Construction of a global map of human gene expression : the process, tools and analysis

This thesis studies human gene expression space using high throughput gene expression data from DNA microarrays. In molecular biology, high throughput techniques allow numerical measurements of expression of tens of thousands of genes simultaneously. In a single study, this data is traditionally obtained from a limited number of sample types with a small number of replicates. For organism-wide analysis, this data has been largely unavailable and the global structure of human transcriptome has remained unknown. This thesis introduces a human transcriptome map of different biological entities and analysis of its general structure. The map is constructed from gene expression data from the two largest public microarray data repositories, GEO and ArrayExpress. The creation of this map contributed to the development of ArrayExpress by identifying and retrofitting the previously unusable and missing data and by improving the access to its data. It also contributed to creation of several new tools for microarray data manipulation and establishment of data exchange between GEO and ArrayExpress. The data integration for the global map required creation of a new large ontology of human cell types, disease states, organism parts and cell lines. The ontology was used in a new text mining and decision tree based method for automatic conversion of human readable free text microarray data annotations into categorised format. The data comparability and minimisation of the systematic measurement errors that are characteristic to each lab- oratory in this large cross-laboratories integrated dataset, was ensured by computation of a range of microarray data quality metrics and exclusion of incomparable data. The structure of a global map of human gene expression was then explored by principal component analysis and hierarchical clustering using heuristics and help from another purpose built sample ontology. A preface and motivation to the construction and analysis of a global map of human gene expression is given by analysis of two microarray datasets of human malignant melanoma. The analysis of these sets incorporate indirect comparison of statistical methods for finding differentially expressed genes and point to the need to study gene expression on a global level.

Exploring privacy for ubiquitous computing: Tools, methods and experiments

Ubiquitous computing is about making computers and computerized artefacts a pervasive part of our everyday lifes, bringing more and more activities into the realm of information. The computationalization, informationalization of everyday activities increases not only our reach, efficiency and capabilities but also the amount and kinds of data gathered about us and our activities. In this thesis, I explore how information systems can be constructed so that they handle this personal data in a reasonable manner. The thesis provides two kinds of results: on one hand, tools and methods for both the construction as well as the evaluation of ubiquitous and mobile systems---on the other hand an evaluation of the privacy aspects of a ubiquitous social awareness system. The work emphasises real-world experiments as the most important way to study privacy. Additionally, the state of current information systems as regards data protection is studied. The tools and methods in this thesis consist of three distinct contributions. An algorithm for locationing in cellular networks is proposed that does not require the location information to be revealed beyond the user's terminal. A prototyping platform for the creation of context-aware ubiquitous applications called ContextPhone is described and released as open source. Finally, a set of methodological findings for the use of smartphones in social scientific field research is reported. A central contribution of this thesis are the pragmatic tools that allow other researchers to carry out experiments. The evaluation of the ubiquitous social awareness application ContextContacts covers both the usage of the system in general as well as an analysis of privacy implications. The usage of the system is analyzed in the light of how users make inferences of others based on real-time contextual cues mediated by the system, based on several long-term field studies. The analysis of privacy implications draws together the social psychological theory of self-presentation and research in privacy for ubiquitous computing, deriving a set of design guidelines for such systems. The main findings from these studies can be summarized as follows: The fact that ubiquitous computing systems gather more data about users can be used to not only study the use of such systems in an effort to create better systems but in general to study phenomena previously unstudied, such as the dynamic change of social networks. Systems that let people create new ways of presenting themselves to others can be fun for the users---but the self-presentation requires several thoughtful design decisions that allow the manipulation of the image mediated by the system. Finally, the growing amount of computational resources available to the users can be used to allow them to use the data themselves, rather than just being passive subjects of data gathering.

