On the functional ordering of biomembranes : Implications for drug binding

Cells are packed with membrane structures, defining the inside and outside, and the different subcellular compartments. These membranes consisting mainly of phospholipids have a variety of functions in addition to providing a permeability barrier for various compounds. These functions involve cellular signaling, where lipids can act as second messengers, or direct regulation of membrane associating proteins. The first part of this study focuses on relating some of the physicochemical properties of membrane lipids to the association of drug compounds to membranes. A fluorescence based method is described allowing for determination of the membrane association of drugs. This method was subsequently applied to a novel drug, siramesine, previously shown to have anti-cancer activity. Siramesine was found to associate with anionic lipids. Especially interesting is its strong affinity for a second messenger lipid phosphatidic acid. This is the first example of a small molecule drug compound specifically interacting with a cellular lipid. Phosphatidic acid in cells is required for the activation of many signaling pathways mediating growth and proliferation. This provides an intriguing possibility for a simple molecular mechanism of the observed anti-cancer activity of siramesine. In the second part the thermal behavior and self assembly of charged and uncharged membrane assemblies was studied. Strong inter-lamellar co-operativity was observed for multilamellar DPPC vesicles using fluorescence techniques together with calorimetry. The commonly used membrane models, large unilamellar vesicles (LUV) and multilamellar vesicles (MLV) were found to possess different biophysical properties as interlamellar interactions of MLVs drive segregation of a pyrene labeled lipid analogue into clusters. The effect of a counter-ion lattice on the self assembly of a cationic gemini surfactant was studied. The presence of NaCl strongly influenced the thermal phase behavior of M-1 vesicles, causing formation of giant vesicles upon exceeding a phase transition temperature, followed by a subsequent transition into a more homogenous dispersion. Understanding the underlying biophysical aspects of cellular membranes is of fundamental importance as the complex picture of the structure and function of cells is evolving. Many of the cellular reactions take place on membranes and membranes are known to regulate the activity of many peripheral and intergral membrane associating proteins. From the point of view of drug design and gene technology, membranes can provide an interesting target for future development of drugs, but also a vehicle sensitive for environmental changes allowing for encapsulating drugs and targeting them to the desired site of action.

Dracocephalum moldavica L. and Melissa officinalis L. : Chemistry and Bioactivities Relevant in Alzheimer’s Disease Therapy

