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Tar-DNA binding protein of 43kDa (TDP-43) mislocalisation from the nucleus to the cytoplasm is the characteristic post-mortem pathology of amyotrophic lateral sclerosis (ALS). TDP-43 mislocalisation occurs in both the brain and spinal cord in 97% of all ALS cases, regardless of whether the origin of disease is genetic or sporadic. Sporadic ALS patients make up the vast majority of ALS, but work to decipher neurodegenerative pathways and develop potential therapeutics is lacking. A critical limitation to understanding and correctly developing new therapeutics to this majority of ALS patients can be attributed to, at least in part, to the inability to effectively model disease without expressing familial genetic mutations. Whilst the aetiology is not clear, clinical studies have shown that one of the earliest changes in ALS patients is increased excitability as well as network changes within the motor cortex. Furthermore, these physiological changes occur before symptom onset in people with familial ALS. The cause of cortical hyperexcitability in ALS is not known. Understanding the physiological effects of TDP-43 mislocalisation, including potential effects of neuron excitability in ALS is an integral step to understanding the how the disease begins and how it progresses through the corticomotor system. To more accurately model sporadic ALS, this thesis utilised two inducible mouse models of wild-type human TDP-43 expressed in forebrain neurons, the first with standard wild-type TDP-43 (TDP-43\(^{WT}\)) and the second with TDP-43 which had an ablated nuclear localisation sequence (TDP-43\(^{ΔNLS}\)). In the TDP-43\(^{ΔNLS}\) mouse model, transgenic TDP-43 cannot enter the nucleus after translation, resulting in accumulation of TDP-43 in the cytoplasm of neurons in the brain. The TDP-43\(^{ΔNLS}\) mouse model replicates sporadic ALS in that it has mislocalised TDP-43, but without any causative ALS mutations. Furthermore, the transgenes in both the TDP-43\(^{ΔNLS}\) and TDP-43\(^{WT}\) mouse models can be expressed in adulthood, thereby mitigating any potential developmental effects and more precisely model the adult onset of the disease. This thesis employed a CamKIIa promotor to localise human TDP-43 to the cortex. With 30 days of induced TDP-43 expression there was substantial human TDP-43 protein in excitatory neurons in the brain, but no cell loss of layer V pyramidal neurons in either the TDP-4343\(^{WT}\) or TDP-43\(^{ΔNLS}\) motor cortex. Chapter two of this thesis analysed dendritic spines, the structure on which excitatory synaptic communication between neurons occurs. With 30 days of mislocalised TDP-43 expression in the brain, there was substantial loss of dendritic spines in basal, apical and apical tuft dendrites on upper motor neurons. However, driving expression of TDP-43 with an intact nuclear localisation sequence caused no such synaptic dysfunction. This shows that the appropriate localisation of TDP-43 is important for excitatory synaptic function in upper motor neurons. The hyperexcitability of upper motor neurons in ALS is hypothesised to be an early, important physiological feature of the disease that could potentially underlie the initiation and progression of the disease. The third chapter of this thesis aimed to investigate how TDP-43 mislocalisation influences functional measures of excitability in upper motor neurons through patch clamp electrophysiology. Intrinsic excitability, excitatory synaptic input and inhibitory synaptic input were measured with 30 days of induced TDP-43 expression to form a series of electrophysiological measures at a single timepoint. TDP-43\(^{ΔNLS}\) neurons were intrinsically hyperexcitable, having both a higher maximum firing frequency and a lower rheobase compared to both WT animals and TDP-43WT expressing mice. TDP43\(^{ΔNLS}\) neurons also had reduced frequency of both mini- and spontaneous excitatory post-synaptic currents, reflecting the loss of synapses observed in chapter two. However, no changes to the frequency or amplitude of mini- and spontaneous inhibitory post-synaptic currents were observed. These are the first experiments to show that mislocalisation of TDP-43 can cause the hyperexcitability of upper motor neurons that is observed in the clinic. This thesis has revealed changes to both intrinsic excitability and excitatory synaptic input following 30 days of induced mislocalised TDP-43 expression. However, determining the first physiological change due to TDP-43 mislocalisation is important for the understanding of disease progression and development of therapeutics for ALS. For the final results chapter of this thesis, a time-course of excitability changes was employed. The first excitability measure to change was identified as increased intrinsic excitability, following 20 days of TDP-43\(^{ΔNLS}\) expression, with excitatory synaptic input changed only at 30 days. Experiments from this chapter determined a timeline of ALS-related excitability changes, providing critical context for the evolution of excitability in ALS. The data from this thesis provides the first evidence that TDP-43 mislocalisation causes synaptic dysfunction alongside aberrant hyperexcitability, linking the earliest clinical symptoms to arise in people with ALS to the mislocalisation of TDP-43. Furthermore, a time-course of TDP-43 mislocalisation induced changes revealed that upper motor neurons first develop hyperexcitability before progressing to develop significant excitatory synapse dysfunction and dendritic spine loss with extended TDP-43 mislocalisation. Findings from this thesis implicate the pathogenic mislocalisation of TDP-43 to the cytoplasm in generating motor cortical hyperexcitability and, perhaps resultant, widespread synaptic dysfunction in ALS, having important consequences for current and future therapeutics.

Among the many different processes proposed for large-scale carbon capture and storage (CCS), high-temperature CO 2 looping has emerged as a favorable candidate due to the low theoretical energy penalties that can be achieved. Many different materials have been proposed for use in such a process, the process requiring fast CO 2 absorption reaction kinetics as well as being able to cycle the material for multiple cycles without loss of capacity. Lithium ternary oxide materials, and in particular Li 2 ZrO 3 , have displayed promising performance, but further modifications are needed to improve their rate of reaction with CO 2 . Previous studies have linked rates of lithium ionic conduction with CO 2 absorption in similar materials, and in this work we present work aimed at exploring the effect of aliovalent doping on the efficacy of Li 2 ZrO 3 as a CO 2 sorbent. Using a combination of X-ray powder diffraction, theoretical calculations, and solid-state nuclear magnetic resonance, we studied the impact of Nb, Ta, and Y doping on the structure, Li ionic motion, and CO 2 absorption properties of Li 2 ZrO 3 . These methods allowed us to characterize the theoretical and experimental doping limit into the pure material, suggesting that vacancies formed upon doping are not fully disordered but instead are correlated to the dopant atom positions, limiting the solubility range. Characterization of the lithium motion using variable-temperature solid-state nuclear magnetic resonance confirms that interstitial doping with Y retards the movement of Li ions in the structure, whereas vacancy doping with Nb or Ta results in a similar activation energy as observed for nominally pure Li 2 ZrO 3 . However, a marked reduction in the CO 2 absorption of the Nb- and Ta-doped samples suggests that doping also leads to a change in the carbonation equilibrium of Li 2 ZrO 3 , disfavoring the CO 2 absorption at the reaction temperature. This study shows that a complex mixture of structural, kinetic, and dynamic factors can influence the performance of Li-based materials for CCS and underscores the importance of balancing these different factors in order to optimize the process.

As he marriage and family enrichment movement has matured issues concerning Ihe selection. mining. and certification of leaden have become more important. Early leaders were self-attained: but successful continuation of the movement. requires a systematic approach for training and verifying the competence of pnctitioneis. This process is complicated by the diversity in the field. To illusrate current approaches to training this article presents in detail he training and certification model used by the Association of Couples for Marriage Enrichment and in less detail the models used by Couples Communication Program. Understanding Us. Family Clusters, and Relationship Enhancement.