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High school counselors support students across three areas or domains: academic, socio-emotional, and college and career development. Growing confusion and tensions around the time and responsibilities of school counselors have accompanied ever-evolving changes with their roles and coincided with continual efforts to address the K-12 and potential post-secondary educational opportunities, especially those from lower socioeconomic and particular racial and ethnic groups. The global health pandemic exacerbated challenges these student populations faced and greatly impacted the work of counselors. This qualitative multi-site case study draws on the triangulation of one-on-one interviews with twelve high school counselors across six school sites, in Southern California, with website and demographic analysis, and analytical memos, to identify institutional and personal influences on counselors' views and perspectives around education and work, and in turn, how counselors assist different student groups with their post-secondary aspirations. Findings indicate that counselors' views of education and work in light of the transition to adulthood; institutional structures and resources (e.g., distributed counseling) between charter and non-charter schools, and institutional aims (e.g., increase college going culture), and perceptions of students and communities, influence how counselors work with students and which pathways they (dis)encourage. Much of their efforts take place considering their views about students embarking on adulthood and what they feel they will be tasked with after high school. This influences the type of information they offer students, which promotes values around living meaningful, successful, and independent lives, as well as prioritizing college over career and technical education pathways. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Over the past twenty years, the number of students undertaking postgraduate taught (PGT) education in the UK has grown substantially, according to the Higher Education Statistics Agency (HESA) This is faster than the growth in the undergraduate (UG) sector over the same period (HESA, 2021). Postgraduates make a significant and growing contribution to the UK economy and to the HE sector specifically. The growth in PGT student numbers represents a positive scenario for universities, most of whom are actively pursuing ways to grow their revenue and differentiate their income streams (Robertson, 2010). Postgraduates' ability to adjust to, and successfully engage with their studies is fundamental to their progression, achievement and satisfaction, all of which are important metrics for universities (Evans et al., 2018). Following a detailed review of the literature, this thesis explores key aspects of students' PGT transition experience. It contributes to the theoretical body of research through the development of a conceptual model recommending appropriate relationship marketing strategies that HEIs can adopt to recruit, retain and support their PGT students through the transition process towards successful outcomes. Employing a qualitative research methodology using in-depth, semi-structured interviews with PGT students, this research was undertaken within a Birmingham-based Business School. The findings outlined the importance of utilising relationship marketing activities with transitioning PGT students by HEIs to: • Influence students' notions of quality and trust through reputation, rankings, accreditation and endorsements. • Support students' commitment and loyalty using special treatment benefits. • Establish early communications with students using CRM systems to develop a relationship at the applicant stage about the pedagogy and what to expect. • Build a rapport, a sense of belonging and a learning community. • Support academic and professional identity construction and satisfaction. • Co-create learning and provide excellent service quality, ensuring retention and satisfaction. • Encourage and support long term relationships with committed PGT students as alumni.

During placental development, the pathways that regulate the invasion of trophoblasts into the decidua will lead to remodelling the uterine vasculature and will eventually give rise to placenta formation. The same pathways get reactivated during cancer development and can lead to tumour cell invasion and the metastatic process. As a consequence, there are striking similarities between the behaviour of tumour cells and the trophoblasts, due to their similar gene expression pattern and protein profile and we set about to determine whether factors which have been shown to play important roles in cancer biology are also expressed and regulate trophoblast function. In this study we have focused on three different metastasis-associated proteins with well-defined roles in cancer progression, which have been closely linked with poor prognosis for cancer patients but have not been greatly studied in the context of placental development. The proteins are a small calcium-binding protein S100P, the ERM protein ezrin and the cytoskeletonmembrane linking protein, IQGAP1. After showing their expression and localisation pattern in human placental villi, we showed that these proteins are highly expressed during the earlier stages of the gestation, suggesting a potential role in early placenta development and implantation. We then studied their expression and localisation in trophoblast cell lines and primary trophoblasts. Using the trophoblast cell lines, through loss-of-function, and where relevant, gain of function studies, we showed that these three metastasis-associated proteins promote trophoblast motility and invasion. We also investigated some of the possible mechanisms that might have been involved in the mentioned pathways including changes in focal adhesions, protein localisation and phosphorylation. We have yet to investigate the underlying mechanisms that link these three proteins to trophoblast motility and invasion, and whether all or two of them work together to make these processes possible.

Although diamond is slowly becoming an advanced technology there is con- tradictory information and misunderstanding surrounding the fundamental electronic attributes of the material system. In particular, the properties of boron doped diamond for electronics on quantum length scales has yet to be fully understood or utilized within devices. In this thesis, new insight into the electronic band structure of boron doped diamond on nano and macro scales is found and novel planar boron doped nanowires are fabricated electronically probed and a new type of side gated diamond nanowire transistor conceived. High quality single crystal diamond with thin δ-shaped boron-doped epi- layers have been thought to offer a viable approach towards transistors that can operate at high speed, high power and high temperatures. δ-doping diamond has been conjectured to achieve high mobilities and carrier con- centrations, properties of real interest for electronic applications. Taking advantage of diamond’s thermal and electronic properties, thin films can be incorporated into realistic nanoscale devices more easily than the parent bulk system. Using angle-resolved-photoemission spectroscopy (ARPES), the electronic structure of bulk and thin films (≈ 2 nm) of boron-doped di- amond are uncovered. Surprisingly, the ARPES measurements do not reveal any significant differences for these systems, irrespective of their physical dimensionality. This suggests that it is possible to grow nearly atomic-scale structures whilst still preserving the properties of bulk diamond, facilitating the use of thin films diamond for devices which necessitate nearly atomic- scale components. Using a range of techniques such as Secondorary Ion Mass, Angle Resolved Photo-emission and Raman Spectroscopy we compare thin boron doped delta layers (BDDδl) and effectively infinite, thick bulk Boron doped di- amond. We see remarkably little electronic difference and hints of low dimensional transport in both films. Using photo-lithography and Reactive Ion Etching processes, macro scale devices are fabricated, these are charac- terized using Hall effect techniques. For the first time, lateral boron doped diamond nanowires are defined using electron beam lithography. These nanowires are then processed into a variety of novel transistor like devices, showing exciting emergent quantum properties as well as classical transistor like behaviour. In developing the techniques and methods to fabricate structures in diamond we find a variety of processes require optimisation and develop a skill base to handle small and sometimes fragile substrates and process them into devices.

