6,525 research outputs found

    Life on a scale:Deep brain stimulation in anorexia nervosa

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    Anorexia nervosa (AN) is a severe psychiatric disorder marked by low body weight, body image abnormalities, and anxiety and shows elevated rates of morbidity, comorbidity and mortality. Given the limited availability of evidence-based treatments, there is an urgent need to investigate new therapeutic options that are informed by the disorder’s underlying neurobiological mechanisms. This thesis represents the first study in the Netherlands and one of a limited number globally to evaluate the efficacy, safety, and tolerability of deep brain stimulation (DBS) in the treatment of AN. DBS has the advantage of being both reversible and adjustable. Beyond assessing the primary impact of DBS on body weight, psychological parameters, and quality of life, this research is novel in its comprehensive approach. We integrated evaluations of efficacy with critical examinations of the functional impact of DBS in AN, including fMRI, electroencephalography EEG, as well as endocrinological and metabolic assessments. Furthermore, this work situates AN within a broader theoretical framework, specifically focusing on its manifestation as a form of self-destructive behavior. Finally, we reflect on the practical, ethical and philosophical aspects of conducting an experimental, invasive procedure in a vulnerable patient group. This thesis deepens our understanding of the neurobiological underpinnings of AN and paves the way for future research and potential clinical applications of DBS in the management of severe and enduring AN

    Deep learning-based multimodality classification of chronic mild traumatic brain injury using resting-state functional MRI and PET imaging

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    Mild traumatic brain injury (mTBI) is a public health concern. The present study aimed to develop an automatic classifier to distinguish between patients with chronic mTBI (n = 83) and healthy controls (HCs) (n = 40). Resting-state functional MRI (rs-fMRI) and positron emission tomography (PET) imaging were acquired from the subjects. We proposed a novel deep-learning-based framework, including an autoencoder (AE), to extract high-level latent and rectified linear unit (ReLU) and sigmoid activation functions. Single and multimodality algorithms integrating multiple rs-fMRI metrics and PET data were developed. We hypothesized that combining different imaging modalities provides complementary information and improves classification performance. Additionally, a novel data interpretation approach was utilized to identify top-performing features learned by the AEs. Our method delivered a classification accuracy within the range of 79–91.67% for single neuroimaging modalities. However, the performance of classification improved to 95.83%, thereby employing the multimodality model. The models have identified several brain regions located in the default mode network, sensorimotor network, visual cortex, cerebellum, and limbic system as the most discriminative features. We suggest that this approach could be extended to the objective biomarkers predicting mTBI in clinical settings

    Beam scanning by liquid-crystal biasing in a modified SIW structure

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    A fixed-frequency beam-scanning 1D antenna based on Liquid Crystals (LCs) is designed for application in 2D scanning with lateral alignment. The 2D array environment imposes full decoupling of adjacent 1D antennas, which often conflicts with the LC requirement of DC biasing: the proposed design accommodates both. The LC medium is placed inside a Substrate Integrated Waveguide (SIW) modified to work as a Groove Gap Waveguide, with radiating slots etched on the upper broad wall, that radiates as a Leaky-Wave Antenna (LWA). This allows effective application of the DC bias voltage needed for tuning the LCs. At the same time, the RF field remains laterally confined, enabling the possibility to lay several antennas in parallel and achieve 2D beam scanning. The design is validated by simulation employing the actual properties of a commercial LC medium

    A view of colonial life in South Australia: An osteological investigation of the health status among 19th-century migrant settlers

