Keittiömaailman matkassa 20 vuotta : Tutkimus erään keittiökalustevalmistajan johtavan markkina-aseman rakentamisesta ja säilyttämisestä

A View into the World of Kitchen: Development and retention of a leading position in the market of kitchen interiors - a case study of 20 years. This study focuses on the development of a kitchen interiors company, presently called Novart Inc., into the leading company of the industry from 1980´s to the present. The objective of the study is to describe the effects of strategic choices, the decisions of the management and the owner´s direction and control to the build up and the retaining of the leading position in the market. From theory point of view, strategic choices refer to com-pany purchases as corporate-level strategies, and business and marketing strategies. The empirical research was carried out in two phases and it is based on various company documents and records, and on the intensive interviews of seven key executives in the company. An abductive research design was utilized. The company gained the leading position in the kitchen market in Finland by company purchases, and the company has been able to retain the position. Firstly the goal was to expand to retail market and, secondly, the company has maintained the balance of supply and demand by closing the purchased production units when needed. The simultaneous use of these two strategic goals is a kind of a new observation, and the strategy may be suitable only for market leaders. During the latter part of the research period the strategy of com-pany purchases has been abandoned and the leading position in the market has been main-tained by developing systematically business and marketing capability. In the business and marketing strategies the distribution channels and the brands have been emphasized. During the research period the company has almost totally abandoned the long distribution channels and started to use its own channels built and named after the main brands. These are A la Carte, Parma and Petra. At the moment, in the beginning of the 21st century, a new distribution channel, the concept of the Kitchen World, is being built in addition to the channels mentioned above. The management´s decision making and the implementation the decisions have been well-considered. The executives emphasized the valuing of the importance of the decisions dif-ferently except the two decisions named the most important ones, i.e., the decisions to start own production of the raw material and to concentrate the business only to one company. The executive staff has also succeeded in managing crisis and threats of bankruptcy, and the company has been managed profitable. During all the four terms of ownership: Puolimatka Corporation, the Hankkija/Novera Corporation, the ownership period of the "bank", and the Nobia Corporate the ownership direction and control has been somewhat different. All the owners have paid attention to economic issues. The direction of cash flows and investments was at its strongest during the Hankkija/Novera term. For the last owner Nobia the production and marketing of the kitchen interiors has been the core business, which thus has strengthened the business and marketing capabilities of the target company of this research. A common denominator during all the four terms of ownership has been owners' trust gained by the professional skills of the management of the target company. This has lead to greater independence of the management of the company and less owners´ direction. Keywords: leading position, marketing strategy, management decisions, acquisition, corporate governance

"Litrasev viinapulloj ja séittemätóista kalijjaa" : Diftongin reduktio ja geminaatio erään pyhäjärvisistä nuorista koostuvan ryhmän puhekielessä

