Isotope reconstructions of East Asian Monsoon behaviour across Glacial Terminations I and II from Lake Suigetsu, Japan (IAP2−18−54)

Understanding the response of the East Asian Monsoon to rising temperatures is crucial in light of recent anthropogenic climate change and the vulnerability of East Asia to future climatic hazards. However, East Asian Monsoon dynamics during warming periods in the late Quaternary are poorly understood, particularly on decadal to millennial timescales. Significant sources of this uncertainty are the spatially and temporally heterogeneous responses of the East Asian Monsoon to submillennial temperature fluctuations. The conflicting patterns observed in available reconstructions of East Asian Monsoon strength suggest that the teleconnections acting during these intervals were complex. Understanding the behaviours of the East Asian Monsoon by accounting for links to remote climatic perturbations allows for a more holistic understanding of deglacial climate changes. A means of tackling this ambiguity is by contributing well−dated, high−resolution records of East Asian Monsoon evolution spanning Glacial Terminations I and II (which typify accessible, contrasting examples of rapid global warming) to the growing network of reconstructions from across the region. The aim of this thesis is to deconvolve East Asian Monsoon evolution during the last two glacial terminations by utilising the unique hydrological distribution of East Asian Monsoon precipitation over Japan to reconstruct both seasonal modes of the system (i.e., the East Asian Winter Monsoon and East Asian Summer Monsoon). This aim is met by the construction of isotope−based, season−specific East Asian Monsoon records across Glacial Terminations I and II using materials from the Lake Suigetsu sediment cores. This thesis is comprised of four interconnected research papers, preceded by an introduction and succeeded by a summary of findings, discussion of relevance, suggestions for future work and conclusions. In the first research paper, we utilise extended contemporary monitoring of the stable isotope composition of precipitation, river water and lake water in the Lake Suigetsu catchment to understand the factors affecting these variables and aid robust interpretation of isotope−based proxy reconstructions from the Lake Suigetsu sediment cores. Our results show that the composition of precipitation was influenced by the dual East Asian Monsoon system, and that these signals were then transferred to the lake system where they were combined with secondary local influences on lake water composition. Based on our knowledge of late Quaternary catchment dynamics, these observations suggest that the palaeo−isotope composition of Lake Suigetsu was closely related to the East Asian Monsoon. In the second research paper, we examine the influence of remote climatic processes on the East Asian Winter Monsoon and East Asian Summer Monsoon in Japan during Glacial Termination I by reconstructing trends in the strength of each seasonal mode. This is achieved using oxygen isotope analysis of diatom silica and compound−specific hydrogen isotope analysis of n−alkanoic acids from the Lake Suigetsu sediment cores. Our results support distinctive seasonal behaviours of the East Asian Monsoon during Glacial Termination I, with evidence for East Asian Winter Monsoon weakening and East Asian Summer Monsoon strengthening. The East Asian Summer Monsoon also exhibited variations in strength which were synchronous with Antarctic temperature fluctuations after 16,000 years ago, which supports a temporally restricted climatic link between Japan and the Southern Hemisphere at this time. In the third research paper, we reconstruct the East Asian Summer Monsoon in Japan during Glacial Termination II, and contrast the findings to those from Glacial Termination I. The reconstruction presented in this chapter, which is based on compound−specific hydrogen isotope analysis of n−alkanoic acids, provides evidence for early East Asian Summer Monsoon strengthening followed by a gradual weakening phase with submillennial−scale variability. Comparison of this record to others derived from mainland China supports the assertion that East Asian Summer Monsoon behaviours during Glacial Termination II were spatially heterogenous. Additionally, the different evolutions of the East Asian Summer Monsoon during Glacial Terminations I and II indicate that the system operated distinctively under contrasting boundary conditions, although the new reconstructions from Japan were consistently more closely linked with Southern Hemisphere (Antarctic) temperatures than Northern Hemisphere (Greenlandic) temperatures during both intervals. The fourth research paper was motivated by a lack of an absolute chronology for the oldest (pre−50,000 years ago) parts of the Lake Suigetsu sediment cores (which includes Glacial Termination II). In this paper, we appraise the luminescence characteristics of the cores using rapid profiling techniques. These are employed across four key time periods in order to assess the application of these methods for the detection of local and environmental shifts, and to assess the suitability of the core materials for luminescence dating. We show that the luminescence characteristics of the cores were susceptible to a range of environmental perturbations, best illustrating local changes by using high−resolution contiguous sampling. The feasibility of future luminescence dating is supported by quantifiable luminescence signals, and first order approximate ages suggest that blue light optically stimulated luminescence dating of feldspar provides the most accurate and most practical assessment of burial age. This technique should be the subject of dating efforts in pursuit of refinements to the Suigetsu core chronology before 50,000 years ago. The findings of this thesis contribute to our collective knowledge of East Asian Monsoon behaviours during glacial terminations. Critically, they represent a geographical expansion of the regional high−resolution record network to include Japan. The value of this process is demonstrated by the decoupled evolutions of each seasonal mode during Glacial Termination I, and a remote link between Antarctic temperatures and East Asian Summer Monsoon evolution in Japan during Glacial Terminations I and II, which were hitherto unconstrained by high resolution analysis. These findings acknowledge and begin to rationalise spatial and temporal heterogeneities in East Asian Monsoon behaviours by comparison to other records. This work highlights the complexity of the East Asian Monsoon, and the value of long records from contrasting deglacial periods for a better comprehension of this system in the context of anthropogenic climate change

