Search

Supply chain management is based on the global concept, where different companies are connected worldwide. Moreover, supply chain performance management is a growing field of study, especially for perishable products. Egyptian dairy producers have suffered a significant drop in their production since 2011, due to the poor quality and quantity of raw milk, changes in governmental regulations, hazard risks, and volatility in consumer taste. This has threatened meeting the increasing market demand for dairy products. Extant literature highlighted the following gaps: limited research assessing the dairy producers' supply chain performance in a detailed view from an operational perspective, and lack of specific performance measures especially in Egypt as a developing country in this context. Therefore, this thesis introduces a best practice performance framework for dairy producers in Egypt to optimise and assess their performance, in terms of sustainable production of safe and secure dairy products to fulfil the Egyptian market demand. The research adopts three theories to explore and understand the research problem. The resource-based view theory is used to identify the operational capabilities and the critical control points within the production. Network theory is used to explore the risks in the wider dairy supply chain and identify solutions to overcome them. Last, the institutional theory is used to understand the pressures faced by dairy producers, all of which will help to develop a best practice performance framework by following the mimetic approach to contrast and compile the performance measures of the top six large Egyptian dairy producers. That is achieved by referring to the Supply Chain Operation Reference (SCOR) model key attributes as a guide. This research utilises a narrative literature review to consolidate the background knowledge on the dairy sector's operations and supply chain risks. Then, classify the different operational and supply chain performance measures and models to provide future research directions based on the research gaps identified. A multiple case-study methodology is adopted in this study. It follows a qualitative research approach across two phases by using the NVivo12 software to conduct a thematic analysis. Firstly, two observations and seventeen exploratory semi structured interviews with key informants within six case studies were conducted to explore the operational capabilities, critical control points and performance measures and the risks affecting large Egyptian dairy producers. Secondly, two focus groups were held with a diversified sample of practitioners, government officials, and suppliers to validate the results of the first phase. The key findings of the research highlighted that those dairy producers performing on a satisfactory level qualify them to adopt the SCOR model to enhance their performance and imitate the dairy producers' practices in developed countries. The following key areas were addressed: 1) identifying the current operational capabilities needed to produce milk products, defining and classifying new critical control points for the production of UHT milk and pasteurised milk which up until now remains vague and not well determined, 2) each producer has designed their performance measures which has left them exposed to vulnerabilities and limits their optimum utilisation of their capabilities and to be able to continually improve. Thus, standardisation of performance measures and sharing of best practice, with a detailed classification for applicability is key for Egyptian dairy producers. A major contribution of this research is the development of an operational and supply chain performance-based best practice framework, based on SCOR, to guide the dairy producers through optimising and enhancing their production of safe and secure dairy products. Further, the research has identified three new SCOR attributes: a) suppliers' improvement and traceability, b) health and safety environment, and c) employees' morale, also seven new critical control points and capabilities. Besides, utilising the qualitative approach to provide in-depth within and cross-case exploration of six large dairy producers' current state. This research also recommends that the government should leverage the small farmers within a milk hub, with a tracking system, to close the gap of raw milk supply shortage to Egypt. That addresses the shortcomings in the extant literature, which will significantly contribute to enhancing the performance and sustainability of the Egyptian dairy industry as a whole, and consequently will benefit the Egyptian economy. That sets the base for future researchers to utilise the proposed best practice for a wider scope of dairy producers with similar characteristics.

In light of increasing concern about the democratic recession spreading across established representative democracies this PhD explores how digital democratic innovations are used in emerging political parties, to involve members and supporters directly in intra-party policy formation and decision-making. This is explored through a case study of Danish political party Alternativet, which constitutes a recent example of an emerging political party that claims to promote and practice new and inclusive ways of doing politics, experimenting with digital technologies for this purpose. In this respect the case of Alternativet illustrates a larger trend of what has been labelled connective parties (Bennett et al., 2017) or movement parties (Porta et al., 2017) by other authors. As with many of these parties, Alternativet experienced electoral success relatively quickly and has been represented in parliament since 2015, and in several local councils since 2017. Thus, Alternativet, like similar emerging parties, is an attempt to combine democratic innovations with party politics and traditional political institutions in liberal representative democracies. This is interesting considering how democratic innovations are often conceptualised in contrast to classic representative political institutions. Both democratic innovations and Internet technologies have promised, but struggled to deliver, an increase and deepening of citizen participation in democratic decision making. While they have demonstrated that they can engage citizens in political questions, it has been a particular challenge to turn engagement into impact on final political decisions. These decisions are usually taken in decision-making fora dominated by political parties, such as governments, parliaments and local councils. So connective parties, such as Alternativet, posses a potential ability to provide consequentiality to citizen participation by combining democratic innovations with party politics. However, so far insufficient attention has been given to the kind of (re-invigorated) democracy these parties promote, and what kind of participation the digital platforms they use facilitate. This thesis address exactly those questions. The study employs a mixed methods approach, combining semi-structured interviews and participant observation with a party member survey. Interviews with key stakeholders in the party and participant observations during a two months visit at the party's national secretariat are used to explore how and why the party uses digital tools to engage party members and supporters in policy formation and decision-making. This includes the motivation to engage members actively in policy formation in the first place. Based on this, the thesis identifies four dimensions of intra-party democracy promoted by the party elite: An aggregative crowd sourcing dimension, a deliberative dimension, a developmental dimension, and a more traditional delegation dimension. Each of the (many) digital platforms used in the party have affordances that speak to each of these dimensions. A survey distributed among party members and supporters is then used to explore the support for each of these four dimensions of intra-party democracy. This data indicates that support for intra-party democracy among the party supporters can reasonably be considered along the same four dimensions. These findings are significant for our understanding of the role both democratic innovations and political parties can play in revitalising democracy.

As a clean and non-greenhouse gas-emitting energy source, nuclear plants are not fully explored due to high costs, low efficiencies and complex designs of incumbent technologies. However, studies indicate high efficiencies and simpler designs are achievable if developed under the Generation IV (Gen IV) framework. The Gen IV framework offers sustainable energy that reduces and recycles the waste at a reduced cost, which is safer and reliable and improves the control in securing nuclear material through features that eliminate proliferation. The objective of this research work was to develop a Nuclear Techno-Economic and Risk Assessment (NuTERA) conceptual tool known as HYPERION under the Gen IV framework, based on constructed algorithms that enable better understanding of the technology for investment purposes. It concentrated on: component and cycle design, Design Point (DP) and Off-Design Point (ODP) performance, control systems, economics, risk assessment and the Levelised Unit Electric Cost (LUEC). The research focused on the Gen IV Gas-cooled Fast Reactor (GFR) and the Very High- Temperature Reactor (VHTR) using helium and considered 3 cycles: Simple Cycle Recuperated (SCR), Intercooled Cycle Recuperated (ICR) and the simplified and novel Intercooled Cycle without recuperation (IC). The HYPERION technical model quantified aspects that affected efficiency, whilst utilising a comprehensive calculation method to derive the ODPs. The HYPERION economic and risk models quantified the Specific Overnight Cost (SOC) including risks which were incorporated as contingencies into the LUEC. The economically optimised results showed that the ICR is the most efficient cycle (53%), followed by the SCR (50%) and then the IC which had an optimised efficiency of 41%; compared to 46% (DP). However, the IC has the best economics at US$5.57ct/kWh compared to the ICR (US$6.97ct/kWh) and the SCR (US$6.98ct/kWh). In fact, the IC is the cheapest clean energy solution in comparison to other generating sources such as solar and wind. It is the 2nd best option whilst coal without carbon capture is the cheapest option. It is important to note that this individual work resulted in 16 publications, comprising 11 journal papers, 4 conference proceedings and 1 book chapter.

