Untersuchungen zur Fachsprache der Ökologie und des Umweltschutzes im Deutschen und Finnischen : Bezeichnungsvarianten unter einem geschichtlichen, lexikographischen, morphologischen und linguistisch-pragmatischen Aspekt

The work integrates research in the language and terminology of various fields with lexicography, etymology, semantics, word formation, and pragmatics. Additionally, examination of German and Finnish provides the work with perspective of contrastive linguistics and the translation of texts in specialized fields. The work is an attempt to chart the language, vocabulary, different textual types, and essential communication-connected features of this special field. The study is primary concerned with internal communication within the field of ecology, but it also provides a comparison of the public discussion of environmental issues in Germany and Finland. The work attempts to use textual signs to provide a picture of the literary communication used on the different vertical levels in the central text types within the field. The dictionaries in the fields of environmental issues and ecology for the individual text types are examined primarily from the perspective of their quantity and diversity. One central point of the work is to clarify and collect all of the dictionaries in the field that have been compiled thus far in which German and/or Finnish ware included. Ecology and environmental protection are closely linked not only to each other but also to many other scientific fields. Consequently, the language of the environmental field has acquired an abundance of influences and vocabulary from the language of the special fields close to it as well as from that of politics and various areas of public administration. The work also demonstrates how the popularization of environmental terminology often leads to semantic distortion. Traditionally, scientific texts have used the smallest number of expressions, the purpose of which is to appeal to or influence the behavior of the text recipient. Particularly in Germany, those who support or oppose measures to protect the environment have long been making concerted efforts to represent their own views in the language that they use. When discussing controversial issues competing designations for the same referent or concept are used in accordance with the interest group to which the speaker belongs. One of the objectives of the study is to sensitize recipients of texts to notice the euphemistic expressions that occur in German and Finnish texts dealing with issues that are sensitive from the standpoint of environmental policy. One particular feature of the field is the wealth and large number of variants designating the same entry or concept. The terminological doublets formed by words of foreign origin and their German or Finnish language equivalents are quite typical of the field. Methods of corpus linguistics are used to determine the reasons for the large number of variant designations as well as their functionality.

Structure informationnelle et constructions du kabyle : Etude de trois types de phrase dans le cadre de la grammaire constructionnelle

Information structure and Kabyle constructions Three sentence types in the Construction Grammar framework The study examines three Kabyle sentence types and their variants. These sentence types have been chosen because they code the same state of affairs but have different syntactic structures. The sentence types are Dislocated sentence, Cleft sentence, and Canonical sentence. I argue first that a proper description of these sentence types should include information structure and, second, that a description which takes into account information structure is possible in the Construction Grammar framework. The study thus constitutes a testing ground for Construction Grammar for its applicability to a less known language. It constitutes a testing ground notably because the differentiation between the three types of sentences cannot be done without information structure categories and, consequently, these categories must be integrated also in the grammatical description. The information structure analysis is based on the model outlined by Knud Lambrecht. In that model, information structure is considered as a component of sentence grammar that assures the pragmatically correct sentence forms. The work starts by an examination of the three sentence types and the analyses that have been done in André Martinet s functional grammar framework. This introduces the sentence types chosen as the object of study and discusses the difficulties related to their analysis. After a presentation of the state of the art, including earlier and more recent models, the principles and notions of Construction Grammar and of Lambrecht s model are introduced and explicated. The information structure analysis is presented in three chapters, each treating one of the three sentence types. The analyses are based on spoken language data and elicitation. Prosody is included in the study when a syntactic structure seems to code two different focus structures. In such cases, it is pertinent to investigate whether these are coded by prosody. The final chapter presents the constructions that have been established and the problems encountered in analysing them. It also discusses the impact of the study on the theories used and on the theory of syntax in general.

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.

The Influence of Constantinople on Middle Byzantine Architecture (843-1204) : A typological and morphological approach at the provincial level.

