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Low molecular weight hydrogels for cell culture and bioprinting
Get PDFLow molecular weight gelators (LMWG) are promising candidates for biomaterials due to their unique properties such as their reversibility and ability to hold large volumes of solvent. However, issues can arise when attempting to gel these materials under conditions acceptable for cell culture. In this thesis, the aim was to develop and comprehensively characterise a LMWG system at physiological pH. We employ a variety of techniques to investigate these materials across different length scales. By doing so, we have highlighted the significance of such characterisation when developing novel non-covalent biomaterials.
We outline how the dipeptide-based LMWG 2NapFF (diphenylalanine protected with a naphthalene group at the N-terminus) produces biocompatible hydrogels when crosslinked with ions present in cell culture media. We also explore the impact of heating and cooling the gelator solution prior to initiating gelation as well as the impact of adding PODS® (micron-scale proteins containing cargo molecules which are gradually released over prolonged peroids) to the system for functionalisation purposes. Our findings reveal that a heating and cooling cycle can be used to adjust the properties of the resulting network without changing the gelator itself. Moreover, it was found that PODS® had minimal effect on the properties of the hydrogel, indicating that they can enhance the bioactivity of the systems without altering the network structure. PODS
Furthermore, we compare the 2NapFF hydrogels previously discussed to a Ureidopyrimidinone (UPy) supramolecular hydrogel system, consisting of a monofunctional building block and bifunctional crosslinker species. We explored the effects of combining these two systems, both with and without the UPy crosslinker. Our results show that the assembly of the combined systems is primarily driven by the UPy component. Furthermore, the UPy crosslinker plays a vital role in the self-sorting of the UPy and 2NapFF components. It was also revealed that for cells to adhere effectively, the bifunctional UPy subunit was crucial to produce a supportive network.
In the final experimental chapter, we investigate the potential of the 2NapFF hydrogels crosslinked with cell culture media as bioinks for extrusion-based 3D printing. Through optimisation of the printing process, it was demonstrated that the type of media used to trigger gelation directly impacted the printability of the systems. As a result, the samples that consistently formed self-supporting structures were selected for printing macrophage cells, which remained viable within the gel after 24 hours. Bioprinting macrophages can be used in applications such as immune system and tumour microenvironment modeling
Towards sustainable and nature-based flood risk management in the Philippines
No full textAbstract not currently available
Scaling the Finnisian ascent: a critical synthesis and analysis of the methodology of John Finnis
No full textPreface pages 1-2
Defining the role of receptor phosphorylation on mGlu5 metabotropic glutamate receptor signal transduction
Get PDFThe type 5 metabotropic glutamate receptor (mGlu5) is a G protein-coupled receptor (GPCR) located on excitatory neurons, and its dysfunction has been linked to multiple neuropathologies such as Alzheimer’s disease (Abd-Elrahman et al., 2020). Previous data form our laboratory on phosphoproteomic analysis of the hippocampus of wildtype mice showed that global mGlu5 phosphorylation increases following a fear conditioning learning and memory test, but the specific role of phosphorylation on signal transduction was not identified. To elucidate the role of mGlu5 phosphorylation, the aim of this thesis was to dissect the signal transduction pathways downstream of G protein versus phosphorylation dependent pathways.
Phosphodeficient mutants of mGlu5 were generated by synthesising a mouse ortholog mGlu5 C-terminus with either all serine residues (mGlu5-PD), or all serine and threonine residues (total phosphodeficient mutant, mGlu5-TPD) mutated to alanine. Signal transduction pathways were assessed by generating stable cell lines expressing either wildtype mGlu5, mGlu5-PD or mGlu5-TPD. In βarrestin 2 recruitment assays, removal of putative phosphorylation sites within the C-terminus of mGlu5 was found to negatively impact the ability of the receptor to recruit β-arrestin 2. In calcium mobilisation, IP1 accumulation, and G protein dissociation assays assessing the Gαq dependent transduction pathway, there was no difference in responses between wildtype and phosphodeficient mutant receptors following agonist stimulation. However, the basal activity was reduced with removal of putative C-terminal phosphorylation sites. To further examine G protein activation, a bioluminescent resonance energy transfer (BRET)-based single genetically encoded biosensor was generated to compare the impact of phosphorylation on mGlu5 G protein activation. Findings with this biosensor revealed a reduced level of G protein activation with the phosphodeficient mutants compared to wildtype receptor.
