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Structural modifications of the RNA-binding protein, fused in sarcoma : implications for amyotrophic lateral sclerosisRobinson, Hannah January 2015 (has links)
Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disease characterised by the loss of upper and lower motor neurons, resulting in progressive paralysis, muscular atrophy and eventual death, on average, within 2-5 years post diagnosis. In ∼5% of patients with familial ALS (fALS), causative mutations occur within the gene encoding the RNA-binding protein, Fused in Sarcoma (FUS). Normally, FUS is predominantly localised to the nucleus and has several known roles in transcription, splicing and mRNA transport. Yet, in ALS patients with mutant forms of FUS, the protein becomes dramatically mislocalised to the cytoplasm and abnormal proteinaceous inclusions of FUS in the cytoplasm are observed post-mortem. Several questions remain: How do large pathological inclusions of FUS form? Is pathology induced via a gain or loss of protein function? Can aggregation in the cytoplasm of this normally nuclear protein be sufficient to produce toxicity? This thesis provides detailed characterisation of a novel pathway through which FUS may aggregate following its mislocalisation to the cytoplasm. This pathway is distinct from recruitment into stressinduced stress granules and can lead to the formation of large RNA-based FUS aggregates in a concentration-dependent manner. It was demonstrated that reduced protein-RNA interaction through transcriptional inhibition resulted in the dissolution and reassembly of these FUS aggregates into higher order RNA-free structures, reminiscent of inclusions seen in ALS-FUS patients. We also show in vivo that an initial insult of FUS aggregation in the cytoplasm is sufficient to elicit ALS-like pathology. In addition, how loss of FUS from the nucleus could affect the nuclear architecture was investigated, highlighting an important role for FUS in the maintenance of a protective subnuclear body, the paraspeckle, the disruption of which may contribute to the pathogenesis of FUSopathies. As such, this thesis identifies several novel mechanisms involved in the development and progression of FUSopathy, which may be useful for future therapeutic strategies targeting ALS caused by FUS mutation.
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Longitudinal follow-up of 22q11.2 Deletion Syndrome : a study of individuals at high risk of schizophreniaChawner, Samuel January 2015 (has links)
22q11.2 Deletion Syndrome (22q11.2DS) is one of the strongest known risk factors for schizophrenia. The syndrome provides a rare opportunity to prospectively examine development that precedes schizophrenia. 22q11.2DS is also associated with a range of psychiatric disorders and cognitive deficits. The overall aim of this thesis is to examine the neuropsychiatric phenotype of 22q11.2DS through a developmental lens. This thesis uses data from Cardiff University’s ECHO (Experiences of CHildren with cOpy number variants) study which includes a longitudinal cohort of children with 22q11.2DS. Development in 22q11.2DS is contrasted to that of the unaffected siblings of children with 22q11.2DS. First psychopathology is examined longitudinally across early adolescence in 22q11.2DS. Children with 22q11.2DS have a significant burden of psychopathology across early adolescence, including attention-deficit/hyperactivity disorder (ADHD), anxiety disorders and autism spectrum disorder (ASD). There is a striking increase in the prevalence of psychotic experiences and a decrease in ADHD prevalence. The ASD phenotype is examined further using a diagnostic interview of developmental history. ASD and subthreshold phenomenology is found to be highly prevalent in the early development of children with 22q11.2DS. Next cognitive development in 22q11.2DS is considered and contrasted to that in unaffected siblings. Cognitive deficits across a range of domains are present in 22q11.2DS. Cognitive development in 22q11.2DS is found to be similar to that reported in children who later develop idiopathic schizophrenia. This is followed by an exploration of the relations between psychopathology and cognitive development in 22q11.2DS. Cognitive development is found to predict the emergence of psychotic experiences and the persistence of ADHD in 22q11.2DS. This thesis extends what is known about the development of the neuropsychiatric phenotype in 22q11.2DS. Furthermore, findings give an insight into the developmental pathways associated with a high risk of developing schizophrenia.
