Dissertations / Theses on the topic 'Lateral interaction'

A lateral jet in a supersonic crossflow creates a highly complex three-dimensional flow field which is not easily predicted. The aim of this research was to assess the use of a RANS based CFD method to simulate a lateral jet in supersonic crossflow interaction by comparing the performance of available RANS turbulence models. Four turbulence models were trialled in increasingly complex configurations; a flat plate, a body of revolution and a body of revolution at incidence. The results of this numerical campaign were compared to existing experimental and numerical data. Overall the Spalart-Allmaras turbulence model provided the best fit to experimental data. The performance of the lateral jet as a reaction control system was assed by calculating the force and moment amplification factors. The predicted flowfield surrounding the interaction was analysed in detail and was shown to predict the accepted shock and vortical structures. The lateral jet interaction flowfield over a body of revolution was shown to be qualitatively the same as that over a flat plate. An experimental facility was designed and manufactured allowing the study of the lateral jet interaction in Cranfield University’s 2 ½” x 2 ½” supersonic windtunnel. The interaction was studied with a freestream Mach number of 1.8, 2.4 & 3.1 and over a range of pressure ratios (50≤PR≤200). Levels of unsteadiness in the interaction were measured using high bandwidth pressure transducers. The level of unsteadiness was quantified by calculating the OASPL of the pressure signal. OASPL was found to increase with increasing levels of PR or MPR and to decrease with increases of Mach number. The levels of unsteadiness found were low with the highest levels found downstream of the jet.

This thesis examines the effect of vehicle dynamics on lateral deterioration of the track alignment. As rail traffic runs along a route, the forces imposed upon the track cause the ballast to settle, and hence the track geometry deteriorates. At a specified value of deterioration the track geometry needs to be restored by tamping or other methods. As the deterioration is mainly in the vertical direction, this aspect has been more widely studied and models have been developed to predict vertical track geometry deterioration. On the other hand, lateral track deterioration is not as well understood, and this thesis aims to fill the gap in this knowledge. However, the understanding of the lateral deterioration mechanisms becomes more important as speed and capacity increase. This thesis describes statistical studies of track lateral deterioration, as well as the development and validation of a vehicle-track lateral dynamic interaction model. This work is undertaken to contribute to the fundamental understanding of the mechanisms of track lateral deterioration, therefore making the effective control and reduction of the lateral deterioration achievable. The statistical analysis provides a better understanding of three aspects of track lateral irregularities, namely: the relationship between vertical and lateral irregularities, the relationship between track curvature and track lateral irregularity and the change in track lateral deterioration over time. The vertical and lateral track irregularity magnitudes are clearly correlated. The track quality in the vertical direction is generally worse than in the lateral direction, however the number of track sections with lateral quality significantly worse than the vertical is non-negligible. The lateral irregularities tend to be larger on curves. It is notable that less than ten percent of the track studied has a constant lateral deterioration due to frequent maintenance activities and bidirectional lateral dynamic forces. Unlike vertical settlement, lateral deterioration develops exponentially in both magnitude and wavelength, and the major influences are found from the irregularities with wavelength longer than 10 m. The change in track lateral irregularity with different curve radii and the lateral deterioration rate are described in separate exponential power functions due to the limitation of the available track data. The parameters for these empirical equations do not remain constant due to the change in track conditions. Current track lateral models mainly focus on lateral failures such as buckling and lateral sliding. The development of lateral track irregularities tends to be studied using representative values of net lateral forces and net L/V (Lateral/Vertical) load ratios. Unlike other track lateral deterioration models, the model developed in this thesis focuses on the development of lateral irregularities based on the dynamic interactions between the vehicles and the track system. This model makes it possible to carry out more integrations and analysis of the track lateral deterioration in a realistic dynamic simulation, using vehicle models, contact conditions, track initial irregularities, and traffic mix more close to the reality. The vehicle-track lateral dynamic interaction model was validated against track geometry data measured on the West Coast Mainline (WCML) in England. It has been found that the model gives a reasonably accurate prediction of the development of lateral track irregularities. However, it also tends to predict a short wavelength deterioration that is not seen in the actual track deterioration. Improvements to the model are suggested by either adding more factors or simplifying the model depending on specific target application. Enhancing the model by including more details, such as longitudinal forces, temperature effect, more layered track systems, uneven track bed conditions and more representative wheel-rail contact conditions etc., may help understand the reason of the additional short wavelength. A sensitivity analysis was performed in order to identify the critical factors that influence lateral track deterioration. The track damage caused by specific vehicles can be controlled by understanding different vehicle dynamics behaviour on a particular track section or route. Vehicles with simple suspension design and heavy axle loads tend to cause more lateral track damage. Within a certain speed range, there will be a critical speed that generates the largest lateral deterioration. Vehicles with different dynamic behaviours can generate a potential offset of the lateral deterioration, so it is possible to design the traffic mix to cancel out the peak deterioration. However, it may not be very practical to redesign the traffic mix due to different traffic requirements. Subsequently, actions can be taken to effectively reduce track lateral deterioration, such as optimise the suspension design, vehicle weight, the selection of an optimal operation speed, and enhance the traffic mix design. As the most important interface between vehicle and track, the wheel-rail contact condition has an extremely large influence on lateral deterioration. Wheel and rail profiles with different wear conditions can cause altered vehicle-track lateral dynamic interaction. It is found that increasingly worn wheel/rail profiles within an acceptable tolerance can effectively reduce the lateral deterioration. Lateral deterioration can also be reduced by increasing all the track stiffness values, damping values and the mass of rails and sleepers, or alternatively, by decreasing the sleeper spacing. The sleeper-ballast interface is found to play the most important role in lateral deterioration. The interfaces between the sleeper and ballast shoulder, crib and base determines the non-linear characteristic such as hysteresis and sliding features. Improving the strength of the sleeper-ballast interface can improve the elastic limits and hysteresis characteristics, hence reducing the lateral deterioration. The findings of the investigation indicate that the model provides in-depth knowledge of the mechanisms influencing lateral deterioration and provides effective solutions with consideration of vehicles, wheel-rail contact and the track system. Further work would include track data with sufficient information in order to develop a more comprehensive empirical model that describes the lateral deterioration, inclusion of more potentially influential factors such as: temperature, ground condition, traffic etc. The model can be improved by taking into account additional factors such as the influence of longitudinal forces from the wheels to the rails, different weather and temperatures, subgrade and ground conditions, etc. The reason for the high frequency noise in the deterioration prediction is not understood yet and it should be discussed in terms of more accurate vehicle simulation results and more comprehensive rail and wheel worn profiles measured on the target track and vehicles. Furthermore, the sleeper-ballast lateral characteristics are not well understood and the previous research in this area is quite limited. To improve on the present work it would be useful to carry out laboratory tests in order to capture more accurately track lateral stiffness and damping values as well as the comprehensive non-linear characteristic of track lateral residual resistance behaviour.

MARCKS-Protein ist in den Signalübertragungsweg der Zelle involviert. Durch einen Adsorptions-/Desorptionszyklus mit der Zellmembran reguliert es die Konzentration bestimmter Botenmoleküle. Im Rahmen dieser Arbeit wurde untersucht, inwieweit strukturelle Änderungen der Membran, verursacht durch die Membran-Protein-Wechselwirkung, mit einem Reaktions-Diffusions-System korrelieren. Die elektrostatische Wechselwirkung von MARCKS-Protein mit negativ geladenen Membranlipiden geschieht an der inneren Seite der Zellmembran. Als Modellsystem lässt sich dies mit einer monomolekularen Lipidschicht an der Wasser-Luft-Grenzfläche realisieren. Anhand von oberflächensensitiven Messungen konnte gezeigt werden, dass die Wechselwirkung von MARCKS mit negativ geladenen Membranlipiden und damit die Adsorption an der Membran, zu einer Änderung der Membrantopologie führt. Damit verbundenen ist auch der partielle Einbau von MARCKS in die Membran, was zu einem größeren molekularen Flächenbedarf führt. Dieser korreliert mit dem Anstieg des lateralen Drucks der Lipidmonoschicht bei konstanter Fläche. Die Desorption von MARCKS kann durch die Wechselwirkung mit PKC induziert werden, detektierbar durch die Reduktion des lateralen Drucks. Bei Vorhandensein eines Reservoirs an MARCKS und PKC oszilliert der laterale Druck, was als zyklische Adsorption und Desorption von MARCKS an bzw. von der Lipidschicht interpretiert wird. Anhand der experimentellen Ergebnisse wurde ein mathematisches Modell entwickelt, dass dieses oszillierende Verhalten als ein Reaktions-Diffusions-System erklärt.

Bibliography: 104-107.<br>The formation of germanides of platinum has been investigated using both conventional thin films and lateral diffusion couples. The investigation was carried out using such established techniques as XRD, RBS and SEM. Using results from both thin film and lateral diffusion couples, a comparison has been made of the behaviour of Pt-Ge system in parameters such as phase formation sequence, growth kinetics and dominant diffusing species. In their sequential order of formation, three distinct phases, Pt₂Ge, PtGe and PtGe₂, have been identified in thin films in the temperature range 200 - 300°C. The first phase, Pt₂Ge, was found not to follow a layered mode of formation. Both PtGe and PtGe₂ phases were found to obey a (t)1/2 law, indicating a diffusion limited growth process. By employing Ti as an inert marker, platinum was observed as the dominant diffusing species during Pt₂Ge formation. On the dominant diffusing species during PtGe and PtGe₂ formation, the thin film results were but tentative. Upon annealing at 500°C/30,90,180min, lateral diffusion couples of Pt rich source (on Ge thin film) resulted in only a limited lateral growth, and multiple phases were not observed. However, when samples of Ge rich source (on Pt thin film) were annealed at the same temperature and times, lateral interaction was observed proceeding on a relatively large scale. Germanium atoms were found to have encroached into the surrounding Pt thin film as far as ±30μm away from the Ge source region, with multiple phases growing simultaneously, viz PtGe₂, PtGe and Pt₂Ge₃. Inside the source region, the composition of the innermost compound corresponded to PtGe₂ phase. Pt₂Ge₃ was located between PtGe₂ and the initial island/thin film interface line. The compound outside the source region was characterised as PtGe. Pt₂Ge₃ phase was observed to have resulted from PtGe₂ disintegration through the mechanism 2PtGe₂ -+ Pt₂Ge₃ + Ge. Plots obtained from μRBS and SEM lateral measurements indicate that the growth of observed phases (PtGe₂, Pt₂Ge₃ and PtGe) all follow a square-root-of-time law, a characteristic of diffusion limited growth process.