The influence of the architecture of the Byzantine capital spread to the Mediterranean provinces with travelling masters and architects. In this study the architecture of the Constantinopolitan School has been detected on the basis of the typology of churches, completed by certain morphological aspects when necessary. The impact of the Constantinopolitan workshops appears to have been more important than previously realized. This research revealed that the Constantinopolitan composite domed inscribed-cross type or cross-in-square spread everywhere to the Balkans and it was assumed soon by the local schools of architecture. In addition, two novel variants were invented on the basis of this model: the semi-composite type and the so-called Athonite type. In the latter variant lateral conches, choroi, were added for liturgical reasons. Instead, the origin of the domed ambulatory church was partly provincial. One result of this study is that the origin of the Middle Byzantine domed octagonal types was traced to Constantinople. This is attested on the basis of the archaeological evidence. Also some other architectural elements that have not been preserved in the destroyed capital have survived at the provincial level: the domed hexagonal type, the multi-domed superstructure, the pseudo-octagon and the narthex known as the lite. The Constantinopolitan architecture during the period in question was based on the Early Christian and Late Antique forms, practices and innovations and this also emerges at the provincial level.

Pathet : Musiikin symboliikka jaavalaisessa varjoteatterissa

The aim of this study is to define and analyse the symbolism hidden in the gamelan music of the Central Javanese, especially in the Yogyakartanese wayang kulit shadow theatre. This dissertation is divided into two parts. The first part deals with the theory, history and practice of Central Javanese shadow theatre. It also presents the tone symbol theory on which this study is based of B. Y. H. Sastrapustaka, the court servant and musician of the sultan s palace of Yogyakarta. For historical comparison, other theories and phenomena that seem to have some connections with the previously mentioned tone symbol theory are presented here as well as the equipment of the shadow theatre, its music, musical instruments and the shadow theatre in general in literature. The theoretic-methodological basis of the study is an enlarged model of research of cultural music, in which a person in the centre of the model with his/her concepts and by his/her behaviour creates a work of art and receives criticism through feedback, while the process of reciprocal action dynamically affects the whole development of the culture in question. In connection with the concepts of the work of art, the manner of approach of this study is also semiotic as the tone symbol theory gives a particular meaning to each musical note. Thus the purpose of this study is to find answers to how the tone symbol theory manifests itself in practical music making, what its origin is, if it is well known or not, and whether shadow theatre music supports this theory. The second part of this dissertation deals with material collected through interviews and observations as well as representative samples of musical pieces for shadow theatre and their analyses. In relation to this a special tool for analysing gamelan music, developed for the purpose of this study, is also presented. Sufficiently versatile material on the essence and meaning of the shadow theatre collected from many puppet masters of an older generation, many of whom are no longer with us, constitutes an important part of this study. This study proves that the tone symbol theory of Sastrapustaka is of tantristic tradition from the Hindu-Javanese period before the 16th century and before the appearance of Islam in Java. The variants of the previously mentioned theory can be found also in other fields of Javanese advanced civilization, such as architecture and dance. But it seems that knowledge about the tone symbolism connected to the shadow theatre especially has only been preserved in the sultan s palace of Yogyakarta and its intimate circles. The outsider puppet masters surely follow the theory, but they do not necessarily know its origin. As a result of the musical analysis, it is obvious that the musical pieces used for the shadow theatre bear different kinds of symbolic meanings which only an initiated person can feel and understand. These meanings are closely related to the plot of the play at the moment.