Oksidatiivisen stressin eli liiallisen reaktiivisten happiyhdisteiden määrän soluissa on jo pitkään arveltu olevan tärkeä Alzheimerin taudin kehittymiseen ja etenemiseen vaikuttava tekijä. Tämän vuoksi kiinnostus erilaisten antioksidanttien (yhdisteitä, jotka neutraloivat näitä happiradikaaleja soluissa) mahdollisia terapeuttisia ominaisuuksia Alzheimerin taudin hoidossa on tutkittu laajalti. Tähän mennessä ei kuitenkaan ole vielä onnistuttu löytämään antioksidanttia, joka olisi hyödyksi Alzheimerin taudin hoidossa. Tämän vuoksi on tärkeää pyrkiä löytämään uusia antioksidanttien lähteitä sekä tutkia niistä löytyviä aktiivisia yhdisteitä. Kiinnostus luonnon antioksidantteja kohtaan on kasvanut voimakkaasti viime aikoina. Huomio on kiinnittynyt erityisesti aromaattisista sekä lääkekasveista löytyviin antioksidantteihin. Lamiaceae- perheeseen kuuluvia tuoksuampiaisyrttiä (Dracocephalum moldavica L.) ja sitruunamelissaa (Melissa officinalis L.) on käytetty Iranissa pitkään sekä ruoanlaitossa että lääkinnässä, minkä vuoksi näiden kasvien uutteiden antioksidanttisisältöä päätettiin analysoida käyttäen useaa erilaista in vitro- menetelmää. Näissä kokeissa ilmeni, että uutteilla oli useita antioksidanttisia vaikutuksia. Näistä antioksidanttisista vaikutuksista vastaavia yhdisteitä pyrittiin tunnistamaan käyttäen HPLC-PDA- tekniikkaa, minkä seurauksena niiden havaittiin sisältävän erilaisia polyfenoleita, kuten hydroksyloituneita bentsoeeni- ja cinnamamidihapon johdannaisia sekä flavonoideja. Kummankin kasvin uutteissa runsaimmin esiintynyt yhdiste oli rosmariinihappo. Sitruunamelissaa (M. officinalis) on käytetty antiikin ajoista alkaen kognitiivisten toimintojen häiriöiden hoidossa. Perustuen tietoon kasvin käytöstä perinteisessä lääkinnässä, sen tehoa Alzheimerin taudin hoidossa on tutkittu viime aikoina kliinisin kokein. Sitruunamelissan todettiinkin olevan hyödyksi lievää ja keskivaikeaa Alzheimeimerin tautia sairastavien potilaiden hoidossa. Väitöskirjan osanan olevasta kooste-artikkelista käy ilmi, että tutkimalla lääkekasvien ominaisuuksia voidaan saada arvokkaita suuntaa-antavia vihjeitä Alzheimerin taudin lääkehoidon kehittämiseen. Tämän perusteella päätettiinkin testatata myös sitruunamelissauutteen kykyä estää asetyylikoliiniesteraasin (AChE) toimintaa, koska tämän entsyymin toiminna estämisen tiedetään olevan hyödyksi Alzheimerin taudin hoidossa. Uute kykeni estämään AChE:n toimintaa, minkä vuoksi uutteen sisältämiä komponentteja päätettiin tutkia terkemmin. Uute jaettiin erilaisiin fraktioihin käyttäen HPLC-menetelmää, minkä jälkeen testattiin jokaisen fraktion kykyä inhiboida AchE. Suurin osa fraktioista kykeni inhiboimaan AChE:n toimintaa selkeästi tehokkaammin, kuin raakauute. Kaikista tehokkainta fraktiota analysoitiin tarkemmin sen aktiivisten yhdisteiden tunnistamiseksi, minkä seurauksena sen sisältämät yhdisteet tunnistettiin cis ja trans-rosmariinihapoiksi. Tässä tutkimuksessa tunnistettujen yhdisteiden hyödyllisyyttä Alzheimerin taudin hoidossa tulisi seuraavaksi tutkia erilaisissa in vivo-malleissa. Lisäksi jäljellä olevien fraktioiden kemiallinen koostumus tulisi selvittää sekä antioksidanttiaktiivisuuden ja AChE:n toiminnan inhiboinnin välistä mahdollista yhteyttä tulisi tutkia tarkemmin. Tämä tutkimus osoittaa tuoksuampiasyrtin (D. moldavica) sekä sitruunamelissan (M. officinalis) sisältävän monenlaisia aktiivisia antioksidantteja. Lisäksi sitruunamelissan sisältämät yhdisteet kykenivät estämään asetyylikoliiniesteraasin (AchE) toimintaa. Nämä tulokset tukevat osaltaan väitöskirjan osana olevan kooste-artikkelin johtopäätöksiä, joiden mukaan etnofarmakologinen kasvitutkimus voi osoittautua erittäin hyödylliseksi kehitettäessä uutta lääkehoitoa Alzheimerin tautiin. Lisäksi tässä väitöskirjassa kuvattu tutkimus osoittaakin, että perinteisesti lääkekasvina käytettyä sitruunamelissaa voidaan mahdollisesti hyödyntää uusien Alzheimerin taudin hoitoon käytettävien lääkkeiden kehityksessä.

The non-literary Latin letters. A study of their syntax and pragmatics

This dissertation studies the language of Latin letters that were written in Egypt and Vindolanda (in northern Britain) during the period 1st century BC 3rd century AD on papyri, ostraca, and wooden tablets. The majority of the texts is, in one way or another, connected with the Roman army. The focus of the study is on syntax and pragmatics. Besides traditional philological methods, modern syntactic theory is used as well, especially in the pragmatic analysis. The study begins with a critical survey of certain concepts that are current in the research on the Latin language, most importantly the concept of vulgar Latin , which, it is argued, seems to be used as an abstract noun for variation and change in Latin . Further, it is necessary to treat even the non-literary material primarily as written texts and not as straightforward reflections of spoken language. An examination of letter phraseology shows that there is considerable variation between the two major geographical areas of provenance. Latin letter writing in Egypt was influenced by Greek. The study highlights the importance of seeing the letters as a text type, with recurring phraseological elements appearing in the body text as well. It is argued that recognising these elements is essential for the correct analysis of the syntax. Three areas of syntax are discussed in detail: sentence connection (mainly parataxis), syntactically incoherent structures and word order (the order of the object and the verb). For certain types of sentence connection we may plausibly posit an origin in spoken Latin, but for many other linguistic phenomena attested in this material the issue of spoken Latin is anything but simple. Concerning the study of historical syntax, the letters offer information about the changing status of the accusative case. Incoherent structures may reflect contaminations in spoken language but usually the reason for them is the inability of the writer to put his thoughts into writing, especially when there is something more complicated to be expressed. Many incoherent expressions reflect the need to start the predication with a thematic constituent. Latin word order is seen as resulting from an interaction of syntactic and pragmatic factors. The preference for an order where the topic is placed sentence-initially can be seen in word order more generally as well. Furthermore, there appears a difference between Egypt and Vindolanda. The letters from Vindolanda show the order O(bject) V(erb) clearly more often than the letters from Egypt. Interestingly, this difference correlates with another, namely the use of the anaphoric pronoun is. This is an interesting observation in view of the fact that both of these are traditional Latin features, as opposed to those that foreshadow the Romance development (VO order and use of the anaphoric ille). However, it is difficult to say whether this is an indication of social or regional variation.

