| 1. |
- Dymek, Mikolaj, 1978-
(author)
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Industrial Phantasmagoria : Subcultural Interactive Cinema Meets Mass-Cultural Media of Simulation
- 2010
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Doctoral thesis (other academic/artistic)abstract
- The video game industry has in three decades gone from a garage hobby to a global multi-billion euro media industry that challenges the significantly older and established cultural industries. After decades of explosive growth the industry surprisingly finds itself in a crisis – in terms of sales, future trajectories and creative paradigms. The global gaming culture receives substantial attention from society, media and academia – but the industry itself appears in comparison as an enigmatic terra incognita with astonishingly little dedicated research. This thesis aims to amend this situation by presenting a study at the cross-section of the video game industry, game studies, literary theory, cultural industries and business studies. It deals with the following question: how does the global game industry relate to its own product, in terms of communication and media dimensions, and what are the (business) consequences, in terms of production, strategy and commercial/creative innovation, of this relationship? This study’s departure point is constituted by a comprehensive description of the industry’s structure, dynamics and processes, based on extensive interviews with industry professionals. It is followed by an examination and comparison of the game industry with other media/cultural industries in relation to their economy and business dynamics. With inconclusive answers regarding the medium-industry relation, this study proceeds by exploring literary theories from the field of game studies, in order to gain insights into the dynamics of medium and industry. Literary theories from ludology and narratology provide rewarding perspectives on this inquiry, since it is found that the ontological dichotomy of simulation vs. respresentation present in the interpretational realm of the game medium is also reflected in the industry and its dynamics. This has pivotal consequences for the analysis of the game industry. This study concludes by positing the current critical condition of the industry as an extremely decisive moment in its history: will it become a truly universal mass-medium, or will it continue down its subcultural path? Subcultural “interactive cinema” meets mass-cultural media of simulation – how will the industry evolve?
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| 2. |
- Forslund, Josefin M. E., 1988-
(author)
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The consequences of DNA lesions for mitochondrial DNA maintenance
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Eukaryotic cells have their own energy-producing organelles called mitochondria. The energy is stored in the adenosine triphosphate (ATP) molecule and is produced via the oxidative phosphorylation process inside the mitochondria. Thirteen of the essential proteins required for this process are encoded on the mitochondrial DNA (mtDNA). To ensure sufficient energy production it is therefore important to maintain mtDNA integrity. MtDNA maintenance is dependent on several factors, which include the replicative DNA polymerase. In humans, the main mitochondrial polymerase is DNA polymerase gamma (Pol γ), whereas in S. cerevisiae the homolog is called Mip1. Defects in the mitochondrial DNA polymerase and mtDNA replication in general cause mitochondrial dysfunction, reduced energy production and, in humans, mitochondrial diseases. DNA damage and non-standard nucleotides are frequently forming obstacles to the DNA replication machinery. One of the proteins that assists the nuclear replication machinery in dealing with DNA damage is the primase-polymerase PrimPol, performing either translesion DNA synthesis or alternatively priming replication restart after DNA damage. More recently, PrimPol was also identified inside the mitochondria. We therefore investigated the potential role of PrimPol to assist the mtDNA replication machinery at the site of mtDNA damage. Our results suggest that PrimPol does not work as a conventional translesion DNA polymerase at oxidative damage in the mitochondria, but instead interacts with the mtDNA replication machinery to support restart after replication stalling.Stalling of DNA replication can also occur at wrongly inserted nucleotides. In this study, we pay extra attention to ribonucleotides, which are non-standard nucleotides in the context of DNA. Ribonucleotides (rNTPs) are normally building blocks for RNA but are occasionally utilized by DNA polymerases during DNA replication. Ribonucleotides are more reactive compared to dNTPs as they have an additional hydroxyl group (-OH). Their presence in the genome can lead to replication stress and genomic instability. In nuclear DNA, ribonucleotides are efficiently removed by the Ribonucleotide Excision Repair (RER) pathway and failure to remove them leads to human disease (e.g., Aicardi-Goutières syndrome). We investigated if ribonucleotides are removed from mtDNA and if not, how the replication machinery can tolerate the presence of ribonucleotides in the mtDNA. By using several yeast strains with altered dNTP pools, we found that the RER pathway is not active in mitochondria. Instead, mitochondria have an innate tolerance to ribonucleotide incorporation in mtDNA and under normal cellular conditions mature human mtDNA contains ~50 ribonucleotides per genome. We show that this ribonucleotide tolerance is the result of human Pol γ’s remarkable abilities to 1) efficiently bypass ribonucleotides in the DNA template and 2) proficiently discriminate against the incorporation of free ribonucleotides during mtDNA replication. Pol γ’s discrimination capability against free ribonucleotides comes with a price. In the presence of high rNTP levels, Pol γ is inhibited in DNA synthesis and could eventually lead to frequent replication stalling. Together, these studies are in line with our hypothesis that ribonucleotides in mtDNA can be tolerated, with the consequence that mtDNA replication is in particular vulnerable to imbalances in rNTP/dNTP ratios.In summary, this study shows that we cannot simply extrapolate our knowledge of nuclear DNA replication stress management to the mtDNA maintenance, highlighting the need to study the molecular mechanism by which the mtDNA replication machinery is able to cope with DNA lesions to prevent loss of mtDNA integrity and disease development.