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    Studies of human skeletal remains contribute to understanding the extent to which conditions prevailing in various past communities were detrimental to health. Few of these studies have evaluated the situation in which the first European colonists of South Australia lived. Colonial Australian skeletal collections are scarce, especially for research purposes. This makes the 19th-century skeletal remains of individuals, excavated from St Mary’s Cemetery, South Australia, a rare and valuable collection. The overarching aim of this thesis was to investigate the general and oral health of this specific group of 19th-century settlers, through the examination of their skeletons and dentitions. Four research papers in this thesis address this overarching aim. The first two papers determine the general skeletal health of the settlers, with a focus on pathological manifestations on bones associated with metabolic deficiencies and the demands of establishing an industrial society. Paper 3 investigated whether Large Volume Micro- Computed Tomography (LV Micro-CT) could be used as a single technique for the analysis of the in situ dentoalveolar complex of individuals from St Mary’s. This led to a detailed investigation of the dentitions of the St Mary’s sample, in paper 4, with the aims of determining the oral health status of these individuals, and understanding how oral conditions may have influenced their general health. The skeletal remains of 65 individuals (20 adults and 45 subadults) from St Mary’s sample were available for the four component investigations using non-destructive techniques - macroscopic, radiographic and micro-CT methods. Signs of nutritional deficiencies (vitamin C and iron) were identified in Paper 1. The findings of paper 2 showed joint diseases and traumatic fractures were seen and that gastrointestinal and pulmonary conditions were the leading causes of death in subadults and adults respectively. Paper 3 found that the LV Micro-CT technique was the only method able to generate images that allowed the full range of detailed measurements across all the oral health categories studied. A combination of macroscopic and radiographic techniques covered a number of these categories, but was more time-consuming, and did not provide the same level of accuracy or include all measurements. Results for paper 4 confirmed that extensive carious lesions, antemortem tooth loss and evidence of periodontal disease were present in the St Mary’s sample. Developmental defects of enamel (EH) and areas of interglobular dentine (IGD) were identified. Many individuals with dental defects also had skeletal signs of co-morbidities. St Mary’s individuals had a similar percentage of carious lesions as the British sample, which was more than other historic Australian samples, but less than a contemporary New Zealand sample. The 19th-century migrants to the colony of South Australia were faced with multiple challenges such as adapting to local environmental conditions as well as participating in the development of settlements, infrastructure and new industries. Evidence of joint diseases, traumatic injuries and health insults, seen as pathological changes and/ or abnormalities on the bone and/or teeth, confirmed that the settlers' health had been affected. The number of burials in the ‘free ground’ area between the 1840s -1870s was greater than the number in the leased plots, reflecting the economic problems of the colony during these early years. Validation of the reliability and accuracy of the LV Micro-CT system for the analysis of the dentoalveolar complex, in situ within archaeological human skull samples, provided a microanalytical approach for the in-depth investigations of the St Mary’s dentition. Extensive carious lesions, antemortem tooth loss and periodontal disease seen in this group would have affected their general health status. The presence of developmental defects (EH and IGD) indicated that many of the settlers had suffered health insults in childhood to young adulthood. Contemporaneous Australian, New Zealand and British samples had comparable findings suggesting that little improvement had occurred in their oral health since arriving in South Australia. In conclusion, the findings of this investigation largely fulfilled the initial aims. Our understanding of the extent to which conditions prevailing in the new colony were detrimental to human health has increased, as has our knowledge of why pathological manifestations and/or abnormalities were seen on the bones and teeth of individuals from the St Mary’s sample. A multiple-method approach, to derive enhanced information has been shown to be effective, whilst establishing a new methodology (LV Micro-CT) for the analysis of dentition in situ in human archaeological skulls. Further, this investigation has digitally preserved data relating to this historical group of individuals for future comparisons.Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 202

    Meso-scale FDM material layout design strategies under manufacturability constraints and fracture conditions

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    In the manufacturability-driven design (MDD) perspective, manufacturability of the product or system is the most important of the design requirements. In addition to being able to ensure that complex designs (e.g., topology optimization) are manufacturable with a given process or process family, MDD also helps mechanical designers to take advantage of unique process-material effects generated during manufacturing. One of the most recognizable examples of this comes from the scanning-type family of additive manufacturing (AM) processes; the most notable and familiar member of this family is the fused deposition modeling (FDM) or fused filament fabrication (FFF) process. This process works by selectively depositing uniform, approximately isotropic beads or elements of molten thermoplastic material (typically structural engineering plastics) in a series of pre-specified traces to build each layer of the part. There are many interesting 2-D and 3-D mechanical design problems that can be explored by designing the layout of these elements. The resulting structured, hierarchical material (which is both manufacturable and customized layer-by-layer within the limits of the process and material) can be defined as a manufacturing process-driven structured material (MPDSM). This dissertation explores several practical methods for designing these element layouts for 2-D and 3-D meso-scale mechanical problems, focusing ultimately on design-for-fracture. Three different fracture conditions are explored: (1) cases where a crack must be prevented or stopped, (2) cases where the crack must be encouraged or accelerated, and (3) cases where cracks must grow in a simple pre-determined pattern. Several new design tools, including a mapping method for the FDM manufacturability constraints, three major literature reviews, the collection, organization, and analysis of several large (qualitative and quantitative) multi-scale datasets on the fracture behavior of FDM-processed materials, some new experimental equipment, and the refinement of a fast and simple g-code generator based on commercially-available software, were developed and refined to support the design of MPDSMs under fracture conditions. The refined design method and rules were experimentally validated using a series of case studies (involving both design and physical testing of the designs) at the end of the dissertation. Finally, a simple design guide for practicing engineers who are not experts in advanced solid mechanics nor process-tailored materials was developed from the results of this project.U of I OnlyAuthor's request

