Lethal weapons : novel approaches for receptor-targeted cancer cell elimination

The currently used forms of cancer therapy are associated with drug resistance and toxicity to healthy tissues. Thus, more efficient methods are needed for cancer-specific induction of growth arrest and programmed cell death, also known as apoptosis. Therapeutic forms of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are investigated in clinical trials due to the capability of TRAIL to trigger apoptosis specifically in cancer cells by activation of cell surface death receptors. Many tumors, however, have acquired resistance to TRAIL-induced apoptosis and sensitizing drugs for combinatorial treatments are, therefore, in high demand. This study demonstrates that lignans, natural polyphenols enriched in seeds and cereal, have a remarkable sensitizing effect on TRAIL-induced cell death at non-toxic lignan concentrations. In TRAIL-resistant and androgen-dependent prostate cancer cells we observe that lignans repress receptor tyrosine kinase (RTK) activity and downregulate cell survival signaling via the Akt pathway, which leads to increased TRAIL sensitivity. A structure-activity relationship analysis reveals that the γ-butyrolactone ring of the dibenzylbutyrolactone lignans is essential for the rapidly reversible TRAIL-sensitizing activity of these compounds. Furthermore, the lignan nortrachelogenin (NTG) is identified as the most efficient of the 27 tested lignans and norlignans in sensitization of androgen-deprived prostate cancer cells to TRAIL-induced apoptosis. While this combinatorial anticancer approach may leave normal cells unharmed, several efficient cancer drugs are too toxic, insoluble or unstable to be used in systemic therapy. To enable use of such drugs and to protect normal cells from cytotoxic effects, cancer-targeted drug delivery vehicles of nanometer scale have recently been generated. The newly developed nanoparticle system that we tested in vitro for cancer cell targeting combines the efficient drug-loading capacity of mesoporous silica to the versatile particle surface functionalization of hyperbranched poly(ethylene imine), PEI. The mesoporous hybrid silica nanoparticles (MSNs) were functionalized with folic acid to promote targeted internalization by folate receptor overexpressing cancer cells. The presented results demonstrate that the developed carrier system can be employed in vitro for cancer selective delivery of adsorbed or covalently conjugated molecules and furthermore, for selective induction of apoptotic cell death in folate receptor expressing cancer cells. The tested carrier system displays potential for simultaneous delivery of several anticancer agents specifically to cancer cells also in vivo.

Selective inhibition of human tankyrases

Tankyrases belong to the Diphtheria toxin-like ADP-ribosyltransferase (ARTD) enzyme superfamily, also known as poly(ADP-ribose) polymerases (PARPs). They catalyze a covalent post-translational modification reaction where they transfer ADP-ribose units from NAD+ to target proteins. Tankyrases are involved in many cellular processes and their roles in telomere homeostasis, Wnt signaling and in several diseases including cancers have made them interesting drug targets. In this thesis project, selective inhibition of human tankyrases was studied. A homogeneous fluorescence-based assay was developed to screen the compound libraries. The assay is inexpensive, operationally easy, and performs well according to the statistical analysis. Assay suitability was confirmed by screening a natural product library. Flavone was identified as the most potent inhibitor in the library and this motivated us to screen a larger flavonoid library. Results showed that flavones were indeed the best inhibitor of tankyrases among flavonoids. To further study the structure-activity relationship, a small library of flavones containing single substitution was screened and potency measurements allowed us to generate structure-activity relationship. Compounds containing substitutions at 4´-position were more potent in comparison to other substitutions, and importantly, hydrophobic groups improved isoenzyme selectivity as well as the potency. A flavone derivative containing a hydrophobic isopropyl group (compound 22), displayed 6 nM potency against TNKS1, excellent isoenzyme selectivity and Wnt signaling inhibition. Protein interactions with compounds were studied by solving complex crystal structures of the compounds with TNKS2 catalytic domain. A novel tankyrase inhibitor (IWR-1) was also crystallized in complex with TNKS2 catalytic domain. The crystal structure of TNKS2 in complex with IWR-1 showed that the compound binds to adenosine site and it was the first known ARTD inhibitor of this kind. To date, there is no structural information available about the substrate binding with any of the ARTD family members; therefore NAD+ was soaked with TNKS2 catalytic domain crystals. However, analysis of crystal structure showed that NAD+ was hydrolyzed to nicotinamide. Also, a co-crystal structure of NAD+ mimic compound, EB-47, was solved which was used to deduce some insights about the substrate interactions with the enzyme. Like EB-47, other ARTD1 inhibitors were also shown to inhibit tankyrases. It indicated that selectivity of the ARTD1 inhibitors should be considered as some of the effects in cells could come from tankyrase inhibition. In conclusion, the study provides novel information on tankyrase inhibition and presents new insight into the selectivity and potency of compounds.