Primestoimenno-otnositel'nye konstrukcii v sovremennom russkom jazyke

Relative Constructions with Pronominal Heads in Contemporary Russian Chapter 1 introduces the distinctive syntactic and semantic properties of Russian relative constructions (RCs), which are then divided into two main classes according to the type of the head phrase. The study concentrates on RCs with pronominal heads, which are systematically compared with noun-headed RCs. Chapter 2 clarifies the categorization of pronouns in Russian. The conclusion is that Russian pronouns include only personal, reflexive and wh-pronouns. The remaining words that are traditionally seen as pronouns are actually functional equivalents of determiners. This idea leads to the suggestion that RCs with these determiner-like words as the only constituent of the head phrase are actually headed by zero pronouns. In the other type of RCs with pronominal heads, the head position is occupied by wh-pronouns with clitics expressing different types of indefiniteness and quantification. Comparison of the two types of pronoun-headed RCs shows that the wh-heads and zero-heads share a number of common properties with respect to the grammatical gender, number and person as well as to the semantic distinction between animates and inanimates. The rest of Chapter 2 gives an overview of various uses of wh-pronouns in Russian and an experimental analysis of RCs headed by pronominal adverbs. Chapter 3 discusses fundamental differences between RCs with noun and pronominal heads. One of the main findings is that the choice of the relative pronoun (kto 'who' and chto 'what' versus kotoryj 'which') is motivated by a tendency to reproduce maximally the essential grammatical and semantic properties of the antecedent. Chapter 4 gives a detailed description of the determiner-like words and wh-based heads used in the two types of RCs with pronominal heads. In addition, several issues related to the syntax and semantics of free relatives are discussed. The conclusion is that there is no need to establish a separate category of free relatives in Russian. Chapter 5 discusses the syntax and semantics of correlative and free concessive constructions. They share a number of properties with pronoun-headed RCs and the two are often confused in Russian linguistics. However, a detailed analysis shows that these constructions must be distinguished from RCs. The study combines the methods of functionally-oriented Russian structuralism with some insights from generative syntax.

La contextualisation du discours radiophonique par des moyens prosodiques. L’exemple de cinq grands philosophes français du XXe siècle

"Radiodiskurssin kontekstualisointi prosodisin keinoin. Esimerkkinä viisi suurta ranskalaista 1900-luvun filosofia" Väitöskirja käsittelee puheen kontekstualisointia prosodisin keinoin. Toisin sanottuna työssä käsitellään sitä, miten puheen prosodiset piirteet (kuten sävelkulku, intensiteetti, tauot, kesto ja rytmi) ohjaavat puheen tulkintaa vanhastaan enemmän tutkittujen sana- ja lausemerkitysten ohella. Työssä keskitytään seitsemään prosodisesti merkittyyn kuvioon, jotka koostuvat yhden tai usean parametrin silmiinpistävistä muutoksista. Ilmiöitä käsitellään sekä niiden akustisten muotojen että tyypillisten esiintymisyhteyksien ja diskursiivisten tehtävien näkökulmasta. Aineisto koostuu radio-ohjelmista, joissa puhuu viisi suurta ranskalaista 1900-luvun filosofia: Gaston Bachelard, Albert Camus, Michel Foucault, Maurice Merleau-Ponty ja Jean-Paul Sartre. Ohjelmat on lähetetty eri radiokanavilla Ranskassa vuosina 1948–1973. Väitöskirjan tulokset osoittavat, että prosodisesti merkityt kuviot ovat moniulotteisia puheen ilmiöitä, joilla on keskeinen rooli sanotun kontekstualisoinnissa: ne voivat esimerkiksi nostaa tai laskea sanotun informaatioarvoa, ilmaista puhujan voimakasta tai heikkoa sitoutumista sanomaansa, ilmaista rakenteellisen kokonaisuuden jatkumista tai päättymistä, jne. Väitöskirja sisältää myös kontrastiivisia osia, joissa ilmiöitä verrataan erääseen klassisessa pianomusiikissa esiintyvään melodiseen kuvioon sekä erääseen suomen kielen prosodiseen ilmiöön. Tulokset viittaavat siihen, että tietynlaista melodista kuviota käytetään samankaltaisena jäsentämiskeinona sekä puheessa että klassisessa musiikissa. Lisäksi tulokset antavat viitteitä siitä, että tiettyjä melodisia muotoja käytetään samankaltaisten implikaatioiden luomiseen kahdessa niinkin erilaisessa kielessä kuin suomessa ja ranskassa. Yksi väitöskirjan osa käsittelee pisteen ja pilkun prosodista merkitsemistä puheessa. Tulosten mukaan pisteellä ja pilkulla on kummallakin oma suullinen prototyyppinsä: piste merkitään tyypillisesti sävelkulun laskulla ja tauolla, ja pilkku puolestaan sävelkulun nousulla ja tauolla. Merkittävimmät tulokset koskevat kuitenkin tapauksia, joissa välimerkki tulkitaan prosodisesti epätyypillisellä tavalla: sekä pisteellä että pilkulla vaikuttaisi olevan useita eri suullisia vastaavuuksia, ja välimerkkien tehtävät voivat muotoutua hyvin erilaisiksi niiden prosodisesta tulkinnasta riippuen.

