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The loss and dysfunction of selected populations of synapses is characteristic of mammalian brain ageing and alterations in these receptive compartments are considered to underpin age-related cognitive decline. Discrete neuro-anatomical regions of the cortical architecture harbour disparate populations of synapses that demonstrate significant heterogeneity with regards to advancing age. Of particular interest is the hippocampus, which is selectively vulnerable during ageing. The hippocampal synaptic architecture exhibits subtle structural and biophysical alterations, which are considered to promote the manifestation of cognitive symptoms in aged patients. This notion of “selective synaptic vulnerability” has been the focal point of a multitude of morphological studies investigating age-related cognitive decline, which have often provided tentative conclusions as to how this phenomenon may be regulated. The molecular correlates bolstering the reported age-dependent morphological and functional shift remain elusive and studies are only now beginning to unravel how discrete organelles, proteins and signalling cascades may hierarchically or synergistically attenuate synaptic function. Until there is considerable comprehension of how functional mediators drive the biochemical substrates regulating age-related cognitive decline, there are limited strategic avenues for the development of efficacious therapeutic interventions that promote successful ageing. To address the phenomenon of selective synaptic vulnerability, we have utilised an unbiased combinatorial approach, including quantitative proteomic analyses coupled with in vivo candidate assessments in lower order animals (Drosophila), to temporally profile regional synapse and synaptic mitochondrial biochemistry during normal healthy ageing. We begin by demonstrating that cortical mitochondria located at the synaptic terminal are morphologically distinct from non-synaptic mitochondria in adult rodents and human patients. Biochemical isolation and purification of discrete mitochondrial subpopulations from control adult rat fore-brain enabled generation of synaptic and non-synaptic mitochondrial molecular fingerprints using quantitative proteomics, which revealed that expression of the mitochondrial proteome is highly dependent on subcellular localisation. We subsequently demonstrate that the molecular differences observed between mitochondrial sub-populations are capable of selectively influencing synaptic morphology in-vivo. Next, we sought to examine how the synaptic mitochondrial proteome was dynamically and temporally regulated throughout ageing to determine whether protein expression changes within the mitochondrial milieu are actively regulating the age-dependent vulnerability of the synaptic compartment. Proteomic profiling of wild-type mouse cortical synaptic and non-synaptic mitochondria across the lifespan revealed significant age-dependent heterogeneity between mitochondrial subpopulations, with aged organelles exhibiting unique protein expression profiles. Recapitulation of aged synaptic mitochondrial protein expression at the Drosophila neuromuscular junction has the propensity to perturb the synaptic architecture, demonstrating that temporal regulation of the mitochondrial proteome may directly modulate the stability of the synapse in vivo. Although we had comprehensively characterised the temporal regulation of rodent cortical mitochondrial subpopulations, providing a number of novel candidates that may be mediating synaptic vulnerability during ageing, we sought to establish whether similar alterations were occurring in the primate brain. Using synaptic isolates from neuroanatomically distinct age-resistant (occipital cortex) and age-vulnerable (hippocampus) regions, we demonstrate that synaptic ageing is brainregion dependent and that discrete populations of synapses significantly differ at a biochemical level in the healthy human and non-human primate brain. Recapitulation of aged hippocampal protein expression with genetic manipulation in vivo revealed numerous novel candidates that have the propensity to significantly modulate multiple morphological parameters at the synapse. Furthermore, we demonstrate that several of these candidates sit downstream of TGFβ1 and activation of the TGFβ1 signalling cascade in hippocampal synaptic populations drives the aberrant expression of selected candidates during ageing. Finally, we show that selective pharmacological inhibition of this pathway rescues synaptic phenotypes in multiple candidate lines. The data affirmed that activation of the TGFβ1 transduction pathway modulates synaptic stability and thus may contribute to the selective vulnerability of hippocampal synapses during ageing.

This work investigates the non-linear elasto-plastic and visco-plastic behaviour of lead free solder material and soldered joints. Specifically, Finite Element (FE) tools were used to better understand the deformations within Ball Grid Array solder joints (BGA), and numerical and analytical methods were developed to quantify the identified constituent deformations. FE material models were based on the same empirical constitutive models (elastic, plastic and creep) used in analytical calculations. The current work recognises the large number of factors influencing material behaviour which has led to a wide range of published material properties for near eutectic SnAgCu alloys. The work discovered that the deformation within the BGA was more complex than is generally assumed in the literature. It was shown that shear deformation of the solder ball could account for less than 5% of total measured displacement in BGA samples. Shear displacement and rotation of the solder balls relative to the substrate are sensitive to the substrate orthotropic properties and substrate geometry (relative to solder volume and array pattern). The FE modelling was used to derive orthotropic FR4 properties independently using published data. An elastic modulus for Sn3.8Ag0.7Cu was measured using homologous temperatures below 0.3. Suggested values of Abaqus-specific creep parameters m and f (not found in literature) for Sn3.8Ag0.7Cu have been validated with published data. Basic verification against simple analytical calculations has given a better understanding of the components of overall specimen displacement that is normally missing from empirical validation alone. A combined approach of numerical and analytical modelling of BGAs, and mechanical tests, is recommended to harmonise published work, exploit new material data and for more informed analysis of new configurations.

Acoustic emissions (AE) can provide information relating to the internal state of a deforming rock sample during laboratory testing and have been utilised to quantify damage progression for time-dependent failure modeling. However, the underlying physical mechanisms that produce AE in different materials and their evolution during the process of damage localisation are not fully understood, particularly in porous media. In order to investigate the sources of laboratory acoustic emissions, a moment tensor inversion was applied to data from triaxial compression experiments on Aue granite and Clashach sandstone. The moment tensor inversion was verified for granite, by comparison with results obtained using a more simplistic source analysis technique. In the non-porous Aue granite, AE sources exhibited a predominantly tensile behaviour in the early stages of AE activity. However, shear sources become dominant in the vicinity of the peak stress. In contrast, during deformation of the Clashach sandstone, which has a significant pre-existing porosity, AE sources are dominated by a collapse signature and generally involve a notable shear component. AE that have a predominantly shear mechanism are also a major contributor to the microscale deformation imaged by the technique, and dominate during shear localisation. A combination of correlation analysis and source analysis was used to elucidate the temporal and spatial evolution of the AE source mechanisms involved in the localisation process, as well as during a temporary hiatus in the progression to failure. The results support the concept that the cascade to failure requires the simultaneous involvement of a range of micromechanical behaviours to maintain the progression of localised damage, and eventual formation of a fault. Localisation of collapse mechanisms was not observed until the final approach to failure. Finally, AE sources produced during brittle deformation of the Clashach sandstone were characterised in detail and compared to microstructural observations representing the integrated effect of all times up to the end of the test, and including smaller structures that may have been formed insufficiently dynamically to produce AE. Equivalent focal mechanisms for these events are presented and the relative proportions of their volumetric and shear components considered. The results indicate that AE sources display a wide spectrum of micromechanical behaviour that is consistent with microstructural observations, indicating that AE mechanisms are representative of ongoing deformation processes within the sandstone. It is argued that moment tensor inversion of acoustic emissions is a powerful tool for elucidating the micromechanical evolution of damage, during the brittle deformation of rock.