Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. The KRAS oncogene is mutated in over 90% of PDACs and plays a pivotal role in tumor progression. Global gene expression profiling of PDAC reveals 3-4 major molecular subtypes with distinct phenotypic traits and pharmacological vulnerabilities, including variations in oncogenic KRAS pathway dependencies. PDAC cell lines of the aberrantly differentiated endocrine exocrine (ADEX) subtype are robustly KRAS-dependent for survival. The KRAS gene is located on chromosome 12p11-12p12, a region amplified in 5-10% of primary PDACs. Within this amplicon, we identified co-amplification of KRAS with the STK38L gene in a subset of primary human PDACs and PDAC cell lines. This provided rationale to determine whether PDAC cell lines are dependent on STK38L expression for proliferation and viability. STK38L (also known as NDR2) encodes a nuclear Dbf2-related (NDR) serine/threonine kinase, which shares homology with Hippo pathway LATS1/2 kinases. We show that STK38L expression levels are elevated in a subset of primary PDACs and PDAC cell lines that display ADEX subtype characteristics, including overexpression of mutant KRAS. RNAi-mediated depletion of STK38L in a subset of ADEX subtype cell lines results in decreased cellular proliferation and increased apoptotic cell death. Concomitant with cytostatic and cytotoxic effects, STK38L depletion causes increased expression of the LATS2 kinase and the cell cycle regulator p21. LATS2 depletion partially rescues the cell proliferation and viability effects of STK38L depletion. Lastly, high STK38L mRNA expression is associated with worse patient prognosis compared to low STK38L expression in PDACs. Taken together, our study uncovers STK38L as a candidate, targetable vulnerability in a subset of molecularly defined PDACs. / 2019-11-01T00:00:00Z

Magister Artium - MA / The departing point of the thesis is that the neglect of African's intellectual heritage within the South African Universities and in public discourse undermines the ability of the post-apartheid government to set its developmental agenda and maximize its democratic potential. The thesis highlights the neglect of Professor Mafeje's scholarly contribution as an example of this neglect and argues that an engagement with his scholarly output might have differently shaped the debate on the thematic issues that are covered in this study. Against this backdrop, this study explores Mafeje's scholarly works in the areas of state, development and democracy, specifically focusing on the insight that we can garner from his scholarly works that will allow us to re-examine the challenges of development. In this context Mafeje's work is examined and situated within the social history of his milieus. The study employs social constructionism to explore the scholarship of Professor Mafeje. An important aspect of this theoretical framework is social embeddedness. Brunner (1990:30) has argued that it is culture, not biology that shapes human life and mind. The important aspect of this approach is that it acknowledges that the way we commonly understand the world, the categories and concepts we use, are historically and cultural specific. Mafeje's ideas make sense when located within complex social contexts in which they were produced. Because he was not producing knowledge in a vacuum, an understanding and appreciation of his ideas must be located within the social history that produced them.

Ve statistických modelů sémantiky jsou významy slov pouze na základě jejich distribuční vlastnosti.Základní zdroj je zde jeden slovník, který lze použít pro různé úkoly, kde se význam slov reprezentovány jako vektory v vektorového prostoru, a slovní podoby jako vzdálenosti mezi jejich vektorových osobnosti. Pomocí silných podobnosti, může vhodnost podmínek uvedených zejména v souvislosti se vypočítá a používá pro celou řadu úkolů, jeden z nich je slovo smysl Disambiguation. V této práci bylo vyšetřeno několik různých přístupů k modelům z vektorového prostoru a prováděny tak, aby k překročení vyhodnocení vlastního výkonu na Word Sense disambiguation úkolem Prague Dependency Treebank.