Cette thèse peut être divisée en deux parties: la reconnaissance des actions et la reconnaissance des émotions. Chaque partie se fait selon deux méthodes, la méthode classique de Machine Learning et le réseau profond. Dans la section Reconnaissance des actions, nous avons d'abord défini un descripteur local basé sur la LMA, pour décrire les mouvements. LMA est un algorithme pour décrire un mouvement en utilisant ses quatre composants: le corps, l'espace, la forme et l'effort. Le seul objectif de cette partie étant la reconnaissance des gestes, seuls les trois premiers facteurs ont été utilisés. L'algorithme DTW, est implémenté pour trouver les similitudes des courbes obtenues à partir des vecteurs descripteurs obtenus par la méthode LMA. Enfin SVM, l'algorithme est utilisé pour former et classer les données. Dans la deuxième partie de cette section, nous avons construit un nouveau descripteur basé sur les coordonnées géométriques de différentes parties du corps pour présenter un mouvement. Pour ce faire, en plus des distances entre le centre de la hanche et les autres articulations du corps et les changements des angles de quaternion dans le temps, nous définissons les triangles formés par les différentes parties du corps et calculons leur surface. Nous calculons également l'aire de la seule frontière 3D conforme autour de toutes les articulations du corps. À la fin, nous ajoutons la vitesse de l'articulation différente dans le descripteur proposé. Nous avons utilisé LSTM pour évaluer ce descripteur. Dans la deuxième partie de cette thèse, nous avons d'abord présenté un module de niveau supérieur pour identifier les sentiments intérieurs des êtres humains en observant leurs mouvements corporels. Afin de définir un descripteur robuste, deux méthodes sont mises en œuvre: La première méthode est la LMA, qui en ajoutant le facteur «Effort» est devenue un descripteur robuste, qui décrit un mouvement et l'état dans lequel il a été effectué. De plus, le second sur est basé sur un ensemble de caractéristiques spatio-temporelles. Dans la suite de cette section, un pipeline de reconnaissance des mouvements expressifs est proposé afin de reconnaître les émotions des personnes à travers leurs gestes par l'utilisation de méthodes d'apprentissage automatique. Une étude comparative est faite entre ces 2 méthodes afin de choisir la meilleure. La deuxième partie de cette partie consiste en une étude statistique basée sur la perception humaine afin d'évaluer le système de reconnaissance ainsi que le descripteur de mouvement proposé<br>This thesis can be divided into two parts: action recognition and emotion recognition. Each part is done in two method, classic method of Machine Learning and deep network. In the Action Recognition section, we first defined a local descriptor based on the LMA, to describe the movements. LMA is an algorithm to describe a motion by using its four components: Body, Space, Shape and Effort. Since the only goal in this part is gesture recognition, only the first three factors have been used. The DTW, algorithm is implemented to find the similarities of the curves obtained from the descriptor vectors obtained by the LMA method. Finally SVM, algorithm is used to train and classify the data. In the second part of this section, we constructed a new descriptor based on the geometric coordinates of different parts of the body to present a movement. To do this, in addition to the distances between hip centre and other joints of the body and the changes of the quaternion angles in time, we define the triangles formed by the different parts of the body and calculated their area. We also calculate the area of the single conforming 3-D boundary around all the joints of the body. At the end we add the velocity of different joint in the proposed descriptor. We used LSTM to evaluate this descriptor. In second section of this thesis, we first presented a higher-level module to identify the inner feelings of human beings by observing their body movements. In order to define a robust descriptor, two methods are carried out: The first method is the LMA, which by adding the "Effort" factor has become a robust descriptor, which describes a movement and the state in which it was performed. In addition, the second on is based on a set of spatio-temporal features. In the continuation of this section, a pipeline of recognition of expressive motions is proposed in order to recognize the emotions of people through their gestures by the use of machine learning methods. A comparative study is made between these 2 methods in order to choose the best one. The second part of this part consists of a statistical study based on human perception in order to evaluate the recognition system as well as the proposed motion descriptor

Amyotrophic Lateral Sclerosis (ALS) is one of the most common motor neuron disease. ALS affects both upper and lower motor neurons, resulting in death within 3-5 years after symptoms onset. The recent identification of at least three RNA binding proteins as responsible for more than 60% of familiar cases of ALS highlighted the possibility that disturbed RNA metabolism could be a major pathogenic mechanism underlying the disease. Among all, FUS is an RNA binding protein, with a mainly nuclear localization, involved in several functions both in the nucleus, such as DNA transcription and RNA metabolism, and in the cytosol, as mRNA transport along the axons. Mutations of FUS, that account for about 5% of familial cases of ALS, mostly occur in the Nuclear Localization Domain (NLS) of the protein, thus inducing the formation of cytoplasmic aggregates, that are detectable in motor neurons of affected patients. FUS is part of the hnRNP family, a class of proteins able to directly bind intronic or exonic sequences to regulate splicing events. It is likely that FUS regulate alternative splicing also through the cooperation with SMN, a protein crucial for the maturation of the spliceosome. Indeed it has been demonstrated that FUS binds with components of the spliceosomalsnRNPs (small nuclear Ribonucleo Proteins, composed by small nuclear RNAs, snRNAU, and a set of different protein co-factors), such as SMN and proteins of the SMN-complex, thus contributing to the assembly and/or the maturation of the spliceosomal machinery. According to the role of FUS in the control of splicing, is not surprising that in FUS-related ALS impairment in the correct alternative splicing regulation occurs. Thisevidence suggests that alternative splicing defects could participate to the disease, linking ALS to another motor neuron disease where not only a deregulation of the splicing machinery occurs, but also, interestingly, SMN functions are directly involved: Spinal Muscular Atrophy (SMA). In SMA, similarly to what happens in ALS, the lower motor neurons are affected and patients, usually newborns, die for respiratory failure within few years after the diagnosis. SMA is caused by the depletion of Smn1gene, that encodes for SMN protein, the major constituent of the complex that mediates the maturation of spliceosomalsnRNPs. Indeed, in SMA patients and in animal models the correct assembly of snRNPs is affected, thus resulting in a general imbalance of the splicing regulation. Altogether these data suggest that FUS and SMN might cooperate to the same molecular pathway, i.e. alternative splicing regulation, and that disturbances in SMN-regulated functions, either caused by depletion of SMN protein (as in the case of SMA), or by pathogenic interactions between FUS and SMN (as in the case of ALS) might be a common theme in both ALS and SMA. This work was aimed at characterizing in vivo the role of SMN in the pathogenesis of FUS-related ALS. To this aim we used a mouse that overexpresses the human wild-type FUS (hFUS +/+) as ALS model, and we analyzed molecular phenotypes usually induced by SMN depletion. In particular, we observed the alteration of the splicing pattern of some target genes, whose splicing has been demonstrated affected in SMA models, that are particularly relevant for motor neuron viability. Furthermore we observed a decrease number of mature snRNPs from nuclei of motor neurons, that is a typical feature of tissues from SMA patients and models, thus suggesting a possible functional overlapping between FUS and SMN. However, molecular phenotypes induced by SMN lowering in SMA, such as the shortage of the RNAUs and their altered assembly in the core of the spliceosome, has not been observed in FUS mice. These data suggest that ALS and SMA converge in the alteration of the same pathway, but probably through different mechanisms. Yet, the shortage of SMN expression in this ALS model, obtained by crossing FUS mice (hFUS +/+) with SMN heterozygous knock-out mice (Smn +/-), did not modify the disease course nor the molecular phenotypes analyzed, thus reinforcing the existence of a complex interplay between FUS and SMN in the regulation of alternative splicing and gene expression.

This paper attempts to isolate some implications for secondary and adult education emerging from an exploratory study of perceived effective interactional communication in a religious organisation. Leaders of the local parishes of the Catholic Church in Australia are in the process of moving from the traditional basic communication structure of an hierarchical model to the lateral and collaborative interaction of a more participative model of management. This descriptive study records the perceptions of a sample of parish workers in the Church throughout Australia as they describe some of the problems they experienced in communication processes and attempted to identify the reason why these problems emerged. In doing so, they also identified the more effective communication processes emerging in this new form of pastoral ministry. They listed a number of attitudes which they believed would lead to greater communication effectiveness and without which genuine constructive communication usually does not take place (Carl Rogers 1957 in Bolton, 1983 p. 259). The media and written communication are not explored, except in their relation to effective meeting procedures. Verbal and non-verbal communication amongst people interacting with one another in the interpersonal organisational setting is the focus of this work. The findings of this study point in the short term, to the need for empowering people engaged in pastoral work with the necessary skills of effective communication processes. In the long term, the paper proposes the need for continuing educational emphasis on communication skills especially in secondary schools when students move towards a more personalised form of self-assertion.