Da hatte das Pferd die Nüstern voll. Gebrauch und Funktion von Phraseologie im Kinderbuch : Untersuchungen zu Erich Kästner und anderen Autoren

Da hatte das Pferd die Nüstern voll. Gebrauch und Funktion von Phraseologie im Kinderbuch. Untersuchungen zu Erich Kästner und anderen Autoren. [Da hatte das Pferd die Nüstern voll. Fraseologian käyttö ja tehtävä lastenkirjallisuudessa. Tutkimuksia Erich Kästnerin ja muiden kirjailijoiden tuotannossa.] Usein oletetaan, että idiomit ovat lapsille vaikeita ymmärtää, koska niiden merkitystä ei voi kokonaisuudessaan johtaa rakenteeseen kuuluvien yksittäisten sanojen merkityksestä. Silti lastenkirjallisuudessa idiomeja käytetään paljon ja monessa eri tehtävässä. Tässä tutkimuksessa tarkistetaan fraseologian (idiomien ja sanalaskujen) käytön koko skaala saksankielisessä lastenkirjallisuudessa Erich Kästnerin (1899-1976) klassikoista tähän päivään asti. Kolmen eri korpuksen avulla (905 idiomiesimerkkiä kuudesta Kästnerin lastenkirjasta, 333 idiomia kahdesta Kästnerin aikuisromaanista ja 580 esimerkkiä kuudesta eri kirjailijoiden kirjoittamasta lastenkirjasta) pyritään vastamaan mm. seuraaviin kysymyksiin: Kuinka paljon ja minkälaisia idiomeja teksteissä käytetään? Miten idiomit sijoitetaan teksteihin, minkälaisia suhteita kontekstiin rakentuu? Millaisia eroavaisuuksia idiomien käytössä on havaittavissa ensinnäkin saman kirjailijan (Kästnerin) lastenkirjojen ja aikuisille tarkoitettujen kirjojen välillä sekä toisaalta eri kirjailijoiden kirjoittamien lastenkirjojen välillä? Tutkimuksesta käy ilmi, että idiomien käyttö vaihtelee lastenkirjallisuudessa ensisijaisesti kirjailijoittain, joka näkyy erilaisten ’fraseologisten profiilien’ esiintyminä. Parafraasien käyttö (idiomin rinnalle asetetaan synonyyminen ei-idiomaattinen ilmaisu) on varsin yleistä kaikissa tutkituissa lastenkirjoissa. Kästnerin lastenkirjoissa parafraasin käyttö on selvästi yleisempää kuin aikuisromaaneissa. Näyttää siltä, että lastenkirjallisuudessa siis tietoisesti tai tiedostumatta otetaan huomioon lasten rajoitettu fraseologinen kompetenssi.