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Identifying health inequalities in individuals with major mental illness (MMI) using routine dataLangan Martin, Julie January 2016 (has links)
Individuals with Major Mental Illness (such as schizophrenia and bipolar disorder) experience increased rates of physical health comorbidity compared to the general population. They also experience inequalities in access to certain aspects of healthcare. This ultimately leads to premature mortality. Studies detailing patterns of physical health comorbidity are limited by their definitions of comorbidity, single disease approach to comorbidity and by the study of heterogeneous groups. To date the investigation of possible sources of healthcare inequalities experienced by individuals with Major Mental Illness (MMI) is relatively limited. Moreover studies detailing the extent of premature mortality experienced by individuals with MMI vary both in terms of the measure of premature mortality reported and age of the cohort investigated, limiting their generalisability to the wider population. Therefore local and national data can be used to describe patterns of physical health comorbidity, investigate possible reasons for health inequalities and describe mortality rates. These findings will extend existing work in this area.
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Electrophysiological and behavioural consequences of cross-modal phase resettingPrinsloo, Kevin Damian January 2017 (has links)
No description available.
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Body perception disturbance in complex regional pain syndromeLewis, Jenny January 2008 (has links)
Complex regional pain syndrome (CRPS) is a painful, debilitating condition that is poorly understood. The syndrome is characterised by pain, motor disturbances and abnormalities in trophic, sudomotor, vascular temperature and sensation. The underlying mechanisms are unknown. Clinical observations have identified a novel phenomenon whereby patients pay little attention to, and fail to care for, their painful affected limb. The literature describes this phenomenon in terms of neglect-like symptoms similar to neurological neglect as described in stroke literature. However, this does not seem to fully fit with or explain the nature of clinical observations. Therefore the aim of the qualitative first study was to more fully describe the phenomenon through an investigation of the patient experience and words used to describe those experiences. Six themes emerged from the data and were as follows: hostile feelings; spectrum of disassociation; disparity between what is apparent and what is felt; distorted mental image of affected parts; awareness of limb position and conscious attention. From these findings a theory emerged which serves to further our understanding of body perception disturbance in CRPS. Based on these findings, the second study aimed to quantify a feature of body perception disturbance by measuring limb position accuracy of those with CRPS compared to Healthy Controls (HC) and those with Rheumatological Pain (RP). The CRPS group were significantly less accurate in positioning of both the affected and unaffected upper limbs (median=9°, Interquartile rang e (IQR), 5.7°-13.3°) compared to both HC (6.5°, IQR, 4°-10.7°) and RP groups (7.7°, IQR, 5 °-11.7°). In the CRPS group position accuracy of the affected limb significantly improved with vision (8.3° in view, 10.7° not in view). Pain intensity was significantly greater in the CRPS (6.5, IQR, 5.4-7.7) than the RP group (4.6, IQR, 3.6-5.7). Based on the findings of this research programme, a definition of body perception disturbance in CRPS is presented. Furthermore, a disrupted body schema model is proposed as an explanation of the central mechanisms responsible for body perception disturbance in CRPS.
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Conformable transistors for bioelectronicsCea, Claudia January 2023 (has links)
The diversity of network disruptions that occur in patients with neuropsychiatric disorders creates a strong demand for personalized medicine. Such approaches often take the form of implantable bioelectronic devices that are capable of monitoring pathophysiological activity for identifying biomarkers to allow for local and responsive delivery of intervention. They are also required to transmit this data outside of the body for evaluation of the treatment’s efficacy.
However, the ability to perform these demanding electronic functions in the complex physiological environment with minimum disruption to the biological tissue remains a big challenge. An optimal fully implantable bioelectronic device would require each component from the front-end to the data transmission to be conformable and biocompatible. For this reason, organic material-based conformable electronics are ideal candidates for components of bioelectronic circuits due to their inherent flexibility, and soft nature.
