Methods to improve gene signal: Application to cDNA microarrays

Microarrays are high throughput biological assays that allow the screening of thousands of genes for their expression. The main idea behind microarrays is to compute for each gene a unique signal that is directly proportional to the quantity of mRNA that was hybridized on the chip. A large number of steps and errors associated with each step make the generated expression signal noisy. As a result, microarray data need to be carefully pre-processed before their analysis can be assumed to lead to reliable and biologically relevant conclusions. This thesis focuses on developing methods for improving gene signal and further utilizing this improved signal for higher level analysis. To achieve this, first, approaches for designing microarray experiments using various optimality criteria, considering both biological and technical replicates, are described. A carefully designed experiment leads to signal with low noise, as the effect of unwanted variations is minimized and the precision of the estimates of the parameters of interest are maximized. Second, a system for improving the gene signal by using three scans at varying scanner sensitivities is developed. A novel Bayesian latent intensity model is then applied on these three sets of expression values, corresponding to the three scans, to estimate the suitably calibrated true signal of genes. Third, a novel image segmentation approach that segregates the fluorescent signal from the undesired noise is developed using an additional dye, SYBR green RNA II. This technique helped in identifying signal only with respect to the hybridized DNA, and signal corresponding to dust, scratch, spilling of dye, and other noises, are avoided. Fourth, an integrated statistical model is developed, where signal correction, systematic array effects, dye effects, and differential expression, are modelled jointly as opposed to a sequential application of several methods of analysis. The methods described in here have been tested only for cDNA microarrays, but can also, with some modifications, be applied to other high-throughput technologies. Keywords: High-throughput technology, microarray, cDNA, multiple scans, Bayesian hierarchical models, image analysis, experimental design, MCMC, WinBUGS.

Distortion of Dimension under Quasiconformal Mappings

Quasiconformal mappings are natural generalizations of conformal mappings. They are homeomorphisms with 'bounded distortion' of which there exist several approaches. In this work we study dimension distortion properties of quasiconformal mappings both in the plane and in higher dimensional Euclidean setting. The thesis consists of a summary and three research articles. A basic property of quasiconformal mappings is the local Hölder continuity. It has long been conjectured that this regularity holds at the Sobolev level (Gehring's higher integrabilty conjecture). Optimal regularity would also provide sharp bounds for the distortion of Hausdorff dimension. The higher integrability conjecture was solved in the plane by Astala in 1994 and it is still open in higher dimensions. Thus in the plane we have a precise description how Hausdorff dimension changes under quasiconformal deformations for general sets. The first two articles contribute to two remaining issues in the planar theory. The first one concerns distortion of more special sets, for rectifiable sets we expect improved bounds to hold. The second issue consists of understanding distortion of dimension on a finer level, namely on the level of Hausdorff measures. In the third article we study flatness properties of quasiconformal images of spheres in a quantitative way. These also lead to nontrivial bounds for their Hausdorff dimension even in the n-dimensional case.

On Games on Non-Wellfounded Sets and Stationary Sets

In this thesis we study a few games related to non-wellfounded and stationary sets. Games have turned out to be an important tool in mathematical logic ranging from semantic games defining the truth of a sentence in a given logic to for example games on real numbers whose determinacies have important effects on the consistency of certain large cardinal assumptions. The equality of non-wellfounded sets can be determined by a so called bisimulation game already used to identify processes in theoretical computer science and possible world models for modal logic. Here we present a game to classify non-wellfounded sets according to their branching structure. We also study games on stationary sets moving back to classical wellfounded set theory. We also describe a way to approximate non-wellfounded sets with hereditarily finite wellfounded sets. The framework used to do this is domain theory. In the Banach-Mazur game, also called the ideal game, the players play a descending sequence of stationary sets and the second player tries to keep their intersection stationary. The game is connected to precipitousness of the corresponding ideal. In the pressing down game first player plays regressive functions defined on stationary sets and the second player responds with a stationary set where the function is constant trying to keep the intersection stationary. This game has applications in model theory to the determinacy of the Ehrenfeucht-Fraisse game. We show that it is consistent that these games are not equivalent.