Islamic banking and finance have received a considerable attention from academics and practitioners after the global financial crisis. Drawing insights from the theoretical and empirical studies about the resilience and the relative stability of Islamic financing alternatives - compared to their conventional peers- during turbulent economic and market conditions, I found that Islamic alternatives are not as less risky and stable as previously presented. This thesis makes a contribution to the asset management literature by examining whether Shari'ah compliant exchange traded funds (ETFs) have potential diversification benefits to a volatile portfolio of investments in emerging markets. The portfolio consists of three asset classes: conventional and fixed-income securities in emerging markets and Shari'ah compliant equity. I utilise a dynamic optimisation strategy to capture the time-variability in correlations between Islamic ETFs and other ETFs and find the optimal portfolios accord-ingly. I back test the results by using a static optimisation strategy and estimating optimal portfolios over two sample periods. The results are new to the literature, since previous empirical evidence is either comparing Islamic and conventional equity or Islamic and conventional bonds using static asset allocation strategies. Furthermore, this thesis contributes to the literature by taking a holistic approach and analyses the role of Islamic banks on both the micro and macro levels. I examine the effect of Islamic banks' financial distress on other financial institutions and the financial system in 10 Muslim majority countries. The research sample comprises 352 conventional and Islamic financial institutions. I do not consider only Islamic banks' specific characteristics and macroeconomic variables, but I also take in consideration the financial linkages and the spillover effects of financial institutions' distress. This research is pivotal, because it fills a research gap when it comes to identifying the systemic relevance and role of Islamic banks in financial systems. Previous research has adopted a top down approach and has identified the effect of the system on Islamic banks. Given the liter-ature about increasing business risks in the Islamic banking sector, I hypothesise that Islamic banks contribute to systemic risk. In addition, I identify whether the effect of Islamic banks' distress on the system is due to the change in their business risks over time. The findings of this thesis are new to the literature and provide implications of great importance. Institutional investors should consider the religion effect when they manage their assets, given the evidence regarding the outperformance of Shari'ah compliant equity relative to their conventional peers. They should also be cautious when using dynamic strategies, because they can be more costly to apply specially in volatile markets such as emerging markets and during crisis periods. For central banks and regulator, they should consider Islamic banks as genetically modified conventional banks). If Islamic banks and financial authorities did not address the routes of inefficiency, insolvency risk, and withdrawal risk in Islamic banks, they will continue to contribute to financial systems' distress.

In this thesis, I examine why accounting is important in debt markets. The thesis consists of three essays. In the first essay, I examine how syndicated loan structure is influenced by financial reporting conservatism. Early theoretical research focuses on the impact of asymmetric information and moral hazard problems on the loan contracting process. I hypothesize that, given their preference for verifiable lower bound measures of earnings and net assets, creditors are likely to value financial reporting conservatism as a means of reducing information asymmetry. Using a firm-year measure of conservatism, I find that the number of non-lead participants is a positive function of the degree of conditional conservatism. In addition, the lead arranger share is negatively associated with the degree of conditional conservatism. I also examine the relation between conditional conservatism and syndicate structure during the financial crisis. The results show that the relation between conditional conservatism and syndicate structure is more pronounced during the financial crisis. The results add further evidence on the role of financial reporting conservatism in resolving information asymmetries in debt markets. In the second essay, I investigate how the firm's financial reporting quality, measured by timely loss-recognition (TLR), affects lenders' decision to participate in cross-border syndicated loan markets. Using a large international sample of syndicated loans encompassing 20 countries, I show that both proportion of foreign lenders in a syndicate and their shares of the loan amount increase in the borrower's TLR. This effect is more pronounced for loans initiated during the financial crisis. In addition, the effect is less pronounced for loans extended to firms with a high international presence' and which reside in the countries with strong creditor protection. The evidence suggests that TLR reduces information asymmetries between lenders' and borrowers in cross-border credit markets where the asymmetry is likely to be most severe. In the third essay, I investigate the impact of large blockholders on the monitoring demands by lenders. Using novel data from US debt contracts, I show that creditors are more likely to require a covenant-compliance certificate (CC) from the borrower's auditor when large blockholders are present in its ownership structure. The effect is less pronounced for firms rated by credit rating agencies. Consistent with the debt-equity conflict hypothesis, I find the presence of transient and passive investors, but not long-term strategic investors, drives the inclusion of the CC provision. The evidence suggests that institutional investors with myopic investment horizons are a cause for concern for creditors, but that additional monitoring may alleviate such concerns.

Since Chomsky (1964) and Ross (1967), wh-movement has received considerable attention in the literature. One of the cross-linguistic phenomena that has appeared in recent works on wh-movement is the issue of optionality - a situation whereby languages allow both wh-movement and wh-in-situ strategies. This thesis aims to investigate the syntax ofwh-questions in one of the optional wh-movement languages, namely, Egyptian Arabic (henceforth EA). It examines whfronting and wh-in-situ strategies which the grammar of EA employs to form whquestions. The theoretical framework within which this study is conducted is the Minimalist Program (henceforth MP) as proposed and developed by Chomsky (1995). The major claim of this study is that EA is mainly a wh-in-situ language whereby wh-phrases are interpreted and assign scope in their base-generated (i.e. in situ) positions. I propose that EA wh-phrases carry weak [wh] features, hence they cannot be attracted to the C-domain. This is why wh-movement of the English type does not take place. The only movement involved in the derivation of the whquestions in situ is the covert movement of a functional category (an operator) which carries the [wh] feature. Thus, wh-phrases in situ are licensed and assign scope via LF movement of formal features to the Spec CP position: a type of movement allowed in the MP. The question remains for the cases where wh-phrases are fronted. I claim that movement in EA is triggered by a feature other than the [wh] feature required for clausal typing, and that wh-phrases appear in a projection other than the CP projection which normally hosts wh-phrases in wh-movement languages such as English. The present study argues that the fronting of wh-phrases in EA is the result of Focus movement, which is triggered on a par with wh-movement. Focus movement involves the movement of wh-phrases to the Spec of Focus projections (FocusPs).

This dissertation examines the ways in which cultural definitions of gender, sex, and race have equally impacted and disrupted women and their relationships in postcolonial culture. Such relationships can be with either with oneself or with others. My argument throughout this project is that colonialism as an act of systematic physical and psychological violence, together with its residual effects that split the individual and his/her community, is a primary cause of transgression. Breaking social boundaries takes place through a process of coding and decoding the body where female characters portrayed from a selected range of fiction demand agency in environments that deny them such power. In order to track the development or loss of feminine identity, I comparatively study the characters and incidents alongside one another to show how oppression, across time and space, can produce different expressions of revolt. Unlike colonized men who are also forced to question the integrity and wholeness of their body, with women the oppression is twofold: she is made inferior by nature of her race and her sex. Until today, this has serious implications that hinder the cultural development and economic progress of postcolonial cultures. Hence, the discussions presented in this project call for a feminist and postcolonial understanding of the corporeal body and challenges Cartesian ethics which conceptualize the mind as superior to the body. Arguably, they contribute to other dualities which participate in similar hierarchical ideals when discussing racial and sexual difference such as, self/other, masculine/feminine, civil/uncivilized. Crossing over different geographies, writers such as, Ahdaf Soueif and Toni Morrison showcase women who reject the dualisms, even if some of their struggles end tragically. Representing postcolonial women in this light invites a less biased understanding of the body as lived, and its reactions as consequent to where and how it goes about such living.