Mesoscopic devices, such as nano-wires, are of interest for the next step in creating spintronic devices. With the ability to manipulate electrons and their spin, spintronic devices may be realised. To that end the different effects found in low-dimensional devices must be studied and understood. In this thesis  the influence that lateral spin-orbit coupling (LSOC) has on a nanowire, with asymmetrical confinement potential, is studied. The nanowire is studied through a numerical approach, using the Hartree-Fock method with Dirac interactions to solve the eigenvalue problem of an idealised infinite nanowire. The nanowire has a split-gate that generates the electrostatic asymmetrical confinement potential. It is found that the lateral spin-orbit coupling has little to no effect without any longitudinal effects in the wire, such as source-drain bias. The electrons will spontaneously create spin-rows in the device due to spin polarization. The spin polarization is triggered by using LSOC, numerical noise or from a weak magnetic field.<br>Mesoskopiska anordningar, som nano-trådar, tros vara ett viktigt steg för att skapa spinnelektronik. För att kunna skapa spinnelektronik behövs kunskap om hur elektroner kan manipuleras. Generellt måste därför existerande fenomen i nanoelektronik studeras. I denna avhandling studeras hur ''lateral spin-orbit koppling'' (LSOC) influerar en nanotråd som har en asymmetrisk potentialbarriär. Hartree-Fock metoden, med Dirac potential för elektron-elektron interaktioner, användes för att beräkna energinivåerna för en idealisk, oändligt lång nanotråd. Nanotråden har en split-gate som alstrar den elektrostatiska, asymmetriska potentialbarriären. "Lateral spin-orbit koppling" visar sig ha minimal effekt då longitudinella effekter, exempelvis spänning, saknas. Elektronerna placerar sig spontant i spinn-rader i tråden vid spontan spinn polarisation. Spinn polarisationen sätts igång av LSOC, numeriska störningar eller från svagt pålagt magnetfält.

The Gautrain Rapid Rail Link (GRRL) is a rail transit system in South Africa that links Johannesburg and Pretoria, as well as Johannesburg and the O.R. Tambo International Airport. Travelling at speeds of up to 160 km/h, the Gautrain system is the first of its kind on the African continent. This dissertation covers an investigation into the relationship between the vertical and lateral forces, speed and superelevation in a GRRL curve. The research described in this dissertation is based on an experiment which involved running a test train through a curve at various speeds, changing the cant of the curve by tamping and repeating the train runs. The cant was changed due to high wheel wear rates. The curve already had a cant deficiency, and this cant deficiency was subsequently increased by reducing the curve’s cant. Assessing the before and after tamping test data validated the existence of the expected relationships between the vertical and lateral rail forces, the speed and the cant. The change in cant had a minimal effect on the magnitude of the vertical forces, although a transfer of loading between the high and low legs did occur. The theory indicates that the 14 % reduction in cant in this curve given all of the other curve characteristics should have resulted in an increase in the lateral forces. There was however a roughly 50 % reduction in the maximum lateral forces after the cant was reduced that can be explained from a train dynamics point of view. In addition, there was an increase in safety due to a reduced derailment ratio at this curve’s normal operating speed of 85 km/h. It is not unreasonable to presume that a 50 % reduction in the maximum lateral forces could lead to a halving of the wear rate of the rail and wheels in this curve with similar results to be expected in other curves on the rail network.<br>Dissertation (MEng)--University of Pretoria, 2016.<br>The Chair in Railway Engineering at the University of Pretoria<br>Civil Engineering<br>MEng<br>Unrestricted

Amyotrophic lateral sclerosis (ALS) is a disease in which the motor neurons die in a progressive manner, leading to paralysis and muscle wasting. ALS is always fatal, usually through respiratory failure when the disease reaches muscles needed for breathing. Most cases are sporadic, but approximately 5–10% are familial. The first gene to be linked to familial ALS encodes the antioxidant enzyme superoxide dismutase-1 (SOD1). Today, more than 160 different mutations in SOD1 have been found in ALS patients.  The mutant SOD1 proteins cause ALS by gain of a toxic property that should be common to all. Aggregates of SOD1 in motor neurons are hallmarks of ALS patients and transgenic models carrying mutant SOD1s, suggesting that misfolding, oligomerization, and aggregation of the protein may be involved in the pathogenesis. SOD1 is normally a very stable enzyme, but the structure has several components that make SOD1 sensitive to misfolding. The aim of the work in this thesis was to study misfolded SOD1 in vivo. Small amounts of soluble misfolded SOD1 were identified as a common denominator in transgenic ALS models expressing widely different forms of mutant SOD1, as well as wild-type SOD1. The highest levels of misfolded SOD1 were found in the vulnerable spinal cord. The amounts of misfolded SOD1 were similar in all the different models and showed a broad correlation with the lifespan of the different mouse strains. The misfolded SOD1 lacked the C57-C146 intrasubunit disulfide bond and the stabilizing zinc and copper ions, and was prinsipally monomeric. Forms with higher apparent molecular weights were also found, some of which might be oligomers. Misfolding-prone monomeric SOD1 appeared to be the principal source of misfolded SOD1 in the CNS. Misfolded SOD1 in the spinal cord was found to interact mainly with chaperones, with Hsc70 being the most important. Only a minor proportion of the Hsc70 was sequestered by SOD1, however, suggesting that chaperone depletion is not involved in ALS.  SOD1 is normally found in the cytoplasm but can be secreted. Extracellular mutant SOD1 has been found to be toxic to motor neurons and glial cells. Misfolded SOD1 in the extracellular space could be involved in the spread of the disease between different areas of the CNS and activate glial cells known to be important in ALS. The best way to study the interstitium of the CNS is through the cerebrospinal fluid (CSF), 30% of which is derived from the interstitial fluid. Antibodies specific for misfolded SOD1 were used to probe CSF from ALS patients and controls for misfolded SOD1. We did find misfolded SOD1 in CSF, but at very low levels, and there was no difference between ALS patients and controls. This argues against there being a direct toxic effect of extracellular SOD1 in ALS pathogenesis. In conclusion, soluble misfolded SOD1 is a common denominator for transgenic ALS model mice expressing widely different mutant SOD1 proteins. The misfolded SOD1 is mainly monomeric, but also bound to chaperones, and possibly exists in oligomeric forms also. Misfolded SOD1 in the interstitium might promote spread of aggregation and activate glial cells, but it is too scarce to directly cause cytotoxicity.

