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(2022)ThesisThis thesis focuses on the development and applications of magnetic resonance electrical properties tomography (MREPT), which is an emerging imaging modality to noninvasively obtain the electrical properties of tissues, such as conductivity and permittivity. Chapter 2 describes the general information about human research ethics, MRI scanner, MR sequence and the method of phase-based MREPT implemented in this thesis. Chapter 3 examines the repeatability of phase-based MREPT in the brain conductivity measurement using balanced fast field echo (bFFE) and turbo spin echo (TSE) sequences, and investigate the effects of compressed SENSE, whole-head B_1 shimming and video watching during scan on the measurement precision. Chapter 4 investigates the conductivity signal in response to short-duration visual stimulus, compares the signal and functional activation pathway with that of BOLD, and tests the consistency of functional conductivity imaging (funCI) with visual stimulation across participants. Chapter 5 extends the use of functional conductivity imaging to somatosensory stimulation and trigeminal nerve stimulation to evaluate the consistency of functional conductivity activation across different types of stimuli. In addition, visual adaptation experiment is performed to test if the repetition suppression effect can be observed using funCI. Chapter 6 explores if resting state conductivity networks can be reliably constructed using resting state funCI, evaluates the consistency of persistent homology architectures, and compares the links between nodes in the whole brain. Chapter 7 investigates the feasibility of prostate conductivity imaging using MREPT, and distinctive features in the conductivity distribution between healthy participants and participants with suspected abnormalities.
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(2023)ThesisPsychological distress is prevalent among university students worldwide, including in Low-and-middle income countries, such as Indonesia. Considering its promising scalability, a culturally relevant Internet-delivered mindfulness intervention has potential to treat psychological distress among Indonesian university students. However, there is no previous research into the development and impact of culturally relevant internet-delivered mindfulness interventions for Indonesian university students, leaving a gap in the research literature. The current thesis aims to: a) develop a culturally adapted internet-delivered mindfulness intervention and evaluate its relevancy for Indonesian university students; b) assess its feasibility and acceptability in a pilot open trial, and c) investigate its effectiveness for treating distress among Indonesian students in a randomised controlled trial. To achieve the thesis objectives, the systematic cultural adaptation framework proposed by Barrera and colleagues (2006; 2013) was employed as a guiding framework for culturally adapting an Australian internet-delivered mindfulness program to be more relevant for Indonesian university students. The development of a culturally adapted internet-delivered mindfulness intervention was achieved through two studies using mixed-methods approach. Study 1 was an online cross-sectional survey of Indonesian students’ openness and preferences toward an internet-delivered mindfulness program. Study 2 engaged Indonesian university students, as well as mindfulness or mental health experts in focus group discussions, structured interviews, and the completion of cultural relevancy questionnaires. The purpose of Study 2 was to gain feedback on an initial version of the culturally adapted program. These studies showed that an internet-delivered mindfulness intervention is relevant for Indonesian university students, but some adjustments needed to be made to enhance its cultural suitability and engagement. Based on these studies, an Indonesian counsellor-guided internet-delivered mindfulness program, called PSIDAMAI (Program Intervensi Mindfulness Daring Mahasiswa Indonesia) was developed. Subsequently, Study 3 assessed the feasibility, acceptability, and preliminary clinical outcomes of counsellor guided PSIDAMAI using a pre-post open trial study design. Study 3 showed that PSIDAMAI was feasible, acceptable, and associated with significant improvements in psychological distress between baseline and post-treatment, with good completion rates (70%). In Study 4, the clinical efficacy of PSIDAMAI was tested in a randomized controlled trial using a wait-list control group as a comparator. Study 4 found that PSIDAMAI was more effective at improving psychological distress compared to the wait-list control group with medium to large between-group effect sizes. The improvements were maintained up to one-month follow-up. In summary, the thesis is the first to demonstrate evidence that a culturally adapted internet-delivered mindfulness intervention is relevant, acceptable, feasible, effective, and has positive impacts for Indonesian university students’ mental health. Thus, strategies for wider implementation within the Indonesian higher education mental health system are now needed.