In this work, first an organic mixed-conducting particulate composite material (MCP) able to form functional electronic components and non-invasively acquire high–spatiotemporal resolution electrophysiological signals by directly interfacing human skin is presented. Secondly, we introduce organic electrochemical internal ion-gated transistors (IGTs) as a high-density, high-amplification sensing component as well as a low leakage, high-speed processing unit.
Finally, a novel wireless, battery-free strategy for electrophysiological signal acquisition, processing, and transmission that employs IGTs and an ionic communication circuit (IC) is introduced. We show that the wirelessly-powered IGTs are able to acquire and modulate neurophysiological data in-vivo and transmit them transdermally, eliminating the need for any hard Si-based electronics in the implant.
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The neuropsychiatry and neuropsychology of Lipoid ProteinosisThornton, H. B. 12 1900 (has links)
Thesis (PhD (Psychiatry))--University of Stellenbosch, 2006. / Lipoid Proteinosis (LiP) is a rare hereditary disease, which often results in bilateral,
symmetrical and circumscribed calcifications in the mesial temporal region (especially
the amygdala). While several case studies have been published on individuals with this
illness, there have been few systematic investigations of the neuropsychiatry and
neuropsychology of a series of patients. Thirty-seven LiP patients were extensively
assessed with standardized neuropsychiatric and neuropsychological measures. Of
these, 27 patients from the Northern Cape in South Africa were matched (for age,
gender, education, language, geographical area) with 53 controls. There was a high
incidence of neuropsychiatric disorders in LiP (more than half of the subjects reported a
history of depression or anxiety and 12% had a diagnosis of schizophrenia). Despite a
wide variance, LiP subjects performed poorly on facial recognition for emotions and on
most neuropsychological measures including intelligence, recall and executive
functioning. These findings are consistent with involvement of the mesial temporal areas
in mood, anxiety, and psychotic symptoms, and in the cognitive-affective processes.
Future work aimed at delineating the associations between the clinical and
neuropsychological findings reported here, for example, with brain-imaging techniques,
is needed.
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Sleep restriction therapy : experimental studiesMiller, Christopher B. January 2014 (has links)
Insomnia is a common disturbance of sleep which can be treated effectively with cognitive behavioural therapy; a multicomponent ‘package’ of cognitive and behavioural strategies. Sleep restriction therapy is thought to be one of the most potent behavioural components of cognitive behavioural therapy. Subjective measures of sleep and daytime functioning improve not only with cognitive behavioural therapy, but also during and following sleep restriction therapy. However, it is unknown when these changes occur or if there are associated objective changes. This thesis addresses these issues, and presents: 1. a review of the literature of therapy and original research; 2. evaluates the nature and timing of changes in self-reported daytime functioning during therapy; 3. profiles potential objective changes (in measurements of sleep, plasma and salivary cortisol concentrations & temperature); and 4. compares patients with different subtypes of insomnia and healthy good sleeping controls for possible differences within the brain that might serve as future targets for treatment. The final general discussion ties together the results of these data-based chapters. The following section aims to provide a brief summary of the overall thesis. This Ph.D. was undertaken as Cotutelle Agreement between the Universities of Glasgow, United Kingdom and Sydney, Australia. Specific chapters relate to the data collection performed at these two sites. Consequently this thesis has been split into specific chapters from where the data were obtained. Chapters four and five consist of data acquired from Glasgow, United Kingdom whilst in chapters six and seven the data were acquired in Sydney, Australia.