    Dissecting the effect of EGF starvation on the signaling and transcriptomic landscapes of the mouse intestinal epithelium

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    Die EGFR-Signalübertragung steuert viele verschiedene zelluläre Prozesse in allen Arten von Epithelzellen, einschließlich des Darmepithels. Diese Prozesse reichen von Proliferation und Wachstum über Differenzierung bis hin zu Autophagie und Apoptose. Die vorliegende Studie zielt darauf ab, die Signalveränderungen zu charakterisieren, die im Darmepithel als Reaktion auf EGF-induzierten Hungerstress stattfinden. Kontraintuitiv führte eine 24-stündige EGF-Starre zu einer deutlichen Phosphorylierung von EGFR, MEK1/2 und ERK1/2, was auf eine Aktivierung dieser Signalachse in Darmzellen hindeutet. Diese Veränderungen waren am signifikantesten in den undifferenzierten CD44-reichen Krypta-Basiszellen. Interessanterweise war die EGF-Starvation-induzierte ERK1/2-Phosphorylierung mit der Hochregulierung einer Untergruppe von ERK-Zielgenen verbunden, bei denen es sich zumeist um primäre Zielgene handelt. Die Überexpression des EGFR-Liganden HBEGF und des FGFR-Liganden FGF1 in ausgehungerten Zellen könnte für die hungerbedingte Zunahme der MAPK-Aktivität verantwortlich sein, obwohl eine erhöhte Sekretion dieser Liganden durch ausgehungerte Organoide nicht bestätigt werden konnte. Dennoch wird die kompensatorische Ligandensekretion durch die Beobachtung gestützt, dass die erneute Zugabe von EGF zu ausgehungerten Organoiden die pERK1/2-Spiegel auf den Ausgangswert zurücksetzt, was bedeutet, dass EGF mit einem anderen von ausgehungerten Zellen sezernierten Liganden um den EGFR konkurriert. Zusätzlich zu HBEGF wurde festgestellt, dass andere Gene, die für den Schutz, das Überleben und die Regeneration des Darmepithels bekannt sind, in ausgehungerten Organoiden überexprimiert werden, wie z. B. Reg3b. Insgesamt können die in dieser Studie berichteten EGF-induzierten Veränderungen der MAPK-Signalübertragung und der globalen Genexpression als ein überlebensförderndes Programm interpretiert werden, das bevorzugt in Darmstammzellen und frühen Vorläuferzellen aktiviert wird.EGFR signaling drives many different cellular processes in all kinds of epithelial cells including the intestinal epithelium. Such processes range from proliferation and growth to differentiation to autophagy and apoptosis. The present study aims to characterize signaling changes that take place in the intestinal epithelium in response to EGF starvation-induced stress using epithelial organoids derived from the mouse duodenum and human colorectal tumor tissue. Counterintuitively, 24 h EGF starvation induced a prominent phosphorylation of EGFR, MEK1/2 and ERK1/2 indicating an activation of this signaling axis in intestinal cells. These changes were most significant in the undifferentiated CD44-high crypt base cells. Interestingly, EGF starvation-induced ERK1/2 phosphorylation was associated with upregulation of a subset of ERK target genes that were mostly primary-response targets. Overexpression of the EGFR ligand HBEGF and the FGFR ligand FGF1 in starved cells may account for starvation-driven increase in MAPK activity, although an increased secretion of these ligands by starved organoids was not confirmed. Nevertheless, compensatory ligand secretion is still supported by the observation that EGF re-addition to starved organoids restores pERK1/2 levels to baseline which implies that EGF competes for EGFR with some other ligand secreted by starved cells. In addition to HBEGF, other genes known to promote protection, survival and regeneration of the intestinal epithelium were found to be overexpressed in starved organoids such as Reg3b. Collectively, EGF starvation-induced changes in MAPK signaling and global gene expression reported in this study can be interpreted as a pro-survival program that gets activated preferentially in intestinal stem cells and early progenitors