A successful knowledge sharing process must take various elements into account, in order to ensure a positive outcome. In such a context, knowledge sharing means, knowledge sharing governance mechanisms and knowledge sharing process are identified as the key elements and enablers for the best knowledge sharing practices. Therefore, integrating various factors related to knowledge sharing phenomenon is an important task, which is ignored in current studies. Hence, this research investigates the knowledge-sharing phenomenon from different perspectives with the aim of providing a comprehensive view of knowledge sharing practices. Key concepts from the literature, i.e. knowledge sharing means, governance mechanisms and process, are integrated into a model and the intrinsic relationship among them is explored to explain how and why a strong approach of knowledge sharing can be achieved. The proposed model of the study is then applied as a critical theoretical tool to investigate medical knowledge sharing practices in NHS Trusts. One of the main challenges that have been argued in the literature, in the context of NHS, is about understanding the ways that sharing medical knowledge can be implemented more effectively. This study thus provides evidence on the medical knowledge sharing approaches which have worked well, and those which have not, with the aim of supporting the NHS Trusts for a better way of sharing medical knowledge. While the main focus here is the case of NHS Trusts, the findings can be useful for other healthcare organisations elsewhere. This study undertakes its philosophical standpoint from the perspective of critical realism, and thus provides an example of the application of the research paradigm in empirical knowledge sharing research. Adopting a dominantly qualitative method, two NHS Trusts are selected to conduct an empirical study to explore medical knowledge sharing practices. Evidence from the study indicates that the proposed model of the study can be seen as a powerful diagnostic tool for understanding knowledge sharing phenomenon, because it can provide a powerful explanation of the motivations and actions of both human and non-human (e.g. ICT) actors who establish the elements of knowledge sharing practices.!This study adds to the body of knowledge via proposing a new way of finding a new set of answers to explain the knowledge sharing practices by developing a holistic model. By using this model, factors that influence the knowledge sharing practices can be investigated and identified under the same umbrella. It also sheds new light on our understanding of the nature of the inner workings of the knowledge sharing process. The four stages of the knowledge sharing process allow scholars to investigate knowledge sharing practices systematically from the pre-implementation stage to implementation and post-implementation stages. Each stage has its own nature; therefore, the causes of the success/failure of knowledge sharing practices can be identified in deep detail. This concept can help to detect which actor(s) is the cause of strong/ weak approach of knowledge sharing, in what stage, and why. In terms of practical relevance, the proposed model of this study can help managers better understand knowledge sharing practices from different perspectives, and take a valuable insight as to how to choose the appropriate knowledge sharing means and governance mechanisms, in order to enable the medical knowledge sharing process more effectively and efficiently. We believe that the model can be applied as a diagnostic tool to determine the root causes of knowledge sharing problems and likely remedial actions.

The educational system has been challenging children through competitive societal information-age education by promoting achievement among students, in preparing children for global excellence. This qualitative research case study of elementary school children's lack in cybersecurity knowledge and awareness served helpful with exploration into cybersecurity awareness phenomena in kindergarten-through-6th grade (K-6) education through gaining an understanding about children's need for awareness of cybersecurity from viewpoints of six elementary schoolteachers, six information technology (IT) experts, and four parents. The intent of this research was to explore perceptions of 15 elementary schoolteachers, five IT experts, and five parents of elementary school children about children's Internet safety measures and needs, in digital-age. This study's participants agreed with the necessity of monitoring children's internetworking, to direct attention on children's ever-increasing need to exercise awareness when playing and learning, depending on the age of children. Interviews of a stratified sample of subpopulations within an upstate New York school district helped to uncover common themes about children's vulnerability characteristics, in which triangulation of study participants' perspectives about children's present character, personal safety, research, and various educational opportunities in elementary schools helped this study's data saturation. The common themes of this study developed through interviews, directed attention to teaching children information safety practices and monitoring children's Internet activities, relative to the age and social development of children through continuing existing programs, which the school districts work with local communities to help to increase children's personal safety. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Magnetostriction of core laminations is one of the main sources of transformer acoustic noise. The magnetostriction of grain oriented silicon steel is extremely sensitive to applied compressive stress. A measurement system using piezoelectric accelerometers has been designed and built. This was optimized for magnetostriction measurements under stress within the range of 10 MPa to -10 MPa on large as-cut sheets. This system was used for characterization of wide range of grain-oriented grades. Laboratories around the world are using many different methods of measurement of the magnetostrictive properties of electrical steel. In response to this level of interest, an international round robin exercise on magnetostriction measurement has been carried out and eight different magnetostriction-measuring systems have been compared. Results show a reasonable correlation between the different methods. In this study the influence of factors such as the domain refinement process, curvature, and geometry on the magnetostriction of 3% grain oriented silicon steel were investigated. The study shows that both laser scribing and mechanical scribing have a similar effect on the sample’s domain structure and would cause an increase in magnetostriction. A proposed domain model was used successfully to estimate the effect of scribing on magnetostriction. Correlation between magnetostriction of 3% grain oriented silicon steel with transformer vibration was investigated. It was shown that increasing the clamping pressure to 4Nm can decrease the out of plane vibration in the joint regions due to the increase of friction and reduction of air gap which reduces the air gap flux and consequently the Maxwell forces. Also it has been shown that the primary source for the differences between the vibration of the cores under the same magnetic excitation and clamping pressure in the measured cores is due to the differences in the magnetostriction characteristics of the grades of electrical steels. Correlations between the magnetostriction harmonics and the vibration of the cores have been determined.