Investigating the impact of lung cancer cell-of-origin on tumour metabolic phenotype and heterogeneity

Non-small-cell lung cancer has been described as highly heterogenous which results in different metabolic phenotypes. There are multiple factors which contribute to this heterogeneity, one of which is the tumour cell-of-origin. In the lung, there are five cell types reported to be cells-of-origin: alveolar epithelial type 2, club, basal, neuroendocrine and bronchioalveolar stem cells. This project focuses on the interaction between the cell-of-origin and the metabolic phenotype of lung cancer, and we aim to assess the contribution of the cell-of-origin to lung cancer metabolic resultant phenotype and heterogeneity. To accomplish this, we have established two complementary model systems, one in vitro and one in vivo. In our in vitro model, we isolated specific lung cell types, including AT2 cells, basal cells, and club cells, utilising their unique cell surface markers. By introducing oncogenic KRAS mutations and deleting the P53 gene, we are creating lineage-restricted organoids. These organoids will serve as valuable tools for characterizing the metabolic aspects of tumours arising from different cell-of-origin backgrounds within an in vitro setting. In our in vivo model, we induced NSCLC tumours in mice with genetic modifications using viral vectors, namely Ad5-mSPC-Cre, Ad5-CC10-Cre, and Ad5- bk5-Cre. These vectors are selectively expressed in AT2, club, and basal cells, respectively. To ensure the validity of our comparisons, we have carefully monitored tumour growth dynamics and burden in these mouse models. Our comprehensive analysis has revealed three distinct transcriptomic subtypes (S1, S2, and Acetate) within these NSCLC tumours. Notably, S1 and Acetate subtypes are enriched in tumours originating from specific cell types. Positron emission tomography (PET) imaging has unveiled metabolic variations, with S1 tumours displaying heightened [18F]FDG uptake and the Acetate subtype exhibiting increased [11C]acetate uptake. Furthermore, our multi-omics approach, encompassing transcriptomics, proteomics, and metabolomics, has exposed disparities in critical metabolic pathways, such as glycolysis, hypoxia response, and apoptosis. In summary, our research provides a comprehensive examination of the metabolic heterogeneity of NSCLC based on the cell-of-origin independently of genomic alterations