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| 3. |
- Högström, Claes, 1979-
(author)
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Fit in to stand out : An experience perspective on value creation
- 2014
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Doctoral thesis (other academic/artistic)abstract
- In order to grow and survive, a firm must create value with consumers in ways that both fit in with consumer demands and stand out from competitors. Focusing on and understanding consumer and firm assessments of value and creation of value has become a central scope in the contemporary strategic management and marketing literature for understanding and explaining firm survival and success. Consequently, the overall aim of this thesis is to provide a conceptually and empirically grounded understanding of consumers’ and managers’ value assessments and behavior in value creation.This thesis draws on a consumer experience perspective and theories on social construction, organizational identity, self-congruence, and the theory of attractive quality, and combines multiple qualitative and quantitative studies. The findings in this thesis shed light on the interplay between consumers, firms, and contextual structures in value creation. Contextual structural, cultural, and political forces are shown to affect and be affected by the shared and individual cognitions of value creation that firms and consumers use in their assessment and creation value.The results of the study enhance the understanding of how firms can adopt various strategic schemas or organizing logics to optimize different types of use value creation when choosing between opposing and contradictive demands in their value creation. Furthermore, the thesis provides a deeper understanding of the hierarchical nature of consumer judgments of value that can be used to enhance the effectiveness of firm prioritizations and as a foundation for future value-creating strategies.
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| 4. |
- Beckius, Göran, 1948-
(author)
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Företagsetik : En studie av etiskt organiserande i några svenska företag
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Although research in business ethics has of late received increased attention from researchers and practitioners, little has been written on the practical effects of its implementation.The aim of the present study is, therefore, to explore the meaning and implications of business ethics from a practical perspective. To these ends, a qualitative study, mainly based on a grounded theory approach, has been carried out. The target of analysis is a corpus material derived from informants from 9 companies ranging from different sectors: 2 from the manufacturing sector, 1 company from the pharmaceutical sector and 6 companies from the financial sector.The results show that almost all the companies under consideration have set up some ethical structures for implementing their ethical practices, and lived up to the embraced ethical values in their business conduct. The results also indicate that the companies have actually responded favorably to the requirements and demands of various stakeholders.Furthermore, the emerging structures constitute the basis of a fully operative concept for organizing and implementing an ethical business conduct in organizations. This concept mainly consists of the following categories: ethics, rules, institutionalization, observing and abiding. These can all be applied separately or as a whole and as such be an instrument for measuring an organizations ethical level.