Service product structure supported by remote diagnostics

Työn tavoitteena oli määrittää etähuoltokonseptin yleinen rakenne sekä selvittää asiakkaille tarjottavia modulaarisia palvelutuotteita. Aluksi selvitettiin huoltokonseptin rakennetta kirjallisuuden ja asiantuntijoiden haastattelujen avulla. Asiantuntijoiden haastattelut toteutettiin vapaamuotoisesti kysymyslistaa apuna käyttäen. Tämän lisäksi työssä pohditaan KM, CRM ja PDM rooleja etähuoltokonseptin kannalta sekä tutkaillaan etähuollon tulevaisuuden näkymiä.Diplomityössä käsitellään modulaarisuutta yleisellä tasolla. Moduularisuus on moniulotteinen termi. Usein sillä tarkoitetaan yrityksen sisäistä tuotekehityksen hallintaa. Toisaalta se voidaan nähdä myös asiakkaalle tarjottavina tuotteina ja tässä diplomityössä on keskitytty tähän puoleen. Loppuosa diplomityöstä käsittelee palvelutuotteiden tuotteistamisprosessia.Diplomityön tuloksena hahmoteltiin etähuolto konseptia ja tutkittiin mahdollisia palvelutuotteita, joita voidaan sisällyttää etähuoltokonseptiin. Tämän lisäksi toteutettiin osa tuotteistamisprosessista. Etähuollon kehittäminen on haasteellista. Haasteeksi jää tuotekehitystoiminnan ja palvelupuolen toiminnan tehostaminen, jotta tuotteita voitaisiin jo suunnittelupuolella kehittää etähuollon tarpeisiin. Kehittäminen vaatii molempien puolien aktiivista osallistumista.

Supplier relationship management capability in the firm's global integration

Organizing is a general problem for global firms. Firms are seeking a balance between responsiveness at the local level and efficiency through worldwide integration. In this, supply management is the focal point where external commercial supply market relations are connected with the firm's internal functions. Here, effective supplier relationship management (SRM) is essential. Global supply integration processes create new challenges for supply management professionals and new capabilities are required. Previous research has developed several models and tools for managers to manage and categorize different supplier relationship types, but the role of the firm's internal capability of managing supplier relationships in their global integration has been a clearly neglected issue. Hence, the main objective of this dissertation is to clarify how the capability of SRM may influence the firm's global competitiveness. This objective is divided into four research questions aiming to identify the elements of SRM capability, the internal factors of integration, the effect of SRM capability on strategy and how SRM capability is linked with global integration. The dissertation has two parts. The first part presents the theoretical approaches and practical implications from previous research and draws a synthesis on them. The second part comprises four empirical research papers addressing the research questions. Both qualitative and quantitative methods are utilized in this dissertation. The main contribution of this dissertation is that it aggregates the theoretical and conceptual perspectives applied to SRM research. Furthermore, given the lack of valid scales to measure capability, this study aimed to provide a foundation for an SRM capability scale by showing that the construct of SRM capability is formed of five separate elements. Moreover, SRM capability was found to be the enabler in efforts toward value chain integration. Finally, it was found that the effect of capability on global competitiveness is twofold: it reduces conflicts between responsiveness and integration, and it creates efficiency. Thus, by identifying and developing the firm's capabilities it is possible to improve performance, and hence, global competitiveness.