Tutkielmassa tarkastellaan erään 16- ja 17-vuotiaista syntyperäisistä pyhäjärvisistä nuorista tytöistä ja pojista koostuvan sosiaalisen ryhmän puhekieltä diftongin reduktion ja geminaatioilmiöiden kautta. Geminaatioilmiöistä tarkastellaan yleisgeminaatiota ja itämurteiden erikoisgeminaatiota mutta pääpaino on itämurteiden erikoisgeminaatiossa. Tutkimuspaikkakunta Pyhäjärvi sijaitsee maantieteellisesti Pohjois-Pohjanmaalla mutta kuuluu lingvistisesti savolaismurteisiin. Tutkielman tavoitteena on selvittää, kuinka elinvoimaisia tarkasteltavaksi valitut piirteet ovat sekä kuinka paljon ja miten ne varioivat ryhmän puhekielessä. Aineistoa analysoidaan pääasiassa kvantitatiivisesti. Kvalitatiivisesti piirteiden käyttöä tarkastellaan etenkin vuorovaikutuksen mutta myös sukupuolen näkökulmasta. Tutkittavia kielenoppaita on kuusi: kolme tyttöä ja kolme poikaa. Tytöt ovat lukio- ja pojat ammattikouluopiskelijoita. Kielenoppaiden muodostama ryhmä pohjautuu yläkouluaikaisiin ystävyyssuhteisiin ja oli jo olemassa ennen aineistonkeruuta. Tutkielman aineistona on 5 tuntia ryhmän jäsenten välisiä keskusteluja: 2,5 tuntia tyttöjen keskistä keskustelua, 1,5 tuntia poikien keskustelua ja 1 tunti keskustelua, jossa kaikki ryhmän jäsenet olivat läsnä koko ryhmän kesken. Kukin keskustelu on tallennettu sekä ääni- että videonauhalle. Nauhoitukset on tehty maalis- ja toukokuussa 2010. Tutkielman kvantitatiivinen analyysi perustuu korvakuulolla tehtyihin mittauksiin ja niihin perustuviin absoluuttisiin frekvensseihin. Sekä diftongin reduktio että molemmat geminaatioilmiöt ovat ryhmän puhekielessä elinvoimaisia piirteitä, joskin diftongin reduktion kohdalla esiintyminen on labiilia. Etenkin yleisgeminaatio on ryhmän puhekielessä, myös idiolekteittain katsottuna, taajaan esiintyvä ja lähes varioimaton piirre: geminoituminen esiintyy täysgeminaattana lähes aina yleisgeminaation sallivissa konteksteissa. Geminoituminen on vahvempaa ensi- kuin jälkitavuissa. Sen sijaan sekä diftongin reduktio että itämurteiden erikoisgeminaatio varioivat ryhmän puhekielessä yleiskielisten ja eriasteisten murteellisten varianttien välillä. Suurin osa diftongeista, niin i-, u- kuin y-loppuisistakin, esiintyy yleiskielisessä muodossa ja redusoituessaan reduktion lievässä asteessa. Itämurteiden erikoisgeminaation mahdollistavissa konteksteissa yleiskielisiä variantteja on niin ikään murrevariantteja enemmän. Murrevarianttien enemmistö on täysgeminaatallisia. Tutkielmassa selviää lisäksi, että eri diftongien ja konsonanttien välillä on ryhmän puhekielessä eroja sekä piirteiden asteittaisessa että määrällisessä esiintymisessä, samoin kuin eri äänneympäristöissä esiintymisessäkin. Myös idiolektien välillä on eroja diftongin reduktion ja itämurteiden erikoisgeminaation esiintymisessä. Aineisto osoittaa, että sekä diftongin reduktion että itämurteiden erikoisgeminaation esiintymisessä on selviä leksikaalisia rajoitteita kielenoppaiden puheessa. Kun diftongi ai tai ei muodostaa lekseemin yksin (ai dialogipartikkelina ja ei kieltosanana), se on yleiskielinen. Diftongi äi puolestaan esiintyy poikkeuksellisen vahvana varianttina affektisissa yhteyksissä lekseemissä äiti. Affektisuus vaikuttaa liittyvän myös konsonanttiyhtymien lj, rp ja rv jälkikomponenttien geminoitumiseen vahvistavasti lekseemeissä kaljaa, turpaan ja hirvee. Tarkasteluun valittujen puhekielen piirteiden esiintymisessä voi havaita säännönmukaisuutta myös lauserakennetta ja kielenkäyttöä laajemmin tarkastelemalla. Referoinnin ja tarinankerronnan yhteydessä diftongin reduktion ja itämurteiden erikoisgeminaation käyttö yleistyy ja vahvistuu. Vahvistuminen on puhetilanteen ja keskusteluun osallistuvien vuorovaikutustehtävien motivoimaa. Tällöin on kyse selvästä murteella tyylittelystä. Itsekorjauksen ja liitepartikkelin -kO avulla muodostettujen kysymysten yhteydessä piirteet puolestaan esiintyvät aineistossa yleiskielisinä. Yleisgeminaatioon edellä mainitut eivät näytä vaikuttavan. Sukupuolten välillä on huomattavissa eroja tarkasteltujen kielenpiirteiden esiintymisessä ja käytössä. Tutkielma osoittaa, että pojat ovat tarkasteluun valittujen kielenpiirteiden valossa jonkin verran tyttöjä murteellisempia. Sukupuolten välisiä murteellisuuseroja voidaan selittää etenkin opiskelupaikkakunnan, koulutuksen, sosiaalisten kontaktien, kielenkäytön tapojen ja vuorovaikutustehtävien avulla. Tutkimus tarjoaa tietoa nykypuhesuomen variaatiosta kolmen puhekielen piirteen kautta. Työ jättää paljon tarkasteltavaa myös tämän tutkielman jälkeiselle tutkimukselle. Edelleen selvitettäväksi jäävät monet muut kielenpiirteet ryhmän puhekielessä. Erityisen mielenkiintoinen tutkimuskohde olisi persoonapronominien variaatio (minä ~ mä ~ mää). Luonnollinen jatke tutkielmalle olisi myös ryhmän reaaliaikainen seuraaminen valittujen kielenpiirteiden osalta.

Pour une éthique du traducteur poéticien

This doctoral thesis starts with a comprehensive introduction seeking to anchor the problematics of the ethics of the poetician translator (a translator of literary and similar texts) in a theoretical framework drawing on moral philosophy. This introductory section is followed by six published papers (four journal articles and two papers from conference proceedings), forming the main body of the thesis, which progressively develop a possible application of this theoretical framework. Starting from the acknowledgement that one of the ethical stakes in translation is constructed around the relation to the foreign and to the other , the translation process is scrutinized through the prism of the philosophies of Dialogue , focusing on how the translating actors relate to their task. The central notions around which philosophies of Dialogue are built are introduced and applied to translation. The question of intersubjective relations, addressed from a philosophical perspective, is developed with the help of the works of Martin Buber, Gabriel Marcel, Emmanuel Levinas and Paul Ric ur. The introductory section presents and explicates the thought of each of these philosophers and extracts the concepts that are then developed in the articles and conference papers collected here. Each paper concentrates on the notions of one of the philosophers referred to above and places these notions in perspective with other philosophies of Dialogue. All the papers contribute to explicating the relationship between the multiple philosophical notions that address the problematics of alterity and the condition of the translator. The work as a whole leads to the idea that the task of the poetician translator is not only to translate a text properly but above all to rouse and increase the desire of linguistic communities to live together.