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| 5. |
- Kashif, Muhammad
(author)
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Integrated Computational and Experimental Approaches for Accelerated Drug Combination Discovery and Development : Applications in Cancer Pharmacology
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Today the norm in modern cancer treatment is to use different forms of drug combinations. Recently anti-cancer treatment using drug combinations has gained increased attention due to the outstanding pharmacotherapeutic opportunities provided by combination therapies. However, the potential of this field is largely unexplored, partly due to the complexities associated with the astronomical number of possible combinations and partly due to the lack of means for quantifying clinically relevant adverse side effects in the early stages of the combination discovery and development process. This has resulted in relatively limited progress in this area. Motivated by this unfortunate state-of-affairs, the research reported in this thesis was aimed at developing and implementing computational and experimental methods to facilitate and accelerate the discovery and development of anti-cancer therapies. In paper I, the largely overlooked concept of therapeutic synergy is re-introduced and demonstrated to be useful already at the level of combination discovery by taking both curative and adverse effects into account. In paper II, a semiautomatic combination discovery platform was developed based on a tailored programming of a pipetting robot system and application of a new in-house developed combination search algorithm, the therapeutic algorithmic combinatorial screen (TACS) algorithm. TACS seems to be the first algorithm of its kind that takes experimental variability into account during the iterative search process. The semiautomatic hardware platform along with TACS can perform de novo or knowledge based combination drug discovery and development without brute force comprehensive search efforts. One promising discovery made using this platform is a combination of the drugs 17-AAG, afungin and trichostatin a for treatment of colorectal cancer carcinoma (CRC). In paper III, an algorithm is developed and applied in order to use single drug induced systemic gene expression profiles for rational drug combination design by assuming additive combination effects. The resulting algorithm, combo-CMap, is applied and validated using a slightly extended version of the freely available Connectivity Map (CMap) database which is currently containing 6190 chemically induced mRNA gene expression signatures. In paper IV, a software (R package) was developed and applied to perform improved synergy/antagonism analysis, in particular joint Loewe and Bliss analyses while taking associated experimental variability into account using non-parametric statistics including bootstrap intervals. Applying this software to the synergy analysis of interaction effects among clinically used and/or relevant drugs in CRC cell lines revealed complex patterns of synergy and antagonism. In conclusion, the work presented here offers important contributions and findings that may accelerate and/or improve different parts of the field of drug combination discovery and development.
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| 6. |
- Nilsson, Miriam, 1984-
(author)
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Studies of the chromatin form of yeast Mediator and the function of its tail module
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Mediator is a large, multifunctional complex that is conserved in eukaryotes. It was first discovered in Saccharomyces cerevisiaeas required for transcriptional activators to function in a reconstituted in vitro system. Mediator is also important for stimulation of basal, unregulated transcription, and transcriptional repression. In yeast, Mediator consists of 25 subunits divided into head, middle, and tail modules, and is intermittently associated with a Cdk8 kinase module (CKM). The head and middle bind to the RNA polymerase II (Pol II) while the tail is responsible for binding to gene-specific transcriptional regulators. Most head and middle subunits are essential, whereas all tail module subunits are encoded by non-essential genes. CKM is mostly involved in transcriptional repression by binding Mediator in a way that sterically blocks the binding of Pol II to Mediator. Mediator is traditionally purified from the ‘non-chromatin’ fraction of whole-cell extracts. Since most Mediator functions occur in a chromatin context, we set out to purify Mediator from the chromatin fraction of cell extracts. We performed affinity-purification using strains expressing epitope-tagged Mediator subunits, combined with mass spectrometry to reveal the composition of chromatin-bound Mediator. We found that Mediator in chromatin interacts with several protein complexes involved in different aspects of gene expression. Several of them, such as CPF, CF IA, and TFIIB have been shown to be involved in gene looping. Using Chromatin immunoprecipitation (ChIP)-seq experiments, we localized Mediator occupancy genome-wide. As expected, we found enrichment of Mediator at gene promoters, but also at Chromatin Interaction Domain boundaries (CIDBs), which are important for chromatin organization and transcriptional regulation. We also investigated the yeast Tail module function in detail. Individually, Tail subunit mutants are non-essential, but med15/med16 or med5/med15 strain are lethal. We used the N-degron system to conditionally deplete Med15/Med16 or Med5/Med15 and studied their effects on global gene expression using MicroArray assays. Several meiosis and sporulation genes were upregulated in the med5/med15 and med15/med16. In support of this, Rck1 which is a repressor of meiosis and sporulation rate in diploid cells, was downregulated in both strains. All strains where Med15 expression was depleted showed downregulation of several target genes for the Ace2 transcription factor which is important for cell cycle progression through the G1 cell cycle phase. Accordingly, all our med15-degron strains showed a G1-phase arrest in flow cytometry assays. Finally, we investigated the tail module subunit Med2 which has a phosphorylation site at position S208. We found that point mutations of S208A led to downregulation of several genes that are usually expressed during anaerobic growth. We also found that a med2 strain was unable to grow under anaerobic conditions.