Edistys ja yhteinen hyvä vapaudenajan ruotsalaisessa poliittisessa kielessä

This dissertation analyses the notions of progress and common good in Swedish political language during the Age of Liberty (1719 1772). The method used is conceptual analysis, but this study is also a contribution to the history of political ideas and political culture, aiming at a broader understanding of how the bounds of political community were conceptualised and represented in eighteenth-century Sweden. The research is based on the official documents of the regime, such as the fundamental laws and the solemn speeches made at the opening and closing of the Diet, on normative or alternative descriptions of society such as history works and economic literature, and on practical political writings by the Diet and its members. The rhetoric of common good and particular interest is thus examined both in its consensual and theoretical contexts and in practical politics. Central political issues addressed include the extent of economic liberties, the question of freedom to print, the meaning of privilege, the position of particular estates or social groups and the economic interests of particular areas or persons. This research shows that the modern Swedish word for progress (framsteg) was still only rarely used in the eighteenth century, while the notion of progress, growth and success existed in a variety of closely related terms and metaphorical expressions. The more traditional concept of common good (allmänna bästa) was used in several variants, some of which explicitly related to utility and interest. The combination of public utility and private interest in political discourse challenged traditional ideals of political morality, where virtue had been the fundament of common good. The progress of society was also presented as being linked to the progress of liberty, knowledge and wealth in a way that can be described as characteristic of the Age of Enlightenment but which also points at the appearance of early liberal thought.

Kuvan ja tekstin välissä : Kuvateksti uutiskuvan ja lehtijutun elementtinä

The study focuses on picture captions: their grammar and interplay with photographs and their position as semi-independent elements of the news stories. The research was conducted in the framework of critical discourse analysis, social semiotic visual theory and fennistic syntactical research. The data consist of 441 press photographs, 1,815 captions and a number of news items from Finnish dailies. The generic structure potential of the caption includes the caption headline, the caption proper, i.e. the verbalization of the picture content, and the frame. In the data, 41 per cent of the captions have a headline, and 44 per cent contain a caption proper. Characteristic of the caption proper is omission of the finite verb and the use of the present tense, both of which have decreased in Finnish papers during the 20th century. The caption proper is typically a main clause, and both subordinate clauses and participal phrases occur mostly in the frame. While comparing caption variants attached to the same pictures, the processes and their participants proved to be identified considerably identically, following the news agency captions. Instead, the reader?s interpretations of a picture could be directed by framing it in different ways. For example, the caption may focus on the only person depicted, deal with a whole group, or give an abstract account of the situation. The caption is a paratext, a typographically marked, semi-independent element of a news story. Between the headline and the caption, four semantic relations have been identified. The caption may be a paraphrase of the headline, or a close-up illustrating an abstract headline with a concrete example. If the name of the person depicted is their only common factor, the relation between the caption and the headline is additive. A specifying caption will give more details than the headline. The caption may complete, repeat, or summarize the body copy. Naturally, most captions completing the story verbalize the content of the picture. As the caption is often based on the story, it may even repeat the body copy verbatim. The summarizing function is probably becoming increasingly important, as most Finnish newspapers have abandoned the use of a separate standfirst.