Principles of Pitch Organization in Béla Bartók's 'Duke Bluebeard's Castle'

The topic of my doctoral thesis is to demonstrate the usefulness of incorporating tonal and modal elements into a pitch-web square analysis of Béla Bartók's (1881-1945) opera, 'A kékszakállú herceg vára' ('Duke Bluebeard's Castle'). My specific goal is to demonstrate that different musical materials, which exist as foreground melodies or long-term key progressions, are unified by the unordered pitch set {0,1,4}, which becomes prominent in different sections of Bartók's opera. In Bluebeard's Castle, the set {0,1,4} is also found as a subset of several tetrachords: {0,1,4,7}, {0,1,4,8}, and {0,3,4,7}. My claim is that {0,1,4} serves to link music materials between themes, between sections, and also between scenes. This study develops an analytical method, drawn from various theoretical perspectives, for conceiving superposed diatonic spaces within a hybrid pitch-space comprised of diatonic and chromatic features. The integrity of diatonic melodic lines is retained, which allows for a non-reductive understanding of diatonic superposition, without appealing to pitch centers or specifying complete diatonic collections. Through combining various theoretical insights of the Hungarian scholar Ernő Lendvai, and the American theorists Elliott Antokoletz, Paul Wilson and Allen Forte, as well as the composer himself, this study gives a detailed analysis of the opera's pitch material in a way that combines, complements, and expands upon the studies of those scholars. The analyzed pitch sets are represented on Aarre Joutsenvirta's note-web square, which adds a new aspect to the field of Bartók analysis. Keywords: Bartók, Duke Bluebeard's Castle (Op. 11), Ernő Lendvai, axis system, Elliott Antokoletz, intervallic cycles, intervallic cells, Allen Forte, set theory, interval classes, interval vectors, Aarre Joutsenvirta, pitch-web square, pitch-web analysis.

Vihanhallintaprojekti ja oikeudenkäynti : Kahden Nyt-liitteessä ja Imagessa ilmestyneen henkilöjutun lähitarkastelua kertomuksen näkökulmasta

Tutkielmassa tarkastellaan kahta aikakauslehtitekstiä eräänä tapana rakentaa henkilöjuttu. Jutut eivät ole vain kuvauksia niistä julkisuuden henkilöistä, joita ne käsittelevät, vaan ne on kirjoitettu kertomuksiksi. Työssä käydään läpi piirteitä, joiden perusteella jutut muodostavat kertomuksen. Tarkastelun kohteena ovat juttujen rakenteet ja juttujen toimijoiden (kertoja-toimittajan, haastateltavan ja lukija-yleisön) roolit ja suhteet. Tavoitteena on selvittää, millaisia merkityksiä juttuihin syntyy sen avulla, että ne on rakennettu kertomuksiksi. Analyysin kohteena olevat henkilöjutut ovat Vihanhallintaprojekti Tuisku (Nyt-liite 49/2006) ja Syytettynä Heli Laaksonen (Image 4/2006). Keskeinen taustateoria on narratologia eli kertomuksen tutkimus. Työssä hyödynnetään myös tekstin tutkimuksen, kognitiivisen kielitieteen ja dialogisuuden tutkimuksen tarjoamia välineitä. Työssä osoitetaan, että henkilöjutut on rakennettu kertomuksiksi ongelmanratkaisumallin avulla. Juttujen aluissa kertoja-toimittaja ilmaisee inhoavansa haastateltavaa, mikä muodostaa ongelman, jota ratkotaan muun muassa haastateltavan tapaamisella ja tämän esiintymistilaisuuteen osallistumalla. Juttuihin muodostuu episodeja, joissa ongelmaa käsitellään eri tavoin. Lopulta saavutetaan ratkaisu, koska kertoja-toimittaja pääsee vihastaan eroon. Ongelmanratkaisumalli tuo juttuihin jännitystä, koska ne etenevät vähitellen kohti ratkaisua. Kertoja-toimittaja rakentaa kertomuksen vaihtelemalla erilaisia rooleja. Roolit ovat henkilöhahmo, ajattelija, havainnoija, ulkopuolinen kertoja ja lainaaja. Roolien avulla kertoja-toimittaja asettaa näyttämölle huomion kohteeksi joko itsensä, haastateltavan, haastattelutilanteen olosuhteet tai jonkin tekstin ulkopuolisen seikan. Roolit vaikuttavat myös näkökulmaan, josta asioita tarkastellaan. Tiettyjä rooleja ilmaisevat tyypillisesti tietyt kielelliset keinot. Roolien vaihtelu synnyttää juttuihin keskusteluja, joissa kertoja-toimittaja, haastateltava ja lukija-yleisö ovat vuorovaikutuksessa keskenään. Nämä keskustelut jäsentävät toimijoiden rooleja ja suhteita. Keskusteluissa muovataan kertoja-toimittajan mielipiteitä haastateltavasta, konstruoidaan lukija-yleisölle useita rooleja ja vaikutetaan haastateltavalle rakentuvan roolin itsenäisyyteen. Tutkimuksessa päädytään siihen, että henkilöjutut rikkovat tietoisesti perinteisen henkilöjutun konventiota rakentamalla kertomuksen, jolla on kaksi päähenkilöä, kertoja-toimittaja ja haastateltava. Päähenkilöiden välisen suhteen voi tulkita kahdella tavalla. Jutut voivat ensinnäkin olla kertoja-toimittajan aitoja kertomuksia hänen haastateltavaan kohdistuvista negatiivisista tunteistaan. Toiseksi on mahdollista tulkita, että kertoja-toimittaja ironisoi jutuissa itseään ja ahdasmielisyyttään. Jutut ovat tyyliltään liioittelevia, mikä vahvistaa ironista tuntua. Kahdella tulkintatavalla teksteihin rakennetaan moniäänisyyttä, jotta ne tavoittaisivat erilaisia yleisöjä.

