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Noise-robust multi-fidelity surrogate modelling for parametric partial differential equations
Get PDFWe address the challenge of constructing noise-robust surrogate models for quantities of interest (QoIs) arising from parametric partial differential equations (PDEs), using multi-fidelity collocation techniques; specifically, the Multi-Index Stochastic Collocation (MISC). In practical scenarios, the PDE evaluations used to build a response surface are often corrupted by numerical noise, especially for the low-fidelity models. This noise, which may originate from loose solver tolerances, coarse discretisations, or transient effects, can lead to overfitting in MISC, degrading surrogate quality through nonphysical oscillations and loss of convergence, thereby limiting its utility in downstream tasks like uncertainty quantification, optimisation, and control. To correct this behaviour, we propose an improved version of MISC that can automatically detect the presence of solver noise during the surrogate model construction and then ignore the exhausted fidelities. Our approach monitors the spectral decay of the surrogate at each iteration, identifying stagnation in the coefficient spectrum that signals the onset of noise. Once detected, the algorithm selectively halts the use of noisy fidelities, focusing computational resources on those fidelities that still provide meaningful information. The effectiveness of this approach is numerically validated on two challenging test cases: a parabolic advection–diffusion PDE with uncertain coefficients, and a parametric turbulent incompressible Navier–Stokes problem. The results showcase the accuracy and robustness of the resulting multi-fidelity surrogate and its capability to extract relevant information, even from under-resolved meshes not suitable for reliable single-fidelity computations
Optimising Computational Methods in B Cell Lymphoma
No full textDiffuse large B-cell lymphoma (DLBCL) is a remarkably heterogeneous disease, presenting significant challenges in the classification, monitoring, and treatment of patients. Throughout my PhD, I set out to address some of these challenges by developing and applying novel computational methods to enhance the robustness and interpretability of high-throughput sequencing data in lymphoma research.
This thesis is structured around three interlinked projects. First, I introduce noisyR, an R package designed to systematically quantify and remove technical noise from sequencing datasets. By focusing on consistency of signal across samples, noisyR helps ensure that downstream analyses like differential expression, enrichment, and network inference are more consistent and interpretable. The package is complemented by bulkAnalyseR, an interactive pipeline that lowers the barrier for researchers to perform robust transcriptomic analysis, supporting open and reproducible science.
Second, I present the results of the DIRECT clinical study of aggressive B-cell lymphoma, which assessed the feasibility of using circulating tumour DNA to monitor patient disease. By implementing advanced error suppression strategies, I helped develop a robust pipeline to perform patient risk stratification, molecular subtyping, and minimal residual disease monitoring in a real-world clinical setting.
Third, I describe a large-scale single-cell perturbational transcriptomics experiment which systematically introduced over 300 wild-type and mutant open reading frames into healthy primary human germinal centre B cells. By combining innovative barcode assignment and novel correlation-based methods for analysis, I characterised the strength and transcriptional consequences of recurrent lymphoma mutations, both reproducing existing knowledge and uncovering novel functional relationships.
Taken together, the results of this thesis advance computational methodology for sequencing data analysis and demonstrate how these tools can generate new biological insights into DLBCL. The approaches developed here improve data quality, reproducibility, and interpretability, and I hope they will lay the groundwork for future translational applications in precision oncology and personalised medicine
Energy landscapes of the water hexamer and octamer for the MB-pol and TIP4P/2005 potentials.