Doctor of Phylosophy (PhD)<br>Schizophrenia is a severe, chronic and disabling mental disorder with a worldwide prevalence of approximately 1 %. It is a lifelong illness characterized by psychotic symptoms which typically first appear in late adolescence/early adulthood. The symptoms of schizophrenia are usually categorized as positive (hallucinations and delusions), negative (blunted affect and poverty of speech) and cognitive (memory, attention and executive function impairments). Schizophrenia is thought to arise from an interaction between several susceptibility genes and environmental factors, one of them being the use of cannabis, the most widely used illicit drug in the world. Human population studies show that cannabis use is associated with schizophrenia, and it is now well recognised that cannabis use increases the risk of developing schizophrenia by approximately twofold. The reasons for the association between cannabis and schizophrenia remain controversial and different theories have been proposed to explain the nature of this relationship. According to the self-medication hypothesis of schizophrenia, patients with psychotic disorders use cannabis to alleviate aversive symptoms of the disorder or the side effects associated with antipsychotic medications. Other theories posit that cannabis is a component cause contributing to the development of schizophrenia. Supporting this, an increasing body of evidence shows that cannabis use increases the incidence and severity of psychotic symptoms and that cannabis use most frequently precedes the onset of schizophrenia. As a large majority of cannabis users do not develop schizophrenia, a gene-environment interaction appears necessary for the development of the disorder. That is, cannabis use may unmask latent schizophrenia in individuals that have a genetic predisposition to the disorder. Family studies provide strong evidence of a genetic contribution to the aetiology of schizophrenia. Several candidate genes are likely involved in the disorder, but this thesis will specifically focus on the neuregulin 1 (NRG1) gene. NRG1 was first proposed as a schizophrenia susceptibility gene in 2002 and linkage studies have since replicated this association in diverse populations around the world. In addition, changes in expression of Nrg1 isoforms and its receptor ErbB4 have been reported in the brain of schizophrenia patients. NRG1 polymorphism has also been associated with cognitive and behavioural differences in schizophrenia patients compared to healthy individuals. Collectively, NRG1 is now recognized as one of the most promising genes that confer an increased risk of developing schizophrenia. The creation of knockout mice lacking a specific gene offers an exciting new approach in the study of mental disorders. While several mutant mice for Nrg1 and ErbB4 receptor have been developed, this thesis focussed on mice that are heterozygous for the transmembrane domain of the Nrg1 gene (named Nrg1 HET mice). These mice exhibit a schizophrenia-like phenotype including hyperactivity that can be used as a reflection of positive symptoms of schizophrenia. Furthermore, they display impairments in social recognition memory and prepulse inhibition (PPI), a model of attentional deficits observed in schizophrenia patients. In addition, the brains of Nrg1 HET contain fewer functional NMDA receptors and more 5-HT2A receptors than wild type-like (WT) animals which is consistent with the neurotransmitters imbalance observed in schizophrenic patients. The phenotype of Nrg1 HET mice is age-dependent, another aspect that mirror the late adolescent/early adulthood onset of schizophrenia symptoms. The present thesis aimed at developing an animal model of genetic vulnerability to cannabinoid-precipitated schizophrenia by utilising Nrg1 HET mice to observe if these animals show an altered behavioural and neuronal response to cannabinoid exposure. We hypothesise that Nrg1 deficiency will alter the neurobehavioural responses of animals to cannabinoids. The experiments detailed within the first research chapter (Chapter 2) aimed at examining the behavioural effects of an acute exposure to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC), in Nrg1 HET mice using a range of behavioural tests of locomotion, exploration, anxiety and sensorimotor gating. Relative to WT control mice, Nrg1 HET mice were more sensitive to both the locomotor suppressant action of THC, as measured in the open field test, and to the anxiogenic effects of THC in the light-dark test, although the effects in this procedure may be confounded by the drug-free hyperactive phenotype of Nrg1 HET mice. Importantly, Nrg1 HET mice expressed a greater THC-induced enhancement in PPI than WT mice. Taken together, the data presented in Chapter 2 show that a deficiency in a schizophrenia susceptibility gene Nrg1 enhanced the behavioural impact of THC. After having established a link between Nrg1 deficiency and increased sensitivity to the behavioural effects of cannabinoids in Chapter 2, Chapter 3 assessed the neuronal activity underlying the effects of an acute THC exposure on Nrg1 HET mice by using c-Fos immunohistochemistry. In the ventral part of the lateral septum (LSV), THC selectively increased c-Fos expression in Nrg1 HET mice with no corresponding effect being observed in WT mice. In addition, a non-significant trend for THC to promote a greater increase in c-Fos expression in Nrg1 HET mice than WT mice was observed in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with Nrg1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-Fos in the shell of the nucleus accumbens and the LSV. Interestingly, the effects of genotype on c-Fos expression, drug-free or following THC exposure, were only observed when animals experienced behavioural testing prior to perfusion. This suggests that an interaction with stress was necessary for the promotion of these effects. As the risk of developing psychosis in vulnerable individuals increases with the frequency of cannabis use, Chapter 4 assessed the effects of repeated exposure to cannabinoids on Nrg1 HET mice. As THC was not available at the time, the synthetic analogue of THC, CP 55,940, was used in this experiment. Behavioural testing showed that tolerance to CP 55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice compared to WT mice. On the contrary, tolerance to the anxiogenic-like effect of CP 55,940 in the light-dark test was observed in WT mice, however no such tolerance occurred to this effect in Nrg1 HET mice. Similarly, no tolerance developed to CP 55,940-induced thigmotaxis in Nrg1 HET mice as measured in the open field. For PPI, on the first day of exposure opposite effects were observed, with CP 55,940 treatment facilitating PPI in Nrg1 HET mice and decreasing it in WT mice. However, the differential effect of CP 55,940 on PPI was not maintained with repeated testing as both genotypes became tolerant to the effects of the cannabinoid on sensorimotor gating. In addition, a selective increase in Fos B/ΔFos B expression, a marker of longer-term neuronal changes, was observed in the LSV of Nrg1 HET mice following chronic CP 55,940 exposure, with no corresponding effect seen in WT mice. These results collectively demonstrate that the neuregulin system is involved in the neuroadaptive response to repeated cannabinoid exposure. One of the main schizophrenia endophenotypes observed in human studies are cognitive impairments of higher executive functions. Thus Chapter 5 aimed to develop a procedure to allow evaluation of cannabis-induced working memory deficits in mice. Few studies have investigated the effects of chronic cannabinoid exposure on memory performance and whether tolerance occurs to cannabinoidinduced memory impairment. Here we studied the effects of repeated exposure to THC on spatial memory and the expression of the immediate early gene zif268 in mice. One group of animals were not pre-treated with THC while another group was given 13 daily injections of THC prior to memory training and testing in the Morris water maze. Both groups were administered THC throughout the memory training and testing phases of the experiment. THC decreased spatial memory and reversal learning, even in animals that received the THC pre-treatment and were tolerant to the locomotor suppressant effects of the drug. Zif268 immunoreactivity was reduced in the CA3 of the hippocampus and in the prefrontal cortex only in non pre-treated animals, indicating that while tolerance to the effects of cannabinoids on neuronal activity arose, cannabinoid-promoted memory impairment in these animals persisted even after 24 days of exposure. Taken together these data demonstrate that the spatial memory impairing effects of THC are resistant to tolerance following extended administration of the drug. Such a model could be applied to Nrg1 HET mice in future studies to observe if cannabinoid-induced working memory impairments and the development of tolerance to this effect are altered relative to WT mice. In conclusion, this thesis provides the first evidence that partial deletion of the schizophrenia susceptibility gene Nrg1 modulates the neurobehavioural actions of acutely and chronically administered cannabinoids. Nrg1 HET mice appear more sensitive to the acute neurobehavioural effects of cannabinoids. Notably, acutely administered THC facilitated attentional function by increasing PPI in Nrg1 HET mice. However, with repeated cannabinoid administration this acute benefit was lost. The Nrg1 HET mice displayed a long-lasting anxiogenic profile that was resistant to tolerance. Conversely, Nrg1 HET mice developed tolerance to the locomotor suppressant and hypothermic effects of cannabinoids more rapidly than WT mice, indicating a distorted neuroadaptive response in these animals. Another major finding of this thesis is that the lateral septum appears to be an important brain region dysregulated by cannabinoids in Nrg1 HET mice. Cumulatively, this research highlights the fact that neuregulin 1 and cannabinoid systems appear to interact in the central nervous system. This may ultimately enhance our understanding of how gene-environment interactions are responsible for cannabis-induced development of schizophrenia.

Caisson or pier foundations are encountered as part of the foundation system of tall structures such as bridges, transmission towers, heliostats, etc, and correspond to rigid blocks of length-to-diameter (D/B) ratio on the order of D/B = 2-6. As a result of their geometry and stiffness characteristics, the mechanisms of load transfer from the superstructure to the surrounding soil and their kinematic response to seismic wave propagation are governed by a complex stress distribution at the pier-soil interface, which cannot be adequately represented by means of simplified Winkler models for shallow foundations or flexible piles. Continuum model solutions, such as 3D finite elements (FE) cannot be employed frequently in practice for the design of non-critical facilities due to the cost and effort associated with these analyses. The objective of this work is to develop a Winkler-type model for the analysis of transversely-loaded caissons, which approximately accounts for all the main soil resistance mechanisms mobilized, while retaining the advantages of simplified methodologies for design at intermediate levels of target accuracy. Investigation of the governing load-transfer mechanisms and development of complex spring functions is formulated on the basis of 3D FE simulations. Initially, the soil-structure stiffness matrix is computed by subjecting the pier to transverse static and dynamic loading at the top, and numerically estimating the response. Complex frequency-dependent functions are next developed for the spring constants by equating the stiffness matrix terms to the analytical expressions developed for the four-spring model. Sensitivity analyses are conducted for optimization of the truncated numerical domain size, finite element size and far-field dynamic boundary conditions to avoid spurious wave reflections. Simulations are next conducted to evaluate the transient response of the foundation subjected to vertically propagating shear waves, and results are compared to the response predicted by means of the 4-spring model. Finally, the applicability of the method is assessed for soil profiles with depth-varying properties. While the methodology developed is applicable for linear elastic media with no material damping, the expressions of complex spring functions may be extended to include hysteretic damping, nonlinear soil behavior and soil-foundation interface separation, as shown in the conclusions.

<p>As more and more people conduct vigilance-based activities at times other than the traditional daytime work hours, the time utilization will continue to escalate in the next century and will further increase the risks of sleepiness-related accidents.</p><p>This project, which is commissioned by Scania CV AB, is to nvestigate the potential of a method for sleepiness detection belonging to esium AB. Our objective is to examine whether Scania CV AB should continue with the investigation of the patent method, and in that case, which patent parameters, that indicate sleepiness, should be more closely inquired. The purpose with the method of patent is to discover a sleepy driving behaviour. This method is based on the interaction that appears between the driver and the vehicle. The interaction consists of small spontaneous corrections with the steering wheel that in this report is called micro communication. How well the interaction is functioning can be measured in degree of interaction, which shows how well the driver and the truck interact with each other. The interaction between the driver and the vehicle is in this report looked upon as answers and questions with a certain reaction time, which appears with a certain answered question frequency. The differences in the signal’s amplitudes are measured in variation in amplitudes.</p><p>Experiments to collect relevant signals have to be conducted in order to investigate the potential with the method of the patent. It is eligible to collect data from a person falling asleep, which implies experiments conducted in a simulator. The experiments are executed in</p><p>a simulator, one test when they are alert and one when they are sleep deprived. Tests are also executed in a Scania truck. The purpose with these experiments is to collect data of the subject’s normal driving pattern in a truck and to investigate if it is possible to obtain</p><p>acceptable data in a truck.</p><p>The sleepiness experiments have indicated that the micro communication takes place in a frequency range of 0.25 to 6.0 Hz. The variables that have been found to detect sleepiness with high reliability are the reaction time and the degree of interaction presented in spectra.</p><p>The validation experiments have shown it is possible to collect exact and accurate data from the lateral acceleration and the steering wheel torque. But, there is more noise in the signals from truck then there is in the signals from the simulator.</p><p>This method for sleepiness detection has, according to the authors, a great potential. However, more experiments have to be conducted. The authors suggest further sleepiness experiments only conducted during night time. The subjects are sufficiently alert in the beginning of the test to receive data from normal driving behaviour. Physiological measurement could be interesting to have by the side of the subjective assessments as an additional base for comparison.</p>