Polarization studies in electromagnetic scattering by small Solar-system particles

In remote-sensing studies, particles that are comparable to the wavelength exhibit characteristic features in electromagnetic scattering, especially in the degree of linear polarization. These features vary with the physical properties of the particles, such as shape, size, refractive index, and orientation. In the thesis, the direct problem of computing the unknown scattered quantities using the known properties of the particles and the incident radiation is solved at both optical and radar spectral regions in a unique way. The internal electromagnetic fields of wavelength-scale particles are analyzed by using both novel and established methods to show how the internal fields are related to the scattered fields in the far zone. This is achieved by using the tools and methods that were developed specifically to reveal the internal field structure of particles and to study the mechanisms that relate the structure to the scattering characteristics of those particles. It is shown that, for spherical particles, the internal field is a combination of a forward propagating wave with the apparent wavelength determined by the refractive index of the particle, and a standing wave pattern with the apparent wavelength the same as for the incident wave. Due to the surface curvature and dielectric nature of the particle, the incident wave front undergoes a phase shift, and the resulting internal wave is focused mostly at the forward part of the particle similar to an optical lens. This focusing is also seen for irregular particles. It is concluded that, for both spherical and nonspherical particles, the interference at the far field between the partial waves that originate from these concentrated areas in the particle interior, is responsible for the specific polarization features that are common for wavelength-scale particles, such as negative values and local extrema in the degree of linear polarization, asymmetry of the phase function, and enhancement of intensity near the backscattering direction. The papers presented in this thesis solve the direct problem for particles with both simple and irregular shapes to demonstrate that these interference mechanisms are common for all dielectric wavelength-scale particles. Furthermore, it is shown that these mechanisms can be applied to both regolith particles in the optical wavelengths and hydrometeors at microwave frequencies. An advantage from this kind of study is that it does not matter whether the observation is active (e.g., polarimetric radar) or passive (e.g., optical telescope). In both cases, the internal field is computed for two mutually perpendicular incident polarizations, so that the polarization characteristics can then be analyzed according to the relation between these fields and the scattered far field.

Oppimisen kohteen ja oppijan vastavuoroinen kehitys : Teleyrityksen asiakaspalvelun työyhteisöjen oppimiskäytäntöjen uudistaminen osana teknologis-taloudellista kumousta

Reciprocal development of the object and subject of learning. The renewal of the learning practices of front-line communities in a telecommunications company as part of the techno-economical paradigm change. Current changes in production have been seen as an indication of a shift from the techno-economical paradigm of a mass-production era to a new paradigm of the information and communication technological era. The rise of knowledge management in the late 1990s can be seen as one aspect of this paradigm shift, as knowledge creation and customer responsiveness were recognized as the prime factors in business competition. However, paradoxical conceptions concerning learning and agency have been presented in the discussion of knowledge management. One prevalent notion in the literature is that learning is based on individuals’ voluntary actions and this has now become incompatible with the growing interest in knowledge-management systems. Furthermore, commonly held view of learning as a general process that is independent of the object of learning contradicts the observation that the current need for new knowledge and new competences are caused by ongoing techno-economic changes. Even though the current view acknowledges that individuals and communities have key roles in knowledge creation, this conception defies the idea of the individuals’ and communities’ agency in developing the practices through which they learn. This research therefore presents a new theoretical interpretation of learning and agency based on Cultural-Historical Activity Theory. This approach overcomes the paradoxes in knowledge-management theory and offers means for understanding and analyzing changes in the ways of learning within work communities. This research is also an evaluation of the Competence-Laboratory method which was developed as part of the study as a special application of Developmental Work Research methodology. The research data comprises the videotaped competence-laboratory processes of four front-line work communities in a telecommunications company. The findings reported in the five articles included in this thesis are based on the analyses of this data. The new theoretical interpretation offered here is based on the assessment that the findings reported in the articles represent one of the front lines of the ongoing historical transformation of work-related learning since the research site represents one of the key industries of the new “knowledge society”. The research can be characterized as elaboration of a hypothesis concerning the development of work related learning. According to the new theoretical interpretation, the object of activity is also the object of distributed learning in work communities. The historical socialization of production has increased the number of actors involved in an activity, which has also increased the number of mutual interdependencies as well as the need for communication. Learning practices and organizational systems of learning are historically developed forms of distributed learning mediated by specific forms of division of labor, specific tools, and specific rules. However, the learning practices of the mass production era become increasingly inadequate to accommodate the conditions in the new economy. This was manifested in the front-line work communities in the research site as an aggravating contradiction between the new objects of learning and the prevailing learning practices. The constituent element of this new theoretical interpretation is the idea of a work community’s learning as part of its collaborative mastery of the developing business activity. The development of the business activity is at the same time a practical and an epistemic object for the community. This kind of changing object cannot be mastered by using learning practices designed for the stable conditions of mass production, because learning has to change along the changes in business. According to the model introduced in this thesis, the transformation of learning proceeds through specific stages: predefined learning tasks are first transformed into learning through re-conceptualizing the object of the activity and of the joint learning and then, as the new object becomes stabilized, into the creation of new kinds of learning practices to master the re-defined object of the activity. This transformation of the form of learning is realized through a stepwise expansion of the work community’s agency. To summarize, the conceptual model developed in this study sets the tool-mediated co-development of the subject and the object of learning as the theoretical starting point for developing new, second-generation knowledge management methods. Key words: knowledge management, learning practice, organizational system of learning, agency