The effects of social networks on work-team effectiveness

This is a study of team social networks, their antecedents and outcomes. In focusing attention on the structural configuration of the team this research contributes to a new wave of thinking concerning group social capital. The research site was a random sample of Finnish work organisations. The data consisted of 499 employees in 76 teams representing 48 different organisations. A systematic literature review and quantitative methods were used in conducting the research: the former primarily to establish the current theoretical position on the relationships among the variables and the latter to test these relationships. Social network analysis was the primary method used in identifying the social-network relations among the work-team members. The first and key contribution of this study is that it relates the structuralnetwork properties of work teams to behavioural outcomes, attitudinal outcomes and, ultimately, team performance. Moreover, it shows that addressing attitudinal outcomes is also important in terms of team performance; attitudinal outcomes (team identity) mediated the relationship between the team’s performance and its social network. The second contribution is that it examines the possible antecedents of the social structure. It is thus one response to Salancik’s (1995) call for a network theory in that it explains why certain network characteristics exist. Itdemonstrates that irrespective of whether or not a team is heterogeneous in terms of age or gender, educational diversity may protect it from centralisation. However, heterogeneity in terms of gender turned out to have a negative impact on density. Thirdly, given the observation that the benefits of (team) networks are typically theorised and modelled without reference to the nature of the relationships comprising the structure, the study directly tested whether team knowledge mediated the effects of instrumental and expressive network relationships on team performance. Furthermore, with its focus on expressive networks that link the workplace to a more informal world, which have been rather neglected in previous research, it enhances knowledge of teams andnetworks. The results indicate that knowledge sharing fully mediates the influence of complementarities between dense and fragmented instrumental network relationships, thus providing empirical validation of the implicit understanding that networks transfer knowledge. Fourthly, the study findings suggest that an optimal configuration of the work-team social-network structure combines both bridging and bonding social relationships.

Making Sense of Shared Leadership. A case study of leadership processes and practices without formal leadership structure in the team context

Leadership is essential for the effectiveness of the teams and organizations they are part of. The challenges facing organizations today require an exhaustive review of the strategic role of leadership. In this context, it is necessary to explore new types of leadership capable of providing an effective response to new needs. The presentday situations, characterized by complexity and ambiguity, make it difficult for an external leader to perform all leadership functions successfully. Likewise, knowledge-based work requires providing professional groups with sufficient autonomy to perform leadership functions. This study focuses on shared leadership in the team context. Shared leadership is seen as an emergent team property resulting from the distribution of leadership influence across multiple team members. Shared leadership entails sharing power and influence broadly among the team members rather than centralizing it in the hands of a single individual who acts in the clear role of a leader. By identifying the team itself as a key source of influence, this study points to the relational nature of leadership as a social construct where leadership is seen as social process of relating processes that are co-constructed by several team members. Based on recent theoretical developments concerned with relational, practice-based and constructionist approaches to the study of leadership processes, this thesis proposes the study of leadership interactions, working processes and practices to focus on the construction of direction, alignment and commitment. During the research process, critical events, activities, working processes and practices of a case team have been examined and analyzed with the grounded theory –approach in the terms of shared leadership. There are a variety of components to this complex process and a multitude of factors that may influence the development of shared leadership. The study suggests that the development process of shared leadership is a common sense -making process and consists of four overlapping dimensions (individual, social, structural, and developmental) to work with as a team. For shared leadership to emerge, the members of the team must offer leadership services, and the team as a whole must be willing to rely on leadership by multiple team members. For these individual and collective behaviors to occur, the team members must believe that offering influence to and accepting it from fellow team members are welcome and constructive actions. Leadership emerges when people with differing world views use dialogue and collaborative learning to create spaces where a shared common purpose can be achieved while a diversity of perspectives is preserved and valued. This study also suggests that this process can be supported by different kinds of meaning-making and process tools. Leadership, then, does not reside in a person or in a role, but in the social system. The built framework integrates the different dimensions of shared leadership and describes their relationships. This way, the findings of this study can be seen as a contribution to the understanding of what constitutes essential aspects of shared leadership in the team context that can be of theoretical value in terms of advancing the adoption and development process of shared leadership. In the real world, teams and organizations can create conditions to foster and facilitate the process. We should encourage leaders and team members to approach leadership as a collective effort that the team can be prepared for, so that the response is rapid and efficient.