Proteine formen während der Endozytose planare Membranen zu gekrümmten Vesikeln um. Im ersten Schritt dieses Prozesses bindet das Protein Epsin an das Rezeptorlipid Phosphatidylinositol-4,5-bisphosphat (PIP₂) und ein vorher ungeordneter Bereich am N-Terminus von Epsin, die <i>epsin N-terminal homology domain</i> (ENTH), bildet eine &#945;-Helix, welche in die Membran insertiert. Im Rahmen dieser Arbeit wurde die Wechselwirkung von ENTH mit PIP₂-haltigen Lipiddoppelschichten unter Verwendung von <i>bottom up</i> Modellsystemen charakterisiert. Die Affinität von ENTH zu PIP₂ wurde für verschiedene Lipidzusammensetzungen und Membrangeometrien untersucht, wobei unabhängig von Lipidzusammensetzung und Membrantopologie ähnliche Bindungskonstanten im hohen nanomolaren Bereich bestimmt wurden. Ausgestülpte porenüberspannende Membranen wurden als Modellsystem etabliert, um die Fähigkeit von ENTH zur Membrankrümmung als Funktion der Lipidzusammensetzung zu charakterisieren. Die Höhe der ausgestülpten Membranen ist durch die laterale Spannung begrenzt. Verursacht durch Insertion der ENTH Helix wuchsen Membranen mit einem hohen Flächenkompressionsmodul. Im Gegensatz dazu rissen Membranen mit einem niedrigen Flächenkompressionsmodul durch die ENTH induzierte Bildung von Membrandefekten. Entgegen der Eigenschaft von ENTH Membranen zu krümmen, wurde an hochgespannten porenüberspannenden Membranen keine Membrantubulierung und -vesikulierung beobachtet. Daher wurde untersucht, ob diese Fähigkeit durch eine hohe laterale Spannung unterdrückt wird. Zu diesem Zweck wurden Riesenvesikel auf einem Glassubstrat adhäriert, wobei die Adhäsionsstärke und in Folge die laterale Spannung als Funktion der Mg²⁺ Konzentration eingestellt werden konnte. ENTH-induzierte Membrantubulierung konnte für Vesikel mit niedriger Spannung nachgewiesen werden und war bei höherer Spannung unterdrückt. Unabhängig von der Membranspannung wurde ein Abflachen der Vesikel nach ENTH-Zugabe beobachtet. Die Ursache hierfür wurde in der durch die insertierte Helix hervorgerufene Reduktion des Flächenkompressionsmoduls gefunden. Die insertierte Helix stört die hydrophoben Wechselwirkungen der Lipidfettsäureketten und das reduzierte Flächenkompressionsmodul verringert die zur Membrankrümmung benötigte Energie. In Kombination mit der durch die insertierte Helix erzeugten lokalen Krümmung ist dies eine molekulare Erklärung für die ENTH-initiierte Bildung eines Vesikels während der Endozytose.

Although it is well established that spacing of piles within a pile group influences the lateral load resistance of that group, additional research is needed to better understand trends for large pile groups (greater than three rows) and for groups in sand. A 15-pile group in a 3x5 configuration situated in sand was laterally loaded and data were collected to derive p-multipliers. A single pile separate from the 15-pile group was loaded for comparison. Results were compared to those of a similar test in clays. The load resisted by the single pile was greater than the average load resisted by each pile in the pile group. While the loads resisted by the first row of piles (i.e. the only row deflected away from all other rows of piles) were approximately equal to that resisted by the single pile, following rows resisted increasingly less load up through the fourth row. The fifth row consistently resisted more than the fourth row. The pile group in sand resisted much higher loads than did the pile group in clay. Maximum bending moments appeared largest in first row piles. For all deflection levels, first row moments seemed slightly smaller than those measured in the single pile. Maximum bending moments for the second through fifth rows appeared consistently lower than those of the first row at the same deflection. First row moments achieved in the group in sand appeared larger than those achieved in the group in clay at the same deflections, while bending moments normalized by associated loads appeared nearly equal regardless of soil type. Group effects became more influential at higher deflections, manifest by lower stiffness per pile. The single pile test was modeled using LPILE Plus, version 4.0. Soil parameters in LPILE were adjusted until a good match between measured and computed responses was obtained. This refined soil profile was then used to model the 15-pile group in GROUP, version 4.0. User-defined p-multipliers were selected to match GROUP calculated results with actual measured results. For the first loading cycle, p-multipliers were found to be 1.0, 0.5, 0.35, 0.3, and 0.4 for the first through fifth rows, respectively. For the tenth loading, p-multipliers were found to be 1.0, 0.6, 0.4, 0.37, and 0.4 for the first through fifth rows, respectively. Design curves suggested by Rollins et al. (2005) appear appropriate for Rows 1 and 2 while curves specified by AASHTO (2000) appear appropriate for subsequent rows.

Group of piles are widely used deep foundation systems to resist lateral and vertical loads. Seismic and static performance of pile groups mostly depend on soil type, pile spacing and pier rigidity. Not many pile lateral load tests have been performed due to high costs. Advanced and complex analytical methods were developed over the years to assess nonlinear lateral pile response. This research is conducted aiming at developing a practical analysis method to verify the lateral performance of pile groups and its effect on overall response of bridge utilizing the available pile lateral load test data. Empirical constants derived from evaluation of lateral load tests are used in a simple formulation to define the nonlinear behavior of the pile-soil system. An analysis guideline is established to model the nonlinear soil-bridge interaction by the help of a general purpose structural analysis program comprising recommendations for various cases. Results of the proposed method is compared to the results of industry accepted advanced methods using response spectrum and nonlinear time history analyses to assess the suitability of this new application. According to the analysis results, proposed simple method can be used as an effective analysis tool for the determination of response of the superstructure.

The official recommendations in geotechnical engineering are according to Swedish practice to install inclined driven piles in order to resist external horizontal loads, which usually consist of windloads. These loads gets counteracted by utilizing the pile's axial load-bearing capacity, however when designing a foundation the use of inclined piles has proven to be problematic from a number of different perspectives. This has made both engineers as well as contractors long for a solution where the piles instead are allowed to be installed vertically, which could be made possible by utilizing the lateral bearing capacity of the pile which occurs in connection with lateral resistance during pile-soil interaction. The present day knowledge about such an engineering procedure in Sweden has proven to be limited and consists mainly of one governing document, namely report 101 published by the Commission on Pile Research. The aim of our study is to test and evaluate the method in report 101 based on a number of different load cases related to lateral load effects during pile-soil interaction. An analytical method reproduced from the Commission on Pile Research's report has been implemented with help of Mathcad, a computer software for reuse of mathematical calculations. Decisive parameters that distinguish the different load cases have included external load impact in pile head, mechanical strength properties of friction or cohesive soil, along with cross-sectional dimensions and reinforcement content of piles etc. The results differed significantly depending on the loadcase, a majority of the given answers were also perceived as unreliable and in a number of load cases the method also failed to obtain an analytical solution. Our conclusion is that it is doubtful whether the elastoplastic method presented in report 101 in the end in practice benefits the engineer tasked with designing, this stands in stark contrast to an increasing demand for easily accessible knowledge within its field.<br>Pålar i samband med grundläggning har sedan en tid tillbaka enligt svensk praxis installerats snedslagna, detta för att med hjälp av pålens axiella bärförmåga motstå yttre horisontell lastpåverkan till följd av exempelvis vindlaster. Att snedställa pålar har visat sig vara problematiskt ur ett flertal olika perspektiv, en lösning som både konstruktörer och entreprenörer efterlängtat är att pålarna istället tillåts installeras rakställda. Detta skulle vara möjligt genom att nyttja pålens transversella bärförmåga som uppstår i samband med sidomotstånd vid interaktion påle-jord. Kunskap kring ett sådant dimensioneringsförfarande i Sverige idag har visat sig vara begränsad och till stor del bestå av ett styrande dokument, nämligen rapport 101 utgiven av Pålkommissionen. I denna studie har en analytisk handberäkningsmetod som återges ur Pålkommissionens rapport implementerats i beräkningsprogrammet Mathcad, detta i syfte att testa och utvärdera metoden utifrån ett flertal olika belastningsfall relaterade till transversell lastpåverkan vid interaktion påle-jord. Avgörande parametrar som skiljt de olika belastningsfallen åt har bl.a. utgjorts av hållfasthetsegenskaper hos friktion- eller kohesionsjord, tvärsnittsdimensioner och armeringsinnehåll hos påle, yttre lastpåverkan i påltopp. Resultaten skiljde sig åt markant beroende på typ av belastningsfall där en majoritet av svaren upplevdes som icke tillförlitliga och till ett flertal olika fall, utifrån vårt försök till implementering, klarade metoden heller inte av att erhålla någon analytisk lösning. Vi finner det därför svårt att tro att den elastoplastiska metoden som återges i rapport 101 i slutändan kommer till någon direkt praktisk nytta, vilket står i tvär kontrast mot ett uppenbart behov där lättillgänglig kunskap inom området efterfrågas.