Debates concerning how churches in the developing world are best resourced in terms of their funding base and the implications of this for other aspects of church life have been conducted for over 150 years. The solutions offered have ranged from the Three-Self theory, with its advocacy of local self-support, to wholesale financial support from abroad, and in between a combination of those methods in a variety of configurations. This thesis focuses on the recent experiences of evangelical Christians in a southern Mozambican context, paying particular attention to three case studies: the Igreja Evangelica Arca da Salvação; the Ministério Centro de Louvor; and the Igreja Reformada em Moçambique. It asks why so many churches in Mozambique are seemingly locked into a dynamic of economic dependency on donors from abroad, but also why it is that in that shared and impoverished national context some churches are attempting, with some success, to resource their own activities. Using accounts and reflections obtained first-hand from Mozambican Christians, the thesis suggests that, alongside important factors such as the historical circumstances surrounding the emergence of each church group or denomination, the vision and agency of leaders in each local congregation are also fundamental to the resourcefulness of the members and the developmental trajectory of the church. In the context of self-governance, the role of such leadership is highlighted as crucial to the emergence of both self-funding and self-propagation. As well as contributing to the debate concerning the resourcing of churches in the developing world, this thesis addresses social theory that is concerned with how and why individuals invest their available resources in the religious communities of which they are part. It also contributes to the study of independent churches in southern Africa, concerning their potency for independent economic development. Finally, this thesis argues that, for the purposes of avoiding the cultivation of unhealthy dependency in national churches, international mission societies and para-church organizations in developed nations would do well to analyse the dynamics of which they are part. Where partnerships consist largely of sponsorship, it is argued, the risk of ongoing unhealthy dependency is high.

As competitively tendering for work is becoming increasingly difficult, and with profit margins reducing, UK construction companies are looking to differentiate their offering to clients. Safely delivering on time, within budget and to the required quality standard is no longer a differentiator in a market where clients are demanding increased value, building information modelling and life cycle provision. Construction companies are therefore looking to extend their activities into business consulting, financing and operational services, which will provide new sources of revenue in addition to their core production activities. This holistic service should provide solutions that meet their client s business needs, not just their building needs, ultimately resulting in long-standing relationships that over time yield a more predictable, long-term return. Over half of the top 20 UK construction companies, by turnover, have stated their intent to provide solutions to their clients - the case study organisation in which this research has been carried out is one of those companies. Part of a group of companies, the case study company, Shepherd Construction Ltd (SCL), has a vision to deliver integrated solutions to their clients, with the ultimate aim being that companies across the group can pool their expertise and deliver a service offering unique to the industry. Existing literature states the characteristics that integrated solutions providers need to possess, and proposes models for how an organisation needs to structure itself to deliver a service. However, the applicability of these models to SCL was unknown, and along with current literature on how to enact the transition pathway being vague, highlighted an area for investigation. Since the aim of integrated solutions provision is the delivery of a service to the client that adds value, it was proposed that lean thinking could provide a means of enacting the P-S transition: the starting point for lean thinking is value (Womack & Jones, 2003). Lean thinking principles (Womack & Jones, 2003) state that value needs to flow through the value stream the series of actions that transform inputs into the completed output raising the further proposition that flow is required through the stages of the integrated solutions lifecycle (the value stream) in order to successfully deliver all aspects of the client s value proposition, i.e. the desired solution. As a long established main-contractor, or product provider, SCL s challenge to transition from products-to-services was set against a backdrop of inconsistent performance and loss of continuity of service at crucial pinch-points in the delivery process. The action research carried out therefore sought to understand these problems and develop practices based on lean thinking that could be implemented in the company to enable consistent delivery of integrated solutions, i.e. enable the products-to-service transition, and in doing so provide the basis for the wider group vision. An abductive approach was taken to the research strategy; the experiences of the participants involved in the changes prompted by the action research process were used to inform the development of new theories and practices, and evaluate them once implemented. The methods used for collecting data and accounting for the experiences of people in the company included observation, both participant and non-participant, semi-structured interviews and analysis of company records. The research findings show that lean thinking has a role to play in enabling an organisation to transition from the provision of products to services. Standard processes and tools, based on lean thinking and developed through the action research framework, are shown to be the basis for consistent and repeatable performance within the phases of the integrated solutions lifecycle. Flow of information through and between phases of the lifecycle is then shown to be essential to ensuring the client s value proposition is realised and information is not lost during the transitions between lifecycle phases. The operational framework for service delivery , one of the practices developed, itself a form of standardised work, draws on lean thinking to provide a structured, yet flexible, means of developing a plan for service delivery that is focused on the client and ensuring the client s definition of value flows through the integrated solutions value stream and is therefore continually understood, and ultimately delivered, by the whole team as the project progresses. The practices developed through the research the standard company management system, operational framework for service delivery , service delivery plan and maturity assessment are shown to have improved consistency and company performance, and to have contributed to improved customer satisfaction (the ultimate aim of delivering a service) such that the company is starting to be perceived in the marketplace as an integrated solutions provider. This research also contributes to existing theory by evidencing that the transition pathway from products-to-services isn t as smooth as current literature portrays. In trying to implement current models in a construction setting, the products-to-service transition has been problematised and deficiencies in existing characteristics and models identified. Along with showing that lean thinking provides a theoretical framework for enacting the products-to-service transition, the hybrid model of the integrated solutions lifecycle developed, along with the maturity assessment, provide new theoretical insights, such as the need for feedback loops between all phases of the lifecycle.