Kaveriporukasta liiketoiminnaksi : Tuotannon häiriöt ja organisaation oppiminen nopeasti muuttuvassa yrityksessä

In the 1990 s the companies utilizing and producing new information technology, especially so-called new media, were also expected to be forerunners in new forms of work and organization. Researchers anticipated that new, more creative forms of work and the changing content of working life were about to replace old industrial and standardized ways of working. However, research on actual companies in the IT sector revealed a situation where only minor changes to existing organizational forms were seen .Many of the independent companies faced great difficulties trying to survive the rapid changes in the products and production forms in the emerging field. Most of the research on the new media field has been conducted as surveys, and an understanding of the actual everyday work process has remained thin. My research is a longitudinal study of the early phases of one new media company in Finland. The study is an analysis of the challenges the company faced in a rapidly changing business field and the attempts to overcome these challenges. The two main analyses in the study focus on the developmental phases of the company and the disturbances in the production process. Based on these analyses, I study changes and learning at work using the methodological framework of developmental work research. Developmental work research is a Finnish variant of the cultural-historical activity theory applied to the study of learning and transformations at work. The data was gathered over a three-year period of ethnographic fieldwork. I documented the production processes and everyday life in the company as a participant observer. I interviewed key persons, video and audio-taped meetings, followed e-mail correspondence and collected various documents, such as agreements and memos. I developed a systematic method for analyzing the disturbances in the production process by combining the various data sources. The systematic analysis of the disturbances depicted a very complex and only partly managed production process. The production process had a long duration, and no single actor had an understanding of it as a whole. Most of the disturbances had to do with the customer relationships. The nature of the disturbances was latent; they were recognized but not addressed. In the particular production processes that I analyzed, the ending life span of a particular product, a CD-ROM, became obvious. This finding can be interpreted in relation to the developmental phase of the production and the transformation of the field as a whole. Based on the analysis of the developmental phases and the disturbances, I formulate a hypothesis of the contradictions and developmental potentials of the activity studied. The conclusions of the study challenge the existing understanding of how to conceptualize and study organizational learning in production work. Most theories of organizational learning do not address qualitative changes in production nor historical challenges of organizational learning itself. My study opens up a new horizon in understanding organizational learning in a rapidly changing field where a learning culture based on craft or mass production work is insufficient. There is a need for anticipatory and proactive organizational learning. Proactive learning is needed to anticipate the changes in production type, and the life cycles of products.

Koulu muistoissa : Tulevat opettajat muistelevat kouluaikaansa

Tutkielmassa tarkasteltiin opettajaksi opiskelevien koulumuistoja ja niissä esiintyviä positiivisia ja negatiivisia kokemuksia koulusta, oppimisesta ja opettajasta. Tutkimusmetodiksi valittiin koulumuistoista kirjoittaminen tarkoituksena helpottaa sekä kokemusten tuomista tietoisuuteen että niiden myöhempää käsittelyä kirjallisina dokumentteina. Opiskelijoita pyydettiin kirjoittamaan erään yhteisen luennon alussa parhaasta ja huonoimmasta koulumuistostaan. Tutkimuksen tarkoituksena oli kartoittaa opiskelijoiden muistoja koulusta. Tutkimuksen avulla pyrittiin myös osittain selittämään kokemuksien yhteyksiä toisiinsa. Tutkimusongelmina esitettiin seuraavat kysymykset: minkälaisia muistoja koulusta tulee ensimmäisenä mieleen, miten opettajan merkitys näkyy kyseisissä muistoissa, minkälaisen kuvan opiskelijoiden muistot antavat koulusta, ja miten muistoissa kuvatut koulukokemukset ovat mahdollisesti vaikuttaneet opiskelijoiden myöhempään elämään. Tutkimusjoukko koostui 101:stä Helsingin yliopiston opettajankoulutuslaitoksen ensimmäisen vuoden opiskelijasta, lastentarhanopettajan, luokanopettajan, kotitalousopettajan sekä käsityöopettajan koulutuslinjoilta. Koulumuistot sijoittuivat pääasiassa peruskouluaikaan, sillä opiskelijoista suurin osa oli alle 25-vuotiaita. Opiskelijoiden kirjoittamat muistot analysoitiin ja tulkittiin kvalitatiivisen tutkimusotteen mukaisesti. Analysointiluokkien muodostamiseen saatiin malli kahdesta aikaisemmasta tutkimuksesta. Ruotsalaisen Pérez Prieton koulukokemustutkimus ja amerikkalaisen Johnson Rothenbergin tutkimus opiskelijoiden koulumuistoista toimivat tämän tutkimuksen tärkeimpinä lähteinä teoriataustassa. Tutkimustulosten mukaan yli puolet opiskelijoiden koulumuistoista liittyi opettajaan. Opettajanvaikutus oli merkittävin negatiivisten muistojen kohdalla ja suurin osa maininnoista esiintyi nöyryytyskokemusten yhteydessä. Nöyryyttävinä koettiin tilanteet, joissa opettaja oli rankaissut julkisesti tai toiminut oppilaan oikeuksia vastaan. Positiivisissa muistoissa opettaja esiintyi noin viidesosassa maininnoista, pääasiassa menestymiskokemusten ja haastavuuden yhteydessä. Menestymiskokemukset,joihin liittyi yleensä itsensä toteuttamisen mahdollisuus, muodostivat suurimman parhaiden koulumuistojen luokan. Myös kaverit ja koulun ilmapiiri olivat merkittäviä tekijöitä niin hyvien kuin huonojenkin kokemusten kohdalla. Muita analysointiluokkia edellisten lisäksi olivat epäonnistuminen, turhautuminen, arvostelu, koulunvaihto ja rehtori. Teoreettisessa viitekehyksessä selvitettiin kokemuksen käsitettä ja sen soveltuvuutta tutkimuksen kohteeksi. Tärkeitä lähteitä tutkimuksen kokemuksellisen luonteen kannalta olivat Deweyn ja Jarvisin teokset, joissa käsiteltiin kokemuksen merkitystä kasvatukselle ja oppimiselle sekä reflektion vaikutusta kokemuksen merkittävyydelle. Lisäksi tarkasteltiin tutkimuksia koulukokemusten merkittävyydestä opettajaopiskelijoille ja opettajan merkityksestä oppilaalle tärkeänä aikuisena. Avainsanat: Koulumuistot, kokemusten tulkinta, opettajaopiskelijat, opettaja merkittävänä henkilönä Keywords: School Memories, Interpretation of Experiences, Future Teachers, Teacher as a Significant Person