Genus i östra Nyland : från dialektutjämning till dialektmarkör

Gender in eastern Nyland – from dialect levelling to identity marking The study of dialect leveling in eastern Nyland focuses on variation and change in the Swedish dialects of Nyland (Fi. Uusimaa) on the south coast of Finland. During the last century the grammatical gender system of the dialects in the area has been reduced from a three-gender system to a two-gender system (cf. Corbett 1991). The present study is based on five linguistic variables in the gender system: the anaphoric pronouns (han, hon, den) when used for inanimates; the neuter pronouns he(t) and de(t) – when used anaphorically or as expletives; and three different types of morphological postposed definite articles. For all these variables, both dialect variants and standard variants are used in the dialects. Within the study of processes of variation and change, the work focuses on the mechanisms of leveling, simplification and reallocation; cf. Trudgill (1986) and Hinskens, Auer Kerswill (2005). With regard to the reductions of the gender system, the possibility that some of these variables might have turned into becoming dialect markers (Labov 1972) in the modern varieties of eastern Nyland is given special attention. The primary data consist of tape recordings with 25 informants done in the 1960s and 1970s. The informants were born in 1881–1913. In addition, recent changes were investigated in detail in tape recordings from 2005–2008 with 15 informants, who were born in the period 1927–1947 or 1976–1988. The study combines quantitative and qualitative methods in the systematic analysis of the data. Theoretically and methodologically the study relies on methods and results from variation studies and socio-dialectology, as well as on methods and results from traditional dialectology; cf. Ahlbäck (1946) and the dictionary of Swedish dialects, Ordbok över Finlands svenska folkmål, (1976–). The results show that there are different strategies among the informants in their use of the features studied. In the modern varieties of the dialects, most of the informants use only two genders, uter and neuter. Of the variables, the masculine pronoun for inanimates, the traditional neuter pronoun he(t) and some variants of the traditional definite articles have received a new function as dialect markers in my data. These changes first affect the gender distinctions, and the function of marking gender is lost; gradually the features then get new functions as dialect markers through processes of dialect leveling and reallocation. These processes are connected to changes taking place in the communities in eastern Nyland because of urbanization. When the dialect speakers experience that the traditional values of both the dialects and the culture are threatened, they begin to mark their dialectal identity by using dialect markers in their speech.

Work Stress and Early Atherosclerosis: Do Genetic Background and Pre-Employment Risk Factors Explain Conflicting Findings?

According to the models conceptualizing work stress, increased risk of health problems arise when high job demands co-occur with low job control (the demand-control model) or the efforts invested by the employee are disproportionately high compared to the rewards received (effort-reward imbalance model). This study examined the association between work stress and early atherosclerosis with particular attention to the role of pre-employment risk factors and genetic background in this association. The subjects were young healthy adults aged 24-39 who were participating in the 21-year follow-up of the ongoing prospective "Cardiovascular Risk in Young Finns" study in 2001-2002. Work stress was evaluated with questionnaires on demand-control model and on effort-reward model. Atherosclerosis was assessed with ultrasound of carotid artery intima-media thickness (IMT). In addition, risk for enhanced atherosclerotic process was assessed by measuring with heart rate variability and heart rate. Pre-employment risk factors, measured at age 12 to 18, included such as body mass index, blood lipids, family history of coronary heart disease, and parental socioeconomic position. Variants of the neuregulin-1 were determined using genomic DNA. The results showed that higher work stress was associated with higher IMT in men. This association was not attenuated by traditional risk factors of atherosclerosis and coronary heart disease or by pre-employment risk factors measured in adolescence. Neuregulin-1 gene moderated the association between work stress and IMT in men. A significant association between work stress and IMT was found only for the T/T genotype of the neuregulin-1 gene but not for other genotypes. Among women an association was found between higher work stress and lower heart rate variability, suggesting higher risk for developing atherosclerosis. These associations could not be explained by demographic characteristics or coronary risk factors. The present findings provide evidence for an association between work stress and atherosclerosis in relatively young population. This association seems to be modified by genetic influences but it does not appear to be confounded by pre-employment adolescent risk factors.

Post-industrial Intervention : An Activity-Theoretical Expedition Tracing the Proximal Development of Forms of Conducting Interventions

Ei saatavilla

Expression of cytochrome P450 enzymes and metabolism of timolol in human ocular tissue