Sosiaali- ja terveydenhuollon teknisten palveluiden tuotteistaminen

Tämän tutkimuksen tarkoituksena oli tutkia Päijät-Hämeen sosiaali- ja terveydenhuollon kuntayhtymän Tukipalvelukeskuksen teknisten palveluiden tulosalueen tuotteistamista ja tuottaa kustannusten laskutuksen periaatteellinen toteutusmalli. Työssä otetaan kantaa palveluiden hinnoittelumalleihin eli kuinka kiinteistöistä ja teknisistä ylläpitopalveluista syntyvät kustannukset voidaan osoittaa niitä käyttäville tulosalueille. Palveluiden jäsentäminen ja suoritteiden yhdistäminen muodostavat palvelutuotteen, jota palveluita käyttävälle asiakkaalle tarjotaan. Tuotekäsitteelle on tyypillistä, että sitä voidaan tuottaa saman sisältöisenä nyt ja tulevaisuudessa. Tuotteita tarjoavan palveluiden tuottajan tuotekriteerit sisältävät selkeät tuoteryhmät, tuotteiden määrällisen mitattavuuden, kuvaavat tuotenimikkeet ja tuotteilla on ostajan näkökulmasta selkeä sisältö ja hinnoittelu. Tuotteistamisen tärkein hyöty on organisaation kustannusrakenteen selkeytyminen, jonka vuoksi tuotteiden määrä, laatu ja hinta tulee olla määriteltävissä. Asiakkaalle voidaan tarjota valmiiksi hinnoiteltuja palveluosia, jolloin palveluiden räätälöinti ja modulointi ovat mahdollisia palveluiden niputtamisella. Ei-kaupallisten instanssien, kuten kuntayhtymien sisäinen laskutus ja tuotteistus mahdollistavat palveluiden standardoimisen ja johdon päätöksenteko toimialakohtaisen kustannustietoisuuden vuoksi paranee. Tutkimuksen alkuosassa paneudutaan palvelun alle kuuluviin käsitteisiin, kuten tuotteistamisajatteluun, palvelupaketteihin, palveluiden laadun mittaamiseen ja palveluiden hinnoitteluun. Lisäksi tutkimuksessa käsitellään teknisten palveluiden hinnoitteluun käytettävän toimintoperusteisen kustannuslaskennan sekä sisäisen vuokraamisen periaatteita. Teoreettisessa viitekehyksessä käsiteltyjä asioita käytettiin hyödyksi sairaanhoitopiireille laadittuun kyselytutkimukseen. Yhdessä teorian ja kyselytutkimuksen kanssa kohdeorganisaatiolle luotiin malli palveluiden tuotteistamiseksi.

Capital Structure and Firm Growth: R&D Intensive Companies

The purpose of this study is to examine and explain firm`s growth impact on capital structure decision-making in research and development intensive companies. Many studies claim that R&D has a pivotal impact on capital structure decisions, but corporate finance theories have often failed to explain these observed patterns. As sales growth is an important concept and objective for R&D firms, it is logical to assume that it plays a vital role in capital structure decisions. This study applies nomothetic research approach. The theoretical part employs a formal conceptual analysis in order to develop the propositions that are tested with empirical data. The empirical part consists of the analysis of three companies; the data is obtained from the annual reports over the period 2003 – 2008. The companies operate in IT- or ICT-industry and are publicly listed. The method for analyzing the case data is based on the financial indicators, which are obtained from the financials of the case companies. These economic indicators describe the capital structure and the financial decision-making of the firms. The method relates to the quantitative studies. Yet, this study extends the analysis beyond the indicators. Specifically, this study addresses the question of what is behind the economic indicators, therefore combining aspects of quantitative and qualitative analysis. The firms examined in this study seem to prefer internal finance during growth. However, external finance seems to be a catalyst for sales growth. Firms strongly prefer equity financing. In growth, the use of equity per capital either increases or stays in a constant level. Over the period 2003 – 2008, the firms were often associated to equity related transactions and short-term debt. Short-term debt was used as a substitute of long-term debt and equity. The case firms also adjusted their capital structure – these adjustments were carried out with short-term debt or equity. The case data also provides implications for the growth signal theory that was developed in this study. Based on the econometric indicators, arguments can be made that equity investors are `attracted` to growing R&D firms. This is because growth helps investors perceive the true type of firm. The findings of this study are best explained by the trade-off theory and the pecking order theory. These corporate finance theories are considered as mainstream. Little support can be found to the implications of the signaling theory and market timing theory.

