Anatomy and Neuroscience - Theses
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ItemEarly neuronal and glial cell changes in diabetic retinopathy(University of Melbourne, 2010)
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ItemModulation of the intermediate-conductance calcium-activated potassium (IKca) channel by protein kinase a (PKA)(University of Melbourne, 2010)
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ItemNeural plasticity and gene-environment interactions in the PLC-?1 knockout mouse(University of Melbourne, 2007)
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ItemNo Preview AvailableTracing Diet and Mobility of Past Human Populations in Greater Mtskheta, Georgia( 2021)The region of Greater Mtskheta (Republic of Georgia) lies in the Southern Caucasus and presents a near continuous record of human occupation throughout the Late Bronze-Early Iron Age (LBA-EIA, 1500-500 BC), Hellenistic Period (400-1 BC) and Roman-Late Antique Period (RLA; AD 1-700). Greater Mtskheta became increasingly urbanised, densely populated and hosted an increasingly complex society during these time periods. Contemporary written sources provide little insight into the lifestyles and social organisation maintained by Mtskheta’s inhabitants; researchers rely heavily on the trace remains of Mtskheta settlements and cemeteries to reconstruct how the inhabitants lived and what resources they consumed. Archaeological investigations reveal that by the 1st century AD, the resident society was multi-cultural, socially stratified and maintained far-reaching trade networks with the Greeks, Romans, Parthians, and Sassanid Persians. Following the 4th century AD a series of cultural changes emerge in Greater Mtskheta cemeteries including a shift in burial customs, the appearance of people with intentionally modified crania and new ‘Eurasian’ styles of grave goods. These changes suggest a novel cultural influence arrived in Mtskheta at this time, which has been tentatively attributed to contact with Eurasian nomadic-pastoralists from the steppe of southern Russia. Stable Isotope analysis of archaeological human and faunal remains can provide insight into the diet composition and mobility of people from ancient times. This research examines carbon, nitrogen and strontium isotope ratios (d13C, d15N, and 87Sr/86Sr) of humans excavated from Greater Mtskheta cemeteries remains dating between 1500 BC-AD 700. Diet was compared between time periods, sites, demographic groups (age-at-death, sex) and cultural groups (burial types, modified/unmodified skulls) to illustrate how dietary access or preferences differed over time and between these groups. Further, analyses were used to examine the role migration played in the onset of cultural changes after the 4th century. d13C and d15N results show Greater Mtskheta residents consumed a mixed C3 and C4 diet in the LBA-EIA, which is consistent with a trend in similar studies of human populations in Inner Asia and the South Caucasus during this time. The human diet in Mtskheta transitioned to a C3-dominated diet by the RLA Period, a trend which was also displayed by 87Sr/86Sr populations in the Kislovodsk basin (North Caucasus). LBA-EIA diets differed between men and women, possibly indicating greater animal product consumption among males of this period; while diets became isotopically homogeneous between sites and demographic groups in the RLA period, at a time when social stratification and complexity in Mtskheta was at its peak. The 87Sr/86Sr results demonstrate some individuals with intentionally modified skulls immigrated to Mtskheta after the 4th century, and these individuals may have originated from the vicinity of the North Caucasus or Alazani Valley. This study demonstrates the Greater Mtskheta human diet changed significantly between the LBA-EIA and the RLA with increasing social complexity, and indicates the Greater Mtskheta inhabitants maintained cultural connections with the surrounding regions throughout these time periods, apparently mirroring regional isotopic trends in diet, and evidently accommodating migrants after the 4th century AD.