Advanced sequencing technologies applied to human cytomegalovirus

The betaherpesvirus human cytomegalovirus (HCMV) is a ubiquitous viral pathogen. It is the most common cause of congenital infection in infants and of opportunistic infections in immunocompromised patients worldwide. The large double-stranded DNA genome of HCMV (236 kb) contains several genes that exhibit a high degree of variation among strains within an otherwise highly conserved sequence. These hypervariable genes encode immune escape, tropism or regulatory factors that may affect virulence. Variation arising from these genes and from an evolutionary history of recombination between strains has been hypothesised to be linked to disease severity. To investigate this, the HCMV genome has been scrutinised in detail over the years using a variety of molecular techniques, most looking only at one or a few of these genes at a time. The advent of high-throughput sequencing (HTS) technology 20 years ago then started to enable more in-depth whole-genome analyses. My study extends this field by using both HTS and the more recently developed long-read nanopore technology to determine HCMV genome sequences directly from clinical samples. Firstly, I used an Illumina HTS pipeline to sequence HCMV strains directly from formalin-fixed, paraffin-embedded (FFPE) tissues. FFPE samples are a valuable repository for the study of relatively rare diseases, such as congenital HCMV (cCMV). However, formalin fixation induces DNA fragmentation and cross-linking, making this a challenging sample type for DNA sequencing. I successfully sequenced five whole HCMV genomes from FFPE tissues. Next, I developed a pipeline utilising the single-molecule, long-read sequencer from Oxford Nanopore Technologies (ONT) to sequence HCMV initially from high-titre cellcultured laboratory strains and then from clinical samples with high HCMV loads. Finally, I utilised a direct RNA sequencing protocol with the ONT sequencer to characterise novel HCMV transcripts produced during infection in cell culture, demonstrating the existence of transcript isoforms with multiple splice sites. Overall, my findings demonstrate how advanced sequencing technologies can be used to characterise the genome and transcriptome of a large DNA virus, and will facilitate future studies on HCMV prognostic factors, novel antiviral targets and vaccine development

Dissecting the function of recurrent complex I truncations in melanoma

Abstract not currently available

Flood dynamics derived from video remote sensing

Flooding is by far the most pervasive natural hazard, with the human impacts of floods expected to worsen in the coming decades due to climate change. Hydraulic models are a key tool for understanding flood dynamics and play a pivotal role in unravelling the processes that occur during a flood event, including inundation flow patterns and velocities. In the realm of river basin dynamics, video remote sensing is emerging as a transformative tool that can offer insights into flow dynamics and thus, together with other remotely sensed data, has the potential to be deployed to estimate discharge. Moreover, the integration of video remote sensing data with hydraulic models offers a pivotal opportunity to enhance the predictive capacity of these models. Hydraulic models are traditionally built with accurate terrain, flow and bathymetric data and are often calibrated and validated using observed data to obtain meaningful and actionable model predictions. Data for accurately calibrating and validating hydraulic models are not always available, leaving the assessment of the predictive capabilities of some models deployed in flood risk management in question. Recent advances in remote sensing have heralded the availability of vast video datasets of high resolution. The parallel evolution of computing capabilities, coupled with advancements in artificial intelligence are enabling the processing of data at unprecedented scales and complexities, allowing us to glean meaningful insights into datasets that can be integrated with hydraulic models. The aims of the research presented in this thesis were twofold. The first aim was to evaluate and explore the potential applications of video from air- and space-borne platforms to comprehensively calibrate and validate two-dimensional hydraulic models. The second aim was to estimate river discharge using satellite video combined with high resolution topographic data. In the first of three empirical chapters, non-intrusive image velocimetry techniques were employed to estimate river surface velocities in a rural catchment. For the first time, a 2D hydraulicvmodel was fully calibrated and validated using velocities derived from Unpiloted Aerial Vehicle (UAV) image velocimetry approaches. This highlighted the value of these data in mitigating the limitations associated with traditional data sources used in parameterizing two-dimensional hydraulic models. This finding inspired the subsequent chapter where river surface velocities, derived using Large Scale Particle Image Velocimetry (LSPIV), and flood extents, derived using deep neural network-based segmentation, were extracted from satellite video and used to rigorously assess the skill of a two-dimensional hydraulic model. Harnessing the ability of deep neural networks to learn complex features and deliver accurate and contextually informed flood segmentation, the potential value of satellite video for validating two dimensional hydraulic model simulations is exhibited. In the final empirical chapter, the convergence of satellite video imagery and high-resolution topographical data bridges the gap between visual observations and quantitative measurements by enabling the direct extraction of velocities from video imagery, which is used to estimate river discharge. Overall, this thesis demonstrates the significant potential of emerging video-based remote sensing datasets and offers approaches for integrating these data into hydraulic modelling and discharge estimation practice. The incorporation of LSPIV techniques into flood modelling workflows signifies a methodological progression, especially in areas lacking robust data collection infrastructure. Satellite video remote sensing heralds a major step forward in our ability to observe river dynamics in real time, with potentially significant implications in the domain of flood modelling science