The main aim of this interdisciplinary project is to examine attempts to codify sexual knowledge in Egypt between 1830 and 1928. Through surveying medical, religious, legal and moral writings on sexuality, this study aims to examine the underlying politics of sexual knowledge and the structures of permissions and prohibitions within which sexual knowledge was articulated in the period under study. The research recognizes that there are several sources that informed people about sexual behaviour in the period under study. However, the study is concerned only with a number of writings that imparted teachings about sex directly or indirectly to the growing literate middle class, and proceeds to discuss their authors and contexts. The study's main focus is the influence of medical and scientific conceptualization of sex differences on the understandings of gender and sexuality. In nineteenth-century Egypt, the study argues, professional medical authorities promoted medical theories that suggested men's innate active sexuality and inability to control their sexual urges. At the same time, professional Egyptian doctors increasingly projected women as mentally and physically fragile because of their reproductive cycle. Women were increasingly viewed as incapable of being sexually spontaneous. To remain healthy, women were advised to suppress their sexual desires to be satisfied only through marital sex. Through examining the interconnections between medical, legal, religious and moral discursive literature on sexual behaviour, this study brings into light the associations between sex, sexuality and the creation and recreation of gender. The study demonstrates that medical perceptions of male and female sexualities were at the core of moral and intellectual discourses on gender equality as well as religious opinions on sex-related issues. Since there was a multiplicity of ideological and activist stands on questions about sexuality and gender in the period under study, the study explores the variety of ways in which nationalists, feminists and religious scholars adopted, borrowed or negotiated with scientific and medical ideas on female sexuality to support their different views on contemporary controversial issues such as gender equality, polygamy etc. Medical and scientific ideas of male and female sexuality had a complex impact on discursive literature on gender and sexuality. On the one hand, they were employed to justify the continuity of patriarchy and the increasing male regulation of female sexuality. On the other hand, they strengthened arguments in support of the participation of women in public life.

In recent years, natural gas has taken over from coal and it has become the second energy source after oil. This is not only because of its economic attractiveness, but also due to environmental concerns. This study is concerned with developing accurate Computational Fluid Dynamics (CFD) numerical models to study two different natural gas combustion systems, namely central heating domestic boilers and thermal cracking furnaces in petrochemical industries, in which the turbulence and the chemical kinetics play a similar role in importance. The first part of the thesis is concerned with developing accurate two-dimensional and three-dimensional CFD models to simulate the premixed flame produced in domestic boilers with a conventional cylindrical premix burner. The second part of the thesis is concerned with developing a three-dimensional CFD model to simulate the turbulent diffusion flame on the fire-side of the radiation section of thermal cracking test furnace coupled with a non-premixed low NO„ floor burner. Although, these two systems produce two different tying of flames, premixed and diffusion, and are used on two different scales in process beating applications, 30 kW and 6 MW, for both of the two systems, the turbulent mixing rate and the chemical reaction rates have comparable values and hence this should be considered in the model. Different combustion models, such as the pre-assumed PDF model with equilibrium chemistry and Eddy Dissipation Concept (EDC) with the detailed GRI 2.11 reaction mechanism, are used to simulate the turbulence-chemistry interactions inside the two combustion systems. Also, The effects of using different turbulence and radiation models and different reaction mechanisms on the accuracy of the predicted results are investigated. For the premixed flame inside domestic boilers, the CFD numerical results are compared with the experimental measurements at different boiler loads to investigate the accuracy of different CFD models. The most accurate validated CFD model is used to investigate the effect of different operating conditions on CO and NO emissions. Furthermore, the design of the 10 kW burner is modified in order to reduce the CO and NO emissions produced from the boiler.

The influence and role of time in consumer behaviour is a domain that has recently received increasing – albeit incomplete – attention in the consumer research literature. Such acknowledgement of the growing appreciation of a time dimension in a range of consumer-related phenomena clearly supports the focus of the present research – the time emphasis of perceived benefits and value sought by a consumer in the context of consumption and adoption of an innovative product category. The research draws upon consumer research and marketing literature, integrating findings from psychology and sociology, to develop two distinct but related conceptual frameworks for empirical investigation. Framework I investigates consumer-related factors as antecedents to the pursuit of temporally emphasised benefits motivating a product‟s consumption behaviour. Framework II investigates the relationship and influence of temporal-based value sought by consumers on a product‟s adoption decision process in terms of its speed, potential outcomes and process dynamics. The main objective is to establish answers to related research questions operationalised using the research vehicle of organic food, a product category representing a rising market trend and an innovative non-durable consumer good. A set of hypotheses is drawn up and empirically examined based on data gathered in the UK from two samples. Data is collected using a large-scale questionnaire-based approach, where each data set is analysed separately along with analyses which combine cases from both samples. The findings and the associated discussion provide important insights and overall support for the conceptualisation presented and developed in this research. General findings indicate that some psychological and behavioural consumer-related factors comprising level of involvement, perceived prior knowledge level and product usage level are more significant antecedents of temporal-based benefits sought than social and demographic factors. Results also show significant associations between temporal-based value sought in organic food and the speed and outcomes of its adoption decision process. In addition, the adoption decision process is found to be temporally dynamic, with active steps that have a carry-over effect on subsequent steps in the process. Findings extend a new temporal perspective to understanding perceived benefits and value of innovative products, offering theoretical and managerial contributions and implications for consumer researchers and marketers in relation to temporal motivations in consumption and adoption behaviour.

Models developed in continuous-time have been used to study the epidemiology and population dynamics of plant hosts, usually in cultivated systems. Here discrete-time SIR–type models are developed which contain parameters representing characteristics of an uncultivated, biennial host plant – systemic, castrating pathogen system. This thesis presents 4 epidemiological model forms representing a generic SIR model, a constant pathogen-induced mortality model, a variable pathogen-induced mortality model, and a model which has an additional phase representing a seedbank. Using a range of parameter values it is possible to produce simulation outcomes with population crashes, cycles and steady-state populations. For each of the models a pathogen epidemic criterion is derived as is a term describing population steady-state values. For the pathogen-induced mortality models, the invasion criteria include a pathogenicity term indicating that the pathogen in part regulates the host population dynamics. The biennial host plant Tragopogon pratensis has been recorded in the Park Grass Experiment and has been described as an outbreak species regulated by the autoecious, demicyclic rust fungus, Puccinia hysterium (Silvertown et al., 2006). The rust is shown to castrate the host plant by reducing the numbers of seed set and the viability of seeds produced by infected individuals. Further characteristics of this host – pathogen system are identified by using the developed models. This is justified as the recurrencerelationships derived from the models fit the observed data, and that the accuracy of the fit is increased with larger values of pathogen-induced mortality. These models produce simulation outcomes that are similar to the host population dynamics. The models also show that the system is governed by density-dependent factors.

The following research focuses on trade union organisations, and in particular trade union officialdom in Egypt. The study examines the extent to which trade union officials at the various levels of the trade union hierarchy are reacting to reforms instigated by structural adjustment policies. The adoption of structural adjustment and economic reform measures as proposed by the World Bank and IMF have resulted in the government's withdrawal of some of the benefits and privileges it accorded to workers. Public sector workers are particularly affected by these changes, thereby posing a challenge to trade union officialdom, since the bulk of trade union membership is within the public sector. Trade union officials are reacting to the reform measures by trying to balance their role as representatives of workers' interests and their role in administering state policy. Whereas in the past these two roles were reconcilable, however, with liberalisation of the economy and the adoption of structural adjustment measures that is no longer tenable. Trade unionism has been weakened by the incorporation of union officials within government corporate structures, making it more difficult for trade union officialdom to challenge the reform measures adopted by the government. Rather, trade union officials are opting for `co-operation' both with the government and with management in enterprises, to the cost of workers. In enterprises, trade union officials emphasise that the interests of work and workers are inseparable. At the level of the confederation and general unions, union officials present themselves as working to keep workers' rights, but also as partners with the government in its drive for growth. By so doing trade union officials are de-politicising trade unionism, and instead focus on economic gains. Union officials are redefining their role away from workers. Trade union action at the various levels is not based on what workers want or demand, but rather on what trade union officials want, in the belief that workers do not truly know their interests. As a result, trade union action has promoted the interests of union officials rather than that of the workers. Trade unionism has become in a sense a shell without a content. However, there is evidence that there are pressures to democratise trade unionism and make it more responsive to worker demands. These pressures are from within the worker base, from trade union officials particularly at the enterprise level who are affilited to political parties, and from external forces like the Islamists. However these forces have their limitations, particularly in the face of institutionalised sectors that are capable of reproducing themselves and promoting their interests.