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ItemComplex spatial 3D anatomy of the tarsal tunnel and the plantar compartments of the foot( 2021)Anatomical understanding of the foot, to a level appropriate to inform precise clinical management, is lacking. Whilst much of the foot is in need of a clear evidence-base, the tarsal tunnel and plantar compartmentalisation of the foot are areas of particular concern for two reasons. First, the anatomy of these areas is readily visualised in a lab setting, so should be well- investigated, yet it is not. Secondly, conditions that affect these areas, such as tarsal tunnel syndrome and plantar compartment syndromes, are common and can be debilitating or even life-threatening. The clinical identification and management of these disorders is varied, has high rates of failure and high rates of patient dissatisfaction from procedures that the clinical team deem successful. Something is amiss, and the confusion and inconsistency in the reviewed literature suggests that imprecise anatomical knowledge may be a prominent contributing factor. The studies presented in this thesis aimed to explore, in sequence, the tarsal tunnel, followed by the medial and lateral columns of the foot. This sequence follows the structures coursing into the plantar aspect of the foot via the tarsal tunnel. These studies aimed to present a detailed anatomical account of these areas by using clear protocols, which involved a variety of dissection, 3D modelling, sectional anatomy and medical imaging techniques. Dissection involved following individual fascicles of soft tissue structures, identifying their orientation and attachments. Each structure was modelled during dissection, as to revaluate the spatial relationships of structures in 3D space post-dissection. Sectional anatomy and medical imaging were used to correlate the dissection findings for what is more readily applied in a clinical setting. The tarsal tunnel roof was described variably in the reviewed literature. The current data demonstrated that the roof is not formed by a singular structure, but through the combination of the passive flexor retinaculum and the dynamic abductor hallucis muscle. The boundaries of the tunnel were defined by the roof, making the description of these tissues of greater importance clinically. The tunnel was also subdivided by fibrous tissues, suggesting that the neurovasculature could be compressed by various surrounding structures. This contrasts much of the reviewed literature and provides anatomical evidence for some failures of surgical release. These data may inform tarsal tunnel surgical care and could increase the effectiveness of these procedures. The plantar aspect of foot was described in the reviewed literature as having anything from zero to ten compartments. Differences in terminology, investigative medium and methodology may have contributed to the variability. The data presented here clearly and consistently demonstrated four distinct compartments of the mid- to hind-foot region: medial, lateral and two central plantar compartments. They had well-defined anatomical boundaries formed by fibrous and muscular intermuscular septae. The relationship of the bounding structures to the muscular and tendinous structures, and the course of the plantar neurovascular bundles was demonstrated digitally in three dimensions. These models may help inform the diagnosis of causative relations for nerve impaction or vascular blockage which lead to compartment syndromes, or simply increase the likelihood of rapid decline in health, such as with foot ulceration in a patient with advanced diabetes. Lower limb amputation and death are common acute sequelae of inadequate treatment of patients in such situations, so improved anatomical understanding may hasten the diagnosis. The studies presented in the form of this thesis provide a technical foundation for future anatomical studies in the foot and other regions of the body. These data provide accurate and reproducible accounts of the complex anatomy of the tarsal tunnel and plantar foot compartments and may have a positive impact on the future care of common foot disorders.
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ItemBenchmarking and developing human pluripotent stem cell models of macrophage biology( 2021)Macrophages are innate immune cells that are found resident in every tissue, and are not only important for host defense, but are also involved in tissue homeostasis, injury, and disease. The advent of human pluripotent stem cells (hPSCs) provides new opportunities to model human macrophages. However, a deeper appreciation of the functional diversity of macrophages, including contextual responsiveness, and innate memory is currently missing from stem cell differentiation studies. Immune responsiveness to pathogenic challenge is known to be impacted by a macrophage's history of prior exposure, but this has not been evaluated in the context of hPSC-derived myeloid cells. This thesis describes the development of a transcriptomic atlas, the Myeloid Atlas, to assess impact of macrophage ontogeny, experimental treatment, and tissue residency on molecular phenotype. In doing so, we have revealed gaps in hPSC-macrophage models, revealing several differences between hPSC-macrophages, peripheral blood monocyte-derived macrophages and primary tissue resident cells. These differences include poor maturation in hPSC-macrophages in the absence of priming signals such as IFN, or repeated exposure to LPS. We demonstrate the requirement for priming in hPSC-macrophages and discover the importance of re-stimulation events in shaping macrophage activation. We further assess phenotypic heterogeneity in both peripheral blood monocyte-derived macrophages and hPSC-macrophages using single-cell RNA sequencing. We demonstrate synchronized population responses to LPS activation and further provide evidence for priming in shaping macrophage responsiveness. Overall, these findings highlight that macrophages are shaped by prior activating, or priming, signals which can be recapitulated in the laboratory using re-stimulation events that shape population phenotypes. The outcomes of this work are expected to improve routine macrophage derivation from hPSC sources, as exploitation of the requirement for in vitro macrophage priming provides future opportunities to shape the quality of acute or long-term macrophage responsiveness for diverse applications.