Koulutuksellisen syrjäytymisriskin ennustettavuus yhteishakuvalintojen kautta tarkasteltuna : koulupudokkuusriskin yhteys oppilaan kognitiiviseen kompetenssiin, koulumenestykseen sekä itseä ja vanhempia koskeviin uskomuksiin

The objective of this study was to find factors that could predict educational dropout. Dropout risk was assessed against pupil’s cognitive competence, success in school, and personal beliefs regarding self and parents, while taking into account the pupil’s background and gender. Based on earlier research, an assumption was made that a pupil’s gender, success in school, and parent’s education would be related with dropping out. This study is part of a project funded by the Academy of Finland and led by Professor Jarkko Hautamäki. The project aims to use longitudinal study to assess the development of pupils’ skills in learning to learn. The target group of this study consisted all Finnish speaking ninth graders of a municipality in Southern Finland. There were in total 1534 pupils, of which 809 were girls and 725 boys. The assessment of learning to learn skills was performed about ninth graders in spring 2004. “Opiopi” test material was used in the assessment, consisting of cognitive tests and questions measuring beliefs. At the same time, pupils’ background information was collected together with their self-reported average grade of all school subjects. During spring 2009, the pupils’ joint application data from years 2004 and 2005 was collected from the Finnish joint application registers. The data were analyzed using quantitative methods assisted by the SPSS for Windows computer software. Analysis was conducted through statistical indices, differences in grade averages, multilevel model, multivariate analysis of variance, and logistic regression analysis. Based on earlier research, dropouts were defined as pupils that had not been admitted to or had not applied to second degree education under the joint application system. Using this definition, 157 students in the target group were classified as dropouts (10 % of the target group): 88 girls and 69 boys. The study showed that the school does not affect the drop-out risk but the school class explains 7,5 % of variation in dropout risk. Among girls, dropping out is predicted by a poor average grade, a lack of beliefs supporting learning, and an unrealistic primary choice in joint application system compared to one’s success in school. Among boys, a poor average grade, unrealistic choices in joint application system, and the belief of parent’s low appreciation of education were related to dropout risk. Keywords educational exclusion, school dropout, success in school, comprehensive school, learning to learn

