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.

Roles of forced nicotine exposure and Comt gene disruption in the development of addiction-related behavioural and neurochemical changes in mice

Activation of midbrain dopamine systems is thought to be critically involved in the addictive properties of abused substances. Drugs of abuse increase dopamine release in the nucleus accumbens and dorsal striatum, which are the target areas of mesolimbic and nigrostriatal dopamine pathways, respectively. Dopamine release in the nucleus accumbens is thought to mediate the attribution of incentive salience to rewards, and dorsal striatal dopamine release is involved in habit formation. In addition, changes in the function of prefrontal cortex (PFC), the target area of mesocortical dopamine pathway, may skew information processing and memory formation such that the addict pays an abnormal amount of attention to drug-related cues. In this study, we wanted to explore how long-term forced oral nicotine exposure or the lack of catechol-O-methyltransferase (COMT), one of the dopamine metabolizing enzymes, would affect the functioning of these pathways. We also wanted to find out how the forced nicotine exposure or the lack of COMT would affect the consumption of nicotine, alcohol, or cocaine. First, we studied the effect of forced chronic nicotine exposure on the sensitivity of dopamine D2-like autoreceptors in microdialysis and locomotor activity experiments. We found that the sensitivity of these receptors was unchanged after forced oral nicotine exposure, although an increase in the sensitivity was observed in mice treated with intermittent nicotine injections twice daily for 10 days. Thus, the effect of nicotine treatment on dopamine autoreceptor sensitivity depends on the route, frequency, and time course of drug administration. Second, we investigated whether the forced oral nicotine exposure would affect the reinforcing properties of nicotine injections. The chronic nicotine exposure did not significantly affect the development of conditioned place preference to nicotine. In the intravenous self-administration paradigm, however, the nicotine-exposed animals self-administered nicotine at a lower unit dose than the control animals, indicating that their sensitivity to the reinforcing effects of nicotine was enhanced. Next, we wanted to study whether the Comt gene knock-out animals would be a suitable model to study alcohol and cocaine consumption or addiction. Although previous work had shown male Comt knock-out mice to be less sensitive to the locomotor-activating effects of cocaine, the present study found that the lack of COMT did not affect the consumption of cocaine solutions or the development of cocaine-induced place preference. However, the present work did find that male Comt knock-out mice, but not female knock-out mice, consumed ethanol more avidly than their wild-type littermates. This finding suggests that COMT may be one of the factors, albeit not a primary one, contributing to the risk of alcoholism. Last, we explored the effect of COMT deficiency on dorsal striatal, accumbal, and prefrontal cortical dopamine metabolism under no-net-flux conditions and under levodopa load in freely-moving mice. The lack of COMT did not affect the extracellular dopamine concentrations under baseline conditions in any of the brain areas studied. In the prefrontal cortex, the dopamine levels remained high for a prolonged time after levodopa treatment in male, but not female, Comt knock-out mice. COMT deficiency induced accumulation of 3,4-dihydroxyphenylacetic acid, which increased further under levodopa load. Homovanillic acid was not detectable in Comt knock-out animals either under baseline conditions or after levodopa treatment. Taken together, the present results show that although forced chronic oral nicotine exposure affects the reinforcing properties of self-administered nicotine, it is not an addiction model itself. COMT seems to play a minor role in dopamine metabolism and in the development of addiction under baseline conditions, indicating that dopamine function in the brain is well-protected from perturbation. However, the role of COMT becomes more important when the dopaminergic system is challenged, such as by pharmacological manipulation.

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.

Ivanov-mistik : Okkul'tnye motivy v poèzii i proze Vjačeslava Ivanova (1907-1919)