Get PDFAmong the numerous interaction potentials available for water, MB-pol and TIP4P/2005 are popular choices to model both gas and condensed phases. Here, we examine the intermediate case of finite clusters for 6 and 8 molecules, with a thorough survey of the energy landscapes using a combination of basin-hopping global optimization and discrete path sampling methods. The two potentials predict qualitatively similar energy landscapes for both the hexamer and octamer. However, important differences arise due to changes in the energetic ordering of corresponding minima, including the global minimum itself. Differences in the classical heat capacities are relatively modest and mostly occur at low temperatures as a result of transitions between competing isomers. The heat capacity peaks can be assigned and interpreted using the temperature gradient of the occupation probabilities and involve only a few minima. The polarizable and flexible MB-pol model is more sophisticated than the rigid, non-polarizable TIP4P/2005 model and produces different intermediates in the isomerization pathways between low-energy configurations of the hexamer. In contrast, the pathways connecting low-lying cubic isomers of the octamer agree quantitatively between the two models, aside from some energetic reordering
Work, Time and Wellbeing: A Quantitative Analysis
Get PDFSince the onset of the COVID-19 pandemic, working-time reduction has become increasing prominent in both academic and popular debate in the UK. Reorganisations of work under the furlough scheme alongside large-scale pilots of the four-day week have highlighted the possibility of a new social order where work monopolises less of our time. The key question that this thesis seeks to examine is whether reductions in paid working time can deliver social benefits, and then how these benefits might be distributed along gender lines. Uniting feminist time-use literature with critical philosophy on self-directed time being central to human freedom, this thesis examines whether women – due to their disproportionate role in performing unpaid work – can access the same benefits of reductions in paid working time compared to men. The thesis employs quantitative methods to answer these questions, exploring the relationship between paid working time, unpaid work, self-directed time, and wellbeing. The thesis also develops a case for a ‘gendered politics of time’ which advocates for a societal reduction in paid working time, but with an equal focus on reducing and distributing unpaid work so access to self-directed time is equally available across society.
Using the Understanding Society Covid-19 panel, the first empirical chapter establishes that shorter working hours are not associated with adverse wellbeing consequences relative to full-time employment, however this was not the case for the cessation of work under the full-furlough scheme. Women in particular saw more substantial negative effects compared to men – prompting further research into the factors that might underpin this mechanism. These factors are then explored in the second empirical chapter - using data from the CTUR’s UK Time Use Survey 6-Wave Sequence across the COVID-19 Pandemic, 2016-2021 – to examine how changes in working hours reshape patterns of time-use, enjoyment, and wellbeing differentially along gender lines. Reductions in paid work led to the reallocation of time across more enjoyable activities for both men and women, however gendered discrepancies remained in relation to unpaid work time and self-directed time.
Moving beyond the pandemic context, the third chapter draws on data from the UK’s largest four-day week pilot to examine how reductions in paid working time influenced weekly time-use and subsequently wellbeing. Importantly, increased time spends on hobbies were found to be associated with both improved life satisfaction and mental health. While women saw relatively larger increases in time spends on hobbies, in absolute terms, men spent more time on hobbies at both the beginning and the end of the pilot – emphasising the continued inequalities women face in realising the benefits of working time reduction.
The final empirical chapter examines population-level preferences (captured using Labour Force Survey data), for paid working hours and how they have changed between 2019 and 2024. Once demographic factors are accounted for, men and women express similar preferences, indicating that gender differences in preferences are not driven by work orientations but rather structural constraints. A declining preference for shorter hours over the study period highlights how economic insecurity, likely due to the cost-of-living crisis, shapes attitudes towards working-time reduction.
Situating the analysis within contemporary policy debates on working-time reduction, the conclusion argues that reductions in paid working time can enhance wellbeing and expand life outside work, but that benefits are unevenly realised along gendered lines. Advancing a ‘gendered politics of time’, it argues that working-time reduction can only deliver equitable wellbeing gains if accompanied by policies that address the unequal distribution of unpaid work, positioning time as a central dimension of social and economic policy
A geometric perspective on the τ -cluster morphism category
Get PDFWe show how the τ-cluster morphism category may be defined in terms of the wall-and-chamber structure of an algebra. This geometric perspective leads to a simplified proof that the category is well-defined
An inverse method for mechanical characterization of heterogeneous diseased arteries using intravascular imaging.