Studies on the mechanism of follitropin action at the cellular level

With a view toward understanding better the mechanism of action of follitropin, an attempt was made using granulosa cells obtained from intact immature estrogenized rats to study in short-term incubations the effect of highly purified ovine follitropin on the binding of the hormone to the cells and the associated aromatase response. A modified radioimmunoassay procedure has been used to monitor unlabeled physiologically fully active follitropin bound to the cell. A linear relationship between the actual amount of hormone bound to the cells and the estradiol produced in vitro has been established. The amount of ovine follitropin bound that can elicit a half-maximal response in estrogen production was calculated to be 400 pg. The number of follitropin binding sites per cell was 375 and the Kd of binding was 3.03 × 10−10 Image . By the addition of ovine follitropin antiserum at different time points of a 4-h incubation period, a continual need for follitropin support for estradiol production has been established.

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.

Cryptographic Software Export Controls in the EU

Certain software products employing digital techniques for encryption of data are subject to export controls in the EU Member States pursuant to Community law and relevant laws in the Member States. These controls are agreed globally in the framework of the so-called Wassenaar Arrangement. Wassenaar is an informal non-proliferation regime aimed at promoting international stability and responsibility in transfers of strategic (dual-use) products and technology. This thesis covers provisions of Wassenaar, Community export control laws and export control laws of Finland, Sweden, Germany, France and United Kingdom. This thesis consists of five chapters. The first chapter discusses the ratio of export control laws and the impact they have on global trade. The ratio is originally defence-related - in general to prevent potential adversaries of participating States from having the same tools, and in particular in the case of cryptographic software to enable signals intelligence efforts. Increasingly as the use of cryptography in a civilian context has mushroomed, export restrictions can have negative effects on civilian trade. Information security solutions may also be took weak because of export restrictions on cryptography. The second chapter covers the OECD's Cryptography Policy, which had a significant effect on its member nations' national cryptography policies and legislation. The OECD is a significant organization,because it acts as a meeting forum for most important industrialized nations. The third chapter covers the Wassenaar Arrangement. The Arrangement is covered from the viewpoint of international law and politics. The Wassenaar control list provisions affecting cryptographic software transfers are also covered in detail. Control lists in the EU and in Member States are usually directly copied from Wassenaar control lists. Controls agreed in its framework set only a minimum level for participating States. However, Wassenaar countries can adopt stricter controls. The fourth chapter covers Community export control law. Export controls are viewed in Community law as falling within the domain of Common Commercial Policy pursuant to Article 133 of the EC Treaty. Therefore the Community has exclusive competence in export matters, save where a national measure is authorized by the Community or falls under foreign or security policy derogations established in Community law. The Member States still have a considerable amount of power in the domain of Common Foreign and Security Policy. They are able to maintain national export controls because export control laws are not fully harmonized. This can also have possible detrimental effects on the functioning of internal market and common export policies. In 1995 the EU adopted Dual-Use Regulation 3381/94/EC, which sets common rules for exports in Member States. Provisions of this regulation receive detailed coverage in this chapter. The fifth chapter covers national legislation and export authorization practices in five different Member States - in Finland, Sweden, Germany, France and in United Kingdom. Export control laws of those Member States are covered when the national laws differ from the uniform approach of the Community's acquis communautaire. Keywords: export control, encryption, software, dual-use, license, foreign trade, e-commerce, Internet

Ihanteena vapaaehtoisuus : Diakoniatyö Porvoon hiippakunnan seurakunnissa, erityisesti Iitin ja Tampereen rovastikunnissa vuosina 1897-1923