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ItemNanosecond Laser Therapy for the Management of Age-related Macular Degeneration( 2021)Age-related macular degeneration (AMD) is a chronic, progressive disease affecting the central retina and remains the leading cause of irreversible vision loss in developed nations. AMD is a multifactorial disease encompassing a complex interplay between ageing, environmental and genetic risk factors which ultimately lead to chronic inflammation and death of photoreceptors. While the pathophysiology of AMD is still not fully understood, recent advances have highlighted the involvement of the innate immune system and RPE dysfunction to be fundamental to the development and progression of this debilitating condition. As such, therapies that can influence these two systems have the potential to slow progression of disease. Despite advances in the treatment of neovascular AMD, there remains no effective treatment for non-neovascular AMD and importantly, interventions that address the progression from early to sight-threatening late AMD remain limited. The progression to late stages is usually slow, providing a large window of opportunity to intervene. Novel laser treatments, specifically short-duration pulsed lasers such as the subthreshold nanosecond laser (SNL), offer a potential therapeutic option. The fundamental aims of this study were to investigate SNL-induced cellular response in the RPE that may have potential benefits for addressing pathologic changes that occur in the RPE/BM interface in AMD, and to determine whether changes to the RPE are associated alterations to systemic innate immunity. SNL treatment, delivered in a single session, to the posterior eye in wildtype mice was confirmed using immunohistochemistry to selectively target the RPE without causing damage to the overlying retina. The laser-ablated RPE monolayer was healed within 3 days post-treatment with evidence indicative of newly proliferated daughter cells. Importantly, this proliferative response was also observed in the non-laser treated fellow eye. RNA sequencing and pathway analysis of laser-treated RPE identified biologically-relevant pathways including the promotion of cell survival and cell proliferation, and the inhibition of inflammation and apoptosis. Together, the fellow eye effect and RNA sequencing results suggest that a SNL-induced systemic change involving innate immunity may likely be involved. Systemic change in leukocyte phagocytosis function following SNL treatment was examined for 12-month old wildtype and in the mouse model of AMD (P2X7-null mice). Real-time flow cytometry showed a laser-induced reduction in total phagocytosis capacity of yellow-green fluorescent beads 3 months following SNL treatment. Subsequent ultrastructural studies in the P2X7-null mice showed a significant thinning of the pathologically thickened Bruch’s Membrane (a hallmark feature in AMD). The role of SNL in altering the systemic response, including phagocytosis and cytokine changes, was investigated in a cohort of patients with intermediate AMD. Similar to the rodent results, a substantial reduction in peripheral monocyte phagocytosis was also observed for all subsets of monocyte populations occurring from 3 months following SNL treatment. This reduction was sustained for at least 12 months post-treatment without any significant recovery to pre-laser levels. Cytometric bead array demonstrated significant changes to cytokine-profile with an acute elevation of 9 to 13 cytokines involved in inflammation (of a total of 13 cytokines) at the 2 weeks to 3 month post-treatment time points using 200 SNL spots. At the 6 month time point, a significant increase in interleukin-6 remains in the laser-treated participants compared to pre-laser levels. In summary, these findings indicate that SNL can induce a rejuvenating response by promoting RPE proliferation in both the treated eye and the non-treated eye while also reducing the thickness of BM in the eye that received SNL treatment. This study also provides evidence that SNL therapy has the potential to modify systemic immune responses, including phagocytosis function and cytokine-profile. Taken together, our results indicate a potential role for SNL treatment of AMD to slow progression of disease.