Mauwake reference grammar

This dissertation provides a synchronic grammatical description of Mauwake, a Papuan (Trans-New Guinea) language of about 2000 speakers on the North Coast of the Madang Province in Papua New Guinea. The theoretical background is that of Basic Linguistic Theory (BLT), used extensively in analysing and writing descriptive grammars. The chapters from morphology to clause level are described from form to function; in the later chapters the function is taken more often as the starting point. Any theory-specific terminology is kept to the minimum and formalisms have been avoided in accordance with BLT principles. Mauwake has a classic 5-vowel system and 14 consonant phonemes. With its simple phonology it is a typical representative of the Madang North Coast languages. For a Papuan language there are relatively few morphophonological alternations. Nouns are either alienably or inalienably possessed. There is no obligatory number marking in nouns or noun phrases. Pronouns have several different forms: five for case and three for other functions. The dative pronouns are treated as [+human] locatives, and they have also grammaticalised as possessives. The verbal morphology is agglutinative and mainly suffixal. Unusual features include two distributive suffixes, and the interaction of the derivational benefactive and the inflectional beneficiary suffixes. The applicative suffix has either transitivising or causative but not benefactive function. The switch-reference system distinguishes between simultaneous and sequential action, as well as same or different subject in relation to the following clause. There are several verbs denoting coming and going, and they may combine with one of three prefixes to indicate bringing and taking. Mauwake is a nominative-accusative type language, and the basic constituent order in a clause is SOV. Subject and object are the only syntactic arguments. There is no indirect object, but a clause can have two or even three objects. A nominalised clause with a finite verb functions as a relative clause or a complement clause; one with a nominalised verb has several different functions. Functional domains described include modality, negation, deixis, quantification, possession and comparison. As there are four negators, Mauwake has more variation in negative expressions than is usual in Papuan languages. Clause chaining is the preferred strategy for joining clauses into sentences, but coordination and subordination of finite clauses are also common. The form of a complement clause depends on whether it is of the fact, action or potential type. Tail-head linkage is used as a cohesive device between sentences. The discourse-level features described are topic and focus.

A Sketch of the Phonology and Grammar of Rajbanshi

This dissertation is a synchronic description of the phonology and grammar of two dialects of the Rajbanshi language (Eastern Indo-Aryan) as spoken in Jhapa, Nepal. I have primarily confined the analysis to the oral expression, since the emerging literary form is still in its infancy. The grammatical analysis is therefore based, for the most part, on a corpus of oral narrative text which was recorded and transcribed from three informants from north-east Jhapa. An informant, speaking a dialect from south-west Jhapa cross checked this text corpus and provided additional elicited material. I have described the phonology, morphology and syntax of the language, and also one aspect of its discourse structure. For the most part the phonology follows the basic Indo-Aryan pattern. Derivational morphology, compounding, reduplication, echo formation and onomatopoeic constructions are considered, as well as number, noun classes (their assignment and grammatical function), pronouns, and case and postpositions. In verbal morphology I cover causative stems, the copula, primary and secondary agreement, tense, aspect, mood, auxiliary constructions and non-finite forms. The term secondary agreement here refers to genitive agreement, dative-subject agreement and patient (and sometimes patient-agent) agreement. The breaking of default agreement rules has a range of pragmatic inferences. I argue that a distinction, based on formal, semantic and statistical grounds, should be made between conjunct verbs, derivational compound verbs and quasi-aspectual compound verbs. Rajbanshi has an open set of adjectives, and it additionally makes use of a restricted set of nouns which can function as adjectives. Various particles, and the emphatic and conjunctive clitics are also considered. The syntactic structures studied include: non-declarative speech acts, phrase-internal and clause-internal constituent order, negation, subordination, coordination and valence adjustment. I explain how the future, present and past tenses in Rajbanshi oral narratives do not seem to maintain a time reference, but rather to indicate a distinction between background and foreground information. I call this tense neutralisation .

Kuluttaminen ja ylhäisaatelin elämäntapa 1700-luvun Ruotsissa

Consumption and the lifestyle of the high nobility in eighteenth-century Sweden This monograph is an analysis of the lifestyle, consumption and private finances of the Swedish high nobility during the eighteenth century (ca 1730 1795). It describes the lifestyle of one noble house, the House of Fersen. The Fersen family represents the leading political, economic and cultural elite in eighteenth-century Sweden. The analysis concentrates on Count Carl von Fersen (1716 1786) and his brother Count Axel von Fersen (1719 1794), their spouses and children. Carl von Fersen was a courtier whilst Axel von Fersen was an officer and one of the leaders of the Francophile Hat party. His son, Axel von Fersen the younger, was in his time an officer and a favourite of Gustavus III, King of Sweden, as well as a favourite and trusted confidant of Marie-Antoinette, Queen of France. The research is based upon the Fersen family s private archives, the Counts personal account books, probate inventories, letters and diaries. The study discusses the Fersens landed property and investments in ironworks and manufacturing, the indebtedness of the high nobility, high offices in civil administration, the militia and at court, as well as marriages as the foundations of noble wealth and power. It analyses the Count von Fersens revenue and expenditure, their career options and personal expenses, their involvement in the building and decorating of palaces, and the servants in service of the Fersen family as well as the ideal nobleman and his consumption. Central themes are inheritance, children s education, marriages and ladies preparing their trousseaux, the nobility ordering luxury goods from France, the consumption of Counts and Countesses before and after marrying and having children, the pleasures of a noble life as well as the criticism of luxury and sumptuousness. The study contributes to the large body of research on consumption and nobility in the eighteenth century by connecting the lifestyle, consumption and private finances of the Swedish high nobility to their European context. Key words: nobility, Fersen, lifestyle, consumption, private finances, Sweden, eighteenth century