Structure-activity relationships in heterogeneous catalysis: a correlation between adsorbate geometry and nitrobenzene hydrogenation with Pd/Al2O3 catalysts

Abstract not currently available

Application of disposable chiral plasmonics for biosensing and Raman spectroscopy

This thesis explores the capabilities of disposable chiral plasmonic metafilm assays, termed Disposable Plasmonic Assays, as a promising platform for biosensing and surface-enhanced Raman spectroscopy. The sensing and Raman properties of these metafilms arise from the excitation of surface plasmons when exposed to incident light. These plasmonic properties strongly depend on the geometric characteristics of the constituent nanostructures found in the metafilms. Specifically, the primary nanostructure employed throughout this research is the chiral 'shuriken' star, which generates chiral electromagnetic fields exhibiting greater chiral asymmetry than circularly polarized light. Monitoring changes in the resonance positions of the characteristic optical rotatory dispersion spectra produced by the Disposable Plasmonic Assays allows for the observation of surface binding events. By measuring resonance shift data and through the utilisation of various gold film functionalisation techniques, these assays are demonstrated as versatile, label-free biosensing platforms capable of specifically detecting a wide range of target proteins and virus particles from complex solutions. Furthermore, the multiplexing performance of these assays is showcased, enabling the detection of multiple different antigens and virions in a single experiment. These results highlight the potential of plasmonic metafilms as rapid and disposable point-of-care immunoassays for diagnostic applications. In addition to biosensing, the chiral geometry of Disposable Plasmonic Assays is exploited for the chiral discrimination of metal nanoparticles and small molecules using Surface Enhanced Raman Spectroscopy (SERS). By linking helicoid shaped gold nanoparticles to the metafilm surface via a dithiol linker, the chiral properties of both nanoparticles and metafilms combine, resulting in the creation of differential electromagnetic 'hotspot' regions based on their symmetry combinations. The electromagnetic intensity in these regions corresponds to the SERS signal obtained from the achiral dithiol linker molecule, facilitating a deeper understanding of the chirally dependent SERS phenomenon. These findings serve to validate and explain the differential SERS data obtained enantiomers of biomolecules and drug molecules from silver modified Disposable Plasmonic Assays

The assessment of low mood, distress and depression in people with severe cognitive and communication impairments following acquired brain injury