This thesis is an attempt to determine the transferability of the findings of some Western studies carried out on Residential burglary, and the applicability of the main methods used for burglary reduction, to societies with different socio-economic structure, in this case Tehran, the capital city of Iran. The thesis will look at patterns of residential burglary found in Tehran and those found by European and American research studies to outline the similarities and differences between them to decide upon the suitability of `opportunity' theories, and ultimately situational preventive measures implemented in some Western countries for the prevention or reduction of burglary in Tehran. Following the failure of social and psychological methods in reducing burglary levels, situational crime prevention has received a great attention in some Western countries during the last few decades. Situational crime prevention policies are aimed at the reduction of crime levels by reducing crime opportunities, through i. e. target-hardening techniques, changes in the management, design, and manipulation of the immediate environment in which crime occurs, which lead to an increase in the risks perceived by a wide range of offenders, also by reducing the benefits of crime. A large proportion of Western criminological studies have carried out their research relying on the assumption which suggests that crime opportunities encourage crime, and that eliminating or blocking crime opportunities will result in the reduction of a large number of residential burglaries. Opportunity theory has adopted the `rationality' and the `routine activity' models of crime to explain when, where, and how burglaries occur. It is assumed that offenders are rational in the selection of crime opportunities that are associated with higher rewards and lower risks of detection. It is also suggested that the routine activities of victims, as well as offenders, play a major role in selecting crime targets that present better opportunities for crime. The main aim of this research is to determine the suitability of situational measures and theories underlying such research to other societies such as Tehran. In order to do so, patterns of residential burglary in Tehran have been examined. An attempt has been made to identify the factors influencing patterns of burglary, and to produce a better understanding of how burglary occurs in Tehran. A comparison between the findings from Tehran and those from Western studies is expected to demonstrate whether the theoretical framework underlying Western studies is capable of explaining burglary patterns in Tehran, and that preventive policies implemented in Western countries are suited to controlling of burglary levels in Tehran. It is hoped that the findings from the current research provide a basis for appropriate crime prevention policies and for future research.

Mitochondrial respiratory chain (MRC) dysfunction has been implicated in a wide variety of neurodegenerative diseases including Leber's hereditary optic neuropathy (LHON), Parkinson's disease (PD), Huntington's disease (HD) and dystonia. The underlying causes of the MRC dysfunction are heterogenous and may be a consequence of primary mtDNA or nuclear mutations, secondary to the underlying disease process or the effects of endogenous toxins. Cybrids have been used to investigate the interactions between the mitochondrial and nuclear genomes, and their effects on MRC dysfunction in LHON and dystonia. Although primary mutations in mitochondrial DNA complex I genes have been identified in LHON, other factors are thought to influence disease expression. While the complex I defect was maintained in the 3460 LHON/206 p° cybrids, it was absent in the 3460 LHON/A549 p° cybrids suggesting the nuclear environment influences the expression of the complex I defect in these 3460 LHON patients and that nuclear factors may contribute to the clinical phenotype. The complex I defect in focal dystonia was not transferred to either mixed or clonal focal dystonia platelet/ A549 p° cybrids lines suggesting it is caused by either a nuclear mutation or a toxin and excludes a mtDNA mutation. The previously reported severe deficiencies of mitochondrial complexes II/III and IV in HD caudate were also seen in HD putamen, and a decrease in aconitase activity was found to parallel the anatomic distribution of HD pathology. In the R6/2 transgenic mouse model of HD there were significant reductions in aconitase and complex IV activities in striatum. The relative sensitivity of complexes II/III and aconitase activity to nitric oxide and the increased immunostaining for inducible nitric oxide synthase and nitrotyrosine in the R6/2 brain supports the hypothesis that defective energy metabolism, excitotoxicity and NO contribute to pathogenesis in HD. Stable inducible cell models of HD and PD have been constructed using mutant and wild-type N-termini of huntingtin, and mutant G209A and wild-type α-synuclein respectively, to facilitate the investigation of the pathophysiology of MRC dysfunction in these disorders.

This thesis consists of two parts. The first pert is a detailed study of The Marriage of Heaven and Hell in the context of Swedenborg's Heaven and Hell and the social background of the eighteenth century. It has five chapters, in the first of which an attempt has been made to sketch an outline of social cohditions and relationship in eighteenth century England. There are two reasons for doing this. First, Blake's writings reflect his contemporary social conditions an class conflict. When he attacks Swedenborg, Newton and Locke, for example, he is indeed attacking as most radical and romantic writers did, the whole social order that they formed and represented. From the evidence thus obtained one may conclue that Blake's Marriage of Heaven and Hell and Swedenborg's' Heaven and Hell must be studied in this social context. 'Heaven' and 'Hell' are not abstract terms. They represent social conditions. 'Heaven' represents the rich and propertied or higher clerical class epitomised by Swedenborg in conflict with 'Hell' which represents the poor and working class epitomised by Blake. Those who are in 'Heaven' are called Angels, and those in 'Hell' Devils. Secondly, Heaven and Hell and The Marriage of Heaven and Hell reflect two contrasting philosophies, two types of social outlook and literature in defence of two opposing interests. Chapter Two shows first that The Marriage of Heaven and Hell is essentially written as moral criticism of Swedenborg's social system, that 'The Argument' in The Marragae refers to Swedenborg's Heaven and Hell and that Rintrah represents Swedenborg as a passive and fallen character who punishes the 'just' man in himself and people in 'Hell'.