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

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

Atomic Layer Deposition of Multicomponent Oxide Materials

Atomic layer deposition (ALD) is a method for thin film deposition which has been extensively studied for binary oxide thin film growth. Studies on multicomponent oxide growth by ALD remain relatively few owing to the increased number of factors that come into play when more than one metal is employed. More metal precursors are required, and the surface may change significantly during successive stages of the growth. Multicomponent oxide thin films can be prepared in a well-controlled way as long as the same principle that makes binary oxide ALD work so well is followed for each constituent element: in short, the film growth has to be self-limiting. ALD of various multicomponent oxides was studied. SrTiO3, BaTiO3, Ba(1-x)SrxTiO3 (BST), SrTa2O6, Bi4Ti3O12, BiTaO4 and SrBi2Ta2O9 (SBT) thin films were prepared, many of them for the first time by ALD. Chemistries of the binary oxides are shown to influence the processing of their multicomponent counterparts. The compatibility of precursor volatilities, thermal stabilities and reactivities is essential for multicomponent oxide ALD, but it should be noted that the main reactive species, the growing film itself, must also be compatible with self-limiting growth chemistry. In the cases of BaO and Bi2O3 the growth of the binary oxide was very difficult, but the presence of Ti or Ta in the growing film made self-limiting growth possible. The application of the deposited films as dielectric and ferroelectric materials was studied. Post-deposition annealing treatments in different atmospheres were used to achieve the desired crystalline phase or, more generally, to improve electrical properties. Electrode materials strongly influenced the leakage current densities in the prepared metal insulator metal (MIM) capacitors. Film permittivities above 100 and leakage current densities below 110-7 A/cm2 were achieved with several of the materials.

Beatific Enjoyment in Scholastic Philosophy and Theology: 1240-1335

This dissertation examines the concept of beatific enjoyment (fruitio beatifica) in scholastic theology and philosophy in the thirteenth and early fourteenth century. The aim of the study is to explain what is enjoyment and to show why scholastic thinkers were interested in discussing it. The dissertation consists of five chapters. The first chapter deals with Aurelius Augustine's distinction between enjoyment and use and the place of enjoyment in the framework of Augustine's view of the passions and the human will. The first chapter also focuses upon the importance of Peter Lombard's Sentences for the transmission of Augustine's treatment of enjoyment in scholastic thought as well as upon Lombard's understanding of enjoyment. The second chapter treats thirteenth-century conceptions of the object and psychology of enjoyment. Material for this chapter is provided by the writings - mostly Sentences commentaries - of Alexander of Hales, Albert the Great, Bonaventure, Thomas Aquinas, Peter of Tarentaise, Robert Kilwardby, William de la Mare, Giles of Rome, and Richard of Middleton. The third chapter inspects early fourteenth-century views of the object and psychology of enjoyment. The fourth chapter focuses upon discussions of the enjoyment of the Holy Trinity. The fifth chapter discusses the contingency of beatific enjoyment. The main writers studied in the third, fourth and fifth chapters are John Duns Scotus, Peter Aureoli, Durandus of Saint Pourçain, William of Ockham, Walter Chatton, Robert Holcot, and Adam Wodeham. Historians of medieval intellectual history have emphasized the significance of the concept of beatific enjoyment for understanding the character and aims of scholastic theology and philosophy. The concept of beatific enjoyment was developed by Augustine on the basis of the insight that only God can satisfy our heart's desire. The possibility of satisfying this desire requires a right ordering of the human mind and a detachment of the will from the relative goals of earthly existence. Augustine placed this insight at the very foundation of the notion of Christian learning and education in his treatise On Christian Doctrine. Following Augustine, the twelfth-century scholastic theologian Peter Lombard made the concept of enjoyment the first topic in his plan of systematic theology. The official inclusion of Lombard's Sentences in the curriculum of theological studies in the early universities stimulated vigorous discussions of enjoyment. Enjoyment was understood as a volition and was analyzed in relation to cognition and other psychic features such as rest and pleasure. This study shows that early fourteenth-century authors deepened the analysis of enjoyment by concentrating upon the relationship between enjoyment and mental pleasure, the relationship between cognition and volition, and the relationship between the will and the beatific object (i.e., the Holy Trinity). The study also demonstrates the way in which the idea of enjoyment was affected by changes in the method of theological analysis - the application of Aristotelian logic in a Trinitarian context and the shift from virtue ethics to normative ethics.