Low mood and depression are thought to be common after brain injury and are traditionally assessed using clinical interviews and self-report mood measures. This is challenging when people have persisting cognitive and receptive communication impairments following severe acquired brain injury. There is limited literature available on mood disorders and how they should be assessed when a person has severe cognitive and receptive communication impairments that impact their self-report and understanding. This thesis focusses specifically on people with severe cognitive impairments and receptive communication difficulties after brain injury with the objectives to (1) establish whether recommended mood measures have been adequately validated on the population of interest, (2) to explore what the current clinical practice of clinical psychologists and medical professionals is when assessing mood in this population; and (3) to establish whether it is possible to gain consensus among professionals on how mood should be assessed when severe cognitive and receptive communication impairments are present. The methods used included a systematic review, online surveys of clinical psychologists and medical professionals, semi-structured interviews with 23 clinical psychologists and nine medical professionals and five focus groups using the nominal group technique. The systematic review found that no self-report measures had been adequately validated with people with severe cognitive and receptive communication impairments after brain injury. One study examining the validity of two observer rated measures did not exclude those severe cognitive impairment in their validation study. These observer scales can tentatively be recommended for use in this population, with further research recommended as this validation study was limited by its size and the small number of severely impaired participants included. Surveys showed that clinicians are adapting the administration of published tools and not using the scores as intended, bringing the validity of their usage into question. The preferred approach of assessment in this population for both groups surveyed was to ask other people about the mood of the person with the brain injury. Thematic analysis of the interviews highlighted issues with the construct of depression after severe brain injury. There was also a view that separate methods are needed when severe cognitive and receptive communication impairment is present, and that the stigma of emotions can be challenging to tolerate which may put pressure on clinical psychologists to contain this and on doctors to prescribe medications. The results of five focus groups showed overlap in their views of the assessment process that should be followed. This allowed for a consensus model to be proposed based on their views. Further work on establishing wider consensus and acceptability of the proposed model with a broader group of professionals would be beneficial in establishing clinical utility. This thesis concludes that people that have persisting severe cognitive and receptive communication impairments after brain injury require a different approach to those with less severe impairments when assessing mood. Self-report measures should not be used in this population. The thesis proposes a formulation based model of assessment for this population. New guidelines need to be developed to ensure improved assessment and management of distress, low mood and depression in those with persisting severe cognitive and receptive communication impairments

The role of nursing in multimorbidity care

Background Multimorbidity (the co-occurrence of two or more chronic conditions in the same person) affects around one in three persons, and it is strongly associated with a range of negative outcomes including worsening physical function, increased health care use, and premature death. Due to the way healthcare is provided to people with multimorbidity, treatment can become burdensome, fragmented and inefficient. In people with palliative conditions, multimorbidity is increasingly common. Better models of care are needed. Methods A mixed-methods programme of research designed to inform the development of a nurse-led intervention for people with multimorbidity and palliative conditions. A mixed-methods systematic review explored nurse-led interventions for multimorbidity and their effects on outcomes. A cross-sectional study of 63,328 emergency department attenders explored the association between multimorbidity, complex multimorbidity (≥3 conditions affecting ≥3 body systems), and disease-burden on healthcare use and inpatient mortality. A focussed ethnographic study of people with multimorbidity and life-limiting conditions and their carers (n=12) explored the concept of treatment burden. Findings Nurse-led interventions for people with multimorbidity generally focus on care coordination (i.e., case management or transitional care); patients view them positively, but they do not reliably reduce health care use or costs. Multimorbidity and complex multimorbidity were significantly associated with admission from the emergency department and reattendance within 30 and 90 days. The association was greater in those with more conditions. There was no association with inpatient mortality. People with multimorbidity and palliative conditions experienced treatment burden in a manner consistent with existing theoretical models. This thesis also noted the effect of uncertainty on the balance between capacity and workload and proposes a model of how these concepts relate to one another. Discussion This thesis addresses a gap in what is known about the role of nurses in providing care to the growing number of people with multimorbidity. A theory-based nurse-led intervention is proposed which prioritises managing treatment burden and uncertainty. Conclusions Nursing in an age of multimorbidity necessitates a perspective shift which conceptualises chronic conditions as multiple overlapping phenomena situated within an individual. The role of the nurse should be to help patients navigate the complexity of living with multiple chronic conditions

Genomic surveillance to guide rabies elimination

Abstract not currently available