Target-based screening projects for bioactive (orphan) compounds have been shown in many cases to be insufficiently predictive for in vivo efficacy, leading to attrition in clinical trials. Phenotypic screening has hence undergone a renaissance in both academia and in the pharmaceutical industry, partly due to this reason. One key shortcoming of this paradigm shift is that the protein targets modulated need to be elucidated subsequently, which is often a costly and time-consuming procedure. In this work, we have explored both improved methods and real-world case studies of how computational methods can help in target elucidation of phenotypic screens. One limitation of previous methods has been the ability to assess the applicability domain of the models, that is, when the assumptions made by a model are fulfilled and which input chemicals are reliably appropriate for the models. Hence, a major focus of this work was to explore methods for calibration of machine learning algorithms using Platt Scaling, Isotonic Regression Scaling and Venn-Abers Predictors, since the probabilities from well calibrated classifiers can be interpreted at a confidence level and predictions specified at an acceptable error rate. Additionally, many current protocols only offer probabilities for affinity, thus another key area for development was to expand the target prediction models with functional prediction (activation or inhibition). This extra level of annotation is important since the activation or inhibition of a target may positively or negatively impact the phenotypic response in a biological system. Furthermore, many existing methods do not utilize the wealth of bioactivity information held for orthologue species. We therefore also focused on an in-depth analysis of orthologue bioactivity data and its relevance and applicability towards expanding compound and target bioactivity space for predictive studies. The realized protocol was trained with 13,918,879 compound-target pairs and comprises 1,651 targets, which has been made available for public use at GitHub. Consequently, the methodology was applied to aid with the target deconvolution of AstraZeneca phenotypic readouts, in particular for the rationalization of cytotoxicity and cytostaticity in the High-Throughput Screening (HTS) collection. Results from this work highlighted which targets are frequently linked to the cytotoxicity and cytostaticity of chemical structures, and provided insight into which compounds to select or remove from the collection for future screening projects. Overall, this project has furthered the field of in silico target deconvolution, by improving the performance and applicability of current protocols and by rationalizing cytotoxicity, which has been shown to influence attrition in clinical trials.

Der Vortrag gibt einen Überblick der Neuerungen im Werkzeug Mechanism der Creo Versionen 1.0 und 2.0. Zudem werden 10 hilfreiche "Tips und Tricks" vorgestellt, welche den Mechanismuseinsatz vereinfachen.

This thesis is an investigation of the call centre labour process focusing on both the way work is organised and experienced by the operators and the management of employee relations inside a local government workplace – The City of Johannesburg (COJ) Call Centre. The City of Johannesburg is used to understand labour process dynamics in local government. Johannesburg was recently named the ‘World’s Second Most Inspiring City’ (by Global City Index, 2014) possessing economic and political influence within and around South Africa. Johannesburg is the economic hub of the country, contributing nine per cent to the South African GDP. But it needs to be emphasised that the focus of this thesis is on the labour process rather than the City of Johannesburg. The nature of work in the COJ local government call centre involves answering calls about water, electricity, refuse removal, accounts and other general municipal services. The government’s objective was to have a more customer centred service delivery plan in compliance with the Batho Pele (People first) framework (RSA, 1997, White Paper on Local Government). This resulted in a shift in the government ‘mantra’ and philosophy from viewing Johannesburg residents as customers rather than citizens. This shift from public administration to New Public Management (NPM) has meant the introduction of private sector business principles into public services. This seeks to improve organisational and individual performance to enhance service delivery within South African municipalities. This is also meant to promote responsive and performance management culture. The study uses Labour Process Theory set out in Labour and Monopoly Capital (LMC-1974) by Harry Braverman to argue for the need to contextualise the labour process debate within the socio-political understanding of work in South Africa. In developing the argument about the narrow analysis of public sector call centres based on economic lines I have reviewed literature on call centres which is influenced by Michel Foucault and Harry Braverman to understand the public sector call centre labour process. Inspired by Adesina (2002) and Mafeje (1981) this study uses a ‘complementarity’ approach to knowledge. This means the local context tends to complement the global trends though not without contradictions within the local context. The case study approach was used for in-depth analysis of the local context through different methods (semi-structured interviews, focus group discussions, observations and survey questionnaires) to collect data from different stakeholders within the City of Johannesburg between 2010 and 2013. The concept of a ‘(dis)connecting city’ is fitting for the COJ as this city connects the rest of Sub-Saharan Africa and South Africa to the world through its commerce and political influence. Based on the challenges experienced in this local government call centre I attempt to show the the politicised nature of the public sector call centre labour process. I use the differential power relations in the frontline between customer and Joburg connect workers to illustrate this point. The lack of emphasis on the politicised nature of public sector call centres within literature is informed by the de-contextualised nature of these call centres. In the end, I argue that public sector call centre labour process is multilayered, contradictory and complicated because of these workers’ role as citizens, customers, community members and service providers from a politicised community environment.

Der Vortrag gibt einen Überblick der Neuerungen im Werkzeug Mechanism der Creo Versionen 1.0 und 2.0. Zudem werden 10 hilfreiche "Tips und Tricks" vorgestellt, welche den Mechanismuseinsatz vereinfachen.