Genomics has been transformative to the study of human evolution and disease. With the dropping cost and increased availability of genome sequencing, it is now possible to probe the genetic mediators of human disease at an unprecedented level. My own research grew out of earlier work on the genomic signatures of natural selection in humans. As an undergraduate, I investigated the evidence for recent positive selection in large-scale genomic data, identifying pathways that appear to be targeted by evolution and prioritizing promising candidate variants for functional follow-up. In medical school, I turned my attention to applying tools in genomics and evolution to the study of human disease. In this thesis, I present the results of that work applied to two major contributors to human morbidity and mortality: infectious disease and malignancy. Motivated by results from earlier work on genomic signals of recent adaptation in a West African population, I investigate genetic resistance to Lassa fever, a viral hemorrhagic disease endemic to West Africa. Focusing on a gene that is critical to Lassa infection and carries a signature of positive selection in the Yoruba population in Nigeria, I demonstrate that the same putative selected haplotype is present in other West African populations, but at different frequencies. Furthermore, I show evidence that the observed differences in frequency show correlation with the geographic distribution of Lassa virus and historical spread of the virus based on viral sequencing data. I test this haplotype for association with Lassa fever and demonstrate evidence of a protective effect. In a genome-wide association study for resistance to Lassa fever, I also identify preliminary genome-wide significant associations and promising variants for replication and follow-up. In the second part of this thesis, I focus on genomic study of human malignancy. I collaborate with a team to investigate the signatures of mutational forces in the cancer genome. We develop a novel computational framework to extract signatures from large-scale tumor sequencing data. Through this approach, we provide unbiased new estimates for the number and characteristics of the mutational processes that shape the cancer genome. We also investigate these signatures at an unprecedented level of resolution and show how they have the potential to reveal new mechanistic insights into the process of DNA damage repair and mutagenesis in cancer. Finally, we show how these signatures can reveal important clinical insights and identify subsets of tumors within the same tumor type that are dominated by different mutational processes. Our results are in stark contrast to the currently accepted model of mutational signatures in cancer, and have broad implications on our fundamental understanding of cancer biology and the future direction of the field. Although the diseases investigated here are diverse, the common theme underpinning my approach is to leverage tools in evolution and genomics to shed new light on the most devastating human diseases. Through this approach, I hope to extend our understanding of the biology of these disease processes, with implications on new therapeutic and public health interventions.

The ability to pattern material response, voxel-by-voxel, to direct actuation and manipulation in macroscopic structures can enable devices that utilize ambient stimuli to produce functional responses at length-scales ranging from the micro- to the macroscopic. Fabricating stimuli-responsive liquid crystalline (LC) polymeric materials, where the molecular director is indexably defined in three-dimensional freeforms can be a key enabler. Here, we exploited the combination of anisotropic magnetic susceptibility of the LC monomers in a reorientable magnetic field and spatially-selective photopolymerization using a digital micromirror device to independently define molecular orientation in light and/or heat responsive multi-material elements, which are additively incorporated into three-dimensional freeforms. This enables structural complexity across length scales in non-trivial geometries which are responsive to either heat or light. In this work, the mechanism of magnetically controlling the molecular orientation of various LC polymeric materials is studied. Based on the results, a new liquid crystalline elastomer (LCE) that can be aligned by low-intensity magnetic field was developed. The proposed platform and new LCE material are further exploited by the development of a battery-free, remotely controlled, bioinspired microflier with potential applications in environmental monitoring. This study can provide the opportunity to expand the applications of molecularly ordered materials to soft robotics and micromechanical devices that are driven by unconventional stimuli. The current and ongoing research works to expand the implementations of this work vision including sub-voxel control over molecular order, endowing multifunctionality, scaling the artificial muscle down to nanoscale, and exploitation of self-sensing and self-regulation are discussed briefly in the end.

The purpose of this study was to explore the lived experiences of first-generation Black men (FGBM) at a predominantly White institution (PWI). Through using Strayhorn's (2012, 2018) college sense of belonging and Tinto's (1993) student integration model of attrition theories, I examined the overall college experiences of FGBM at a PWI. When first-generation college students enter college, they are faced with academic, social, and financial challenges that make navigating college difficult (Ishitani, 2006). Additionally, Black undergraduate male students are faced with microaggressions, discrimination, alienation, stereotype, and cultural issues when they enroll in college (Harper, 2012; Strayhorn, 2008). These experiences have made navigating college more difficult for FGBM. This study advanced the research by looking at the association between FGBM's sense of belonging on campus and their overall campus integration at a predominantly White institution. The findings of this research indicated that FGBM experienced a sense of belonging on campus; however, most participants felt that their sense of belonging was limited to a smaller community at South Jersey University. This subcommunity was referred to as Black South Jersey University and consisted of many students of color, including Black student population, and social events that targeted Black students. That sense of connectedness to their subcommunity, faculty/staff, and peers enhanced FGBM's campus integration and sense of belonging.