Glaucoma is a group of progressive optic neuropathies causing irreversible blindness if not diagnosed and treated in the early state of progression. Disease is often, but not always, associated with increased intraocular pressure (IOP), which is also the most important risk factor for glaucoma. Ophthlamic timolol preparations have been used for decades to lower increased intraocular pressure (IOP). Timolol is locally well tolerated but may cause e.g. cardiovascular and pulmonary adverse effects due to systemic absorption. It has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. However, only limited information is available on timolol metabolism in the liver or especially in the human eye. The aim of this work was to investigate metabolism of timolol in human liver and human ocular tissues. The expression of drug metabolizing cytochrome P450 (CYP) enzymes in the human ciliary epithelial cells was studied. The metabolism of timolol and the interaction potential of timolol with other commercially available medicines were investigated in vitro using different liver preparations. The absorption of timolol to the aqueous humor from two commercially available products: 0.1% eye gel and 0.5% eye drops and the presence of timolol metabolites in the aqueous humor were investigated in a clinical trial. Timolol was confirmed to be metabolized mainly by CYP2D6 as previously suggested. Potent CYP2D6 inhibitors especially fluoxetine, paroxetine and quinidine inhibited the metabolism of timolol. The inhibition may be of clinical significance in patients using ophthalmic timolol products. CYP1A1 and CYP1B1 mRNAs were expressed in the human ciliary epithelial cells. CYP1B1 was also expressed at protein level and the expression was strongly induced by a known potent CYP1B1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The CYP1B1 induction is suggested to be mediated by aryl hydrocarbon receptor (AHR). Low levels of CYP2D6 mRNA splice variants were expressed in the human ciliary epithelial cells and very low levels of timolol metabolites were detected in the human aqueous humor. It seems that negligible amount of CYP2D6 protein is expressed in the human ocular tissues. Timolol 0.1% eye gel leads to aqueous humor concentration high enough to achieve therapeutic effect. Inter-individual variation in concentrations is low and intraocular as well as systemic safety can be increased when using this product with lower timolol concentration instead of timolol 0.5% eye drops.

Candidate gene studies on cardiovascular traits

Cardiovascular diseases (CVD) are a major cause of death and disability in Western countries and a growing health problem in the developing world. The genetic component of both coronary heart disease (CHD) and ischemic stroke events has been established in twin studies, and the traits predisposing to CVD, such as hypertension, dyslipidemias, obesity, diabetes, and smoking behavior, are all partly hereditary. Better understanding of the pathophysiology of CVD-related traits could help to target disease prevention and clinical treatment to individuals at an especially high disease risk and provide novel pharmaceutical interventions. This thesis aimed to clarify the genetic background of CVD at a population level using large Nordic population cohorts and a candidate gene approach. The first study concentrated on the allelic diversity of the thrombomodulin (THBD) gene in two Finnish cohorts, FINRISK-92 and FINRISK-97. The results from this study implied that THBD variants do not substantially contribute to CVD risk. In the second study, three other candidate genes were added to the analyses. The study investigated the epistatic effects of coagulation factor V (F5), intercellular adhesion molecule -1 (ICAM1), protein C (PROC), and THBD in the same FINRISK cohorts. The results were encouraging; we were able to identify several single SNPs and SNP combinations associating with CVD and mortality. Interestingly, THBD variants appeared in the associating SNP combinations despite the negative results from Study I, suggesting that THBD contributes to CVD through gene-gene interactions. In the third study, upstream transcription factor -1 (USF1) was analyzed in a cohort of Swedish men. USF1 was associated with metabolic syndrome, characterized by accumulation of different CVD risk factors. A putative protective and a putative risk variant were identified. A direct association with CVD was not observed. The longitudinal nature of the study also clarified the effect of USF1 variants on CVD risk factors followed in four examinations throughout adulthood. The three studies provided valuable information on the study of complex traits, highlighting the use of large study samples, the importance of replication, and the full coverage of the major allelic variants of the target genes to assure reliable findings. Although the genetic basis of coronary heart disease and ischemic stroke remains unknown, single genetic findings may facilitate the recognition of high-risk subgroups.