The subject of this work is the mysticism of Russian poet, critic and philosopher Vjacheslav Ivanov (1866-1949). The approach adopted involves the textual and discourse analysis and findings of the history of ideas. The subject has been considered important because of Ivanov's visions of his dead wife, writer Lydia Zinovieva-Annibal, which were combined with audible messages ("automatic writings"). Several automatic writings and descriptions of the visions from Ivanov's archive collections in St.Petersburg and Moscow are presented in this work. Right after the beginning of his hallucinations in the autumn of 1907, Ivanov was totally captivated by the theosophical ideas of Anna Mintslova, the background figure for this work. Anna Mintslova, a disciple of Rudolf Steiner's Esoteric School, offered Ivanov the theosophical concept of initiation to interpret paranormal phenomena in his intimate life. The work is divided into three main chapters, an introduction and aconclusion. The first chapter is called The Mystical Person: Anthropology of Ivanov and describes the role of the inner "Higher Self" in Ivanov's views on the nature of human consciousness. The political implications of the concepts, "mystical anarchism" and "sobornost" (religious unity) are also examined. The acquaintance and contacts with Anna Mintslova during 1906-1907 gave a framework to Ivanov's search for an organic society and personal religious experience. The second part, Mystics of Initiation and Visionary Aesthetics describes the influence of the initiation concept on Ivanov's aesthetic views (mainly "realistic symbolism"). On the other hand, some connections between the imagery of his visions and symbols in his verses of that period are established. Since Mintslova represented the ideas of Rudolf Steiner in Russia, several symbols shared by Steiner and Ivanov ("rose", "rose and cross") have been another subject of investigation. The preference for strict verse form in the lyrics of Ivanov's visionary period is interpreted as an attempt to place his own poetic creation within two traditions, a mystical and literary one. The third part of this work, Mystics of Hope and Terror, examines Ivanov's conception of Russia in connection with Mintslova's ideas of occult danger from the East. Ivanov's view of the "Russian idea" and his nationalistic idea during World War I are considered as a representation of the fear of the danger. Ivanov's interpretation of the October revolution is influenced by the theosophical concept of the "keeper of the threshold" which occurs in the context of the discourse of occult danger.

Measuring attitudes in translation: a study of Nokia business reports

Background Contemporary Finnish, spoken and written, reveals loanwords or foreignisms in the form of hybrids: a mixture of Finnish and foreign syllables (alumiinivalua). Sometimes loanwords are inserted into the Finnish sentence in their raw form just as they are found in the source language (pulp, after sales palvelu). Again, sometimes loanwords are calques, which appear Finnish but are spelled and pronounced in an altogether foreign manner (Protomanageri, Promenadi kampuksella). Research Questions What role does Finnish business translation play in the migration of foreignisms into Finnish if we consider translation "as a construct of solutions determined by the ideological constraints and conflicts characterizing the target culture" (Robyns 1992: 212)? What attitudes do the Finns display toward the presence of foreignisms in their language? What socio-economic or ideological conditions (Bassnett 1994: 321) are responsible for these attitudes? Are these conditions dynamic? What tools can be used to measure such attitudes? This dissertation set out to answer these and similar questions. Attitudes are imperialist (where otherness is both denied and transformed), defensive (where otherness is acknowledged, transformed, and vilified), transdiscursive (a neutral attitude to both otherness and transformation), or finally defective (where alien migration is acknowledged and "stimulated") (Robyns 1994: 60). Methodology The research method follows Rose's schema (1984: 8): (a) take an existing theory, (b) develop from it a proposition specific enough to be tested, (c) devise a scheme that tests this proposition, (d) carry through the scheme in practice, (e) draw up results and discuss conclusions in relation to the original theory. In other words, the method attempts an explanation of a Finnish social phenomenon based on systematic analyses of translated evidence (Lewins 1992: 4) whereby what really matters is the logical sequence that connects the empirical data to the initial research questions raised above and, ultimately to its conclusion (Yin 1984: 29). Results This research found that Finnish translators of the Nokia annual reports used a foreignism whenever possible such as komponentin instead of rakenneosa, or investoida instead of sijoittaa, and often without any apparent justification (Pryce 2003: 203-12) more than the translator's personal preference. In the old documents (minutes of meetings of the Board of Directors of Osakeyhtio H. Saastamoinen, Ltd. dated 5 July 1912-1917, a NOPSA booklet (1932), Enzo-Gutzeit-Tornator Oy document (1938), Imatra Steel Oy Annual Report 1964, and Nokia Oy Annual Report 1946), foreignisms under Haugen's (1950: 210-31) Classification #1 occurred an average of 0.6 times, while in the new documents (Nokia 1998 translated Annual Reports) they occurred an average of 6.5 times. That big difference, suggests transdiscursive and defective attitudes in Finnish society toward the other. In the 1850s, Finnish attitudes toward alien persons and cultures were hardened, intolerant and prohibitive because language politics were both nascent and emerging, and Finns adopted a defensive stance (Paloposki 2002: 102 ff) to protect their cultural and national treasures such as language and folklore. Innovation The innovation here is that no prior doctoral level research measured Finnish attitudes toward foreignisms using a business translation approach. This is the first time that Haugen's classification has been modified and applied in target language analysis. It is hoped that this method would be replicated in similar research in the future. Applications For practical applications, researchers with interest in languages, language development, language influences, language ideologies, and power structures that affect national language policies will find this thesis useful, especially the model for collecting, grouping, and analyzing foreignisms that has been demonstrated here. It is intended to document for posterity current attitudes of Finns toward the other as revealed in business translations from 1912-1964, and in 1998. This way, future language researchers would be able to explore a time-line of Finnish language development and attitudes toward the other. Communication firms may also find this research interesting. In future, could the model we adopted be used to analyze literary texts or religious texts for example? Future Trends Though business documents show transdiscursive attitudes, other segments of Finnish society may show defensive or imperialist attitudes. When the ideology of industrialization changes in the future, will Finnish attitudes toward the other change as well? Will it then be possible to use the same kind of analytical tools to measure Finnish attitudes? More broadly, will linguistic change continue in the same direction of transdiscursive attitudes, or will the change slow down or even reverse into xenophobic attitudes? Is this our model culture-specific or can it be used in the context of other cultures? Conclusion There is anger against foreignisms in Finland as newspaper publications and television broadcasts show, but research shows that a majority of Finns consider foreignisms and the languages from which they come as sources of enrichment for Finnish culture (Laitinen 2000, Eurobarometer series 41 of July 1994, 44 of Spring 1996, 50 of Autumn 1998). Ideologies of industrialization and globalization in Finland have facilitated transdiscursive tendencies. When Finland's political ideology was intolerant toward foreign influences in the 1850s because Finland was in the process of consolidating her nascent country and language, attitudes toward the importation of loanwords also became intolerant. Presently, when industrialization and globalization became the dominant ideologies, we see a shift in attitudes toward transdiscursive tendencies. Ideology is usually unseen and too often ignored by translation researchers. However, ideology reveals itself as the most powerful factor affecting language attitudes in a target culture. Key words Finnish, Business Translation, Ideology, Foreignisms, Imperialist Attitudes, Defensive Attitudes, Transdiscursive Attitudes, Defective Attitudes, the Other, Old Documents, New Documents.