Elite Bargaining and the Evolution of Centre-Periphery Relations in Post-Soviet Russia : A Comparative Analysis

This work is concerned with presenting a modified theoretical approach to the study of centre-periphery relations in the Russian Federation. In the widely accepted scientific discourse, the Russian federal system under the Yeltsin Administration (1991-2000) was asymmetrical; largely owing to the varying amount of structural autonomy distributed among the federation s 89 constituent units. While providing an improved understanding as to which political and socio-economic structures contributed to federal asymmetry, it is felt that associated large N-studies have underemphasised the role played by actor agency in re-shaping Russian federal institutions. It is the main task of this thesis to reintroduce /re-emphasise the importance of actor agency as a major contributing element of institutional change in the Russian federal system. By focusing on the strategic agency of regional elites simultaneously within regional and federal contexts, the thesis adopts the position that political, ethnic and socio-economic structural factors alone cannot fully determine the extent to which regional leaders were successful in their pursuit of economic and political pay-offs from the institutionally weakened federal centre. Furthermore, this work hypothesises that under conditions of federal institutional uncertainty, it is the ability of regional leaders to simultaneously interpret various mutable structural conditions then translate them into plausible strategies which accounts for the regions ability to extract variable amounts of economic and political pay-offs from the Russian federal system. The thesis finds that while the hypothesis is accurate in its theoretical assumptions, several key conclusions provide paths for further inquiry posed by the initial research question. First, without reliable information or stable institutions to guide their actions, both regional and federal elites were forced into ad-hoc decision-making in order to maintain their core strategic focus: political survival. Second, instead of attributing asymmetry to either actor agency or structural factors exclusively, the empirical data shows that both agency and structures interact symbiotically in the strategic formulation process, thus accounting for the sub-optimal nature of several of the actions taken in the adopted cases. Third, as actor agency and structural factors mutate over time, so, too do the perceived payoffs from elite competition. In the case of the Russian federal system, the stronger the federal centre became, the less likely it was that regional leaders could extract the high degree of economic and political pay-offs that they clamoured for earlier in the Yeltsin period. Finally, traditional approaches to the study of federal systems which focus on institutions as measures of federalism are not fully applicable in the Russian case precisely because the institutions themselves were a secondary point of contention between competing elites. Institutional equilibriums between the regions and Moscow were struck only when highly personalised elite preferences were satisfied. Therefore the Russian federal system is the product of short-term, institutional solutions suited to elite survival strategies developed under conditions of economic, political and social uncertainty.

Functional Analysis of MrpL55, Vig and Mat1 Acting at the Crossroad of Cell Cycle, Transcription and Metabolism Regulation