Ecosystem architecture design: endogenous and exogenous structural properties

The aim of this dissertation is to bridge and synthesize the different streams of literature addressing ecosystem architecture through a multiple‐lens perspective. In addition, the structural properties of and processes to design and manage the architecture will be examined. With this approach, the oft‐neglected actor‐structure duality is addressed and both the position and structure, and action and process are under scrutiny. Further, the developed framework and empirical evidence offer valuable insights on how firms collectively create value and individually appropriate value. The dissertation is divided into two parts. The first part comprises a literature review, as well as the conclusions of the whole study, and the second part includes six research publications. The dissertation is based on three different reasoning logics: abduction, induction and deduction; related qualitative and quantitative methodologies are utilized in the empirical examination of the phenomenon in the information and communication technology industry. The results suggest firstly that there are endogenous and exogenous structural properties of the ecosystem architecture. Out of these, the former ones can be more easily influenced by a particular actor whereas the latter ones are taken more or less for granted. Secondly, the exogenous ecosystem design properties influence the value creation potential of the ecosystem whereas the endogenous ecosystem design properties influence the value appropriation potential of a particular actor in the ecosystem. Thirdly, the study suggests that there is a relationship between endogenous and exogenous structural properties in that the endogenous properties can be leveraged to create and reconfigure the exogenous properties whereas the exogenous properties prose opportunities and restrictions on the use of endogenous properties. In addition, the study suggests that there are different emergent and engineered processes to design and manage ecosystem architecture and to influence both the endogenous and exogenous structural properties of ecosystem architecture. This study makes three main contributions. First, on the conceptual level, it brings coherence and direction to the fast growing body of literature on novel inter‐organizational arrangements, such as ecosystems. It does this by bridging and synthetizing three different streams of literature, namely the boundary, design and orchestration conception. Secondly, it sets out a framework that enhances our understanding of the structural properties of ecosystem architecture; of the processes to design and manage ecosystem architecture; and of their influence on the value creation potential of the ecosystem and the value capture potential of a particular firm. Thirdly, it offers empirical evidence of the structural properties and processes.

”Kielestä kiinni”. Kuudesluokkalaisten maahanmuuttajaoppilaiden suomen kielen tason vaihtelut