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

Approaching Sacred Pregnancy : The Cult of the Visitation and Narrative Altarpieces in Late Fifteenth-Century Florence

The study focuses on the Visitation as a narrative subject of altarpieces in late fifteenth-century Florence. Although the Visitation was a well-known story in both verbal and visual representations since the early medieval period, it became a popular subject of altarpieces only towards the end of the fifteenth century. In this study, the first part provides an overview of the complex religious and historical background to an emerging cult of the Visitation. Devotional practices focusing on the Visitation belong in a context of late medieval Marian devotion and in 1389 a new feast of the Visitation was introduced into the liturgical calendar of the Catholic Church. Because of the ongoing schism within the Catholic Church, the feast was not unanimously accepted across Western Europe until the later part of the fifteenth century. Contrary to a widely disseminated view, the feast of the Visitation cannot be associated with Franciscan spirituality, but was rather a clearly defined Dominican project that primarily emphasised the importance of peace and unity within the Christian Church. Simultaneously with the gradual acceptance of the new feast, visual representations of the Visitation began to appear at the centre of altarpieces. The Visitation exemplifies an increasing preference for narrative subjects within the genre of the altarpiece. The second part of the study presents an analysis of the concept of the narrative altarpiece and highlights the complexities involved in combining a narrative content with the traditional devotional function of the altarpiece. In detailed case studies some prominent art works produced in Florence between 1490 and 1503 are discussed within a framework of contextual analysis, narrative theory and iconography. Altarpieces by Domenico Ghirlandaio, Piero di Cosimo and Mariotto Albertinelli represent visual manifestations of a cult of the Visitation with roots in late medieval devotional practices. At the same time, the altarpieces highlight the multiple functions of altarpieces in a culture where art works responded to a variety of social and religious needs. Building on earlier studies, each case study presents new insights and evidence not considered in previous art historical research.

Half-occlusion processing in stereoscopic vision

This study investigated questions related to half-occlusion processing in human stereoscopic vision: (1) How does the depth location of a half-occluding figure affect the depth localization of adjacent monocular objects? (2) Is three-dimensional slant around vertical axis (geometric effect) affected by half-occlusion constraints? and (3) How the half-occlusion constraints and surface formation processes are manifested in stereoscopic capture? Our results showed that the depth localization of binocular objects affects the depth localization of discrete monocular objects. We also showed that the visual system has a preference for a frontoparallel surface interpretation if the half-occlusion configuration allows multiple interpretation alternatives. When the surface formation was constrained by textures, our results showed that a process of rematching spreading determines the resulting perception and that the spreading can be limited by illusory contours that support the presence of binocularly unmatched figures. The unmatched figures could be present, if the inducing figures producing the illusory surface contained binocular image differences that provided cues for quantitative da Vinci stereopsis. These findings provide evidence of the significant role of half-occlusions in stereoscopic processing.