These results demonstrate that phosphorylation of the mGlu5 C-terminus appears to predominantly modulate ligand-independent signalling through the G protein-coupled pathway, whilst phosphorylation of C-terminal serine and threonine residues impacts ligand-dependent and ligand-independent β-arrestin 2 recruitment. Therefore, understanding the impact of mGlu5 phosphorylation on receptor signalling is likely to be crucial when considering the therapeutic potential of this receptor
Longer-term effects of SARS-CoV-2 infection on blood vessels and blood pressure
Get PDFIntroduction:
This thesis aims to address critical gaps in our understanding of the interplay between COVID-19 infection, Renin-Angiotensin-Aldosterone System (RAAS) dysregulation, and hypertension. The first objective investigates whether COVID-19 infection increases the risk of developing hypertension post-recovery by conducting a prospective follow-up of non-hypertensive individuals over a 12-month period, assessing blood pressure and endothelial function. The second objective explores the role of RAAS dysregulation in post-COVID-19 hypertension by analysing RAAS pathway components and blood pressure changes in the same cohort. The third objective seeks to determine if whether individuals post COVID-19 have any differences in QoL utilising EQ-5D-3L instrument (EQ-5D-3L Index and Visual Analog Scale (VAS) scores). The fourth objective examines the association of ACE inhibitors and different antihypertensive drug classes and statins on the risk of SARS-CoV-2 infection using longitudinal studies and machine learning techniques to analyse linked electronic health records, adjusting for confounding variables.
Methods:
To assess whether COVID-19 increases the risk of hypertension post-recovery, we conducted a 12-month follow-up of non-hypertensive individuals. Blood pressure and endothelial function were monitored using ambulatory blood pressure monitoring and brachial flow-mediated dilation. Quality of life (QoL) was measured with the EQ-5D-3L questionnaire. RAAS components and blood pressure changes were analysed to investigate RAAS dysregulation. Advanced machine learning techniques were applied to estimate individual treatment effects (ITE) for the four major classes of antihypertensive drugs in comparison to statins across two distinct time frames of the COVID-19 pandemic.
Results:
There was a significant rise in blood pressure among recovered COVID-19 patients, with systolic pressure increasing by 4.57 mmHg and diastolic by 4.46 mmHg over 12 months compared to controls. A 3.15% reduction in flow-mediated dilation (FMD) suggested endothelial dysfunction. No significant difference in RAAS fingerprinting was observed. While recovered COVID-19 participants reported lower QoL, this was not statistically significant at 12 months follow-up. Our machine learning model found ACE inhibitors and statins were associated with increased SARS-CoV-2 infection risk, while thiazides showed mixed effects, and beta blockers and calcium channel blockers were associated with decreased risk.
Discussion:
The increase in blood pressure seen 12 months after recovery from COVID-19 suggest the need for prioritising cardiovascular monitoring in post-COVID-19 era. Although RAAS fingerprinting showed no significant difference, the blood pressure rise and reduced FMD suggest RAAS dysregulation may contribute to post-infection hypertension. Machine learning-based ITE estimation could potentially revolutionise studies of drug efficacy and adverse reactions, especially when randomised controlled trials are impractical.
Conclusion:
This thesis advances our understanding of COVID-19's cardiovascular consequences and provides insights for future mechanistic studies and clinical and public health policies. The observed blood pressure rise, and potential endothelial dysfunction post-recovery indicate the need for vigilant cardiovascular monitoring. The use of machine learning to estimate individual effects of antihypertensive drugs on COVID-19 risk underscores the importance of personalised treatment. Further research should elucidate long-term cardiovascular impacts and develop targeted interventions
Enhancing robustness and adaptability in motion intent recognition: a multimodal approach with advanced neural networks and meta-learning
No full textAbstract not currently available
Exploring the mechanisms of acemannan bioactivity in a novel collagen-PEG hydrogel scaffold for skin tissue engineering
No full textAbstract not currently available
Essays on information economics under ambiguity
Get PDFThis thesis consists of three chapters, each examining the impact of ambiguity on a specific economic problem.
Chapter 1, Competitive Insurance Market Under Ambiguity, extends the classic Stiglitz and Rothschild model to a setting where insurers face ambiguity about the composition of their customers. Using the epsilon-contamination framework, I characterize insurance contracts in a screening game under ambiguity, considering two scenarios: pooling equilibrium and separating equilibrium. Additionally, I provide a criterion that guarantees the existence of a separating equilibrium under ambiguity—an outcome not observed in the standard no-ambiguity model.
Chapter 2, Moral Hazard Under Ambiguity, examines the principal-agent problem in which both the principal and the agent face ambiguity about the stochastic relationship between the agent’s effort and the project outcome. The chapter explores the optimal contract when effort is observable and the sub-optimal contract when effort is unobservable, within the context of ambiguity aversion. I specify conditions under which the principal’s decision to induce high or low effort under ambiguity aligns with the decision in the absence of ambiguity.
Chapter 3, Cheap Talk With Ambiguous Beliefs, explores the cheap talk problem in the spirit of Crawford-Sobel (CS), introducing ambiguity by relaxing the assumption that both the sender and receiver know the actual distribution of the private message. The chapter examines CS-like partition equilibria in cases of small, complete, and intermediate ambiguity, using various frameworks to model ambiguity. It offers new insights into how ambiguity influences agents’ behavior in strategic communication games
Perylene bisimide hydrogels: optimisation of supramolecular systems for developing electrogenic tissue mimicry
No full textAbstract not currently available
Development of a cross-reactive fluorescent sensor array for the detection of liver fibrosis
No full textAbstract not currently available
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