Thesis (Ph.D)--Industrial and Systems Engineering, Georgia Institute of Technology, 2010.<br>Committee Chair: Kemp, Charles; Committee Member: Glass, Jonathan; Committee Member: Griffin, Paul; Committee Member: Howard, Ayanna; Committee Member: Thomaz, Andrea. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Negli ultimi decenni si è assistito ad un crescente utilizzo dei micropali, sia come fondazioni di nuove costruzioni in zona sismica, che per il retrofit di fondazioni esistenti danneggiate. È dunque essenziale approfondire la conoscenza del loro comportamento dinamico sotto carichi orizzontali. Vista la carenza di dati sperimentali, è stata eseguita una campagna prove su due micropali singoli verticali e su un gruppo di quattro micropali inclinati realizzati in un deposito alluvionale. I micropali investigati sfruttano la tecnologia Tubfix. Sono state eseguite prove di vibrazione ambientale, prove di impatto, prove di rilascio (vibrazioni libere) e prove in condizioni di vibrazioni forzate. Inoltre sono state eseguite prove di carico ciclico sui micropali singoli, per valutare l’evoluzione della rigidezza orizzontale della testa del palo con il numero di cicli e con lo sviluppo di fenomeni non lineari (tra tutti, il distacco all’interfaccia micropalo-terreno). Per stimare l’influenza della tipologia e dell’intensità del carico, delle modalità esecutive e dell’inclinazione, i risultati delle prove dinamiche sono presentati in termini di frequenze fondamentali, smorzamento e forme modali ottenute dagli accelerometri sulla testa del palo e dagli estensimetri disposti lungo il fusto. Vengono inoltre proposte funzioni di impedenza derivate sperimentalmente sia per i micropali verticali che per il gruppo. I dati sperimentali sono stati confrontati con i risultati ottenuti da diversi modelli opportunamente calibrati: dapprima un approccio teorico per l’interazione dinamica 3D di pali singoli ed in gruppo, verticali o inclinati, è stato utilizzato per simulare le prove di impatto. Successivamente sono stati sviluppati modelli 3D, attraverso un codice commerciale agli Elementi Finiti, con diverse caratteristiche in termini di proprietà del terreno, del micropalo e dell’interfaccia, che permettessero di stimare il comportamento dei micropali in campo lineare e non lineare sotto forze dinamiche orizzontali.<br>Micropiles are increasingly used both as new foundation system for buildings in seismic zone, and for the retrofit of existing structures damaged by earthquakes. Hence, it is essential to enhance the knowledge of their dynamic behaviour under horizontal loading. Given the lack of dynamic field tests data, an experimental campaign is carried out, including both two single vertical micropiles and a group of 4 inclined micropiles embedded in alluvial soils. Ambient vibration, impact load, free vibration and forced vibration tests are performed to evaluate the micropiles dynamic behaviour under small to large deformations. Moreover, two-way cyclic horizontal load tests are carried out on the single vertical micropiles to evaluate the evolution of micropile head horizontal stiffness with the number of loading cycles, and with the development of non linear phenomena (among all, the opening of a gap at the soil-micropile interface). To evaluate the influence of loading intensity and typology, execution steps and inclination on the behaviour of micropiles, results are presented in terms of fundamental frequencies, damping and modal shapes obtained from accelerometers at the pile head and strain gages along the shaft. Impedances functions are also experimentally derived for the single micropiles and the group. The experimental data are then compared with numerical results obtained exploiting different models, properly calibrated: a 3-D theoretical approach for the dynamic interaction analysis of vertical and inclined micropile groups is adopted to simulate impact load tests on the single micropiles and on the group. Moreover, different 3-D FE models are developed in a commercial code, having different properties in terms of soil, pile and interface behaviour, to evaluate the response of micropiles in the linear and non-linear range, under dynamic horizontal forces.

La Sclérose Latérale Amyotrophique (SLA) est une maladie dégénérative des neurones moteurs. Sa signature est la présence d’inclusions cytoplasmiques ubiquitinées (synonyme de protéostasie défaillante) majoritairement positives pour TDP-43, une protéine de liaison aux ARNs. Les altérations de l’autophagie et du métabolisme des ARNs sont particulièrement étudiées dans la SLA. Cette thèse explore le rôle de TDP-43 dans la régulation de l’autophagie et particulièrement sur les récepteurs de l’autophagie p62 et OPTN ainsi que leur kinase activatrice TBK1. Chez l’embryon de poisson zèbre, la sous-expression de tardbp (codant pour tdp-43) conduit à un phénotype moteur altéré que nous associons à une régulation négative de tbk1. De l’ARN humain de TBK1 améliore ce phénotype. Sur des cellules SH-SY5Y, une sous-expression de TARDBP conduit à un profil d’expression de gènes clés de l’autophagie contradictoire à celui du poisson zèbre. Cependant, activer l’autophagie basale grâce à la Torine 1 conditionne l’effet d’une déplétion de TDP-43 sur l’expression de p62/SQSTM1 et TBK1. De plus, la Torine 1 inhibe les liaisons de TDP-43 aux ARNs de RAPTOR et OPTN mais promeut celles avec p62/SQSTM1 et TBK1. Dans ces cellules, la surexpression progressive de TDP-43 conduit potentiellement à des effets antagonistes sur p62/SQSTM1. Plus globalement, moduler TARDBP se traduit par une apparition de phénomènes caractéristiques de la protéinopathie TDP-43 chez les patients SLA. Parallèlement, des techniques de visualisation des ARNs in vivo et in vitro sont développées. Ce travail met en lumière la faculté de TDP-43 à s’adapter au contexte cellulaire et d’influer différemment sur l’autophagie<br>Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease of motoneurons. Its histological hallmark is the presence of ubiquitin-positive cytoplasmic inclusions in motor neurons of patients which indicates defective proteostasis. In the majority of cases, these inclusions are positive for TDP-43, an RNA-binding protein. Alterations of autophagy and RNA metabolism are widely investigated in ALS. This thesis explores the role of TDP-43 on autophagy regulation with a focus on autophagy receptors p62 and OPTN and their upstream activator TBK1. In the zebrafish embryo, knockdown of tardbp leads to an altered motor phenotype and correlates with a downregulation of tbk1. Human TBK1 RNA ameliorates this phenotype in a significant manner. In SH-SY5Y cells, knockdown of TARDBP leads to a profile of expression of key autophagy genes that is in opposition with the one obtained in the zebrafish. However, activating basal autophagy through Torin 1 treatment unveils conditional effect of TDP-43 on p62/SQSTM1 and TBK1. Moreover, Torin 1 treatment inhibits binding of TDP-43 to RAPTOR and OPTN mRNAs but promotes novel binding to p62/SQSTM1 and TBK1 mRNAs. In these cell lines, increasing overexpression of TARDBP also seems to affect p62/SQSTM1 in different manners. Overall, modulating TARDBP expression is accompanied by the appearance of characteristic traits of TDP-43 pathology in ALS. In parallel, techniques to visualize target RNAs in vivo and in vitro are being developed. This work highlights TDP-43 ability to adapt to cellular context and affect autophagy in different manners

Proteins are the most important molecules in the cell since they take care of most of the biological functions which resemble life. To ensure that everything is working properly the cell has a rigorous control system to monitor the proper function of its proteins and sends old or dysfunctional proteins for degradation. Unfortunately, this system sometimes fails and the once so vital proteins start to misbehave or to accumulate and in the worst case scenario these undesired processes cause the death of their host. One example is Amyotrophic Lateral Sclerosis (ALS); a progressive and always fatal neurodegenerative disorder that is proposed to derive from accumulation of aberrant proteins. Over 140 mutations in the human gene encoding the cytosolic homodimeric enzyme Cu/Zn-Superoxide Dismutase (SOD1) are linked to ALS. The key event in SOD1 associated ALS seems to be the pathological formation of toxic protein aggregates as a result of initially unfolded or partly structured SOD1-mutants. Here, we have compared the folding behaviour of a set of ALS associated SOD1 mutants. Based on our findings we propose that SOD1 mediated ALS can be triggered by a decrease in protein stability but also by mutations which reduce the net charge of the protein. Both findings are in good agreement with the hypothesis for protein aggregation. SOD1 has also been found to be able to interact with mitochondrial membranes and SOD1 inclusions have been detected in the inter-membrane space of mitochondria originating from the spinal cord. The obvious question then arose; does the misfolding and aggregation of SOD1 involve erroneous interactions with membranes? Here, we could show that there is an electrostatically driven interaction between the reduced apo SOD1 protein including ALS associated SOD1-mutants and charged lipid membrane surfaces. This association process changes the secondary structures of these mutants in a way quite different from the situation found in membrane free aqueous environment. However, the result show that mutants interact with charged lipid vesicles to lesser extent than wildtype SOD1. This opposes the correlation between decreased SOD1 stability and disease progression. We therefore suggest that the observed interaction is not a primary cause in the ALS mechanism.

Abstract Artificial Life is an interdisciplinary scientific and engineering enterprise investigating the fundamental properties of living systems through the simulation and synthesis of life-like processes in artificial media. One of the avenues of investigation is autonomous robots and agents. Mimicking of the growth and adaptation of a biological neural circuit in an artificial medium is a challenging task owing to our limited knowledge of the complex process taking place in a living organism. By combining several developmental mechanisms, including the chemical, mechanical, genetic, and electrical, researchers have succeeded in developing networks with interesting topology, morphology, and function within Artificial Computational Chemistry. However, most of these approaches still fail to create neural circuits able to solve real problems in perception and robot control. In this thesis a phenomenological developmental model called a Stochastic Evolutionary Neuron Migration Process (SENMP) is proposed. Employing a spatial encoding scheme with lateral interaction of neurons for artificial neural networks, which represent candidate solutions within a neural network ensemble, neurons of the ensemble form problem-specific spatial patterns with the desired dynamics as they migrate under the selective pressure. The approach is applied to gain new insights into development, adaptation and plasticity in neural networks and to evolve purposeful behaviors for mobile robots. In addition, the approach is used to study the relationship of spatial patterns, composed of interacting entities, and their dynamics. The feasibility and advantages of the approach are demonstrated by evolving neural controllers for solving a non-Markovian double pole balancing problem and by evolving controllers that exhibit navigation behavior for simulated and real mobile robots in complex environments. Preliminary results regarding the behavior of the adapting neural network ensemble are also shown and, particularly, a phenomenon exhibiting Hebbian-like dynamics. This thesis is a step toward a long range goal that aims to create an intelligent robot that is capable of learning complex skills and adapts rapidly to environmental changes.