Androgen receptor-dependent and independent functions of ARIP4

Androgen receptor (AR) is necessary for normal male phenotype development and essential for spermatogenesis. AR is a classical steroid receptor mediating actions of male sex steroids testosterone and 5-alpha-dihydrotestosterone. Numerous coregulators interact with the receptor and regulate AR activity on target genes. This study deals with the characterization of androgen receptor-interacting protein 4 (ARIP4). ARIP4 binds DNA, interacts with AR in vitro and in cultured yeast and mammalian cells, and modulates AR-dependent transactivation. ARIP4 is an active DNA-dependent ATPase, and this enzymatic activity is essential for the ability of ARIP4 to modulate AR function. On the basis of sequence homology in its ATPase domain, ARIP4 belongs to the SNF2 family of proteins involved in chromatin remodeling, DNA repair, and homologous recombination. Similar to its closest homologs ATRX and Rad54, ARIP4 does not seem to be a classical chromatin remodeling protein in that it does not appear to form large protein complexes in vivo or remodel mononucleosomes in vitro. However, ARIP4 is able to generate superhelical torsion on linear DNA fragments. ARIP4 is covalently modified by SUMO-1, and mutation of six potential SUMO attachment sites abolishes the ability of ARIP4 to bind DNA, hydrolyze ATP, and activate AR function. ARIP4 expression starts in early embryonic development. In mouse embryo ARIP4 is present mainly in the neural tube and limb buds. In adult mouse tissues ARIP4 expression is virtually ubiquitous. In mouse testis ARIP4 is expressed in the nuclei of Sertoli cells in a stage-dependent manner. ARIP4 is also present in the nuclei of Leydig cells, spermatogonia, pachytene and diplotene spermatocytes. Testicular expression pattern of ARIP4 does not differ significantly in wild-type, FSHRKO, and LuRKO mice. In the testis of hpg mice, ARIP4 is found mainly in interstitial cells and has very low, if any, expression in Sertoli and germ cells. Heterozygous Arip4+/ mice are fertile and appear normal; however, they are haploinsufficient with regard to androgen action in Sertoli cells. In contrast, Arip4 / embryos are not viable. They have significantly reduced body size at E9.5 and die by E11.5. Compared to wild-type littermates, Arip4 / embryos possess a higher percentage of apoptotic cells at E9.5 and E10.5. Fibroblasts derived from Arip4 / embryos cease growing after 2-3 passages and exhibit a significantly increased apoptosis and decreased proliferation rate than cells from wild-type embryos. Our findings demonstrate that ARIP4 plays an essential role in mouse embryonic development. In addition, testicular expression and AR coregulatory activity of ARIP4 suggest a role of ARIP4-AR interaction in the somatic cells of the testis.

Novel Multiple Sclerosis Predisposing Genetic Variants Outside the HLA Region

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Both environmental factors and several predisposing genes are required to generate MS. Despite intensive research these risk factors are still largely unknown, the pathogenesis of MS demyelination is poorly understood, and no curative treatment exists. Both prevalence and familial occurrence of MS are exceptionally high in a Finnish population subisolate, Southern Ostrobothnia, presumably due to enrichment of predisposing genetic variants within this region. Previous linkage scan on MS pedigrees from Southern Ostrobothnia detected three main MS loci on chromosomes 5p, 6p (HLA) and 17q. Linkage studies in other populations have also provided independent evidence for the location of MS susceptibility genes in these regions. Further, these loci are syntenic to the experimental autoimmune encephalomyelitis (EAE) susceptibility loci of rodents. In this thesis work an effort was made to localize MS predisposing alleles of the linked loci outside the HLA region by studying familial MS cases from the Southern Ostrobothnia isolate. Analysis of the 5p locus revealed one region, flanking the complement component 7 (C7) gene. The identified relatively rare haplotype seems to have a fairly large effect on genetic susceptibility of MS (frequency MS 12%, controls 4%; p=0.000003, OR=2.73). Evidence for association with alleles of the region and MS was seen also in more heterogeneous populations. Convincingly, plasma C7 protein levels and complement activity correlated with the risk haplotype identified. The finding stimulated us to study other complement cascade genes in MS. No evidence for association could be observed with the complement component coding genes outside 5p. A scan of the 17q locus provided evidence for association with variants of the protein kinase C alpha (PRKCA) gene (p=0.0001). Modest evidence for association with PRKCA was observed also in Canadian MS families. Finally we used a candidate gene based approach to identify potential MS loci. Mutations of DAP12 and TREM2 cause a recessively inherited CNS white matter disease PLOSL. Interestingly, DAP12 and TREM2 are located in MS regions on 6p and 19q, and we tested them as potential candidate genes in the Finnish MS sample. No evidence for association with MS was observed. This thesis provides an example of how extended families from special populations can be utilized in fine-mapping of the linked loci. A first relatively rare MS variant was identified utilizing the strength of a Finnish population subisolate. This variant seems to have an effect on activity of the complement system, which has previously been suggested to have an important role in the pathogenesis of MS.