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(2024)ThesisAnti-GD2 immunotherapy has significantly enhanced survival of high-risk neuroblastoma patients however efficacy is strongly hampered by the immunosuppressive tumour microenvironment. Given the emerging link between copper and immune evasion, we assessed the impact of copper chelation therapy on neuroblastoma using the agents tetraethylenepentamine (TEPA) and the clinically approved analogue triethylenetetramine (TETA; marketed as Cuprior®). Using the preclinical TH-MYCN model, we performed single-cell RNA sequencing supported by OPAL multiplex immunohistochemistry and cytokine profiling to assess cellular and molecular changes occurring with TEPA treatment in the neuroblastoma tumour microenvironment. Copper chelation was observed to successfully deplete intratumoural copper to reinvigorate anti-tumour immunity as signalled by increased infiltration and activity of pro-inflammatory immune cells, specifically N1 neutrophils. Mechanistic in vitro assays reveal sequestration of copper by neuroblastoma cells causing dysregulated neutrophil function, with successful reversal upon TEPA treatment. Findings propose a novel mechanism of immune evasion, highlighting copper chelation as a therapeutic strategy to counteract immunosuppression. Copper chelation is further shown to increase GD2 expression, while also enhancing neutrophil antibody-dependent cellular cytotoxicity in vitro. Using the TH-MYCN model, TEPA was found to potentiate anti-GD2 therapy to achieve durable tumour control. This was associated with increased Fc-receptor-bearing natural killer and CD11B+ myeloid cells capable of performing antibody-dependent cellular cytotoxicity. Finally, we evaluated TETA for repurposing as a novel immunomodulatory agent. Comparative in vitro studies with TEPA confirm the ability of TETA to deplete intratumoural copper and downregulate immune checkpoint proteins Programmed Death-Ligand 1 (PD-L1) and indoleamine-pyrrole 2,3-dioxygenase (IDO). Using the preclinical NXS2 model, TETA exhibited an exceptional safety profile without altering copper levels or GD2 expression in healthy nerve tissue. Combination with anti-GD2 therapy achieved durable tumour control with no relapses occurring after treatment cessation and was similarly associated with infiltration of pro-inflammatory immune cells. Collectively, study findings credential copper chelation as a non-toxic strategy to overcome the immunosuppressive tumour microenvironment and improve neuroblastoma patient outcomes.
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(2024)ThesisAn important question in Biology is how biological systems' complexity has expanded while the number of protein-coding genes has remained mostly stable. Previous research has shown that increased biological complexity has arisen partly from the dynamic generation of unique cell-specific transcriptomes. However, studies of tissues across distant animal lineages have shown that gene expression is highly conserved between the same tissues in different species. Hence, gene expression alone is unlikely to explain the expansion in complexity across vertebrate evolution. Instead, it is becoming evident that the plethora of post-transcriptional mechanisms expanding transcriptomic diversity underlies these advances. Among these, alternative splicing (AS), the process by which multiple distinct transcripts and protein variants express a single gene, appears to be the most widespread, as it regulates more than 95% of multi-exon genes. However, further layers of post-transcriptional regulation are known to impact tissue-specific evolution. These include the creation of non-coding RNAs, alternative promotor usage (APU), and alternative cleavage and polyadenylation (APA). In this thesis, I first focus on circular RNAs (circRNAs) as they are the product of back-splicing, affecting transcriptome complexity. Comparisons of circRNAs in human and mouse have shown that most human circRNAs are absent in mouse, suggesting a rapid expansion of circRNA molecules during evolution. Thus, I used transcriptomes of primate species to understand the evolutionary dynamics of circRNA in closely related species. I found that most circRNAs across primates are species-specific. Still, a small subset has a conserved neural expression. Such conserved circRNAs have longer downstream introns due to the insertion of novel retrotransposons than non-conserved circRNAs. Another limitation in the literature is the usage of is the use of short-read sequencing technology. Therefore, the conservation of full transcript expression and the coordinated regulation of AS, APA and APU events across evolution remains unknown. Thus, in the present thesis, I used comparative transcriptomics across vertebrate species to assess the conservation of mRNA isoforms and coordinated splicing events of AS, APA and APU using direct RNA Nanopore long-read sequencing. I found that most conserved coordinate splicing events are associative and tissue-specific. Still, a set of conserved coordinate splicing events is expressed across multiple tissues and regulates basic cellular functions. Altogether, in my thesis, I showcase the effect of distinct evolutionary processes affecting transcriptome complexity and its impact on phenotypic complexity.