Esta tese apresenta os princípios e a formulação de um modelo não-linear de atrito estático em interface de concreto areia. A hipótese básica para desenvolvimento das equações consiste na ocorrência do atrito de deslizamento (atrito verdadeiro), do atrito de rolamento (rearranjo das partículas) e da dilatância (variação de volume durante o cisalhamento). A solução analítica do modelo considera o efeito da rugosidade da superfície de contato, da curva granulométrica da areia e do seu estado de compacidade inicial. Foram realizados ensaios de cisalhamento direto com carga normal constante em interface de contato entre concreto e areia com seção de 500 mm x 500 mm com o objetivo de permitir a calibração do modelo proposto. É discutida e sugerida a incorporação da equação constitutiva desse modelo em análises de interação solo-estrutura via método dos elementos finitos. Sua aplicabilidade é demonstrada através da análise 1D e 2D de estacas de atrito executadas em areia e submetidas a carregamentos de compressão<br>This thesis presents the principles and formulation underlying a concrete-sand interface nonlinear static friction model. The basic hypothesis employed in the development of the model equation takes into account the interface sliding friction (true friction), a rolling friction (particle rearrangement) and dilatancy(volume variation during shear). The model analytical solution considers the effect of roughness of the contact surface, the grain size distribution and its initial state of compactness of the sand. To calibrate the proposed model, a direct shear stress test under constant load was carried out along a 500mm x 500mm section concrete-sand interface. Furthermore, a discussion and suggestion of the inclusion of the model constitutive equation applied to the analysis of soil-structure interaction using the finite element method are presented. The applicability of the proposed model is proven through the analysis of 1-D and 2-D skin friction piles made of sand mass subjected to compression load

Extreme heat and temperature fluctuation in Queensland result in buckling of railway tracks which jeopardize the safety of train operation and cost huge sums to repair. This thesis carried out an elaborate investigation on the issue of track buckling and provided several approaches to mitigate the risks of track buckling to enable safer trains and lower maintenance costs for railway operators in Australia.

Our society is heavily and intrinsically dependent on energy transformation and usage. In a world scenario where resources are being depleted while their demand is increasing, it is crucial to optimize every process. During the last decade the concept of energy efficiency has become a leitmotif in several fields and has directly influenced our everyday life: from light bulbs to airplane turbines, there has been a general shift from pure performance to better efficiency. In this vein, we focus on the mobility and tractive efficiency of off-road vehicles. These vehicles are adopted in military, agriculture, construction, exploration, recreation, and mining applications and are intended to operate on soft, deformable terrain. The performance of off-road vehicles is deeply influenced by the tire-soil interaction mechanism. Soft soil can drastically reduce the traction performance of tires up to the point of making motion impossible. In this study, a tire model able to predict the performance of rigid wheels and flexible tires is developed. The model follows a semi-empirical approach for steady-state conditions and predicts basic features, such as the drawbar pull, the driving torque and the lateral force, as well as complex behaviors, such as the slip-sinkage phenomenon and the multi-pass effect. The tractive efficiency of different tire-soil configurations is simulated and discussed. To investigate the handling and the traction efficiency, the tire model is implemented into a four-wheel vehicle model. Several tire geometries, vehicle configurations (FWD, RWD, AWD), soil types, and terrain profiles are considered to evaluate the performance under different simulation scenarios. The simulation environment represents an effective tool to realistically analyze the impact of tire parameters (size, inflation pressure) and torque distribution on the energy efficiency. It is verified that larger tires and decreased inflation pressure generally provide better traction and energy efficiency (under steady-state working conditions). The torque distribution strategy between the axles deeply affects the traction and the efficiency: the two variables canâ t clearly be maximized at the same time and a trade-off has to be found.<br>Ph. D.

The present work investigates the mechanisms underpinning the integration of local signals (either local orientations, positions or directions) into whole configurations. The investigation is composed of three studies that try to disentangle the issue using a contour integration paradigm. Each of them focuses on a specific aspect of the problem. Study one compares two integration models: the first is the well known “association field model”, based on local lateral interactions between adjacent receptive fields tuned to similar orientation (in primary visual area V1). The second is a second-stage filter that follows rectification of first-order filters. Study two tests, instead, the idea that a local cooperative system is responsible for the integration of directional signals. In addition it investigates whether such a mechanism could explain the “motion facilitation effect” usually found with dynamic (compared to static contours). Finally, study three extends findings from study two recording Visual Evoked Potentials (VEPs) elicited by static and dynamic contours. My findings provide support to the idea that a mechanism based on local lateral interactions in V1 could account for the integration of static contours, whereas a local cooperative mechanism could account for the integration of static contours. Moreover, these two mechanisms interact, in a way that the cooperative motion system facilitates or impairs the input feeding the static association field.<br>Questa tesi investiga i meccanismi responsabili dell’integrazione di segnali locali (siano essi orientazioni, posizioni o direzioni di elementi locali) in configurazioni globali. Il lavoro si compone di tre studi, che provano a dare una risposta alla domanda attraverso l’utilizzo di un paradigma di integrazione di contorni. Ciascuno studio approfondisce uno specifico aspetto del problema. Il primo studio confronta due modelli di integrazione: il primo è il celebre “campo associativo”, basato su connessioni laterali (presenti nella corteccia visiva primaria) tra campi recettivi adiacenti e sensibili per orientazioni locali simili. Il secondo modello è un filtro di second’ordine che riceve come input il risultato di un processo di rettificazione dell’output filtri di primo ordine. Il secondo studio verifica, invece, se un sistema cooperativo locale spiega in maniera esaustiva l’integrazione di segnali locali di direzione. Inoltre, questo studio investiga anche la possibilità che il suddetto meccanismo cooperativo possa spiegare la “facilitazione data dal movimento” che si trova, di solito, quando si confronta la abilità di rilevare un la presenza di un contorno dinamico rispetto ad uno statico. In ultimo, lo studio tre amplia i risultati del secondo studio, avvalendosi di una tecnica di registrazione di potenziali evocati elicitati da contorni statici e dinamici. Nel complesso, i tre studi supportano l’idea che un sistema basato su connessioni laterali (presenti nella corteccia visiva primaria) possa determinare l’integrazione di contorni statici, mentre un sistema cooperativo spiega l’integrazione di segnali di movimento locali. In aggiunta, questi due sistemi interagiscono continuamente, con il sistema di movimento che determina la qualità dell’input che sarà utilizzato, successivamente, dal sistema associativo statico.

Most of the older reinforced concrete (RC) buildings have columns that are deficient when the current code requirements are considered. Therefore, performance of the columns determines the performance of the structure under the effects of earthquake induced lateral loads. It is recognized that no provision is proposed in TEC2007 to estimate the failure type called flexure-shear. Behavior of columns having probability of failing in flexure-shear failure mode is mostly underestimated by TEC2007 procedures. In addition, failure type classification of columns performed according to the linear and nonlinear procedures of TEC2007 needs to be examined with respect to the test results to cover all failure types including flexure-shear failure in order to lead the engineers develop economical and realistic retrofit solutions. In this study, different methods are explored to obtain reliable estimates for the performance of code deficient shear critical RC columns. Special considerations are given to Axial-Shear-Flexure interaction (ASFI) approach due to its mechanical background. After examination of different approaches, ASFI method with proposed modifications was selected as the most reliable model and lateral load-displacement analyses were performed on a database of shear critical columns. Findings were compared with the estimations of the nonlinear procedure given in Turkish Earthquake Code (TEC2007) for database columns. In addition, drift capacity equations and simplified safe drift capacity equations are proposed in light of statistical studies on the selected column specimens. In the last part of the study, performance evaluation of columns according to nonlinear procedures of FEMA 356, TEC2007, ASCE/SEI 41 update supplement, and EUROCODE 8 were conducted.

Le renforcement des sols en zone sismique par des colonnes ballastées et/ou des inclusions rigides représente une alternative prometteuse et de plus en plus répandue par rapport aux solutions lourdes de fondations sur pieux. On sait que les pieux subissent, du fait de leur rigidité, des moments très importants au niveau de la liaison chevêtre-pieu. Les inclusions rigides surmontées d'un matelas granulaire permettent de mieux dissiper les efforts inertiels transmis par la superstructure, mais peuvent nécessiter des armatures si ce matelas n'est pas suffisamment épais. On peut penser que la colonne à module mixte (CMM) offre une solution combinant l'effet " matelas " à travers sa partie supérieure en colonne ballastée plus flexible et l'effet stabilisateur de la colonne inférieure. Cette thèse présente dans une première partie l'étude expérimentale réalisée au Laboratoire 3S-R (Grenoble) sur des modèles réduits à l'échelle 1/10 afin d'analyser la réponse de ces systèmes sous différentes charges statiques et dynamiques. Le modèle physique se compose d'une semelle carrée reposant directement sur l'argile renforcée. Le chargement vertical et horizontal, statique et dynamique est appliqué par l'intermédiaire de la fondation. Une instrumentation a été placée au niveau de la semelle pour obtenir la réponse globale du système, ainsi que dans la partie rigide inférieure du modèle pour évaluer la répartition des efforts entre inclusion et partie flexible supérieure. Une attention toute particulière a été donnée à la simulation de l'effet inertiel d'un séisme. Les profils de moments, d'efforts tranchants et de déplacements en fonction de la profondeur déterminés à partir de 20 extensomètres répartis régulièrement sur toute la hauteur de la partie rigide ont permis d'étudier l'influence de la hauteur de la colonne ou du matelas. La comparaison entre les déplacements dynamiques de la semelle et les courbes P-y (pression latérale P fonction du déplacement latéral y de la tête de pieu), permet de quantifier la dissipation de l'énergie dans les différentes parties du système. Les résultats expérimentaux montrent que la partie supérieure souple absorbe l'essentiel de l'énergie inertielle sismique. Une modélisation numérique 3D confirme les tendances observées expérimentalement et souligne l'importance du rôle de la zone de transition entre partie souple et partie rigide.