Performance assessments have become the norm for evaluating language learners' writing abilities in international examinations of English proficiency. Two aspects of these assessments are usually systematically varied: test takers respond to different prompts, and their responses are read by different raters. This raises the possibility of undue prompt and rater effects on test-takers' scores, which can affect the validity, reliability, and fairness of these tests. This study uses data from the Michigan English Language Assessment Battery (MELAB), including all official ratings given over a period of over four years (n=29,831), to examine these issues related to scoring validity. It uses the multi-facet extension of Rasch methodology to model this data, producing measures on a common, interval scale. First, the study investigates the comparability of prompts that differ on topic domain, rhetorical task, prompt length, task constraint, expected grammatical person of response, and number of tasks. It also considers whether prompts are differentially difficult for test takers of different genders, language backgrounds, and proficiency levels. Second, the study investigates the quality of raters' ratings, whether these are affected by time and by raters' experience and language background. It also considers whether raters alter their rating behavior depending on their perceptions of prompt difficulty and of test-takers' prompt selection behavior. The results show that test-takers' scores reflect actual ability in the construct being measured as operationalized in the rating scale, and are generally not affected by a range of prompt dimensions, rater variables, or test taker characteristics. It can be concluded that scores on this test and others whose particulars are like it have score validity, and assuming that other inferences in the validity argument are similarly warranted, can be used as a basis for making appropriate decisions. Further studies to develop a framework of task difficulty and a model of rater development are proposed. [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.]

Numerous studies in the behaviour sciences are concerned with the role of human values as a determinant of human behaviour. In recent years an increasing attention is being paid to the subject of human values in the managerial context. Students of managerial behaviour agree that the value system of an individual manager is one of the factors which affect his behaviour at work. The main objective of this research is to investigate the feasibility of classifying the managerial workforce in Egypt into different types according to their systems of values, and to demonstrate how data about types of managers could be used in improving managerial performance in Egypt. Another objective of this study is to investigate the role of culture in the formation of the value system of a specific cultural group. To carry out these investigations, a theoretical framework was developed. Two instruments were included in this framework: (1) The Personal Value Questionnaire (P.V.Q.) [developed by G.W. Ailport]. (2) The Managerial value Questionnaire (M.V.Q.) [developed in this study). Both instruments were based on the work of the German philosopher Edward Spranger "Types of Men", in which he classified human personalities into six types according to six classes (dimensions) of values (i.e. Theoretical, Economic, Aesthetic, Social, Political and Religious values). The data of this study was derived from: (1) A national sample of 256 Egyptian managers. (2) Two cultural groups ((246 Egyptian business students] and (595 American business students from D. Palmer's study of "Personal Values and managerial Decision]). The Egyptian Managers: Personal and managerial value profiles of the Egyptian managers were identified. Although the two profiles appeared to be dissimilar, a link between them was found. This indicates that the value system of the Egyptian manager is not simply a unitary system which expresses a single profile (a rank order of importance) of the six value dimensions in both personal and managerial lives. Rather, it is an interlocking network of dominant ( personal) and variant (managerial) patterns of values. When used as a discriminatory variable, the managerial value profile proved to be useful in identifying four types of managers that exist in Egyptian society (i.e. Economic, Social, Political, and Religious managers). The four types differ in their primary value orientations and are expected to differ in their organizational performance, especially in their perception of daily problems, their interpretation of the organization policies and goals, and their dealing with individuals and groups. The analysis of the managerial value profiles of the four types of managers suggests that only the Economic and Religious managers could be motivated to serve the objectives of business organizations in Egypt. They are expected to give a predominant position to such organization's goals as high productivity, organizational growth and profit maximization. The Two Cultural Groups: A cultural contrast of the personal value profiles of Egyptian and American business students marked five significant differences between the two groups. The analysis of these differences emphasized the role of Islamic culture in shaping the personal value profile of the Egyptian group. Finally, a proposed model (including six dimensional equations) for the classification of a specific manager into one of the four types (i.e. Economic, Social, Political, and Religious managers) was designed.

This is a study of two causally related issues, industrial and trade imbalances in the former East African Common Market (EACH) from mainly 1962 to the break up of that Common Market in 1977 Industrial imbalances among the three member countries of the EACM, Kenya, Tanzania and Uganda, was the principal cause of the trade imbalances And the two forms of imbalances were a source of political sensitivity in Uganda and especially in Tanzania This sensitivity, which reflected a belief that the operation of the EACM had been inequitable, was a threat to the existence of that economic integration scheme in the early 1960s This study analyses the nature, the causes and the dynamics of the industrial and trade imbalances for the sixteen year period mentioned above Both quantitative and qualitative evaluations are made in order to establish the effectiveness of the mechanisms which were devised to correct the two forms of imbalances The study focuses on one of the corrective mechanisms, the East African Development Bank (EADB), which still operates today It was expected to reduce industrial disparities between Kenya and the other two countries Four perspectives concerning the operation of the EADB are adopted for the purposes of evaluating the effectiveness of this instrument The first is fund allocation The EADB was supposed to allocate the funds at its disposal according to a prescribed formula The second perspective is about countries' capacity to absorb the funds allocated to them The third concerns the relative importance of the EADB as a source of finance for projects, in comparison with the other sources of finance which the study calls the Non-Bank sources Finally, the EADB's effectiveness as a mechanism for correcting industrial disparities is evaluated from the standpoint of the performance of the projects in Kenya, Tanzania and Uganda The EADB was also expected to make its three member countries increasingly complementary in industrial field The measure of success it achieved in this direction is assessed It is found that the EADB was not an effective instrument for reducing industrial imbalances between Kenya and the other two countries There are several explanations for this First, the EADB did not have adequate funds Second, finance absorption in Kenya was higher than in either Tanzania or Uganda and the EADB had hardly any power over that factor Third, the EADB's contribution of finance to the cost of projects was small The Non-Bank sources were a more important source of finance Fourth, Kenya's capacity to generate investment greatly exceeded that of either Tanzania or Uganda Therefore, given that the Bank was a minor source of finance for the projects it cofinanced, its "balancing effect" was greatly offset by the "disparity effect" arising from Kenya's greater capacity to generate investment Finally, Kenya had more successful projects than either of the two countries And the amount of investment in those projects (effective investment) was far in excess of the amount of effective investment in either of the two countries An examination of the determinants of the success and failure of projects revealed that the EADB had scarcely any control of those determinants The study concludes that the reduction of industrial imbalances objective was unrealistic This conclusion is partly arrived at by evaluating the performance of the EADB It is also reached by taking into consideration the findings that during the active lifetime of the East African Community (EAC), 1968-1977, there had been a general trend towards industrial disparity between Kenya and her two Partner States Trade imbalances moved in the same direction For Kenya and Uganda, that trend goes back to 1962 The EADB was also ineffective as an instrument for making its member countries increasingly complementary in industrial field This was chiefly because there was no agreement between these countries on the harmonization of industrial development in the EAC The principal lessons of this study are the following To begin with, it is unrealistic to try to bring about balanced economic development among members countries of an economic integration scheme if conditions for economic growth in those members differ Secondly, as long as those members accept a high degree of intercountry trade, imbalances in trade between those countries will exist This should not, however, unduly raise political sensitivity of the member countries in trade deficit unless their share of trade in their economic block is falling and if they can not in the present or future induce investors operating in national boundaries to exploit the presence of a multinational market In connection with the EADB, it is argued that it could contribute more to the economic welfare of its member countries in two main ways The first is that it should be able to mobilize more concessionary funds than it did in the past The point is that the EADB should utilize increasingly soft loans such as those it obtained from the Scandinavian countries The second way, is for the EADB to strive harder than it has done in the past to raise the number of successful projects in its member countries Ways in which this goal may be achieved are found in the concluding chapter 8, of the thesis.