Boundaries in Action : An Activity-theoretical Study of Development, Learning, and Change in Health Care Organization for Patients with Multiple and Chronic Illnesses

This study examines boundaries in health care organizations. Boundaries are sometimes considered things to be avoided in everyday living. This study suggests that boundaries can be important temporally and spatially emerging locations of development, learning, and change in inter-organizational activity. Boundaries can act as mediators of cultural and social formations and practices. The data of the study was gathered in an intervention project during the years 2000-2002 in Helsinki in which the care of 26 patients with multiple and chronic illnesses was improved. The project used the Change Laboratory method that represents a research assisted method for developing work. The research questions of the study are: (1) What are the boundary dynamics of development, learning, and change in health care for patients with multiple and chronic illnesses? (2) How do individual patients experience boundaries in their health care? (3) How are the boundaries of health care constructed and reconstructed in social interaction? (4) What are the dynamics of boundary crossing in the experimentation with the new tools and new practice? The methodology of the study, the ethnography of the multi-organizational field of activity, draws on cultural-historical activity theory and anthropological methods. The ethnographic fieldwork involves multiple research techniques and a collaborative strategy for raising research data. The data of this study consists of observations, interviews, transcribed intervention sessions, and patients' health documents. According to the findings, the care of patients with multiple and chronic illnesses emerges as fragmented by divisions of a patient and professionals, specialties of medicine and levels of health care organization. These boundaries have a historical origin in the Finnish health care system. As an implication of these boundaries, patients frequently experience uncertainty and neglect in their care. However, the boundaries of a single patient were transformed in the Change Laboratory discussions among patients, professionals and researchers. In these discussions, the questioning of the prevailing boundaries was triggered by the observation of gaps in inter-organizational care. Transformation of the prevailing boundaries was achieved in implementation of the collaborative care agreement tool and the practice of negotiated care. However, the new tool and practice did not expand into general use during the project. The study identifies two complementary models for the development of health care organization in Finland. The 'care package model', which is based on productivity and process models adopted from engineering and the 'model of negotiated care', which is based on co-configuration and the public good.

Measuring and tracking quality factors in Free and Open Source Software projects

Free and Open Source Software (FOSS) has gained increased interest in the computer software industry, but assessing its quality remains a challenge. FOSS development is frequently carried out by globally distributed development teams, and all stages of development are publicly visible. Several product and process-level quality factors can be measured using the public data. This thesis presents a theoretical background for software quality and metrics and their application in a FOSS environment. Information available from FOSS projects in three information spaces are presented, and a quality model suitable for use in a FOSS context is constructed. The model includes both process and product quality metrics, and takes into account the tools and working methods commonly used in FOSS projects. A subset of the constructed quality model is applied to three FOSS projects, highlighting both theoretical and practical concerns in implementing automatic metric collection and analysis. The experiment shows that useful quality information can be extracted from the vast amount of data available. In particular, projects vary in their growth rate, complexity, modularity and team structure.