Fumarate Hydratase and Succinate Dehydrogenase in Neoplasia

Germline mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell cancer (HLRCC). FH is a nuclear encoded enzyme which functions in the Krebs tricarboxylic acid cycle, and homozygous mutation in FH lead to severe developmental defects. Both uterine and cutaneous leiomyomas are components of the HLRCC phenotype. Most of these tumours show loss of the wild-type allele and, also, the mutations reduce FH enzyme activity, which indicate that FH is a tumour suppressor gene. The renal cell cancers associated with HLRCC are of rare papillary type 2 histology. Other genes involved in the Krebs cycle, which are also implicated in neoplasia are 3 of the 4 subunits encoding succinate dehydrogenase (SDH); mutations in SHDB, SDHC, and SDHD predispose to paraganglioma and phaeochromocytoma. Although uterine leiomyomas (or fibroids) are very common, the estimations of affected women ranging from 25% to 77%, not much is known about their genetic background. Cytogenetic studies have revealed that rearrangements involving chromosomes 6, 7, 12 and 14 are most commonly seen in fibroids. Deletions on the long arm of chromosome 7 have been reported to be involved in about 17 to 34 % of leiomyomas and the small commonly deleted region on 7q22 suggests that there might be an underlying tumour suppressor gene in that region. The purpose of this study was to investigate the genetic mechanisms behind the development of tumours associated with HLRCC, both renal cell cancer and uterine fibroids. Firstly, a database search at the Finnish cancer registry was conducted in order to identify new families with early-onset RCC and to test if the family history was compatible with HLRCC. Secondly, sporadic uterine fibroids were tested for deletions on 7q in order to define the minimal deleted 7q-region, followed by mutation analysis of the candidate genes. Thirdly, oligonucleotide chips were utilised to study the global gene expression profiles of uterine fibroids in order to test whether 7q-deletions and FH mutations significantly affected fibroid biology. In the screen for early-onset RCC, 214 families were identified. Subsequently, the pedigrees were constructed and clinical data obtained. One of the index cases (RCC at the age of 28) had a mother who had been diagnosed with a heart tumour, which in further investigation turned out to be a paraganglioma. This lead to an alternative hypothesis that SDH, instead of FH, could be involved. SDHA, SDHB, SDHC and SDHD were sequenced from these individuals; a germline SDHB R27X mutation was detected with loss of the wild-type allele in both tumours. These results suggest that germline mutations in the SDHB gene predispose to early-onset RCC establishing a novel form of hereditary RCC. This has immediate clinical implications in the surveillance of patients suffering from early-onset RCC and phaeochromocytoma/paraganglioma. For the studies on sporadic uterine fibroids, a set of 166 fibroids from 51 individuals were collected. The 7q LOH mapping defined a commonly deleted region of about 3.2 mega bases in 11 of the 166 tumours. The deletion was consistent with previously reported allelotyping studies of leiomyomas and it therefore suggested the presence of a tumour suppressor gene in the deleted region. Furthermore, the high-resolution aCGH-chip analysis refined the deleted region to only 2.79Mb. When combined with previous data, the commonly deleted region was only 2.3Mb. The mutation screening of the known genes within the commonly deleted region did not reveal pathogenic mutations, however. The expression microarray analysis revealed that FH-deficient fibroids, both sporadic and familial, had their distinct gene expression profile as they formed their own group in the unsupervised clustering. On the other hand, the presence or absence of 7q-deletions did not significantly alter the global gene expression pattern of fibroids, suggesting that these two groups do not have different biological backgrounds. Multiple differentially expressed genes were identified between FH wild-type and FH-mutant fibroids, and the most significant increase was seen in the expression of carbohydrate metabolism-related and hypoxia inducible factor (HIF) target genes.

Studies of the genetic epidemiology of cardiovascular disease: focus on inflammatory candidate genes

Cardiovascular disease (CVD) is a complex disease with multifactorial aetiology. Both genetic and environmental factors contribute to the disease risk. The lifetime risk for CVD differs markedly between men and women, men being at increased risk. Inflammatory reaction contributes to the development of the disease by promoting atherosclerosis in artery walls. In the first part of this thesis, we identified several inflammatory related CVD risk factors associating with the amount of DNA from whole blood samples, indicating a potential source of bias if a genetic study selects the participants based on the available amount of DNA. In the following studies, this observation was taken into account by applying whole genome amplification to samples otherwise subjected to exclusion due to very low DNA yield. We continued by investigating the contribution of inflammatory genes to the risk for CVD separately in men and women, and looked for sex-genotype interaction. In the second part, we explored a new candidate gene and its role in the risk for CVD. Selenoprotein S (SEPS1) is a membrane protein residing in the endoplasmic reticulum where it participates in retro-translocation of unfolded proteins to cytosolic protein degradation. Previous studies have indicated that SEPS1 protects cells from oxidative stress and that variations in the gene are associated with circulating levels of inflammatory cytokines. In our study, we identified two variants in the SEPS1 gene, which associated with coronary heart disease and ischemic stroke in women. This is, to our knowledge, the first study suggesting a role of SEPS1 in the risk for CVD after extensively examining the variation within the gene region. In the third part of this thesis, we focused on a set of seven genes (angiotensin converting enzyme, angiotensin II receptor type I, C-reactive protein (CRP), and fibrinogen alpha-, beta-, and gamma-chains (FGA, FGB, FGG)) related to inflammatory cytokine interleukin 6 (IL6) and their association with the risk for CVD. We identified one variant in the IL6 gene conferring risk for CVD in men and a variant pair from IL6 and FGA genes associated with decreased risk. Moreover, we identified and confirmed an association between a rare variant in the CRP gene and lower CRP levels, and found two variants in the FGA and FGG genes associating with fibrinogen. The results from this third study suggest a role for the interleukin 6 pathway genes in the pathogenesis of CVD and warrant further studies in other populations. In addition to the IL6 -related genes, we describe in this thesis several sex-specific associations in other genes included in this study. The majority of the findings were evident only in women encouraging other studies of cardiovascular disease to include and analyse women separately from men.