Three topics are reviewed: the use of photosensitive protecting groups, the photochemistry of azides and the reactions of nitrenes formed by the decomposition of azides. The photolysis of a suitable aryl azide is proposed as the basis for a photosensitive protecting group for carboxylic acids and alcohols. This is based on the finding that the methyl ether and benzoate ester or ortho-azido-β-phenethyl alcohol produced indole and, in the latter case, benzoic acid on photolysis. The photolysis of this and related systems was investigated. A better yield of benzoic acid (65-70%) was obtained by irradiating 5-azido-4-benzoyloxymethyl-l-methoxynaphthalene. This result led to the attempt to prepare 4-azido-5-benzoyloxyphenanthrene, which was expected to give benzoic acid quantitatively on photolysis. Attempts to prepare this via a 4-carbonylnitrene-5-hydroxymethylphenanthrene intermediate failed. A novel Schmidt reaction for a lactone and a new reaction of N-tosyloxyimides with sodium borohydride are described in this section. The nitrite ester of 4-hydroxy-4-methy1-1, 2, 3, 4, 5, 6, 7, 8- octahydrophenanthrene was photolysed to give 4-hydroxy-4-methy1-5- oximino-1, 2, 3, 4, 5, 6, 7, 8-octahydrophenanthrene. The Semmler aromatisation of this and related compounds was investigated and applied to the eventual formation of 4-amino-5-methylphenanthrene. This amine could not be converted to an azide and its diazonium derivative underwent a Nascarelli reaction under very mild conditions. Some nitration reactions were investigated with a view to using them in synthesis. The stability of an aryl azide to free radicals was discovered when ortho-azidotoluene was converted to ortho-azidobenzyl bromide with N-bromosuccinimide.

In self-interacting dark matter (SIDM) halos undergoing gravothermal evolution, the cores of halos are driven into the short-mean-free-path (SMFP) regime and undergo core collapse. In this dissertation, I study generic SIDM models with velocity-dependent cross-sections and elastic scattering, in SIDM halos experiencing gravothermal collapse. We study the structure and dynamics of halo cores in the SMFP and discover a new approximate universality deep in the SMFP regime. This new SMFP universality allows for the mapping of velocity- dependent cross sections to constant ones in this regime, offering improved predictions for physics occurring in the SMFP evolution of SIDM halos. We devise a semi-analytic recipe to predict the entire SMFP evolution of halos with our newfound SMFP universality by relating this new phase to the long-mean-free-path (LMFP) regime. This methodology streamlines the procedure of acquiring core properties within the SMFP regime and allows for estimates of the minimum mass of the black hole left behind, using simply the initial halo characteristics and particle physics parameters.

Knowledge Graphs (KGs) have applications in many domains such as Finance, Manufacturing, and Healthcare. While recent efforts have created large KGs, their content is far from complete and sometimes includes invalid statements. Therefore, it is crucial to refine the constructed KGs to enhance their coverage and accuracy via KG completion and KG validation. It is also vital to provide human-comprehensible explanations for such refinements, so that humans have trust in the KG quality. Enabling KG exploration, by search and browsing, is also essential for users to understand the KG value and limitations towards down-stream applications. However, the large size of KGs makes KG exploration very challenging. While the type taxonomy of KGs is a useful asset along these lines, it remains insufficient for deep exploration. In this dissertation we tackle the aforementioned challenges of KG refinement and KG exploration by combining logical reasoning over the KG with other techniques such as KG embedding models and text mining. Through such combination, we introduce methods that provide human-understandable output. Concretely, we introduce methods to tackle KG incompleteness by learning exception-aware rules over the existing KG. Learned rules are then used in inferring missing links in the KG accurately. Furthermore, we propose a framework for constructing human-comprehensible explanations for candidate facts from both KG and text. Extracted explanations are used to insure the validity of KG facts. Finally, to facilitate KG exploration, we introduce a method that combines KG embeddings with rule mining to compute informative entity clusters with explanations.

Purpose: A careful examination of Ladder Logic program reveals it’s hierarchicalnature and components, which makes it interpret able. Perhaps, using data miningtechniques to interpret the top level and sub level components can be really useful.This seems like a classification problem. The application of machine learning algorithmson the features extracted from ladder logic can give insights of the whole ladderlogic code. The components and their interactions are intuitive which certainly addto the probability of getting better results. The learning in the PLC programmingcan be alleviated by converting the existing PLC code to commonly used formatssuch as JSON, XML etc. The goal is to consume ladder logic sample, break it downinto minor components, identify the components and interactions between them andlater write them to JSON. As Ladder logic is the most commonly used programminglanguage for PLCs we decided to start the experiment with Ladder logic program samples.Feature engineering combined with machine learning techniques should provideaccurate results for the Ladder Logic data.Methods: The data set contains 6623 records for top level classification with 1421ALARM, 150 STEP SEQUENCE, 96 SOLENOID samples and 5304 UNCLASSIFIEDand 84472 records for sub level classification which contains sub level componentsof the all the ALARM and STEP SEQUENCE samples from the top level dataset. We extract the initial top level and sub level features from GX works. Theiiadvanced features like Sequence, LATCH and comments are extracted by parsingthe information from the output of GX works. The final set of features for Toplevel classification consists of basic features, advanced features, and comments. Dataset for Sub level classification has few more features apart from the already existingfeatures from the top level such as previous instruction - next instruction features(3Window), bi-gram features of the instructions and top level class( the result of toplevel classification). The result of top level classification and sub level classificationare filled into a JSON object which is later written to a JSON file.Results: We have classification results from the top level and sub level. Decisiontrees seem to work the best for both Top Level and Sub level classifications. Sincethe features are discrete we tried Decision trees, Naive Bayes and Support vectormachines. Performance result of each of them was: Decision Tree : Accuracy- 0.91, F1-macro- 0.90, F1-micro 0.90 Naive Bayes : Accuracy- 0.85 , F1-macro- 0.80,F1-micro 0.85 LinearSVC : Accuracy- 0.88 , F1-macro- 0.88, F1-micro 0.88For Sub level classification decision trees out perform any of the other classifiersDecision Tree : Accuracy- 0.90 , F1-macro- 0.91, F1-micro 0.90 Naive Bayes :Accuracy- 0.80 , F1-macro- 0.80, F1-micro 0.81 LinearSVC : Accuracy- 0.75 , F1-macro- 0.78, F1-micro 0.79Conclusions: A decision tree is the best suitable classifier for the purpose here. Thetuning of Decision tree classifier played important role in improving the performance.Using entropy as the classification criteria and restricted the depth of the tree to 6improved the performance of the classifier by 6