Pharmacogenetic Variation at CYP2D6, CYP2C9, and CYP2C19: Population Genetic and Forensic Aspects

Pharmacogenetics deals with genetically determined variation in drug response. In this context, three phase I drug-metabolizing enzymes, CYP2D6, CYP2C9, and CYP2C19, have a central role, affecting the metabolism of about 20-30% of clinically used drugs. Since genes coding for these enzymes in human populations exhibit high genetic polymorphism, they are of major pharmacogenetic importance. The aims of this study were to develop new genotyping methods for CYP2D6, CYP2C9, and CYP2C19 that would cover the most important genetic variants altering the enzyme activity, and, for the first time, to describe the distribution of genetic variation at these loci on global and microgeographic scales. In addition, pharmacogenetics was applied to a postmortem forensic setting to elucidate the role of genetic variation in drug intoxications, focusing mainly on cases related to tricyclic antidepressants, which are commonly involved in fatal drug poisonings in Finland. Genetic variability data were obtained by genotyping new population samples by the methods developed based on PCR and multiplex single-nucleotide primer extension reaction, as well as by collecting data from the literature. Data consisted of 138, 129, and 146 population samples for CYP2D6, CYP2C9, and CYP2C19, respectively. In addition, over 200 postmortem forensic cases were examined with respect to drug and metabolite concentrations and genotypic variation at CYP2D6 and CYP2C19. The distribution of genetic variation within and among human populations was analyzed by descriptive statistics and variance analysis and by correlating the genetic and geographic distances using Mantel tests and spatial autocorrelation. The correlation between phenotypic and genotypic variation in drug metabolism observed in postmortem cases was also analyzed statistically. The genotyping methods developed proved to be informative, technically feasible, and cost-effective. Detailed molecular analysis of CYP2D6 genetic variation in a global survey of human populations revealed that the pattern of variation was similar to those of neutral genomic markers. Most of the CYP2D6 diversity was observed within populations, and the spatial pattern of variation was best described as clinal. On the other hand, genetic variants of CYP2D6, CYP2C9, and CYP2C19 associated with altered enzymatic activity could reach extremely high frequencies in certain geographic regions. Pharmacogenetic variation may also be significantly affected by population-specific demographic histories, as seen within the Finnish population. When pharmacogenetics was applied to a postmortem forensic setting, a correlation between amitriptyline metabolic ratios and genetic variation at CYP2D6 and CYP2C19 was observed in the sample material, even in the presence of confounding factors typical for these cases. In addition, a case of doxepin-related fatal poisoning was shown to be associated with a genetic defect at CYP2D6. Each of the genes studied showed a distinct variation pattern in human populations and high frequencies of altered activity variants, which may reflect the neutral evolution and/or selective pressures caused by dietary or environmental exposure. The results are relevant also from the clinical point of view since the genetic variation at CYP2D6, CYP2C9, and CYP2C19 already has a range of clinical applications, e.g. in cancer treatment and oral anticoagulation therapy. This study revealed that pharmacogenetics may also contribute valuable information to the medicolegal investigation of sudden, unexpected deaths.

The Functions and Regulation of Ornithine Decarboxylase

Ornithine decarboxylase (ODC) regulates the synthesis of polyamines which are involved in many cellular functions e.g. proliferation and differentiation. Due to its critical role, ODC is a tightly regulated enzyme by antizymes and antizyme inhibitors. If the regulation fails, the activity of ODC increases and may lead to malignant transformation of a cell. Increased ODC activity is found in many common cancers, including colon, prostate, and breast cancer. In a transformed cell, dynamics of the actin cytoskeleton is disturbed. A small G-protein, RhoA regulates organization of the cytoskeleton, and its overactivity increases malignant potential of the cell. The present results indicate that covalent attachment of polyamines by transglutaminase is a physiological means of regulating the activity of RhoA. The translocation of RhoA to the plasma membrane, where it exerts its activity is dependent on the presence of catalytically active ODC. As the overactivity of ODC and RhoA are implicated in cell transformation, the results provide a mechanistic explanation of the interrelationship between the polyamine metabolism and the reorganization of the actin cytoskeleton occurring in cancer cells. ODC and polyamines have also an important role in the function of central nervous system. They participate in the regulation of brain morphogenesis in embryos. In adult nervous tissue, polyamines regulate K+ and glutamate channels. K+ inward rectifying channels control membrane potentials and NMDA-type glutamate receptors (NMDAR) regulate synaptic plasticity. High ODC activity and polyamine levels are considered important in the development of ischemic brain damage and they are implicated in the pathogenesis of Alzheimer s disease (AD). A homolog of ODC was cloned from a human brain cDNA library, and several alternatively spliced variants were detected in human brain and testis. The novel protein was nevertheless devoid of ODC catalytic activity. It was subsequently found to be a novel inductor of ODC activity and polyamine synthesis, called antizyme inhibitor 2 (AZIN2). The accumulation of AZIN2 in vesicle-like formations along the axons and beneath the plasma membrane of neurons as well as in steroid hormone producing Leydig cells and luteal cells of the gonads implies that AZIN2 plays a role in secretion and vesicle trafficking. An accumulation of AZIN2 was detected also in specimens of AD brains. This increased expression of AZIN2 was specific for AD and was not found in brains with other neurodegenerative diseases including CADASIL or dementia with Lewy bodies.