Da das maligne Melanom der Haut ein Tumor mit einer weltweit steigenden Inzidenz ist und die Erhebung der Lebensqualität der Patienten im Zuge der personalisierten Medizin über eine verbesserte Compliance einen entscheidenden Einfluss auf den Ausgang der Erkrankung hat, wurde im Rahmen des europäischen Forschungsprojektes „Personalized Medicine“ („P-Medicine“) der Fragebogen „ALGA questionnaire“ entwickelt, um die psychokognitiven Merkmale von Patienten mit einer onkologischen Erkrankung zu erheben. Ziel dieser Untersuchung war es, speziell ausgewählte Ergebnisse des Fragebogens bezüglich der körperlichen, seelischen und sozialen Situation von Patienten, welche an einem malignen Melanom erkrankt waren, in Abhängigkeit der tumorspezifischen Parameter darzustellen, um eine aktive Patiententeilnahme an dem Behandlungsplan zu fördern („patient empowerment“), gezielter auf die Bedürfnisse der Patienten einzugehen und anhand einer gemeinsamen Grundlage, Entscheidungen zu treffen („shared decision making“). Dabei waren Alter, Geschlecht, Tumortyp und Tumordicke, Clark Level, Ulzerationen des Primärtumors, Tumorstadium nach AJCC 2009 sowie Laborwerte wie beispielsweise der Tumormarker S-100 als prognostische Parameter der Patienten definiert worden. 87 Patienten mit malignem Melanom, darunter 43 männliche und 44 weibliche Patienten, welche sich sowohl in der Nachsorge als auch in aktueller Therapie der Erkrankung befanden, haben in einem Alter von 27 bis 82 Jahren an der Klinik für Dermatologie, Venerologie und Allergologie am Universitätsklinikum des Saarlandes in Homburg an dieser Untersuchung teilgenommen. Das mittlere Alter betrug 57 Jahre. Eine Mehrheit von 38% befand sich im Stadium I, eine Minderheit von 12% im Stadium IV der Erkrankung. Mit 54% lag am häufigsten ein noduläres malignes Melanom vor. Aufgrund einer freiwilligen Teilnahme muss ein möglicher „selection bias“ beachtet werden. Zudem liegt eine Limitation bezüglich des Ortes und der Teilnehmeranzahl vor. Daher sind die Studienteilnehmer in dieser Untersuchung nicht repräsentativ. Bis auf eine Relation zwischen der Überzeugung, Ziele zu erreichen und dem Tumormarker S-100 konnte keine Abhängigkeit zwischen den Ergebnissen des Fragebogens und den tumorspezifischen Parametern festgestellt werden. Die Mehrheit der Patienten zeigte sich weder körperlich noch seelisch eingeschränkt oder finanziell beeinträchtigt. Auch ein Ansprechpartner war mehrheitlich immer vorhanden. Es muss jedoch beachtet werden, dass sich die Mehrzahl der Patienten in einem frühen Tumorstadium befand. Unabhängig vom Tumorstadium lagen ein deprimiertes Gefühl sowie eine freizeitliche Einschränkung vor. Diese Ergebnisse unterstreichen die Bedeutung der subjektiven Bewertung einer Erkrankung hinsichtlich des Krankheitsprogresses und der Prognose. Da die Angst vor einem Tumorprogress in jedem Stadium der Erkrankung bestehen kann, sollte jedem Melanompatienten psychosoziale Unterstützung angeboten werden. Gleichzeitig scheint die allgemeine Lebensqualität von Überlebenden einer Melanomerkrankung mit der Lebensqualität der generellen Bevölkerung vergleichbar zu sein. Zur genaueren Beurteilung der Lebensqualität und seelischen Gesundheit von Patienten mit malignem Melanom müssen weitere Kriterien, wie zum Beispiel der Zeitpunkt der Erstdiagnose in Bezug auf den Zeitpunkt der Beantwortung des Fragebogens oder vorhandene Komorbiditäten zum Diagnosezeitpunkt berücksichtigt werden.

Deformation and stress fields in an elastic/viscoelastic isotropic/anisotropic half-plane/half-space due to dislocation sources are of great importance since they enable us to explain or predict the phenomena that occur in the Earth sciences as well as fracture mechanics. Motivated by these important applications, this dissertation attempts to answer this important question “what are the elastic/viscoelastic responses in an isotropic/anisotropic half-plane/half-space and how important is the role of anisotropy or viscoelasticity”. To address these key concerns, several important problems are solved. As the starting point, the analytical closed-form solution for the stress fields induced by a non-uniform displacement discontinuity of finite length in an isotropic elastic half-plane has been derived. Several numerical problems are solved to prove the correctness of the presented solution and demonstrate its important applications in crack and fault analysis. Many rock masses in the Earth show evidence of overall transversely isotropic or anisotropic elastic/viscoelastic behavior. This motivates the author to find the stress fields in anisotropic and/or viscoelastic domains. As the first step in this direction, the stress fields due to a rectangular opening in a transversely isotropic domain with an irregular surface topography were derived. This problem is of great importance in civil and mining industry. Second, we continued and finished the classic works on finding the stress and deformation fields due to strike-slip, dip-slip, and tensile faults in half-spaces made of different materials (isotropic/anisotropic; elastic/viscoelastic, etc.). We solved the problem for transversely isotropic viscoelastic and anisotropic elastic half-spaces. Several practical problems have been solved to first, prove the correctness of the presented solutions and second, to investigate the effect of anisotropy and viscoelasticity on the stress and displacement fields. The results indicate that the effects of anisotropy and viscoelasticity are significant and one should consider both effects to have a realistic model to simulate and predict the response of the Earth due to fault activities.

Several perspectives of network security and energy efficiency were investigated and a scheme is proposed for each. A new approach is introduced to enhance communication security among nodes based on the threshold secret sharing technique and traditional symmetric key management. In the proposed scheme, key distribution is online, which means key management is conducted whenever a message needs to be communicated.

Abstract: School buildings are one of the most important educational and learning environments and the appropriate design of these spaces has a significant impact in enhancing both students’ and teachers’ performance, comfort and satisfaction. As a result, the preliminary design evaluation and optimization of school buildings should be given a significant consideration. The key factor in design optimization of a school building is defining the users' expectations, which is qualitative and subjective in nature. To capture these qualitative and imprecise aspects of the problem, and optimize school building design parameters a multi-criteria fuzzy expert system is employed and the design evaluation and optimization model is developed. Different school building design parameters such as; building orientation and layout, envelope features, indoor air quality as well as day-lighting systems are investigated as part of the design evaluation and optimization process. The fuzzy expert system is used to analyze the optimal values of a list of parameters associated with the building design process to enhance the learning environment for school buildings. This method employs both quantitative and qualitative design performance parameters and allows for comparison analysis between different design alternatives in order to achieve the objectives of the study.