Cell proliferation, transcription and metabolism are regulated by complex partly overlapping signaling networks involving proteins in various subcellular compartments. The objective of this study was to increase our knowledge on such regulatory networks and their interrelationships through analysis of MrpL55, Vig, and Mat1 representing three gene products implicated in regulation of cell cycle, transcription, and metabolism. Genome-wide and biochemical in vitro studies have previously revealed MrpL55 as a component of the large subunit of the mitochondrial ribosome and demonstrated a possible role for the protein in cell cycle regulation. Vig has been implicated in heterochromatin formation and identified as a constituent of the RNAi-induced silencing complex (RISC) involved in cell cycle regulation and RNAi-directed transcriptional gene silencing (TGS) coupled to RNA polymerase II (RNAPII) transcription. Mat1 has been characterized as a regulatory subunit of cyclin-dependent kinase 7 (Cdk7) complex phosphorylating and regulating critical targets involved in cell cycle progression, energy metabolism and transcription by RNAPII. The first part of the study explored whether mRpL55 is required for cell viability or involved in a regulation of energy metabolism and cell proliferation. The results revealed a dynamic requirement of the essential Drosophila mRpL55 gene during development and suggested a function of MrpL55 in cell cycle control either at the G1/S or G2/M transition prior to cell differentiation. This first in vivo characterization of a metazoan-specific constituent of the large subunit of mitochondrial ribosome also demonstrated forth compelling evidence of the interconnection of nuclear and mitochondrial genomes as well as complex functions of the evolutionarily young metazoan-specific mitochondrial ribosomal proteins. In studies on the Drosophila RISC complex regulation, it was noted that Vig, a protein involved in heterochromatin formation, unlike other analyzed RISC associated proteins Argonaute2 and R2D2, is dynamically phosphorylated in a dsRNA-independent manner. Vig displays similarity with a known in vivo substrate for protein kinase C (PKC), human chromatin remodeling factor Ki-1/57, and is efficiently phosphorylated by PKC on multiple sites in vitro. These results suggest that function of the RISC complex protein Vig in RNAi-directed TGS and chromatin modification may be regulated through dsRNA-independent phosphorylation by PKC. In the third part of this study the role of Mat1 in regulating RNAPII transcription was investigated using cultured murine immortal fibroblasts with a conditional allele of Mat1. The results demonstrated that phosphorylation of the carboxy-terminal domain (CTD) of the large subunit of RNAPII in the heptapeptide YSPTSPS repeat in Mat-/- cells was over 10-fold reduced on Serine-5 and subsequently on Serine-2. Occupancy of the hypophosphorylated RNAPII in gene bodies was detectably decreased, whereas capping, splicing, histone methylation and mRNA levels were generally not affected. However, a subset of transcripts in absence of Mat1 was repressed and associated with decreased occupancy of RNAPII at promoters as well as defective capping. The results identify the Cdk7-CycH-Mat1 kinase submodule of TFIIH as a stimulatory non-essential regulator of transcriptional elongation and a genespecific essential factor for stable binding of RNAPII at the promoter region and capping. The results of these studies suggest important roles for both MrpL55 and Mat1 in cell cycle progression and their possible interplay at the G2/M stage in undifferentiated cells. The identified function of Mat1 and of TFIIH kinase complex in gene-specific transcriptional repression is challenging for further studies in regard to a possible link to Vig and RISC-mediated transcriptional gene silencing.

Molecular details of phage phi6 RNA-dependent RNA synthesis

For most RNA viruses RNA-dependent RNA polymerases (RdRPs) encoded by the virus are responsible for the entire RNA metabolism. Thus, RdRPs are critical components in the viral life cycle. However, it is not fully understood how these important enzymes function during viral replication. Double-stranded RNA (dsRNA) viruses perform the synthesis of their RNA genome within a proteinacous viral particle containing an RdRP as a minor constituent. The phi6 bacteriophage is the best-studied dsRNA virus, providing an excellent background for studies of its RNA synthesis. The purified recombinant phi6 RdRP is highly active in vitro and it possesses both RNA replication and transcription activities. The crystal structure of the phi6 polymerase, solved in complex with a number of ligands, provides a working model for detailed in vitro studies of RNA-dependent RNA polymerization. In this thesis, the primer-independent initiation of the phi6 RdRP was studied in vitro using biochemical and structural methods. A C-terminal, four-amino-acid-long loop protruding into the central cavity of the phi6 RdRP has been suggested to stabilize the incoming nucleotides of the initiation complex formation through stacking interactions. A similar structural element has been found from several other viral RdRPs. In this thesis, this so-called initiation platform loop was subjected to site-directed mutagenesis to address its role in the initiation. It was found that the initiation mode of the mutants is primer-dependent, requiring either an oligonucleotide primer or a back-priming initiation mechanism for the RNA synthesis. The crystal structure of a mutant RdRP with altered initiation platform revealed a set of contacts important for primer-independent initiation. Since phi6 RdRP is structurally and functionally homologous to several viral RdRPs, among them the hepatitis C virus RdRP, these results provide further general insight to understand primer-independent initiation. In this study it is demonstrated that manganese phasing could be used as a practical tool for solving structures of large proteins with a bound manganese ion. The phi6 RdRP was used as a case study to obtain phases for crystallographic analysis. Manganese ions are naturally bound to the phi6 RdRP at the palm domain of the enzyme. In a crystallographic experiment, X-ray diffraction data from a phi6 RdRP crystal were collected at a wavelength of 1.89 Å, which is the K edge of manganese. With this data an automatically built model of the core region of the protein could be obtained. Finally, in this work terminal nucleotidyl transferase (TNTase) activity of the phi6 RdRP was documented in the isolated polymerase as well as in the viral particle. This is the first time that such an activity has been reported in a polymerase of a dsRNA virus. The phi6 RdRP used uridine triphosphates as the sole substrate in a TNTase reaction but could accept several heterologous templates. The RdRP was able to add one or a few non-templated nucleotides to the 3' end of the single- or double-stranded RNA substrate. Based on the results on particle-mediated TNTase activity and previous structural information of the polymerase, a model for termination of the RNA-dependent RNA synthesis is suggested in this thesis.