The use of Long Short Term Memory (LSTM) networks continues to yield better results in natural language processing tasks. One area which recently has seen significant improvements is semantic dependency parsing, where the current state-of-the-art model uses a multilayer LSTM combined with an attention-based scoring function to predict the dependencies. In this thesis the state of the art model is first replicated and then extended to include features based on syntactical trees, which was found to be useful in a similar model. In addition, the effect of part-of-speech tags is studied. The replicated model achieves a labeled F1 score of 93.6 on the in-domain data and 89.2 on the out-of-domain data on the DM dataset, which shows that the model is indeed replicable. Using multiple features extracted from syntactic gold standard trees of the DELPH-IN Derivation Tree (DT) type increased the labeled scores to 97.1 and 94.1 respectively, while the use of predicted trees of the Stanford Basic (SB) type did not improve the results at all. The usefulness of part-of-speech tags was found to be diminished in the presence of other features.

Fatigue is a difficult phenomenon to study because the response can vary based upon task-specific (i.e. contraction type, intensity, position– vs. load-matching and muscle group/joint region) and subject-specific (i.e. sex and age) variables. Although numerous investigations have provided insight into muscle fatigue, further efforts were needed to better characterize the influence of age, sex, joint/muscle group, contraction type, and task complexity have upon fatigue. The primary purpose of this series of three studies was to identify and characterize the influences of potential moderating variables (i.e., sex, joint, age, contraction type, and task complexity) upon fatigue resistance during voluntary muscle contraction fatigue tasks through both empirical (systematic review and meta-analysis) and experimental methods. In general, women demonstrated either the same or better fatigue resistance than men (men never better), the sex advantage was joint specific not systematic, old men were more fatigue resistant than young men, task complexity was not an influential factor and fatigue differences were more readily apparent under isometric conditions. The inclusion of empirical and experimental methods helped clarify the driving factors of localized muscle fatigue. This in turn will better direct future study design and power for mechanistic, training and performance response studies.

Research in the late 1990s and early 2000s projected that the number of people aged 50 and older who needed treatment for illicit drug use and abuse of prescribed medications to increase from approximately 1.7 million in 2001 to approximately 4.4 million in 2020. The purpose of this study was to examine how gender, marital status, employment status, and primary referral source predicted treatment outcomes with this older population. Of interest was how these predictions could better prepare treatment providers to treat individuals born between 1946 and 1964 who are addicted to substances. This quantitative study used an archival database, the Treatment Episode Dataset-Discharges (TEDS-D) from the Substance Abuse and Mental Health Services Administration. A discriminant function analysis revealed significance in the predictor variables with treatment outcomes. The second research question asked whether the criminal justice system/legal system alone, as the primary referral source, could predict treatment outcomes. A chi-square test revealed the primary referral source had a significant impact on treatment outcomes. These findings have implications for positive social change by empowering practitioners working with the older adult generation in substance abuse treatment to recognize the changing roles of retirement. These findings may, in turn, help those adults cope with physical health problems and loss of mobility, foster social supports within the community, and address the mental health problems among this population.

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