Tämän tutkimuksen tarkoituksena on selvittää, minkälaista vaihtelua esiintyy maahanmuuttajaoppilaiden suomen kielen taidoissa peruskoulun kuudennella luokalla. Tutkimuksen tavoitteena on myös selvittää, minkälainen yhteys taustamuuttujilla (sukupuoli, äidinkieli, maahantuloikä, maahantulon syy, maassaoloaika ja vanhempien koulutausta) ja opetusjärjestelyillä, kuten perusopetukseen valmistavalla opetuksella, suomi toisena kielenä -opetuksella ja oman äidinkielen opetuksella, on suomen kielen taidon tasoon. Lisäksi tutkimuksen tavoitteena on selvittää oppilaan käyttämän kielen (suomen kieli ja äidinkieli) yhteyttä suomen kielen taidon tasoon. Tutkimusmetodina toimi mixed methods -tutkimus, ja tutkimuksen lähestymistapoja olivat kvantitatiivinen survey-tutkimus ja kvalitatiivinen sisällön analyysi. Tutkimukseen osallistui 219 maahanmuuttajaoppilasta 20:stä Turun koulusta. Tutkimusaineisto kerättiin Turun erityisopettajien ja suomi toisena kielenä -opettajien laatiman kielitestipaketin avulla. Oppilaan suullista ja kirjallista tuottamista arvioivat lasta opettavat opettajat eurooppalaisen viitekehyksen kielitaitotasojen kriteereitä käyttäen. Oppilaat arvioivat omaa äidinkielen ja suomen kielen taitoaan. Lisäksi oppilaat ja vanhemmat täyttivät tutkijan laatimat taustatietolomakkeet. Kielitestien tulosten mukaan oppilaista yli puolella oli tyydyttävä suomen kielen taito. Kaikista neljästä kielellisestä osiosta maahanmuuttajataustaiset oppilaat menestyivät parhaiten rakennekokeessa ja sanelussa, kun taas kuullun ja luetun ymmärtämisen tulokset olivat heikompia. Opettajien arviointien perusteella oppilaiden suulliset taidot vastasivat keskimäärin itsenäisen kielenkäyttäjän osaajan tasoa (B2) ja kirjoittamistaidot kynnystasoa (B1). Oppilaiden suomi toisena kielenä -arvosanan keskiarvo oli 7,26. Suomessa asumisen kestolla, maahantulon syyllä, äidinkielellä, maahantuloiällä, ja vanhempien koulutaustaustalla oli tilastollisesti merkitsevä yhteys suomen kielen taidon tasoon. Mitä kauemmin oppilaat olivat asuneet Suomessa ja mitä nuorempina he olivat tulleet Suomeen, sitä paremmin he menestyivät kielitesteissä. Paluumuuttajat menestyivät kielitaitotehtävissä kaikkein parhaiten ja pakolaiset heikoiten. Somalinkieliset erottuivat muista kieliryhmän edustajista heikoimpina suomen kielen taidon tasoltaan. Venäjänkieliset ja vietnaminkieliset saavuttivat parhaat tulokset kaikissa mittareissa. Erityisesti äidin korkeampi koulutustaso oli yhteydessä oppilaiden korkeampaan suomen kielen taidon tasoon. Oppilaat arvioivat suomen kielen taitonsa omaa äidinkieltään paremmaksi puhumisessa, lukemisessa ja kirjoittamisessa. Parhaiten eri mittareissa menestyivät oppilaat, jotka eivät olleet osallistuneet perusopetukseen valmistavaan opetukseen eivätkä erilliseen suomi toisena kielenä -opetukseen. Omaa äidinkieltään enemmän opiskelleet menestyivät kielitaitotehtävissä paremmin kuin vähän aikaa omaa äidinkieltään opiskelleet, mutta yhtä hyvin kuin ne, jotka eivät olleet opiskelleet omaa äidinkieltään lainkaan. Oppilaat, jotka puhuivat kaveriensa kanssa sekä omaa äidinkieltään että suomen kieltä, osoittautuivat kielitaidon tasoltaan paremmiksi kielitesteissä ja opettajien arvioinneissa.

Social class as a factor for the construction of a musician’s identity : The Musician’s social background and identity questionnaire (MSBIQ) – a cross-sectional comparative quantitative online survey research study of music students at two higher education institutions in Finland

There is currently little empirical knowledge regarding the construction of a musician’s identity and social class. With a theoretical framework based on Bourdieu’s (1984) distinction theory, Bronfenbrenner’s (1979) theory of ecological systems, and the identity theories of Erikson (1950; 1968) and Marcia (1966), a survey called the Musician’s Social Background and Identity Questionnaire (MSBIQ) is developed to test three research hypotheses related to the construction of a musician’s identity, social class and ecological systems of development. The MSBIQ is administered to the music students at Sibelius Academy of the University of Arts Helsinki and Helsinki Metropolia University of Applied Sciences, representing the ’highbrow’ and the ’middlebrow’ samples in the field of music education in Finland. Acquired responses (N = 253) are analyzed and compared with quantitative methods including Pearson’s chi-square test, factor analysis and an adjusted analysis of variance (ANOVA). The study revealed that (1) the music students at Sibelius Academy and Metropolia construct their subjective musician’s identity differently, but (2) social class does not affect this identity construction process significantly. In turn, (3) the ecological systems of development, especially the individual’s residential location, do significantly affect the construction of a musician’s identity, as well as the age at which one starts to play one’s first musical instrument. Furthermore, a novel finding related to the structure of a musician’s identity was the tripartite model of musical identity consisting of the three dimensions of a musician’s identity: (I) ’the subjective dimension of a musician’s identity’, (II) ’the occupational dimension of a musician’s identity’ and, (III) ’the conservative-liberal dimension of a musician’s identity’. According to this finding, a musician’s identity is not a uniform, coherent entity, but a structure consisting of different elements continuously working in parallel within different dimensions. The results and limitations related to the study are discussed, as well as the objectives related to future studies using the MSBIQ to research the identity construction and social backgrounds of a musician or other performing artists.