Get PDFThe increasing prevalence of finite element (FE) simulations in the study of atherosclerosis has spawned numerous inverse FE methods for the mechanical characterization of diseased tissue in vivo. Current approaches are however limited to either homogenized or simplified material representations. This paper presents a novel method to account for tissue heterogeneity and material nonlinearity in the recovery of constitutive behavior using imaging data acquired at differing intravascular pressures by incorporating interfaces between various intra-plaque tissue types into the objective function definition. Method verification was performed in silico by recovering assigned material parameters from a pair of vessel geometries: one derived from coronary optical coherence tomography (OCT); one generated from in silico-based simulation. In repeated tests, the method consistently recovered 4 linear elastic (0.1 ± 0.1% error) and 8 nonlinear hyperelastic (3.3 ± 3.0% error) material parameters. Method robustness was also highlighted in noise sensitivity analysis, where linear elastic parameters were recovered with average errors of 1.3 ± 1.6% and 8.3 ± 10.5%, at 5% and 20% noise, respectively. Reproducibility was substantiated through the recovery of 9 material parameters in two more models, with mean errors of 3.0 ± 4.7%. The results highlight the potential of this new approach, enabling high-fidelity material parameter recovery for use in complex cardiovascular computational studies
Structural and functional analysis of the Bacillus cereus GerI inosine-responsive spore germinant receptor
No full textBacterial endospores are metabolically dormant yet can rapidly return to vegetative growth upon exposure to nutrients through the process of germination. Spore germination is triggered by specific chemical nutrients binding to cognate germinant receptors (GRs) in spores’ inner membrane. These GRs function as ligand-gated ion channels and are composed of clusters of at least three subunits. Given their central role in germinant recognition and discrimination, elucidating 3D structures of GR subunits is a key part of efforts to understand the mechanism(s) of spore germination. Here we present the crystal structure of the N-terminal domain of the Bacillus cereus GerIA protein (GerIANTD), a component of the inosine-responsive GerI GR. GerIANTD adopts a conformation homologous to substrate-binding proteins in bacterial ABC transporters. NMR chemical shift perturbation and site-directed mutagenesis identified GerIANTD residues potentially involved in inosine binding or critical for germinosome assembly in B. cereus spores, the absence of which abrogated inosine-induced germination. Molecular modelling and mutagenesis identified residues in the GerIB subunit forming germinant and cation-binding sites. GerQ, the second GR that contributes to inosine germination in B. cereus spores, was capable of complementing hypomorphic gerI alleles in several instances, demonstrating cooperative restoration of function despite being incapable of initiating germination to inosine in gerI null spores. Collectively, our results provide new insights into GR subunit function and the molecular basis of the B. cereus germinative response to inosine
A Novel Natural Element Method for Assessing Phreatic Line in Flood Defense Structures
No full textThe assessment of flood defense structures is essential for community resilience and disaster prevention. Within these structures, the potential for erosion and piping mechanisms poses critical risks, often leading to severe infrastructure damage. Breach initiation and growth are the main causes of dam and levee failure, which is directly affected by the phreatic line. This study introduces a natural element method (NEM) formulation with Sibson interpolation specifically tailored to directly estimate the phreatic line in homogeneous earthen embankments, avoiding conventional mesh generation and reducing preprocessing effort. The main innovation is the combination of a mesh-free NEM scheme with an iterative free-surface update dedicated to phreatic line tracking, rather than full embankment flow field simulation. Comparative analyses and validation against existing data emphasize the method’s strength. Validation against piezometric data from a railway embankment in Cumbria (UK) and the IJkdijk full-scale test levee (Netherlands) shows average relative errors below 2% and maximum errors under 10%, demonstrating that the proposed NEM approach can reproduce observed phreatic levels with high accuracy using relatively few nodes. These results indicate that the method provides an accurate and practically attractive tool for phreatic line assessment in flood defense structures, suitable for integration into levee and embankment safety evaluations
A smartphone analogy to explore the origin of animals
No full textHow animals evolved from their unicellular ancestor is a fundamental biological question. The fact that all animals are monophyletic—sharing a single common ancestor—implies their origin from unicellular eukaryotes was likely driven by rare and highly advantageous innovations. While the fossil record and initial genomic comparisons suggested animals originated by the rapid acquisition of many novel genes, new research on animal’s closest unicellular relatives reveals most of those genes originated before animals evolved. Here we present a new model for animal origins, which shares similarities with the origin of one of the greatest technological innovations of our time: the smartphone. We show that the origin of both animals and smartphones was due to the integration and repurposing of pre-existing components driven by a novel “operating system”, rather than the sudden emergence of many new parts. This model offers testable predictions and a new theoretical framework for understanding complex biological innovation