Breast cancer is the leading cause of cancer death in women. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer which is associated with a poor clinical outcome in comparison to other breast cancer subtypes. In TNBC a high stroma content is associated with a poor prognosis. Cancer-associated fibroblasts (CAFs) are key components of the tumour stroma and are responsible for secreting and remodelling the extracellular matrix (ECM). The role of soluble signalling by CAFs in cancer progression is well established. In contrast, the means by which they contribute to cancer progression by altering the mechanical properties of the tumour microenvironment remains to be clarified. Therefore, the aim of this work was to identify differences in TNBC-associated fibroblasts as compared to normal breast fibroblasts and determine their function in TNBC progression. In order to achieve this, we have characterised normal breast fibroblasts and TNBC patient-derived CAFs using immunofluorescence, live cell imaging and traction force microscopy. We have then established 2D and 3D in vitro co-culture models to study the interactions between fibroblasts and HCC1143 cells using live cell imaging and immunofluorescence. Finally, we have analysed the effect of CAF-derived ECM, particularly hyaluronan, on HCC1143 by generating fibroblast-derived ECM. We observed that in 2D and 3D, the TNBC CAFs showed an increased capacity to induce the nuclear localisation of the oncogenic transcriptional co-regulator YAP in HCC1143, as compared to normal breast fibroblasts. The CAFs also exhibited increased cellular contractile forces, and these forces were required for CAFs to compress clusters of TNBC cells, and to induce the nuclear localisation of YAP. Finally, we show that CAF-derived hyaluronan is an alternative mechanism by which CAFs can promote the nuclear localisation of YAP in HCC1143. Taken together, these observations support the hypothesis that the contractile forces and hyaluronan production of CAFs promote TNBC via the nuclear translocation of YAP. This highlights the importance of the physical properties of the tumour microenvironment in and progression of TNBC and suggests that CAFs can be targets for future drug-development against TNBC.

Programmed cell death pathways are crucial for maintaining homeostasis, eliminating damaged or diseased cells before they can cause harm. Thus, the understanding of the mechanisms involved in these pathways is necessary for future therapeutic development. Pyroptosis, a pro-inflammatory lytic form of cell death, restricts the growth of both pathogens and cancer cells and effectively stimulates immune responses. In this study I characterised the mechanism resulting in pyroptosis of colorectal cancer cell (CRC) lines infected by a tumour-colonising bacterium, enteropathogenic Escherichia coli (EPEC). EPEC uses a type III secretion system to inject virulence factors, called effectors, into the host cytosol. The translocated intimin receptor (Tir), an essential effector that inserts into the host plasma membrane and binds to the bacterial outer membrane protein intimin to establish the intimate attachment of the bacteria, activates pyroptosis in CRC cells. Pyroptosis is initiated by Tir-dependent extracellular Ca2+ influx through the mechanosensitive cation channel TRPV2, followed by the internalisation of the bacterial cell wall component lipopolysaccharide (LPS). Cytosolic LPS can be recognised by caspase-4, which then cleaves and activates the pore-forming protein gasdermin D to facilitate cell lysis. As pyroptosis and its downstream immune stimulation is detrimental to EPEC colonisation, multiple other bacterial effectors are employed to counteract pyroptosis at different stages. Importantly, this Tir-dependent cell death mechanism is largely conserved among the caspase-4- and GSDMD-expressing CRC cells of different genetic backgrounds. This study identifies a novel bacterial virulence factor-mediated pyroptotic mechanism effective in killing CRC cells that could potentially be exploited for future cancer therapy development.

Bacterial conjugation is a contact-dependent form of horizontal gene transfer where DNA is transferred in a unidirectional manner from a donor to recipient bacterium. It is also a key driver of the spread of antimicrobial resistance plasmids within clinically important pathogens. The intimate attachment of cells within a conjugating pair is crucial for efficient DNA transfer. However, the mechanism underlying the formation of tight mating junctions, which occurs through a process termed mating pair stabilization (MPS), is unclear. This work describes how variants of the plasmid-encoded outer membrane protein TraN interact with different receptors on recipient cells to mediate MPS. Using a reporter plasmid generated from the Klebsiella pneumoniae carbapenem resistance plasmid pKpQIL, mutations in the major outer membrane porin OmpK36 were found to reduce plasmid uptake in recipients. Meanwhile, substitution of traN on this plasmid with traN from two related plasmids, the Shigella flexneri resistance plasmid, R100-1 and the prototypical F plasmid, revealed that these TraN variants mediate dependency on recipient OmpW and OmpA respectively instead. Structural analysis showed that TraN from pKpQIL forms a complex with OmpK36 via the insertion of a β-hairpin structure into one of the subunits of the trimeric porin. Combining bioinformatic analysis and structural predictions using AlphaFold, four additional TraN variants were identified. All seven TraN variants could be classified into four groups based on their structural similarity and associated receptors: TraNα (OmpW), TraNβ (OmpK36), TraNγ (OmpA) and TraNδ (OmpF). Species specificity was also observed during MPS as not all homologues of a receptor are recognized by each TraN. This specificity was reflected in the real-world host distribution of conjugative IncF plasmids suggesting that MPS plays an influential role in shaping the host range of these plasmids. These findings provide a precedent for developing strategies that target MPS to mitigate resistance gene dissemination.

Abstract: Clinical Practice Guidelines (CPGs) offer concise instruction on the optimal care for the patient based on the latest clinical findings. The main benefit of a CPG is to improve the quality of care, and the consistency of care. It is been shown that passive dissemination of CPGs, like publishing in a medical journal, is ineffective in changing practice behavior. Nevertheless, integrating CPG knowledge into clinical systems, such as decision support systems, has shown to be more effective. In order to best benefit from the knowledge in the CPGs, an interest in automatically formalizing medical knowledge contained in CPGs has grown. This dissertation describes a new framework to automate a subset of the common CPGs formalization research problems. Our framework follows a multi-step approach, which has been shown to be a good strategy for CPG formalization. One of the major sub-problem to automate the formalization of CPGs is to detect ambiguity in CPGs and resolve it automatically. In this dissertation we described two unsupervised algorithms to the resolve ambiguities in CPGs.

Abstract: Nucleosides are essential for RNA and DNA synthesis. They also play a central role in other cellular metabolic pathways, and modulate a diverse array of physiological processes, including renal and cardiovascular function and neurotransmission. Due to their hydrophilic nature, specialized integral membrane proteins known as nucleoside transporters (NTs) are required for transport across cell membranes. In humans, the cation-coupled concentrative nucleoside transporter (CNT) family is represented by three members, hCNT1, hCNT2, and hCNT3. hCNT3, the most functionally versatile hCNT, is a cation-nucleoside symporter that transports both purine and pyrimidine nucleosides, as well as anticancer and antiviral nucleoside drugs. Produced as a recombinant protein in the Xenopus oocyte heterologous expression system, hCNT3 has been shown to have a Na+:uridine coupling ratio of 2:1, in contrast to hCNT1/2 which have Na+:uridine coupling ratios of 1:1. One of the two Na+-binding sites of hCNT3 also accepts H+. Recently, the crystal structure of a bacterial hCNT ortholog (vcCNT from Vibrio cholerae) has been reported. Based upon the crystal structure of vcCNT and previous mutagenesis studies of hCNTs, four amino acid residues (N336, V339, T370, and I371) were postulated to coordinate Na+ (and hydronium ion) binding within the primary cation-binding site of hCNT3. To test this hypothesis, electrophysiological studies were performed on oocytes producing wild-type hCNT3 or engineered forms of the transporter in which each of the four residues were individually mutated to cysteine. The results show marked changes in Na+- and H+-coupling consistent with these residues forming the primary cation-binding site of hCNT3. Mutation of the corresponding residues in hCNT1 and characterization of wild-type and mutant forms of vcCNT in oocytes provide supporting evidence for this conclusion.