Quantitative refinement of reaction-based biomodels

In the field of molecular biology, scientists adopted for decades a reductionist perspective in their inquiries, being predominantly concerned with the intricate mechanistic details of subcellular regulatory systems. However, integrative thinking was still applied at a smaller scale in molecular biology to understand the underlying processes of cellular behaviour for at least half a century. It was not until the genomic revolution at the end of the previous century that we required model building to account for systemic properties of cellular activity. Our system-level understanding of cellular function is to this day hindered by drastic limitations in our capability of predicting cellular behaviour to reflect system dynamics and system structures. To this end, systems biology aims for a system-level understanding of functional intraand inter-cellular activity. Modern biology brings about a high volume of data, whose comprehension we cannot even aim for in the absence of computational support. Computational modelling, hence, bridges modern biology to computer science, enabling a number of assets, which prove to be invaluable in the analysis of complex biological systems, such as: a rigorous characterization of the system structure, simulation techniques, perturbations analysis, etc. Computational biomodels augmented in size considerably in the past years, major contributions being made towards the simulation and analysis of large-scale models, starting with signalling pathways and culminating with whole-cell models, tissue-level models, organ models and full-scale patient models. The simulation and analysis of models of such complexity very often requires, in fact, the integration of various sub-models, entwined at different levels of resolution and whose organization spans over several levels of hierarchy. This thesis revolves around the concept of quantitative model refinement in relation to the process of model building in computational systems biology. The thesis proposes a sound computational framework for the stepwise augmentation of a biomodel. One starts with an abstract, high-level representation of a biological phenomenon, which is materialised into an initial model that is validated against a set of existing data. Consequently, the model is refined to include more details regarding its species and/or reactions. The framework is employed in the development of two models, one for the heat shock response in eukaryotes and the second for the ErbB signalling pathway. The thesis spans over several formalisms used in computational systems biology, inherently quantitative: reaction-network models, rule-based models and Petri net models, as well as a recent formalism intrinsically qualitative: reaction systems. The choice of modelling formalism is, however, determined by the nature of the question the modeler aims to answer. Quantitative model refinement turns out to be not only essential in the model development cycle, but also beneficial for the compilation of large-scale models, whose development requires the integration of several sub-models across various levels of resolution and underlying formal representations.

Edistyneen oppijan suomen konstruktiopiirteitä korpusvetoisesti: avainrakenneanalyysi