Durant le développement, l’innervation d’une zone précise du cerveau par certaines branches axonales est un mécanisme encore mal compris. Afin d’aborder cette question, je me suis intéressée aux axones rétiniens qui innervent deux cibles principales du système visuel : le corps genouillé latéral dorsal (CGLd) et le colliculus supérieur. J’ai étudié le rôle de la protéine de guidage Sémaphorine 6D et de son récepteur Plexine-A1 dans l’innervation spécifique du CGLd par les axones rétiniens. J’ai ainsi découvert que chez les souris Sema6D-/- et Plexine-A1-/-, le tractus optique (formé par les axones rétiniens) entre dans le CGLd au lieu de le contourner et certains axones rétiniens innervent des régions ectopiques de l’autre côté du tractus optique. De plus, l’analyse des souris simple ou double hétérozygotes indique que ces deux protéines interagissent avec un mécanisme dose-dépendant. Grâce à des expériences de perte et de gain de fonction par électroporation rétinienne in utero, j’ai pu montrer la nécessité de Sema6D et de Plexine-A1 dans la rétine pour l’innervation des axones rétiniens et ce via des effets non cellulaire autonomes. Ces résultats révèlent un mécanisme dose-dépendant dans lequel Sema6D et PlexineA1 interagissent et assurent une communication axone-axone permettant l’innervation précise du CGLd par une sous-population d’axones rétiniens<br>During development, axons branch at precise points to innervate a specific brain target, yet the mechanisms at hand are still unclear. To address this question, I used retinal axons forming the optic tract that innervate two principal targets of the visual system: the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus. I investigated the role of the guidance receptor Plexin-A1and its ligand Semaphorin-6D (Sema6D) in this targeting process. Here I highlight a new type of phenotype in Plexin-A1-/- or Sema6D-/- mice. In these mice, the optic tract enters in the dLGN instead of circumscribing it and some retinal axons innervate ectopic regions at the other side of the optic tract. Furthermore, the analysis of simple or double heterozygotes mice reveals that Plexin-A1 and Sema6D interact together with a dose-dependent effect. Using loss and gain of function experiments (via retinal in utero electroporation), I showed that both are necessary in the retina for proper retinal innervation through non-cell autonomous effects. All these results reveal for the first time a dose-dependent mechanism, in which Sema6D and Plexin-A1 interact together. They monitor axon-axon communication to allow the correct innervation of the dLGN by a subpopulation of retinal axons

Lateral connectivity within cortical areas is pervasive in the mammalian neocortex. The lateral interaction between cortical minicolumns mediated by such connections has been shown to play a critical role in cortical function and cognition, and has been used to explain the emergence of large-scale patterns such as cortical maps. Further evidence suggests that aspects of cortical representation of learnt sensory stimuli may be encoded in the synaptic strengths of lateral connections. This thesis builds upon a program of existing computational neuroscience research, which has identified plasticity in lateral interactions as the key component of cortical functional organisation, to ask whether a neurobiologically plausible computational model of cortical self-organisation can be used to investigate how synaptic plasticity and adaptation in lateral cortical interactions modifies the structure of pre-existing cortical representations and how it affects their decoding. The inhibitory sharpening theory is proposed, based on computer simulations, that shows how repetition suppression is compatible with an increase in the strength of the inhibitory interactions between cortical units co-active during the presentation of the same adapter stimulus due to Hebbian learning. A key prediction of the theory is then derived, that stimuli that produce overlapping patterns of cortical activity, that is that activate a common sub-set of neurons, may produce mutual interference that should be reflected both in changes to the neural signal and in higher level cognition. The predictions of the theory are tested with two approaches, a neuroimaging experiment to measure the magnitude of repetition suppression in a protocol compatible with that used in the simulations, and a behavioural experiment.

Ce travail est une contribution a l'etude de l'interaction sol granulaire-structure. A partir des travaux de boulon et plytas, nous perfectionnons un modele d'interface sol-structure. Ce modele, vectoriel, bidimensionnel est du type incremental a dependance directionnelle. Il consiste en une interpolation a partir de chemins de cisaillement d'interface determines. Dans un second temps, nous mettons en uvre un programme utilisant la methode des equations integrales aux frontieres en axisymetrie dans le but de resoudre un probleme aux limites comportant un contact entre deux solides elastiques. Enfin nous appliquons ce programme pour simuler un essai d'arrachement de clou de renforcement effectue en chambre de calibration. Les resultats numeriques sont compares aux donnees experimentales et analyses

In this thesis, the lateral interactions involved in conversion of synthesis gas, a mixture of H2 and CO, to methane over Fe(100) and the effect they have on the kinetics of the process is explored. Understanding the methanation of syngas allows for a better understanding of the initial stages of Fischer-Tropsch synthesis. Density functional theory was used to calculate the energies and properties of simple methanation adsorbates on an Fe(100) surface. All of the parameters were tested and optimized in order to find a balance between efficiency and accuracy. A number of configurations were calculated to investigate nearest neighbour and next nearest neighbour interactions. An energetic break down of the lateral interactions is postulated using the components of the Hamiltonian. The charges associated with the different atoms in each configuration were identified using the Mulliken population analysis and the Bader population analysis. These gave insights into configurations which displayed large electrostatic lateral interactions. Lateral interactions were investigated using larger unit cells than typically utilized in molecular modelling up to now (viz. p(4x4) and p(3x2) unit cells) to enable the estimation of nearest neighbour and next nearest neighbour interactions. When using larger p(4x4) unit cells for CO adsorption on Fe(100), the results showed that the heat of adsorption can differ by as much as 0.24 eV at 0.25 ML. It was concluded that lateral interactions are a function of local coverage (i.e. number of nearest and next nearest neighbours) and not necessarily global coverage. Nearest neighbour interactions are typically repulsive and much larger than next nearest neighbour interactions, which varied between repulsive and attractive interactions. While this is not a unique conclusion it did allow for the creation lateral interaction matrices that vary with temperature. The study has shown that lateral interactions can be broken down into kinetic and potential energy and an inverse relationship exists between these component energies. If this relationship is truly understood, then the total energy can be calculated knowing either kinetic or potential energy instead of both. This would then give additional value to well explored electrostatic interaction models. The lateral interactions were empirically related to nearest neighbour and next nearest neighbour interactions. Two kinetic studies were investigated in this thesis and in both cases, mean field approximations and quasi chemical approximation (QCA) were used and compared to incorporate lateral interactions into the kinetics. The mean field approximation over estimates the lateral interactions and considers global coverage while the QCA approximation considers probability of local combinations. The first kinetic study was a simulated CO TPD experiment on Fe(100). The mean field approximation was an improvement on systems which considered no lateral interactions but did not describe all the aspects observed in the experimental TPD. The prediction by the quasi-chemical approximation shows good agreement for the desorption of associatively bound CO. The deviation observed for the dissociatively adsorbed CO is attributed to the presence of alternative pathways for the adsorbed species (specifically the diffusion of oxygen into the lattice of the solid). A microkinetic model for the methanation of syngas over Fe(100) was also created. The results showed that different methods of lateral interaction incorporation resulted in significantly different coverage profiles and reaction energy profiles. Both methods showed a build-up of oxygen on the surface towards the end of the simulation. The build-up of oxygen on the surface of Fe(100) may indicate that iron-based catalysts need to undergo phase changes to complete the catalytic cycle.

Amyotrophic Lateral Sclerosis is the most common type of motor neuron disease, characterized by progressive degeneration of the upper and lower motor neurons. Sufferers present with symptoms of muscle weakness and this quickly develops on to paralysis and finally death due to respiratory failure within 5 years of disease onset. Although the majority of cases are sporadic, about 10% are familial and it is hoped that through the investigation of these few cases a greater understanding of the disease process, the reasons for its delayed onset and vulnerability of motor neurons will be achieved. Recently a novel mutation linked to ALS was discovered in an evolutionary conserved protein named Vesicle associated membrane protein (VAMP) associated protein B (VAPB). VAPB is an integral type II membrane protein localised at the Endoplasmic Reticulum and thought to have a role in protein transport. The orthologue in Drosophila has been shown to be involved in the homeostatic regulation of bouton formation at the Neuromuscular Junction through an association with the microtubule network. To elucidate the mechanism through which this protein causes ALS, Pennetta et al have created a Drosophila model of the disease by expressing the mutated orthologue in the fly. To complement this model, I have undertaken a number of biochemical experiments to look for potential interactors of the VAP proteins. The yeast two hybrid system utilises the yeast GAL4 transcriptional activator to indicate a protein interaction within a yeast cell and can be used to test a cDNA library for interactors. Through this technique a number of interesting binding partners have been found that may play crucial roles in the progression of the disease.

This thesis proposes a new Hollow Flange Steel Plate Girder (HFSPG) by welding industrially available cold-formed Rectangular Hollow Sections (RHS) to a web plate for use in long span construction. Design procedures presented in the national and international design guidelines were reviewed and suitable improvements were made to accurately predict the structural behaviour and capacities of HFSPGs by undertaking detailed experimental and numerical studies into their unique structural behaviour. Local buckling/yielding, global buckling and local-global interaction failures were all considered in this thesis.