The human-restricted, typhoidal Salmonella Paratyphi A (S. Paratyphi A) and S. Typhi are the major causes of enteric (typhoid) fever and are endemic in regions with poor sanitation. Despite the recent increased rate of S. Paratyphi A isolation from patients in Asia, its pathogenesis remains largely unknown. Asymptomatic chronic carriage in the gallbladder is encountered in about 5% of patients and is facilitated by efficient immune evasion. In this study, we have shown that bile changes the expression of > 5% of genes in S. Paratyphi A, including both bile tolerance and virulence-associated genes. S. Paratyphi A and S. Typhi may differentially regulate certain metabolic pathways in response to bile. Furthermore, a clinical S. Paratyphi A isolate appears to exhibit distinct regulatory mechanisms. As inflammasomes have been shown to play a key role in Salmonella infection, we also investigated their role following infection of macrophages with S. Paratyphi A, using S. Typhi and S. Typhimurium as controls. This work demonstrates that S. Paratyphi A and S. Typhi induce pyroptosis, which is lower than that triggered by S. Typhimurium. While the pathway activated during S. Typhi infection remains unclear, S. Paratyphi A-triggered pyroptosis occurs via activation of caspase-1, caspase-4, caspase-8 and NLRP3. Both S. Paratyphi A and S. Typhi require their SPI-1 injectisome to enable inflammasome activation. However, while the Vi antigen of S. Typhi is dispensable for limiting pyroptosis, the S. Paratyphi A FepE-mediated synthesis of very long O-antigen chains impairs macrophage cell death and a ΔfepE mutant elicited enhanced inflammasome activation. Very long O-antigen chains can also act as an inflammasome dampening mechanism in S. Typhimurium, but reduced fepE expression indicates that this strategy is not exploited by this pathogen. Therefore, this work points towards distinct mechanisms of virulence by S. Paratyphi A, highlighting the need for a systematic characterisation of its molecular pathogenesis.

The mouse pathogen Citrobacter rodentium is commonly used to model colitis such as that caused by infection with enterohaemorrhagic E. coli (EHEC). The translocation of effector proteins into host cells via a type III secretion system (T3SS) is instrumental in the infectivity of C. rodentium, enteropathogenic E. coli (EPEC) and EHEC. Disease severity during infection with C. rodentium is dependent on host genetics. Whilst C. rodentium pathogenesis has been well characterised in the C57BL/6 mouse model, which exhibits mild self-limiting disease, less is known about infection in C3H/HeNCrl mice, which exhibit severe fatal colitis. To characterise C. rodentium infection in C3H/HeNCrl mice and elucidate the contribution of the multifunctional T3SS effector protein Map, in vivo monitoring and -omics techniques were employed. C. rodentium infection signatures were accelerated in C3H/HeNCrl mice with uniform colonisation of the colonic mucosa observed by 3 days post infection. The presence of either Map or EspF effectors was demonstrated to be essential for colonisation. In addition, a Map-dependent increase in colonic oxygenation upon infection was observed, likely due to Map-induced mitochondrial disruption. Global proteomic analysis of infection-induced changes in intestinal epithelial cells revealed a switch from mitochondrial metabolism to aerobic glycolysis and lactate fermentation characterised by higher abundance of SGLT4, LDHA and MCT4. In contrast to C57BL/6 mice, the pattern recognition receptors NLRP3 and ALPK1 were specifically induced in C3H/HeNCrl from 6 DPI at the transcriptional and translational level. Activation the ALPK1/TIFA axis, was demonstrated following in vitro infection of a TIFA-reporter cell line with C. rodentium. Activation was dependent on the ADP-heptose biosynthesis pathway, but independent of a functional T3SS. Together, this study reveals temporal IECs’ responses during severe infectious colitis including changes to cellular replication, innate immunity and metabolism.

The human diarrhoeal pathogens enteropathogenic Escherichia coli, enterohaemorrhagic E. coli and their murine analogue Citrobacter rodentium are a family of enteric bacteria that cause characteristic attaching and effacing lesions at the site of intestinal colonisation. Lesion formation and successful infection depends on a Type III Secretion System and its cognate effector proteins. Once translocated into the host cytosol, effectors subvert several mammalian cell processes to create and maintain an infectious niche. With the advent of high-throughput screening techniques, the rate of effector discovery has surpassed their biochemical investigation. This work therefore explores the function of seven effectors, three uncharacterised and four previously described. Through machine learning algorithms, two completely novel C. rodentium effectors were identified and designated NleN and NleO. While nleN encodes a truncation of a conserved effector, NleO disrupts the host cytoskeleton by binding and cleaving the Rho GTPase Rac1 at a unique scission site. A third C. rodentium effector, EspS, which has previously demonstrated to modulate intestinal pathology, binds the host mitochondrial protein TRIAP1 and contributes to the remodelling of host lipids during infection of C57Bl/6 mice. Finally, the contribution of EspZ, TccP, EspT and NleG to the recently described pyroptotic cell death pathway in human macrophages is explored. The findings presented herein contribute to the ever-growing repertoire of effector protein knowledge and underscore the importance of studying effector synergy during infection.

Unstructured textual data is rapidly growing and practitioners from diverse disciplines are expe- riencing a need to structure this massive amount of data. Topic modeling is one of the most used techniques for analyzing and understanding the latent structure of large text collections. Probabilistic graphical models are the main building block behind topic modeling and they are used to express assumptions about the latent structure of complex data. This dissertation address four problems related to drawing structure from high dimensional data and improving the text mining process. Studying the ebb and flow of ideas during critical events, e.g. an epidemic, is very important to understanding the reporting or coverage around the event or the impact of the event on the society. This can be accomplished by capturing the dynamic evolution of topics underlying a text corpora. We propose an approach to this problem by identifying segment boundaries that detect significant shifts of topic coverage. In order to identify segment boundaries, we embed a temporal segmentation algorithm around a topic modeling algorithm to capture such significant shifts of coverage. A key advantage of our approach is that it integrates with existing topic modeling algorithms in a transparent manner; thus, more sophisticated algorithms can be readily plugged in as research in topic modeling evolves. We apply this algorithm to studying data from the iNeighbors system, and apply our algorithm to six neighborhoods (three economically advantaged and three economically disadvantaged) to evaluate differences in conversations for statistical significance. Our findings suggest that social technologies may afford opportunities for democratic engagement in contexts that are otherwise less likely to support opportunities for deliberation and participatory democracy. We also examine the progression in coverage of historical newspapers about the 1918 influenza epidemic by applying our algorithm on the Washington Times archives. The algorithm is successful in identifying important qualitative features of news coverage of the pandemic. Visually convincing results of data mining algorithms and models is crucial to analyzing and driving conclusions from the algorithms. We develop ThemeDelta, a visual analytics system for extracting and visualizing temporal trends, clustering, and reorganization in time-indexed textual datasets. ThemeDelta is supported by a dynamic temporal segmentation algorithm that integrates with topic modeling algorithms to identify change points where significant shifts in topics occur. This algorithm detects not only the clustering and associations of keywords in a time period, but also their convergence into topics (groups of keywords) that may later diverge into new groups. The visual representation of ThemeDelta uses sinuous, variable-width lines to show this evolution on a timeline, utilizing color for categories, and line width for keyword strength. We demonstrate how interaction with ThemeDelta helps capture the rise and fall of topics by analyzing archives of historical newspapers, of U.S. presidential campaign speeches, and of social messages collected through iNeighbors. ThemeDelta is evaluated using a qualitative expert user study involving three researchers from rhetoric and history using the historical newspapers corpus. Time and location are key parameters in any event; neglecting them while discovering topics from a collection of documents results in missing valuable information. We propose a dynamic spatial topic model (DSTM), a true spatio-temporal model that enables disaggregating a corpus's coverage into location-based reporting, and understanding how such coverage varies over time. DSTM naturally generalizes traditional spatial and temporal topic models so that many existing formalisms can be viewed as special cases of DSTM. We demonstrate a successful application of DSTM to multiple newspapers from the Chronicling America repository. We demonstrate how our approach helps uncover key differences in the coverage of the flu as it spread through the nation, and provide possible explanations for such differences. Major events that can change the flow of people's lives are important to predict, especially when we have powerful models and sufficient data available at our fingertips. The problem of embedding the DSTM in a predictive setting is the last part of this dissertation. To predict events and their locations across time, we present a predictive dynamic spatial topic model that can predict future topics and their locations from unseen documents. We showed the applicability of our proposed approach by applying it on streaming tweets from Latin America. The prediction approach was successful in identify major events and their locations.