The Ideal of Volunteerism. An institutional approach to social welfare work in the parishes of the Diocese of Porvoo especially in the deaneries of Iitti and Tampere, Finland, in the years 1897-1923 Social welfare work (also known as diakonia) has achieved a high status in the Evangelical Lutheran Church of Finland. Since 1944, provisions of the Finnish Church Act have obliged each parish to employ at least one deacon or deaconess. This study sets out to examine the background and development of social welfare work in the Evangelical Lutheran Church of Finland from the 1890s to the 1920s, by which time social welfare work had become an established practice in the Church. The study investigates the development of social welfare work on the level of parishes. The main source material was collected from sixteen parishes in the Diocese of Porvoo especially in the deaneries of Iitti and Tampere. In the 1890s, two approaches were used in church social work in Finland. The dioceses of Kuopio, Savonlinna and Turku pursued a congregational approach to social work, while the Diocese of Porvoo employed an institutional approach, mainly because of the influence of Bishop Herman Råbergh. This study charts the formation of church social work in Finnish parishes, which took place during a period of tension between the two approaches. The institutional approach to church social work adopted by the Diocese of Porvoo was based on the German system of Asisters= houses@, in which deaconess institutes sent parish sisters to serve congregations. The parish or, in many cases, a separate association dedicated to church social work paid an annual fee to the deaconess institute, which took care of the parish sisters in old age. In the institutional approach, volunteers were recruited to carry out church social work. It was considered as inappropriate to use tax revenue or other public funding for church social work, which was supposed to be based on Christian love for one=s fellow humans and the needy, and for which only voluntary financial contributions were supposed to be used. In the congregational approach, church social work was directly based on the efforts of the parish. The approach relied on the administrative bodies of parishes and the Church, and tax revenue collected by the parishes, as well as other forms of public funding, could be used to carry out the social welfare work. The parishes employed deacons and deaconesses and paid their salaries. The approaches described above were not pursued in their ideal forms; instead, many variations existed. However, in principle, the social welfare work undertaken by the parishes of the Diocese of Porvoo was based on the institutional approach, while the congregational approach was largely employed elsewhere in Finland. Both of the approaches were viable. Parishes began to employ deacons and deaconesses as of the 1890s. The number of parishes which had hired a deacon or deaconess increased particularly in the 1910s, by which time 60% of parishes had employed one. This level was maintained until 1944 when each parish in the Evangelical Lutheran Church of Finland was obliged to employ a deacon or deaconess. Deaconesses usually worked as travelling nurses. The autonomous status of Finland as part of the Russian Empire did not give Finns the right to develop legislation on social affairs and health care. Consequently, the legislation process did not begin until Finland gained its independence in 1917. The social welfare work carried out by parishes and a number of voluntary organisations satisfied the emerging need for medical treatment in Finnish society. Neither the government nor the municipalities had sufficient resources to provide this treatment. Based on the ideal of volunteerism, the institutional social work practiced in the Diocese of Porvoo ran into serious difficulties at the end of the First World War. Because of severe inflation, prices began to rise as of 1915 and tripled in 1917-1918. During the same period, Finnish society went through a deep crisis which escalated into Civil War in spring 1918. This period of economic and social turmoil marked a turning-point which led to a weakening of the status of institutional social work in parishes. Voluntary efforts were no longer sufficient to maintain the practice. In contrast, congregational social work, which was based on public funding, was able to cope with the changes and survived the crisis. The approach to social work adopted by the Diocese of Porvoo turned out to be no more than a brief detour in the history of social work in the Evangelical Lutheran Church of Finland. At the start of the 1920s, the two approaches were integrated into a common vision for establishing church social work as a statutory practice in parishes.

