (iii) do speakers use semantic or morphophonological cues more robustly when both are available. Chapter 2 comprises a corpus-based study in which a novel corpus of 2,327 Kîîtharaka nouns was compiled, with each noun coded for a set of semantic and morphophonological features. The Tolerance Principle (Yang, 2016) was used to measure the predicted productivity of each feature. The results indicate that morphophonological features are predicted to be highly productive in Kîîtharaka. However, among the tested semantic features, only a few were predicted to be productive, specifically Human, Tree, and some evaluative features (Augmentative, Pejorative, Diminutive). Interestingly, the feature Human is only productive for a specific subset of nouns, suggesting a possible interaction between features. The chapter concludes with a discussion on the underlying reasons for these results and their implications for Kîîtharaka, as well as for the broader study of gender assignment in Bantu languages. In Chapter 3, we address the empirical question of whether these features are indeed used by Kîîtharaka speakers productively. To address this, we conducted two behavioral (wug-task-style) experiments to ascertain the psychological reality of a series of semantic and morphophonological features respectively. The experiments test whether participants are sensitive to semantic and morphophonological cues in isolation when classifying novel Kîîtharaka nouns. The results indicate that speakers are sensitive to two inherent semantic features, Human and Fruit, as well as evaluative features like Augmentative, Pejorative, and Diminutive. Conversely, they show robust sensitivity to all tested morphophonological features when classifying novel nouns. These findings suggest that semantic features are generally less productive than morphophonological features in the Kîîtharaka nominal classification system. However, given that morphophonology is productive in the same classes where semantics is productive, there is an empirical question regarding which cues speakers use more reliably when both are present. In Chapter 4, therefore, we investigate the relative importance of semantics and morphophonology as cues to nominal classification in the language. In this experiment, participants were shown novel nouns with target nominal morphology, along with corresponding images, and were asked to provide a missing agreement prefix on a dependent word. The results indicate that speakers’ use of semantic and morphophonological cues differ depending on whether a noun is human or non-human.
Participants tended to choose semantic assignment for human nouns and morphophonological cues for non-human nouns. We argue that this differential choice of assignment cue may stem from the general importance of human-ness (or animacy) across cognition. Kîîtharaka speakers may find human nouns conceptually more salient than non-human ones, reflecting a broader cognitive bias in forming linguistic categories. Conversely, morphophonology is more reliable for nonhuman nouns, possibly because the semantic assignment rules for these nouns are less grounded in core categorization and are generally less reliable. Chapters 5 and 6, address two additional aspects of variation in the nominal domain—the representation of nominal modifier order and gender-number order—aiming to illustrate what Kîîtharaka can reveal about these phenomena more generally. Chapter 5 investigates underlying constraints on morpheme ordering in the context of gender and number marking. The study compares English, Italian, and Kîîtharaka speakers, who have different L1 experiences with gender morphology, to determine if there are biases in the ordering of these morphemes. The results indicate a bias towards placing the gender morpheme closest to the noun, providing empirical support for certain theories of gender morphosyntax and suggesting that cognitive biases influence morpheme ordering across languages.
In Chapter 6, a similar investigation is conducted on the representation of nominal modifier order. The study examines whether Kîîtharaka speakers, whose language follows a unique word order (N>DEM>ADJ, with the adjective furthest from the noun), exhibit similar (underlying) cognitive preferences to English speakers, where the adjective is closest to the noun. Data is collected from monolingual Kîîtharaka speakers with little to no exposure to English. The findings show that Kîîtharaka speakers’ word order preferences mirror those of English speakers, supporting the hypothesis that universal cognitive representation plays a role in shaping word order. Overall, this dissertation concludes that through a comprehensive empirical investigation incorporating quantitative data analyses and behavioural experiments, the complexities associated with various morphosyntactic phenomena can be demystified, not only in Bantu, but in other languages more generally
Mapping the Fragments – Justice and Security in Somalia
Get PDFThis report analyses justice and security dynamics in Somalia through a comparative study of Kismayo and Galkayo, applying Bell and Wise’s (2022) framework on fragmented peace-conflict spaces. It examines how governance and security arrangements in these towns reflect broader Somali state formation processes.
Kismayo, a key seaport under Jubbaland administration, operates as a territorially limited transcalar space with centralized governance shaped by Islamist influences and Al-Shabaab’s presence. The city has achieved relative stability and credible justice provision but faces challenges related to political exclusion. Galkayo, a divided town between Puntland and Galmudug, exemplifies a borderland mediation space where governance remains contested and security arrangements fluid, requiring ongoing negotiation among multiple actors. Despite a 2017 peace agreement, instability persists.
Both towns also function as route-of-passage spaces, serving as trade corridors that influence justice and security. Their differing political orders underscore the need for localized, adaptive peace and security interventions. The study highlights the importance of tailoring strategies to specific governance dynamics while ensuring alignment with broader national peacebuilding efforts
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