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Neural correlates of prospective memory : an EEG and ICA approachCruz San Martin, Gabriela Paz January 2014 (has links)
Have you ever entered a room and wondered ‘What am I supposed to do here?’ or have you ever forgotten to turn off the oven, hang your clothes to dry or make a phone call. These examples illustrate the relevance of ‘prospective memory’ or ‘delayed intentions’ in our daily life activities. Prospective memory is the ability to remember to do something after a delay. This thesis addresses three questions relevant to understand maintenance and execution of intentions: Is attention required to retrieve delayed intentions? What does monitoring mean in the context of prospective memory? Is prospective memory a discrete memory system or it is based on already known attentional and memory mechanisms? To answer these questions, we used electroencephalography (EEG), in (traditional) non-movement and free-movement experimental paradigms. We explored the neural substrate of prospective memory across its different stages: (1) holding intentions during a delay, (2) detecting the right context to perform the delayed intention, and (3) retrieving the content of the intention (the action to be performed). Two types of prospective memory tasks were used: Event-based prospective memory (performing a delayed intention in response to an external cue) and time-based prospective memory (performing the intention at a particular time). Results indicate that: prospective memory always requires attention, at least in experimental contexts; monitoring involves different mechanisms depending on the particular features of the prospective memory task and; prospective memory is not a discrete memory system, but relies on well-established mechanisms for attention and executive control.
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The motor nerve terminal is a novel regulator of anti-ganglioside antibodies in mouse models of autoimmune neuropathyCunningham, Madeleine Elizabeth January 2015 (has links)
Autoimmune neuropathies are a group of conditions resulting from inflammatory attack of the peripheral nervous system (PNS). Guillain-Barré syndrome (GBS), an acute autoimmune neuropathy, presents in both axonal and demyelinating forms. Axonal forms of GBS are caused by autoantibodies which target gangliosides on peripheral nerves. Here, they cause axonal damage via activation of the complement pathway. In ex vivo preparations, anti-ganglioside antibodies have been shown to cause complement-mediated injury to the node of Ranvier and the motor nerve terminal. Of these two vulnerable sites, the motor nerve terminal has recently been shown to be able to internalise anti-ganglioside antibody while the node of Ranvier does not. Rabbit models have demonstrated that immunisation with ganglioside results in a motor axonal neuropathy but no such model currently exists in mice. This is partially due to the fact that wildtype mice respond poorly when immunised with ganglioside and partially due to the requirement of an exogenous complement source to cause injury. This laboratory has recently developed GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice with complex ganglioside expression restricted to neurons and glia, respectively. This thesis aimed to develop a mouse model of GBS by actively immunising these mice with ganglioside liposomes. Subsequently, the aims were expanded to look at the clearance of the antibodies by membranes which express their ganglioside target. To complete these aims, wildtype, GalNAcT-/-, GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice were compared. Following immunisation with liposomes containing GD1b, wildtype mice responded poorly as demonstrated by low presence of immunoglobulin in their sera. Conversely, GalNAcT-/- mice, which lack complex gangliosides, showed high presence of immunoglobulin in their sera. GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice showed intermediate levels. This was assumed to be due to varying levels of tolerance to “self” lipids among the mice. However, when normal human serum was introduced, GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice did not show any complement-mediated injury. Based upon evidence from ELISpots from the splenocytes of these mice, there did not appear to be any major differences in anti-GD1b antibody-producing cells among genotypes. The possibility that the antibodies produced by these mice were being removed by internalisation was investigated at the NMJ ex vivo and in vivo. Ex vivo, antibodies against complex gangliosides were demonstrated to be cleared in a receptor-dependent and activity-dependent manner. Following passive immunisation with pathogenic monoclonal antibody in vivo, serum levels of the antibody were cleared rapidly in wildtype mice but remain elevated at 7 days in GalNAcT-/- mice. GalNAcT-/--Tg(neuronal) mice cleared antibody at an intermediate rate. Non-pathogenic antibodies were not cleared from the circulation over the 7 days from any of the three genotypes. These results have demonstrated that levels of anti-ganglioside antibody can be regulated by receptor-dependent internalisation, especially at the motor nerve terminal. These studies have highlighted this structure as a novel regulator of anti-ganglioside antibody in vivo. The clearance of antibody is also dependent on the ability of the antibody to bind to living tissue; therefore antibodies detected in patient serum may not represent pathogenic, disease-causing antibodies. These factors may profoundly influence host vulnerability to antibody-mediated disease by affecting circulating levels of pathological antibodies.
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