Spirituality of Finnish peacekeepers

The previous academic research on Finnish peacekeeping has clarified the operative and historical aspects of Finnish peacekeeping lacking the view of an individual who does the actual peacekeeping work. This research is based on the underlying theoretical assumption of human beings possessing different kinds of talents and intelligences creating a holistic entity. In this broad perspective spirituality was explored as an umbrella concept, as a holistic ability or talent, that can be explored as the deepest aspect of defining what it means to be human. The theoretical framework incorporated the concept of an intelligence, which is defined in Gardner's theory of multiple intelligences as the ability to solve problems, or to create products, that are valued within one or more cultural settings (Gardner, 1993, x). The viability of this theory was studied in the sample of Finnish peacekeepers. Spirituality in the theoretical and conceptual horizon was viewed as an extension of Gardner's theory of intelligences as one potential Gardnerian intelligence candidate. In addition to Gardner's theory, spirituality was explored as sensitivity which includes capacities such as sensing awareness, sensing mystery and sensing value (Hay, 1998). Also the practical aspects of spirituality were taken in account as shown in our everyday lives giving us the direction and influencing our social responsibilities and concerns (Bradford, 1995). Spirituality was explored also involving the element of the peacekeepers' community, the element of personal moral orientations and in the domain of religion and coping. The purpose of this research aimed in two dimensions. First, the aim was to outline the intelligence profile and the spiritual sensitivity profile of peacekeepers. Second, the aim was to understand qualitatively the nature of peacekeepers' spirituality The research interests were studied with different kinds of peacekeepers. Applying the mixed methods approach the research was conducted in two phases: first the former SFOR peacekeepers (N=6) were interviewed and the data was analysed. Inspired by the primary findings of these interviews, the data for the case-study of one peacekeeper was collected in co-operation with one former SFOR peacekeeper (N=1). In the second phase the data was collected from KFOR peacekeepers through the quantitative MI-Survey and the spiritual sensitivity survey (N=195). The quantitative method was used to outline the intelligence profile and the spiritual sensitivity profile of peacekeepers (N=195). In the mixed methods approach this method highlighted the general overview of intelligence traits and spiritual sensitivity of peacekeepers. In the mixed methods approach the qualitative method including interviews (N=6) and a case-study of one peacekeeper (N=1) increased subjective, qualitative information of spirituality of peacekeepers. The intelligence profile of peacekeepers highlighted the bodily-kinesthetic and interpersonal dimensions as the practical and social aspects of peacekeepers. Strong inter-item dependencies in the intrapersonal intelligence profile meant that peacekeepers possess a self-reflection and self-knowledge component and they reflect on deep psychological and philosophical issues. Regarding the spiritual sensitivity, peacekeepers found awareness-sensing, mystery-sensing, value-sensing and community-sensing important. The community-sensing emphasised a strong will to advance peace and to help people who are in need: things that are close to the heart of the peacekeepers. These results depicted practicality, being socially capable, and reflecting one's inner world as essential to peacekeepers. Moreover, spirituality as peacekeepers' moral endeavour became clearer because the sub-model of their community-sensing described morally charged destinations: advancing peace and helping people in need. In the qualitative findings peacekeepers articulated justice orientation and rule-following characterising the nature of peacekeepers' moral attitude and moral call (Kohlberg, 1969). An ethic of care (Gilligan, 1982) describes mainly female moral orientation, but the findings revealed that an ethic of care is also an important agent supporting strongly male peacekeepers in their aim to carry out qualitatively good peacekeeping work. The moral endeavour was voiced, when the role of religion in coping meant the assessment of the a way of life, a way of conduct, a way of being truthful to one's own values in confusing surroundings. The practical level of spiritual and religious contemplation was voiced as morally charged inner motivation to fulfil one's duties and at the same time to cope with various peacekeeping challenges. The results of different data sets were combined and interpreted as the moral endeavour, which characterises peacekeepers' spirituality. As the combining result, the perspective of peacekeepers' spirituality is considered moral or at least morally charged.

Threshold level of defocus to produce an accommodation response

To investigate the threshold level of defocus that induces a measurable objective change in accommodation response to a target at an intermediate distance.

EU Multi-level Governance in the Making - The Community Initiative LEADER+ in Finland and Germany

In order to fully understand the process of European integration it is of paramount importance to consider developments at the sub-national and local level. EU integration scholars shifted their attention to the local level only at the beginning of the 1990s with the concept of multi-level governance (MLG). While MLG is the first concept to scrutinise the position of local levels of public administration and other actors within the EU polity, I perceive it as too optimistic in the degree of influence it ascribes to local levels. Thus, learning from and combining MLG with other concepts, such as structural constructivism, helps to reveal some of the hidden aspects of EU integration and paint a more realistic picture of multi-level interaction. This thesis also answers the call for more case studies in order to conceptualise MLG further. After a critical study of theories and concepts of European integration, above all, MLG, I will analyse sub-national and local government in Finland and Germany. I show how the sub-national level and local governments are embedded in the EU s multi-level structure of governance and how, through EU integration, those levels have been empowered but also how their scope of action has partially decreased. After theoretical and institutional contextualisation, I present the results of my empirical study of the EU s Community Initiative LEADER+. LEADER stands for Liaison Entre Actions de Développement de l'Économie Rurale , and aims at improving the economic conditions in Europe s rural areas. I was interested in how different actors construct and shape EU financed rural development, especially in how local actors organised in so-called local action groups (LAGs) cooperate with other administrative units within the LEADER+ administrative chain. I also examined intra-institutional relations within those groups, in order to find out who are the most influential and powerful actors within them. Empirical data on the Finnish and German LAGs was first gathered through a survey, which was then supplemented and completed by interviewing LAG members, LAG-managers, several civil servants from Finnish and German decision-making and managing authorities and a civil servant from the EU Commission. My main argument is that in both Germany and Finland, the Community Initiative LEADER+ offered a space for multi-level interaction and local-level involvement, a space that on the one hand consists of highly motivated people actively contributing to the improvement of the quality of life and economy in Europe s countryside but which is dependent and also restricted by national administrative practices, implementation approaches and cultures on the other. In Finland, the principle of tri-partition (kolmikantaperiaatte) in organising the executive committees of LAGs is very noticeable. In comparison to Germany, for instance, the representation of public administration in those committees is much more limited due to this principle. Furthermore, the mobilisation of local residents and the bringing together of actors from the local area with different social and institutional backgrounds to become an active part of LEADER+ was more successful in Finland than in Germany. Tri-partition as applied in Finland should serve as a model for similar policies in other EU member states. EU integration changed the formal and informal inter-institutional relations linking the different levels of government. The third sector including non-governmental institutions and interest groups gained access to policy-making processes and increasingly interact with government institutions at all levels of public administration. These developments do not necessarily result in the empowering of the local level.