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| 7. |
- Andersson, Claes, 1978-
(author)
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Fusing Domain Knowledge with Data : Applications in Bioinformatics
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Massively parallel measurement techniques can be used for generating hypotheses about the molecular underpinnings of a biological systems. This thesis investigates how domain knowledge can be fused to data from different sources in order to generate more sophisticated hypotheses and improved analyses. We find our applications in the related fields of cell cycle regulation and cancer chemotherapy. In our cell cycle studies we design a detector of periodic expression and use it to generate hypotheses about transcriptional regulation during the course of the cell cycle in synchronized yeast cultures as well as investigate if domain knowledge about gene function can explain whether a gene is periodically expressed or not. We then generate hypotheses that suggest how periodic expression that depends on how the cells were perturbed into synchrony are regulated. The hypotheses suggest where and which transcription factors bind upstreams of genes that are regulated by the cell cycle. In our cancer chemotherapy investigations we first study how a method for identifiyng co-regulated genes associated with chemoresponse to drugs in cell lines is affected by domain knowledge about the genetic relationships between the cell lines. We then turn our attention to problems that arise in microarray based predictive medicine, were there typically are few samples available for learning the predictor and study two different means of alleviating the inherent trade-off betweeen allocation of design and test samples. First we investigate whether independent tests on the design data can be used for improving estimates of a predictors performance without inflicting a bias in the estimate. Then, motivated by recent developments in microarray based predictive medicine, we propose an algorithm that can use unlabeled data for selecting features and consequently improve predictor performance without wasting valuable labeled data.
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| 8. |
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| 9. |
- Håkansson, Pelle, 1973-
(author)
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Ribonucleotide reductase and DNA damage
- 2006
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Doctoral thesis (other academic/artistic)abstract
- A prerequisite for a multicellular organism to survive is the ability to correctly replicate and repair DNA while minimizing the number of heritable mutations. To achieve this, cells need a balanced supply of deoxyribonucleoside triphosphates (dNTPs), the precursors for DNA synthesis. The rate-limiting step in de novo biosynthesis of dNTPs is catalyzed by the enzyme ribonucleotide reductase (RNR). The classic eukaryotic RNR enzyme consists of a large and a small subunit. Together, these subunits form a heterotetrameric RNR complex. The larger subunit harbours active sites whereas the smaller subunit contains a stable tyrosyl free radical. Both subunits are required for RNR activity. Since failure to correctly regulate de novo dNTP biosynthesis can lead to misincorporation of nucleotides into DNA, genetic abnormalities and cell death, RNR activity is tightly regulated. The regulation of RNR activity involves cell cycle-specific expression and degradation of the RNR proteins, as well as binding of allosteric effectors to the large RNR subunit. In this thesis, in vitro assays based on purified recombinant RNR proteins, in combination with in vivo assays, have been used successfully to study the regulation of RNR activity in response to DNA damage. I present new findings regarding the function of an alternative mammalian RNR small subunit, and on the role of a small RNR inhibitor protein of fission yeast, during normal growth and after DNA damage. I also show conclusively that there are fundamental differences in the regulation of dNTP biosynthesis between the cells of higher and lower eukaryotes after DNA damage.
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| 10. |
- Lennerfors, Thomas Taro, 1979-
(author)
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The Vicissitudes of Corruption : Degeneration - transgression - jouissance
- 2007
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Doctoral thesis (other academic/artistic)abstract
- In a time when corruption is receiving increasing media coverage and when many claim to wage a war on corruption, this book brings up the need for a problematisation and an increased understanding of the different manifestations – the vicissitudes – of corruption and also what measures are taken against it. The book advances the claim that corruption is tightly related to modernity and particularly to a transgression of the public / private dichotomy. It furthermore explores ancient, postmodern and psychoanalytic critiques of the modern understanding of corruption. The ancient perspective stems from theorists arguing that there is an ancient core meaning of corruption, i.e. degeneration. This perspective is also informed by a discussion about virtues based on Alasdair MacIntyre. The postmodern perspective is based on Zygmunt Bauman. It is held that corruption is the remnant of the classification of the world into the public and the private, caused by the inherent ambiguity of reality. The psychoanalytic perspective, based on Jacques Lacan and Slavoj Žižek, deepens the analysis and relates corruption to stolen enjoyment – jouissance. These different understandings of corruption are used to analyse primarily bribery in Swedish public sector procurement. In interviews, project managers responsible for public procurement give their account not only of bribes and gifts, but also about partiality and objectivity in supplier evaluations. Using these interviews and theoretical perspectives, the book problematises corruption and investigates how it is addressed and externalised with clear rules, virtues and rituals separating the public role from the private .
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