Huntington's disease (HD) is caused by a CAG repeat expansion in HTT on chromosome 4. Onset and progression are inversely correlated with repeat length, but a significant proportion of the variability in each is due to modifiers elsewhere in the genome. Recent genome-wide association studies have identified the DNA repair genes FAN1 and MSH3 as modifiers of onset and progression respectively. This thesis finds that variants associated with HD disease course also influence onset in other polyglutamine diseases, suggesting a shared pathogenic mechanism involving DNA repair. In blood from HD patients there is significant transcriptional dysregulation, particularly involving immune, metabolic and DNA repair pathways, which correlates with disease severity, parallels dysregulation seen in the most affected HD brain regions and overlaps with Alzheimer's disease. To study the role of DNA repair, several cell models of somatic instability were developed, including patient-derived lymphoblasts and induced pluripotent stem cells, which show exponential repeat expansion that continues in differentiated medium spiny neurons (MSNs). In a FAN1 knockout U20S cell model of HD, FAN1 is shown to protect against repeat instability, and this function is dependent on protein concentration and CAG repeat length, but does not require its nuclease activity. shRNA-mediated FAN1 knockdown accelerates repeat expansion in both patient-derived iPSCs and MSNs. Through chromatin immunoprecipitation, FAN1 is shown to bind, but not specifically target, CAG repeat DNA. AAV9-mediated miRNA Fan1 knockdown in the striatum and liver of R6/2 mice did not accelerate repeat expansion, likely because only 23% knockdown was achieved. Illumina sequencing of the MSH3 region that influences HD progression identified a repeat variant that is associated with decreased MSH3 expression, reduced somatic expansion, delayed onset and slower progression in HD and myotonic dystrophy type 1 (DM1). These results suggest MSH3 promotes and FAN1 protects against repeat instability, which in turn influences the course of repeat expansion diseases.

Huntington's disease (HD) is a monogenic neurodegenerative disorder with no known cure. Selisistat is a novel, highly potent Sirt1 inhibitor with supportive pre-clinical data. Facilitation of autophagy and amelioration of transcriptional dysregulation are proposed as mechanisms of action. A first in disease Phase 1B study showed safety and tolerability. The peripheral immune dysfunction in HD could be modulated by Sirtuins which have both pro and anti-inflammatory activities. However selisistat did not alter the cytokine profile in this study. Phase 2 data over a longer duration was also well tolerated however potential hepatotoxicity is a concern. Sub-analysis of clinical assessments did not reveal any significant effect. Confirmation of proposed mechanisms of action is lacking and no Phase III studies are planned. Significant clinical heterogeneity exists in HD phenotypes which must reflect differing neuronal susceptibilities. A novel total motor score based sub-division of HD phenotypes failed to demonstrate any changes in a whole brain voxel-based morphometry (VBM) analysis. Clinical assessment alone lacks sensitivity over shorter time-spans in HD, and thus reliable, tolerable and sensitive biomarkers are required. Optical coherence tomography is a potential novel biomarker. The hypothesis that neuroretinal structures may be surrogate marker of intracranial disease was tested in a pilot biomarker study, the first of its kind in HD. Evidence of a statistically significant (p < 0.01) reduction in macular volume in HD subjects versus age and sex-matched controls is seen. No change in RFNL measures was seen. A correlation with increasing disease severity on ordinal regression was also noted. No correlation of macular volume and RNFL thickness with change in whole brain and caudate volumes. Furthermore, OCT was well tolerated by the majority of participants. Retinal abnormalities in HD have been confirmed in three subsequent independent OCT studies.

In the context of Wireless Sensor Networks (WSN), the interactions of the sensors in order to provide service to a specific job is a significant issue. Services provided by WSNs include collecting data from the environment and aggregating them to address queries, or processing the collected data and using the result to adjust a number of environmental parameters such as temperature and moisture. In WSNs, a number of nodes may need to be used by the same job simultaneously and these nodes usually need to interact with one another. A number of studies have been conducted to minimize the overhead of such interactions and to optimize the energy and other resources utilized in the process. It is desirable in WSNs that enough resources be assigned to the jobs in such a way that the jobs can acquire their needed resources as fast as possible. The distances among the sensors that are assigned to carry out a specific job typically constitute an important factor in saving energy in the context of communications among this sensors. This thesis concerned introducing a clustering algorithm to enhance the efficiency of resource assignment by reducing the distances among the cooperating sensors. Furthermore, in the proposed algorithm, clusters are formed with different sizes in order to be able to assign just enough number of sensors to a requested job. The sizes of the clusters in the network were determined based on an input to the algorithm that contained the initial number of required clusters of each size. The algorithm forms clusters in such a way that the clusters' sizes are adapted to the input for the network for the purpose of serving the incoming jobs better. Upon providing a different input, the algorithm adaptively changes the network's clusters. In this thesis, a basic version of the clustering algorithm was developed. In the simulation results, several issues were recognized and resolved by revising/extending the initial version of the algorithm. In a second extension, the algorithm was complimented by attaching the isolated nodes (i.e., nodes not assigned to any cluster) to the clusters that did not obtain a sufficient number of nodes. The clustering algorithm was executed with a pseudo-randomly generated input. The results showed that the number of clusters with each size matched the requirements for the given input. The algorithm was also run with 100 different pseudo-randomly generated inputs and rectangular-grid networks of different sizes.

Adaptive signal cancellation has been a topic of interest in many applications such as preventing radar jamming and cancelling noise and distortion in amplifiers. This work focuses on using adaptive signal cancellation to cancel the direct path signal straight from a transmitting antenna to a receiving antenna in a radar system. The theory, simulation, and design of a 2.4GHz cancellation scheme are presented, and it is shown that 45.84dB of attenuation is possible. The design is based on analog components, which sets it apart from many systems based on digital signal processors. System issues that limit the possible attenuation are discussed, and possible future work based on this project is also presented.