Assessment of In-House Natural Product and Synthetic Compound Libraries Based on In vitro Inhibition of Cholinesterases

The first line medication for mild to moderate Alzheimer s disease (AD) is based on cholinesterase inhibitors which prolong the effect of the neurotransmitter acetylcholine in cholinergic nerve synapses which relieves the symptoms of the disease. Implications of cholinesterases involvement in disease modifying processes has increased interest in this research area. The drug discovery and development process is a long and expensive process that takes on average 13.5 years and costs approximately 0.9 billion US dollars. Drug attritions in the clinical phases are common due to several reasons, e.g., poor bioavailability of compounds leading to low efficacy or toxic effects. Thus, improvements in the early drug discovery process are needed to create highly potent non-toxic compounds with predicted drug-like properties. Nature has been a good source for the discovery of new medicines accounting for around half of the new drugs approved to market during the last three decades. These compounds are direct isolates from the nature, their synthetic derivatives or natural mimics. Synthetic chemistry is an alternative way to produce compounds for drug discovery purposes. Both sources have pros and cons. The screening of new bioactive compounds in vitro is based on assaying compound libraries against targets. Assay set-up has to be adapted and validated for each screen to produce high quality data. Depending on the size of the library, miniaturization and automation are often requirements to reduce solvent and compound amounts and fasten the process. In this contribution, natural extract, natural pure compound and synthetic compound libraries were assessed as sources for new bioactive compounds. The libraries were screened primarily for acetylcholinesterase inhibitory effect and secondarily for butyrylcholinesterase inhibitory effect. To be able to screen the libraries, two assays were evaluated as screening tools and adapted to be compatible with special features of each library. The assays were validated to create high quality data. Cholinesterase inhibitors with various potencies and selectivity were found in natural product and synthetic compound libraries which indicates that the two sources complement each other. It is acknowledged that natural compounds differ structurally from compounds in synthetic compound libraries which further support the view of complementation especially if a high diversity of structures is the criterion for selection of compounds in a library.

Regulation and Function of GATA Transcription Factors in Adrenocortical Tumors and Granulosa Cells