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ItemThe Clinical Anatomy of the Hallucal Sesamoids and their Attachments( 2021)The hallucal sesamoid bones are essential, but poorly understood, features of the first, or great, toe complex. With the associated structures of the foot, collectively termed the first ray, this complex is essential for optimal foot function. Disorders of this region present symptomatically in a broad range from intermittent discomfort through to a complete inability to walk or weight-bear. Pain in this region may also be enough to interrupt sleep and a range of daily tasks. Given the perceived importance of the hallucal sesamoids to this complex, it is perhaps surprising to discover the anatomy of the hallucal sesamoids, and particularly their interaction with neighbouring tissues, is poorly understood. One major consequence of this is the lack of a clear, consistent anatomical foundation for the diagnosis, treatment (including surgically) and management of these disorders. This thesis will document a series of studies which aim to collectively enhance the anatomical understanding of the hallucal sesamoids and their relations. After exploring the historical context of the hallucal sesamoids, reviewing the current anatomical and clinical literature, and establishing some key concepts about the presence, absence and variability of these bones, a series of detailed studies will be presented. Using a multi-modal approach that includes dissection, 3D modelling, medical imaging and sectional anatomy (macro and micro), the key tissues thought to interact with the hallucal sesamoids will be investigated: the adductor and abductor hallucis muscles, the plantar aponeurosis, the flexor hallucis brevis muscle and a range of highly specialised ligaments. The ligaments include the deep transverse metatarsal and sesamophalangeal, , amongst others, along with interactions with other tissues such as tendon tunnels, plantar plates and joint capsules. Of particular importance when considering the function of these structures is their attachment to skeletal tissues, such as the hallucal sesamoids. There is contention over what tissues are attached to each of the two hallucal sesamoids. These studies provide a detailed, quantified and uniquely visualised account of the attachments to each bone, and to neighbouring structures. This comprehensive account provides a strong basis for the development of more anatomically informed diagnostic approaches and clinical management of disorders of this area. The key findings presented in this thesis include definitive three dimensional mapping of the detailed attachments to each hallucal sesamoid. These dispel common misconceptions that the sesamoids are engulfed by a single tissue, or that they do not have substantial connections to a range of structures. These data strongly demonstrate these sesamoids have multidirectional interactions which maintain their dynamic position through the gait cycle, but are also particularly vulnerable to injury, including iatrogenic injury. In fact, poor post-operative outcomes from surgical treatments in this area may be attributable to a lack of anatomical understanding. Studies demonstrate the intimate relationships between structures often targeted for surgical release and those which must be maintained. These relations, and particularly the innovative three-dimensional visualisations developed from these data, may inform significant advances in first ray health care.
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ItemThe adult Drosophila salivary gland: developing a new epithelial research model( 2021)Arthropod-borne viruses, also known as arboviruses, are transmitted to humans through arthropod bites. Viruses such as Dengue, West Nile, and Zika are transmitted through mosquito bites and cause serious illness in humans. These viruses are injected into a human host in the saliva of a feeding mosquito, a process that hinges on the virus invading the mosquito’s salivary glands. Therefore, a deep understanding of insect salivary glands is an important step in learning how to control arboviruses. One of the world’s most popular research organisms, Drosophila melanogaster, is a relative of the mosquito and of other insect disease vectors. Drosophila salivary glands could provide an excellent model for studying the transmission of arboviruses, unfortunately extraordinarily little is known about the glands of adult Drosophila. The aim of this research project was to develop the adult Drosophila salivary glands as a research model for studying the interactions between arboviruses and insect salivary glands. Since little is known about the glands, my investigations focused on understanding the structure, function, and maintenance of the cells within the salivary gland. To understand the structure of salivary glands, I first investigated the structure of the organ, before looking closely at individual cells. I characterised the structure of the cells by investigating localisation of cell-junctions, cytoskeletal elements, and cell-polarity markers. I also observed the establishment of these morphological features throughout different stages of development. Second, by combining the structural data with investigations into intracellular signals and membrane channels, I provided a hypothesis of the functions of salivary gland cells. Then, by analysing cell division and cell-maintenance pathways in the salivary glands, I provided an insight to how the salivary gland cell population is maintained. From this project the salivary glands emerged as a multifaceted research model that could be used to investigate arboviral diseases, epithelial tissues, and amitotic division.