An operational-level multi-stage mine production timetabling model for optimally synchronising drilling, blasting and excavating operations

This paper proposes a new multi-stage mine production timetabling (MMPT) model to optimise open-pit mine production operations including drilling, blasting and excavating under real-time mining constraints. The MMPT problem is formulated as a mixed integer programming model and can be optimally solved for small-size MMPT instances by IBM ILOG-CPLEX. Due to NP-hardness, an improved shifting-bottleneck-procedure algorithm based on the extended disjunctive graph is developed to solve large-size MMPT instances in an effective and efficient way. Extensive computational experiments are presented to validate the proposed algorithm that is able to efficiently obtain the near-optimal operational timetable of mining equipment units. The advantages are indicated by sensitivity analysis under various real-life scenarios. The proposed MMPT methodology is promising to be implemented as a tool for mining industry because it is straightforwardly modelled as a standard scheduling model, efficiently solved by the heuristic algorithm, and flexibly expanded by adopting additional industrial constraints.

Sustainable development indicators : Much wanted, less used?

For the past twenty years, several indicator sets have been produced on international, national and regional levels. Most of the work has concentrated on the selection of the indicators and on collection of the pertinent data, but less attention has been given to the actual users and their needs. This dissertation focuses on the use of sustainable development indicator sets. The dissertation explores the reasons that have deterred the use of the indicators, discusses the role of sustainable development indicators in a policy-cycle and broadens the view of use by recognising three different types of use. The work presents two indicator development processes: The Finnish national sustainable development indicators and the socio-cultural indicators supporting the measurement of eco-efficiency in the Kymenlaakso Region. The sets are compared by using a framework created in this work to describe indicator process quality. It includes five principles supported by more specific criteria. The principles are high policy relevance, sound indicator quality, efficient participation, effective dissemination and long-term institutionalisation. The framework provided a way to identify the key obstacles for use. The two immediate problems with current indicator sets are that the users are unaware of them and the indicators are often unsuitable to their needs. The reasons for these major flaws are irrelevance of the indicators to the policy needs, technical shortcomings in the context and presentation, failure to engage the users in the development process, non-existent dissemination strategies and lack of institutionalisation to promote and update the indicators. The importance of the different obstacles differs among the users and use types. In addition to the indicator projects, materials used in the dissertation include 38 interviews of high-level policy-makers or civil servants close to them, statistics of the national indicator Internet-page downloads, citations of the national indicator publication, and the media coverage of both indicator sets. According to the results, the most likely use for a sustainable development indicator set by policy-makers is to learn about the concept. Very little evidence of direct use to support decision-making was available. Conceptual use is also common for other user groups, namely the media, civil servants, researchers, students and teachers. Decision-makers themselves consider the most obvious use for the indicators to be the promotion of their own views which is a form of legitimising use. The sustainable development indicators have different types of use in the policy cycle and most commonly expected instrumental use is not very likely or even desirable at all stages. Stages of persuading the public and the decision-makers about new problems as well as in formulating new policies employ legitimising use. Learning by conceptual use is also inherent to policy-making as people involved learn about the new situation. Instrumental use is most likely in policy formulation, implementation and evaluation. The dissertation is an article dissertation, including five papers that are published in scientific journals and an extensive introductory chapter that discusses and weaves together the papers.