Molecular Biomonitoring during Rhizoremediation of Oil-Contaminated Soil

Rhizoremediation is the use of microbial populations present in the rhizosphere of plants for environmental cleanup. The idea of this work was that bacteria living in the rhizosphere of a nitrogen-fixing leguminous plant, goat's rue (Galega orientalis), could take part in the degradation of harmful monoaromatic hydrocarbons, such as benzene, toluene and xylene (BTEX), from oil-contaminated soils. In addition to chemical (e.g. pollutant concentration) and physical (e.g. soil structure) information, the knowledge of biological aspects (e.g. bacteria and their catabolic genes) is essential when developing the rhizoremediation into controlled and effective bioremediation practice. Therefore, the need for reliable biomonitoring methods is obvious. The main aims of this thesis were to evaluate the symbiotic G. orientalis - Rhizobium galegae system for rhizoremediation of oil-contaminated soils, to develop molecular methods for biomonitoring, and to apply these methods for studying the microbiology of rhizoremediation. In vitro, Galega plants and rhizobia remained viable in m-toluate concentrations up to 3000 mg/l. Plant growth and nodulation were inhibited in 500 mg/l m-toluate, but were restored when plants were transferred to clean medium. In the greenhouse, Galega showed good growth, nodulation and nitrogen fixation, and developed a strong rhizosphere in soils contaminated with oil or spiked with 2000 mg/l m-toluate. The high aromatic tolerance of R. galegae and the viability of Galega plants in oil-polluted soils proved this legume system to be a promising method for the rhizoremediation of oil-contaminated soils. Molecular biomonitoring methods were designed and/or developed further for bacteria and their degradation genes. A combination of genomic fingerprinting ((GTG)5-PCR), taxonomic ribotyping of 16S rRNA genes and partial 16S rRNA gene sequencing were chosen for molecular grouping of culturable, heterogeneous rhizosphere bacteria. PCR primers specific for the xylE gene were designed for TOL plasmid detection. Amplified enzyme-coding DNA restriction analysis (AEDRA) with AluI was used to profile both TOL plasmids (xylE primers) and, in general, aromatics-degrading plasmids (C230 primers). The sensitivity of the direct monitoring of TOL plasmids in soil was enhanced by nested C23O-xylE-PCR. Rhizosphere bacteria were isolated from the greenhouse and field lysimeter experiments. High genetic diversity was observed among the 50 isolated, m-toluate tolerating rhizosphere bacteria in the form of five major lineages of the Bacteria domain. Gram-positive Rhodococcus, Bacillus and Arthrobacter and gram-negative Pseudomonas were the most abundant genera. The inoculum Pseudomonas putida PaW85/pWW0 was not found in the rhizosphere samples. Even if there were no ecological niches available for the bioaugmentation bacterium itself, its conjugative catabolic plasmid might have had some additional value for other bacterial species and thus, for rhizoremediation. Only 10 to 20% of the isolated, m-toluate tolerating bacterial strains were also able to degrade m-toluate. TOL plasmids were a major group of catabolic plasmids among these bacteria. The ability to degrade m-toluate by using enzymes encoded by a TOL plasmid was detected only in species of the genus Pseudomonas, and the best m-toluate degraders were these Pseudomonas species. Strain-specific differences in degradation abilities were found for P.oryzihabitans and P. migulae: some of these strains harbored a TOL plasmid - a new finding observed in this work, indicating putative horizontal plasmid transfer in the rhizosphere. One P. oryzihabitans strain harbored the pWW0 plasmid that had probably conjugated from the bioaugmentation Pseudomonas. Some P. migulae and P. oryzihabitans strains seemed to harbor both the pWW0- and the pDK1-type TOL plasmid. Alternatively, they might have harbored a TOL plasmid with both the pWW0- and the pDK1-type xylE gene. The breakdown of m-toluate by gram-negative bacteria was not restricted to the TOL pathway. Also some gram-positive Rhodococcus erythropolis and Arthrobacter aurescens strains were able to degrade m-toluate in the absence of a TOL plasmid. Three aspects of the rhizosphere effect of G. orientalis were manifested in oil-contaminated soil in the field: 1) G. orientalis and Pseudomonas bioaugmentation increased the amount of rhizosphere bacteria. G. orientalis especially together with Pseudomonas bioaugmentation increased the numbers of m-toluate utilizing and catechol positive bacteria indicating an increase in degradation potential. 2) Also the bacterial diversity, when measured as the amount of ribotypes, was increased in the Galega rhizosphere with or without Pseudomonas bioaugmentation. However, the diversity of m-toluate utilizing bacteria did not significantly increase. At the community level, by using the 16S rRNA gene PCR-DGGE method, the highest diversity of species was also observed in vegetated soils compared with non-vegetated soils. Diversified communities may best guarantee the overall success in rhizoremediation by offering various genetic machineries for catabolic processes. 3) At the end of the experiment, no TOL plasmid could be detected by direct DNA analysis in soil treated with both G. orientalis and Pseudomonas. The detection limit for TOL plasmids was encountered indicating decreased amount of degradation plasmids and thus, the success of rhizoremediation. The use of G. orientalis for rhizoremediation is unique. In this thesis new information was obtained about the rhizosphere effect of Galega orientalis in BTEX contaminated soils. The molecular biomonitoring methods can be applied for several purposes within environmental biotechnology, such as for evaluating the intrinsic biodegradation potential, monitoring the enhanced bioremediation, and estimating the success of bioremediation. Environmental protection by using nature's own resources and thus, acting according to the principle of sustainable development, would be both economically and environmentally beneficial for society. Keywords: molecular biomonitoring, genetic fingerprinting, soil bacteria, bacterial diversity, TOL plasmid, catabolic genes, horizontal gene transfer, rhizoremediation, rhizosphere effect, Galega orientalis, aerobic biodegradation, petroleum hydrocarbons, BTEX