Ensikielen jälkeen opittavan kielen tutkimusta ja suomi toisena kielenä alaa sen osana ovat koko niiden olemassaolon ajan hallinneet samat peruskysymykset: millaista oppiminen on eri vaiheissa ja eri ympäristöissä, sekä mikä oppimisessa on yleistä ja toisaalta mikä riippuu opittavasta kielestä ja oppijoiden kielitaustasta. Sähköisten oppijankielen tutkimusaineistojen eli korpusten lisääntymisen myötä tutkijat voivat aiempaa helpommin tutkia näitä ilmiöitä määrällisesti ja tarkastella oppijankielen sisäistä vaihtelua ja sen suhdetta tyypilliseen ensikieliseen kielenkäyttöön kielen eri osa-alueilla käyttöpohjaisesti eli todelliseen kielenkäyttöön pohjautuen. Tekninen kehitys on tuonut mukanaan aineisto- eli korpusvetoisuuden kaltaisia uusia tapoja lähestyä tutkimusaineistoa, jolloin tyypillisiä tutkimuskysymyksiä ”Miksi?” ja ”Miten?” edeltää kysymys: ”Mikä?”. Tässä väitöskirjassa tarkastellaan edistyneiden suomenoppijoiden kirjoitettua akateemista kieltä ja suhteutetaan suomen oppimiselle ominaisia seikkoja käyttöpohjaisen mallin perusolettamuksiin. Aineisto on suomea toisena kielenä käyttävien opiskelijoiden tenttivastauksia, ja se on osa Edistyneiden suomenoppijoiden korpusta. Tutkimus on osin metodologinen, sillä väitöskirjassa esitellään ja siinä sovelletaan uutta korpusvetoista avainrakenneanalyysi-menetelmää, jonka avulla aineistoa lähestytään ilman hypoteeseja siitä, mitkä kielen ilmiöt ovat ominaisia edistyneelle oppijansuomelle. Tutkimus kuuluu kieliopin tutkimuksen piiriin, ja se nojaa kognitiivisen konstruktiokieliopin ajatukseen abstraktiudeltaan vaihtelevista konstruktioista kielijärjestelmän perusyksiköinä. Tulokset puoltavat menetelmän sovellettavuutta kielen oppimisen tutkimukseen, sillä sen avulla kyettiin tunnistamaan konstruktioita, jotka erottavat edistyneitä oppijoita ensikielisistä kirjoittajista (esim. modaaliset verbiketjut), eri ensikieliä puhuvia suomenoppijoita (esim. konjunktiot) sekä konstruktioita, joiden käyttö muuttuu ajan kuluessa (esim. preteriti ja preesens). Monet havaitut erot ovat akateemisen kirjoittamisen erityispiirteitä, mikä tukee ajatusta kielen käyttö- ja kontekstikohtaisesta oppimisesta. Tuloksia voidaan yhtäältä soveltaa akateemisen kielitaidon opetuksessa. Toisaalta menetelmää voidaan käyttää kielenoppimisen tutkimuksen ohella uusien näkökulmien kartoittamiseksi erilaisten tai eri-ikäisten tekstien tyypillisten ominaisuuksien ja erojen tutkimuksessa.

From protein structure to function with bioinformatics

It has long been known that amino acids are the building blocks for proteins and govern their folding into specific three-dimensional structures. However, the details of this process are still unknown and represent one of the main problems in structural bioinformatics, which is a highly active research area with the focus on the prediction of three-dimensional structure and its relationship to protein function. The protein structure prediction procedure encompasses several different steps from searches and analyses of sequences and structures, through sequence alignment to the creation of the structural model. Careful evaluation and analysis ultimately results in a hypothetical structure, which can be used to study biological phenomena in, for example, research at the molecular level, biotechnology and especially in drug discovery and development. In this thesis, the structures of five proteins were modeled with templatebased methods, which use proteins with known structures (templates) to model related or structurally similar proteins. The resulting models were an important asset for the interpretation and explanation of biological phenomena, such as amino acids and interaction networks that are essential for the function and/or ligand specificity of the studied proteins. The five proteins represent different case studies with their own challenges like varying template availability, which resulted in a different structure prediction process. This thesis presents the techniques and considerations, which should be taken into account in the modeling procedure to overcome limitations and produce a hypothetical and reliable three-dimensional structure. As each project shows, the reliability is highly dependent on the extensive incorporation of experimental data or known literature and, although experimental verification of in silico results is always desirable to increase the reliability, the presented projects show that also the experimental studies can greatly benefit from structural models. With the help of in silico studies, the experiments can be targeted and precisely designed, thereby saving both money and time. As the programs used in structural bioinformatics are constantly improved and the range of templates increases through structural genomics efforts, the mutual benefits between in silico and experimental studies become even more prominent. Hence, reliable models for protein three-dimensional structures achieved through careful planning and thoughtful executions are, and will continue to be, valuable and indispensable sources for structural information to be combined with functional data.