The objective of this research is to match the characteristics of the axes of the machine cutting tool by adjusting the nontraditional parameters, which are the axial inertias (or time constants), dampings, and loop gains. Three methods are proposed. The first methodology (artificial inertia adjustment) is based on a self-tuned real-time system. The fast axis is slowed down to follow the slow axis by adding an artificial inertia to the fast axis (through changing the tachometer gain in real-time). To carry out this method, the time constant and loop gain of each axis are estimated using a recursive least squares algorithm. In the first method, the transients of the estimates of all the axes will affect the computation of the controller gains of the faster axis. Therefore, to further improve the contour error precision of the machine parts, the second method is proposed, which is indirect model reference adaptive control. In this method, the transients of the estimates of only one axis will affect the computation of the controller gains of that axis. Using this method, the corrective action is based upon the difference between the parameters of a reference model and that of the process. The reference model is the explicit realization of the desired system. As a result, the second method has resulted in slightly less contour error. In order to improve the contour error precision of the machine parts one step further, the third method (direct model reference adaptive control) is proposed. In this method, the corrective action is now based on the difference between the performance of the reference model and that of the process. Consequently, the contour error is slightly less than the other two methods. In both direct and indirect model reference adaptive control methods, the control objective is to manipulate the nontraditional parameters in order to maintain zero axial mismatch. The constraint is to maintain identical time constants and loop gains in all the axes. In all the proposed methods, software has been used to compensate for the dynamic deficiency of the machine tool. (Abstract shortened by UMI.).

The innate immune system is known to play a significant role in the pathogenesis of Huntington’s disease (HD). However, whether the myeloid cell activation and inflammation associated with neurodegeneration and disease progression in HD is protective or damaging remains to be clearly defined. Here, neuronal-myeloid cell interactions were examined in novel co-culture models of HD, with the aim of investigating the contribution of myeloid cells to neurotoxicity or neuroprotection in the pathogenesis of HD. HD and non-HD human NSC-derived neuronal cell lines expressing human huntingtin (HTT; full-length or exon 1) were developed and characterised. These cell lines can be differentiated into mature neuronal cultures, and HD neuronal cultures expressing mutant HTT exon 1 exhibit several characteristics of pathologically affected neurons in the HD patient brain. Additionally, a novel technique was discovered for the induced differentiation of primary blood monocyte cultures, from healthy volunteers or HD patients, into microglia-like cells (BMD-microglia). BMD-microglia are similar to human brain-resident microglia in vivo by both morphological and antigenic criteria. In co-culture, BMD-microglia rescued HD neurons from mutant HTT-induced neurotoxicity and reduced neuronal death. This was associated with elevated levels of brain-derived neurotrophic factor (BDNF) release and M2 polarisation shift. During chronic stimulation, HD patient BMD-microglia became more M2-polarised than healthy volunteer BMD-microglia and released BDNF at three-fold higher levels. In contrast, BMD-macrophages, differentiated from primary monocyte cultures from healthy volunteers or HD patients, were neurotoxic in co-culture with HD or non-HD neurons, and this was associated with increased release of the proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)α. Inherent dysfunctional upregulation of cytokine release was also demonstrated in HD patient monocytes. Overall, the findings presented in this Thesis highlight myeloid cell phenotypes as an important modulator of neurotoxicity in HD, and harnessing the innate immune system in order to promote neuroprotective myeloid cell phenotypes whilst inhibiting neurotoxic phenotypes is an attractive therapeutic target. Laquinimod, a novel immunomodulatory drug which has been shown to have beneficial effects in multiple sclerosis patients, was shown here to dampen hyper-reactive cytokine production in HD patient monocytes. Modulation of peripheral immune responses has previously been demonstrated to impact on central pathology and disease progression in HD, and therefore laquinimod may be a promising candidate for dampening the harmful effects of a dysfunctional innate immune system in HD.

Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Expression of the mutant (m)HTT protein is the primary cause of disease pathology, so lowering intracellular levels of mHTT is a promising therapeutic strategy. The aim of this thesis was to achieve allele-selective suppression of mHTT using siRNA targeted to single nucleotide polymorphisms (SNPs) in the HTT gene. HD patients were genotyped for three SNPs before the mRNA and protein knockdown efficacy of a panel of siRNAs was tested in primary human myeloid cells. Functional validation was carried out by characterising the effects of selective siRNAs on the cells' hyper-reactive cytokine profile. In parallel, RNA sequencing was used to carry out the first whole transcriptome analysis of primary human HD myeloid cells. HD myeloid cells are functionally abnormal, and there is mounting interest in the peripheral immune system as a modifier of HD progression. In contrast with previous studies that have required stimulation to elicit phenotypic abnormalities, this thesis demonstrates significant transcriptional changes in unstimulated HD monocytes, including increased resting expression of proinflammatory cytokines. Pathway analysis revealed enrichment of gene sets relating to innate immunity and inflammation, while upstream regulator analysis suggests this transcriptional dysregulation is mediated by abnormal basal activation of the NFĸB intracellular signalling pathway; this was later confirmed by western blotting. These data are consistent with a priming effect of mHTT, whereby resting dysfunction leads to an exaggerated response once a stimulus is encountered. Finally, the contribution of adaptive immunity to HD peripheral immune dysfunction is yet to be satisfactorily investigated. This thesis demonstrates that mHTT expression does not affect the intrinsic phenotype of human HD T lymphocytes, suggesting that HD peripheral immune disturbance is not universal but is primarily the result of altered innate immunity.