    Serial sectioning block-face imaging of post-mortem human brain

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    No current imaging technology can directly and without significant distortion visualize the defining microscopic features of the human brain. Ex vivo histological techniques yield exquisite planar images, but the cutting, mounting and staining they require induce slice-specific distortions, introducing cross-slice differences that prohibit true 3D analysis. Clearing techniques have proven difficult to apply to large blocks of human tissue and cause dramatic distortions as well. Thus, we have only a poor understanding of human brain structures that occur at a scale of 1–100 μm, in which neurons are organized into functional cohorts. To date, mesoscopic features which are critical components of this spatial context, have only been quantified in studies of 2D histologic images acquired in a small number of subjects and/or over a small region of the brain, typically in the coronal orientation, implying that features that are oblique or orthogonal to the coronal plane are difficult to properly analyze. A serial sectioning optical coherence tomography (OCT) imaging infrastructure will be developed and utilized to obtain images of cyto- and myelo-architectural features and microvasculature network of post-mortem human brain tissue. Our imaging infrastructure integrates vibratome with imaging head along with pre and post processing algorithms to construct volumetric OCT images of cubic centimeters of brain tissue blocks. Imaging is performed on tissue block-face prior to sectioning, which preserves the 3D information. Serial sections cut from the block can be subsequently treated with multiplexed histological staining of multiple molecular markers that will facilitate cellular classification or imaged with high-resolution transmission birefringence microscope. The successful completion of this imaging infrastructure enables the automated reconstruction of undistorted volume of human tissue brain blocks and permits studying the pathological alternations arising from diseases. Specifically, the mesoscopic and microscopic pathological alternations, as well as the optical properties and cortical morphological alternations of the dorsolateral prefrontal cortical region of two difference neurodegeneration diseases, Chronic Traumatic Encephalopathy (CTE) and Alzheimer’s Disease (AD), were evaluated using this imaging infrastructure

    Investigation of quantitative magnetic resonance imaging and microRNA profiling of equine distal interphalangeal joint osteoarthritis

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    Osteoarthritis (OA) is reported to be one of the most prevalent diseases in aging horses and it significantly affects high motion joints of the equine distal limb with the distal interphalangeal joint (DIPJ) frequently affected. OA is characterised by cartilage degeneration, in addition to deterioration of other joint tissues including synovium, subchondral bone and ligaments. Joint degeneration causes pain, lameness, poor performance and can lead to premature euthanasia. Chondrocytes are the primary cell type of cartilage and they have limited ability for repair and replication. Early detection of cartilage damage is therefore essential to help prevent irreversible cartilage degeneration and progression of OA. There are no diagnostic tools available to diagnose early onset of disease in either human or veterinary medicine which has led to exploration of quantitative magnetic resonance imaging (MRI) techniques such as T2 mapping. During cartilage deterioration the collagen and proteoglycan content decreases and it is replaced by free water which increases cartilage T2 relaxation time. A small number of T2 mapping studies have been performed in equine joints using high field systems (3.0 T) however, there have not been any T2 mapping studies using low field (0.27 T) MRI, which is the most widely available system in UK equine practice. The first objective of this study was to validate a T2 mapping sequence on a low field MR system and investigate whether T2 relaxation time increases in cartilage with higher OARSI (Osteoarthritis Research Society International) histology scores. Furthermore, the study then aimed to verify low field T2 measurements with the gold standard measurement at high field. Another approach to detect early OA is analysis of microRNAs in biofluids. MicroRNAs are small noncoding RNAs that regulate gene expression at the post-transcriptional level by inhibiting translation or degrading target messenger RNA. During cellular damage microRNA profiles change, which can be associated with specific diseases. The second objective of this research was to identify differentially expressed microRNAs in the plasma and synovial fluid of horses with mild and severe DIPJ OA through small RNA-sequencing; diagnosis of OA was based on macroscopic and histological evaluation. This was followed by microRNA mimic and inhibitor transfection experiments to determine the effects of selected OA related microRNAs on equine chondrocytes in monolayer culture. To investigate the first objective eight phantoms with known T2 values underwent low field MRI to validate the T2 mapping sequence on the low field MR system and then 38 ex vivo DIPJs were imaged. A further 9 ex vivo DIPJs were imaged on both the low and high field MR system. After imaging, the DIPJs were disarticulated and samples collected for histology. Sections were graded using the OARSI scoring system. The T2 relaxation time corresponding to the section of cartilage tissue sampled was then calculated. The study successfully validated a T2 mapping sequence on a low field MR system and there was a positive correlation between low and high field T2 measurements. Results found a higher mean T2 (83-104 ms) in pathological cartilage tissue examined in this study compared to normal equine cartilage tissue, which is reported to be 40-61 ms. However, the T2 relaxation time did not increase with increasing OARSI grades in the samples analysed in this study. Small RNA-sequencing demonstrated three microRNAs (miR-16, miR-25 and miR-92a) were significantly downregulated in equine synovial fluid from horses with severe OA (P In conclusion, this thesis presents the first study to investigate quantitative T2 mapping of cartilage on a low field MR system. T2 relaxation time did not increase with increasing OARSI grades however, additional developments enhancing spatial resolution may enable T2 mapping to become a useful diagnostic tool in the future. The thesis also presents novel data on the role of miR-92a in the equine chondrocyte and further research developing in vitro 3D culture systems to allow retention of the chondrogenic phenotype will permit more studies to investigate miR-92a in the future
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