A complete spinal cord transection results in loss of all supraspinal motor and bladder control below the level of the injury. The neural circuitry in the lumbosacral spinal cord, however, can generate locomotor patterns in the hindlimbs of rats and cats with the aid of motor training, epidural stimulation and/or administration of monoaminergic agonists. Gerasimenko et al., (2003) first reported the use of electrical stimulation to facilitate locomotion in chronic decerebrated cats. Ichiyama et al (2005) then demonstrated that epidural electrical stimulation of the spinal cord can induce rhythmic, alternating hindlimb locomotor activity in chronic spinal rats. Stimulation at the L2 spinal segment at frequencies between 30 and 50 Hz consistently produced successful bilateral stepping. Similar epidural stimulation at other spinal segments were less effective, e.g., epidural stimulation at the T13 or L1 evoked rhythmic activity in only one leg and stimulation at the L3, L4, or L5 produced mainly flexion movements. More recently, completely paralyzed (motor complete, sensory incomplete) human subjects were implanted with a commercially available spinal cord electrode array and stimulation package originally designed for pain suppression (Harkema et al., 2011). Stimulation of specific spinal segments (caudal electrodes, ~ S1 spinal level) in combination with the sensory information from the lower limbs and weeks of stand training was sufficient to generate full weight-bearing standing. These subjects also recovered some voluntary control of movements of the toe, ankle, and the entire lower limb, but only when epidural stimulation was present. Thus it appears that the epidural stimulation provided excitation of lumbosacral interneurons and motoneurons that, when combined with the weak excitatory activity of descending axons that were not otherwise detectable, achieved a level of excitation that was sufficient to activate the spinal motor circuits. These results demonstrate that some patients clinically diagnosed as having complete paralysis can use proprioceptive input combined with some synaptic input from descending motor signals, perhaps residual but functionally silent without epidural stimulation to the spinal motor circuits to generate and control a range of motor functions during epidural stimulation. The mechanisms of pharmacological and/or epidural electrical stimulation that enable motor control (eEmc) in the spinal circuitry for locomotion are still not clearly understood. During standing, a single bipolar epidural stimulus between L2 and S1 produces three types of evoked responses, i.e., early (ER, latency 1-3 ms), middle (MR, latency 4-6 ms), and late (LRs, latency >7 ms) in the hindlimb muscles in both intact (Gerasimenko et al., 2006) and spinal (Lavrov et al., 2006) rats. Similar responses were observed during rhythmic locomotor-like EMG activity in the hindlimb muscles of spinal rats while stepping on a motorized treadmill in the presence of epidural stimulation (40 Hz) between L2 and S1 (Lavrov et al., 2008). In addition, the time course of the re-emergence of the LRs was similar to that for the recovery of stepping after a complete spinal cord injury (SCI), indicating that LRs are a potential biomarker of functional recovery (Lavrov et al., 2006). The results demonstrate that spinal rats can stand and step when the spinal cord is stimulated (tonic 40 Hz stimulation) by electrodes located at specific sites on the spinal cord and at specific frequencies of stimulation. The quality of stepping and standing was dependent on the location of the electrodes on the spinal cord, the specific stimulation parameters, and the orientation of the cathode and anode. spinal cord stimulation triggered evoked potentials in flexor and extensors muscles form a 'foot print' of the physiological state of the spinal cord. Chronic subthreshold stimulation enabled greater activity in completely transected rats but only with stimulation. Spinal cord stimulation at specific frequencies resulted in partial bladder control.

Enteropathogenic Escherichia coli (EPEC) is a human-restricted, clinically significant diarrhoeagenic pathogen that colonises the gut mucosa of hosts via the formation of characteristic attaching and effacing (A/E) lesions. To establish infection and cause disease, EPEC subverts a range of host cell processes through the injection of a suite of bacterial effector proteins into host cells via a Type 3 Secretion System (T3SS). EPEC virulence is critically reliant on the T3SS-delivered Translocated intimin receptor (Tir), which triggers actin polymerisation at the bacterial attachment site in intestinal epithelial cells. However, the manner in which EPEC effector proteins activate and subvert signalling pathways in human immune cells, such as macrophages, remains to be established. During infection the innate immune compartment of the intestinal mucosa plays a pivotal role in antimicrobial immunity, and activation of inflammasome signalling pathways is central to bacterial clearance. This has been established in vivo using the model A/E pathogen Citrobacter rodentium. Interestingly, although evolutionarily closely related to the enteric pathogens Citrobacter, Salmonella and Shigella, the EPEC T3SS needle and flagellin proteins evade detection by inflammasomes. Currently EPEC-induced inflammasome activation in human macrophages is poorly understood. Here I show that infection of human primary macrophages with EPEC rapidly induces NLRP3-inflammasome-driven pyroptosis in a strictly Tir-dependent manner. Mechanistically, Tir-induced actin polymerisation, either via Tir tyrosine phosphorylation and the Nck-N-WASP-ARP2/3 actin polymerisation pathway, or through Tir and the Nck-mimicking effector TccP, stimulated rapid caspase-4-dependent inflammasome responses. Notably, in contrast to caspase-4-driven pyroptosis induced by non-pathogenic E. coli or cytosolic LPS, both pyroptosis and cytokine processing in response to EPEC infection required NLRP3, ASC and caspase-1, and occurred independently of pannexin-1. This study identifies a surprising and indispensable role for both human caspase-4 and NLRP3 in detecting EPEC, and an essential role for pathological actin polymerisation by a bacterial effector in inflammasome activation.

Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) are important agents of infectious diarrhoea in humans. Together with the murine-restricted pathogen Citrobacter rodentium, EPEC and EHEC are attaching and effacing (A/E) pathogens that cause hallmark A/E lesions upon colonisation. Their pathogenesis is underpinned by the injection of effector proteins into the host cytosol via the type III secretion system (T3SS), orchestrating subversion of several eukaryotic pathways. However, the individual roles of many effector proteins are not fully understood. Among these are the NleG family of effectors proteins, which harbour a conserved C-terminus that structurally resembles a eukaryotic E3 ubiquitin ligase domain. C. rodentium has three NleG homologs: NleG1, NleG7 and NleG8, which are translocated into eukaryotic cells via the T3SS as demonstrated herein. Biochemical investigations confirmed that NleG1 and NleG8 exhibit E3 ligase activity, reliant on a conserved proline residue P163/P177 that mediates the interaction between E3 and E2 enzymes. As bacteria lack a ubiquitin system, the NleGs are thought to exploit the host ubiquitin code, a notion supported by our findings that NleG7 and NleG8 cause re-localisation of ubiquitin in cultured cells. Both NleG7 and NleG8 bind ubiquitin by yeast two-hybrid assay and the enzymatic activity of NleG8 is required for cytotoxicity in a yeast model. In vivo, single ∆nleG and double ∆nleG7 ∆nleG8 gene deletions did not affect C. rodentium colonisation of the murine gut, but a triple nleG deletion mutant demonstrated attenuated colonisation, suggesting that NleGs contribute to C. rodentium virulence. Reduced faecal Lipocalin 2, an antimicrobial peptide and marker of gut inflammation, was also observed. Significant efforts to find NleG substrates by yeast two-hybrid and mass spectrometry-based screens using transgenic cell lines are outlined, and this work provides a strong foundation for further studies into NleG biology to give insight into A/E pathogenesis.