Palladin, a novel microfilament protein

Palladin is a novel actin microfilament associated protein, which together with myotilin and myopalladin forms a novel cytoskeletal IgC2 domain protein family. Whereas the expression of myotilin and myopalladin is limited mainly to striated muscle, palladin is widely expressed in both epithelial and mesenchymal tissues, including heart and the nervous system. Palladin has a complex genetic structure and it is expressed as several different sized and structured splice variants, which also display differences in their expression pattern and interactions. In muscle cells, all the family members localize to the sarcomeric Z-disc, and in non-muscle cells palladin also localizes to the stress-fiber-dense regions, lamellipodia, podosomes and focal adhesions. A common feature of this protein family is the binding to α-actinin, but other interactions are mostly unique to each member. Palladin has been shown to interact with several proteins, including VASP, profilin, Eps8, LASP-1 and LPP. Its domain structure, lack of enzymatic activity and multiple interactions define it as a molecular scaffolding protein, which links together proteins with different functional modalities into large complexes. Palladin has an important role in cytoskeletal regulation, particularly in stress fiber formation and stabilization. This assumption is supported by several experimental results. First, over-expression of palladin in non-muscle cells results in rapid reorganization of the actin cytoskeleton and formation of thick actin bundles. Second, the knock-down of palladin with anti-sense and siRNA techniques or knock-out by genetic methods leads to defective stress fiber formation. Furthermore, palladin is usually up-regulated in situations requiring a highly organized cytoskeleton, such as differentiation of dendritic cells, trophoblasts and myofibroblasts, and activation of astrocytes during glial scar formation. The protein family members have also direct disease linkages; myotilin missense mutations are the cause of LGMD1A and myofibrillar myopathy. Palladin mutations and polymorphisms, on the other hand, have been linked to hereditary pancreatic cancer and myocardial infarction, respectively. In this study we set out to characterize human palladin. We identified several palladin isoforms, studied their tissue distribution and sub-cellular localization. Four novel interaction partners were identified; ezrin, ArgBP2, SPIN90 and Src-kinase.The previously identified interaction between palladin and α-actinin was also characterized in detail. All the identified new binding partners are actin cytoskeleton associated proteins; ezrin links the plasma membrane to the cytoskeleton, ArgBP2 and SPIN90 localize, among other structures, to the lamellipodia and in cardiomyocytes to the Z-disc. Src is a transforming tyrosine kinase, which besides its role in oncogenesis has also important cytoskeletal associations. We also studied palladin in myofibroblasts, which are specialized cells involved in diverse physiological and pathological processes, such as wound healing and tissue fibrosis. We demonstrated that palladin is up-regulated during the differentiation of myofibroblasts in an isoform specific manner, and that this up-regulation is induced by TGF-β via activation of both the SMAD and MAPK signalling cascades. In summary, the results presented here describe the initial characterization of human palladin and offer a basis for further studies.