Transcription factors play a key role in tumor development, in which dysfunction of genes regulating tissue growth and differentiation is a central phenomenon. The GATA family of transcription factors consists of six members that bind to a consensus DNA sequence (A/T)GATA(A/G) in gene promoters and enhancers. The two GATA factors expressed in the adrenal cortex are GATA-4 and GATA-6. In both mice and humans, GATA-4 can be detected only during the fetal period, whereas GATA-6 expression is abundant both throughout development and in the adult. It is already established that GATA factors are important in both normal development and tumorigenesis of several endocrine organs, and expression of GATA-4 and GATA-6 is detected in adrenocortical tumors. The aim of this study was to elucidate the function of these factors in adrenocortical tumor growth. In embryonal development, the adrenocortical cells arise and differentiate from a common pool with gonadal steroidogenic cells, the urogenital ridge. As the adult adrenal cortex undergoes constant renewal, it is hypothesized that undifferentiated adrenocortical progenitor cells reside adjacent to the adrenal capsule and give rise to daughter cells that differentiate and migrate centripetally. A diverse array of hormones controls the differentiation, growth and survival of steroidogenic cells in the adrenal gland and the gonads. Factors such as luteinizing hormone and inhibins, traditionally associated with gonadal steroidogenic cells, can also influence the function of adrenocortical cells in physiological and pathophysiological states. Certain inbred strains of mice develop subcapsular adrenocortical tumors in response to gonadectomy. In this study, we found that these tumors express GATA-4, normally absent from the adult adrenal cortex, while GATA-6 expression is downregulated. Gonadal markers such as luteinizing hormone receptor, anti-Müllerian hormone and P450c17 are also expressed in the neoplastic cells, and the tumors produce gonadal hormones. The tumor cells have lost the expression of melanocortin-2 receptor and the CYP enzymes necessary for the synthesis of corticosterone and aldosterone. By way of xenograft studies utilizing NU/J nude mice, we confirmed that chronic gonadotropin elevation is sufficient to induce adrenocortical tumorigenesis in susceptible inbred strains. Collectively, these studies suggest that subcapsular adrenocortical progenitor cells can, under certain conditions, adopt a gonadal fate. We studied the molecular mechanisms involved in gene regulation in endocrine cells in order to elucidate the role of GATA factors in endocrine tissues. Ovarian granulosa cells express both GATA-4 and GATA-6, and the TGF-β signaling pathway is active in these cells. Inhibin-α is both a target gene for, and an atypical or antagonistic member of the TGF-β growth factor superfamily. In this study, we show that GATA-4 is required for TGF-β-mediated inhibin-α promoter activation in granulosa cells, and that GATA-4 physically interacts with Smad3, a TGF-β downstream protein. Apart from the regulation of steroidogenesis and other events in normal tissues, TGF-β signaling is implicated in tumors of multiple organs, including the adrenal cortex. Another signaling pathway found often to be aberrantly active in adrenocortical tumors is the Wnt pathway. As both of these pathways regulate the expression of inhibin-α, a transcriptional target for GATA-4 and GATA-6, we wanted to investigate whether GATA factors are associated with the components of these signaling cascades in human adrenocortical tumors. We found that the expression of Wnt co-receptors LRP5 and LRP6, Smad3, GATA-6 and SF-1 was diminished in adrenocortical carcinomas with poor outcome. All of these factors drive inhibin-α expression, and their expression in adrenocortical tumors correlated with that of inhibin-α. The results support a tumor suppressor role previously suggested for inhibin-α in the mouse adrenal cortex, and offer putative pathways associated with adrenocortical tumor aggressiveness. Unraveling the role of GATA factors and associated molecules in human and mouse adrenocortical tumors could ultimately contribute to the development of diagnostic tools and future therapies for these diseases.

Unraveling the helix of change : An activity-theoretical study of health care change efforts and their consequences

M.A. (Educ.) Anu Kajamaa from the University of Helsinki, Center for Research on Activity, Development and Learning (CRADLE), examines change efforts and their consequences in health care in the public sector. The aim of her academic dissertation is, by providing a new conceptual framework, to widen our understanding of organizational change efforts and their consequences and managerial challenges. Despite the multiple change efforts, the results of health care development projects have not been very promising, and many developmental needs and managerial challenges exist. The study challenges the predominant, well-framed health care change paradigm and calls for an expanded view to explore the underlying issues and multiplicities of change efforts and their consequences. The study asks what kind of expanded conceptual framework is needed to better understand organizational change as transcending currently dominant oppositions in management thinking, specifically in the field of health care. The study includes five explorative case studies of health care change efforts and their consequences in Finland. Theory and practice are tightly interconnected in the study. The methodology of the study integrates the ethnography of organizational change, a narrative approach and cultural-historical activity theory. From the stance of activity theory, historicity, contradictions, locality and employee participation play significant roles in developing health care. The empirical data of the study has mainly been collected in two projects, funded by the Finnish Work Environment Fund. The data was collected in public sector health care organizations during the years 2004-2010. By exploring the oppositions between distinct views on organizational change and the multi-site, multi-level and multi-logic of organizational change, the study develops an expanded, multidimensional activity-theoretical framework on organizational change and management thinking. The findings of the study contribute to activity theory and organization studies, and provide information for health care management and practitioners. The study illuminates that continuous development efforts bridged to one another and anchored to collectively created new activity models can lead to significant improvements and organizational learning in health care. The study presents such expansive learning processes. The ways of conducting change efforts in organizations play a critical role in the creation of collective new practices and tools and in establishing ownership over them. Some of the studied change efforts were discontinuous or encapsulated, not benefiting the larger whole. The study shows that the stagnation and unexpected consequences of change efforts relate to the unconnectedness of the different organizational sites, levels and logics. If not dealt with, the unintended consequences such as obstacles, breaks and conflicts may stem promising change and learning processes.