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterised by devastating physical, behavioural and mental dysfunction. Accumulating evidence indicates that abnormal white matter (WM) is a major hallmark of the disease, with both macro- and microstructural changes apparent before manifest diagnosis. This thesis is an investigation of WM in HD and uses various imaging and cognitive techniques to address some key challenges. Firstly, the development of reliable structural measurement techniques sensitive to longitudinal change may aid characterisation of subtle abnormalities before disease onset. Secondly, optimised diffusion imaging techniques which incorporate superior image processing tools will further understanding as to why changes are harder to find in the premanifest stage and will increase sensitivity to detect them. Thirdly, the development of novel, hypothesis-driven neuropsychological tasks will help detect heterogeneous cognitive decline in individuals in the earliest disease stages. To address these challenges, firstly, a novel corpus callosum (CC) segmentation technique is developed and applied to a large clinical cohort revealing disease-related reduction in baseline CC volume and elevated rates of change over 24 months in both premanifest and manifest HD participants. Secondly, an investigation of template effects in diffusion image analysis reveals consistency between analyses using three customised templates and evidence of the superiority of tensor-based registration over scalar-based registration is demonstrated. An exploratory investigation into the association between brain volume and WM diffusivity is also presented and disease-specific changes in HD gene-carriers are reported. Lastly, two specially designed, pathology-targeted cognitive tasks are applied to a premanifest HD cohort. Abnormal interhemispheric transfer from the non-dominant to dominant hemisphere as well as altered attentional processing and impaired automaticity is revealed. By developing techniques to characterise WM pathology and explore cognitive deficits, this thesis improves our understanding of the role of WM degeneration in the premanifest and early stages of HD.

Huntington’s Disease (HD) is a devastating hereditary neurodegenerative disease for which there are currently only symptomatic treatments. Several potentially curative pharmaceutical and genetic therapies are however in varying stages of development and therefore an increasing number of large-scale clinical trials of disease-modifying therapies are imminent. There is consequently a need for biomarkers which are sensitive to beneficial attenuation of disease-related changes. Functional, neuroimaging and biochemical biomarkers have been developed in HD (Andre et al. 2014;Weir et al. 2011). Neuroimaging biomarkers are strong candidates based on their clear relevance to the neuropathology of disease, proven precision and superior sensitivity compared with some standard functional measures (Tabrizi et al. 2011;Tabrizi et al. 2012). Their use in early-stage clinical trials, as surrogate end-points providing initial evidence of biological effect, is becoming increasingly common. Comparison of biomarkers in HD will help to clarify which measures, over varying time intervals, are most sensitive to disease progression. Additionally, the identification of robust fully-automated methods, comparable to manual and semi-automated gold-standards, would facilitate large-scale volumetric analysis. These methods however require validation in observational studies of neurodegenerative disease before they can be applied to sensitive clinical trial data. This thesis will develop and evaluate biomarkers for use in HD; both furthering our understanding of the disease and in preparation for use as end-points in clinical trials. A direct comparison of the sensitivity of diffusion and volumetric imaging biomarkers to HD-related change will be reported for the first time. Several exploratory imaging investigations are also described which enhance current knowledge of the relationship between neuroimaging metrics, brain functioning and behaviour, additionally strengthening the argument for the clinical relevance of neuroimaging measures as surrogate end-points in HD. The thesis will conclude with a comprehensive biomarker evaluation in early-stage HD, along with suggested strategies for selection of primary and secondary trial end-points based on effect sizes and corresponding sample size requirements.

I was interested in history while I was in school and I pursued this interest as a history student at the University of Tabriz where I graduated in history in 1973. Apart from a major part of our studies in history, which were about the Iranian and foreign dynasties, we had to study a great deal about the lives of individual Kings; but hardly any space was allocated to the history of social and political movements in Iran. The names of patriots and political thinkers such as K̲h̲iyābānī were not, for political reasons, mentioned. These movements, however, no matter how briefly they were covered in our history books, were still able to arouse my curiosity and interest in discovering more about these movements and their leaders. In 1977 I decided to undertake research in modern history. My decision coincided with social and political upheavals in Iran which resulted in the revolution of 1979. This by itself strengthened my conviction that we must study and understand our history in its particular social and political content. That is to say revolts and revolutions are not something which appear suddenly, but are the product and result of historical developments in which peoples, as a living force, have taken part. These revolts and revolutions are, in fact, the manifestations of longstanding social injustices and oppressions which have been imposed on the people by despotic kings, irresponsible governments and reactionary rulers. In recent social upheavals of Iran I witnessed how thousands of sincere people and patriots gave their lives and wished to free their country from age old backwardness. This reflected the continuation of the constitutional revolution and K̲h̲iyābānī's uprising (1910-1920). Since my grandfather Mīrzā Muḥammad Tagī Ṭabāṭabā'ī K̲h̲ātambak̲hs̲h̲ was involved in the constitutional revolution and K̲h̲iyābānī's uprising and I naturally had heard a lot about K̲h̲iyābānī through my relatives, both personal curiosity and historical interest made me choose K̲h̲iyābānī as the subject of my research. Some books and articles have been written about K̲h̲iyābānī which are either very superficial or based on misrepresentation. They are superficial because they have not attempted to explain why and how K̲h̲iyābānī's uprising began and the reasons for its success and failure and the role of central government in Tehran in this event is not examined. K̲h̲iyābānī's original speeches and works have not been studied in depth. The opposition to K̲h̲iyābānī's uprising has misrepresented him in different ways. The most striking aspect of this is the fact that he has been accused by his political opponents over and over again of being a "separatist". Some historians have even either spelt K̲h̲iyābānī's name wrongly or copied the errors of others. I came to Edinburgh and was accepted as a postgraduate student in October 1979, and then went to London where I studied and examined the British Foreign office archives and also studied in the British Library. Through the Edinburgh University Library I received some books and newspapers in Russian, French, English, Persian and Azari. Three times I travelled to Iran where I could consult the Iranian Parliamentary documents, newspapers, books and interviewed a number of Iranians who either participated in or had valuable memories of K̲h̲iyābānī's uprising. It is hoped, therefore, that the present study will shed a great deal of light upon a hitherto much-neglected episode in modern Iranian history.