Molecular Genetic Background of Tumours in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a hereditary tumour predisposition syndrome. Its phenotype includes benign cutaneous and uterine leiomyomas (CLM, ULM) with high penetrance and rarer renal cell cancer (RCC), most commonly of papillary type 2 subtype. Over 130 HLRCC families have been identified world-wide but the RCC phenotype seems to concentrate in families from Finland and North America for unknown reasons. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. FH encodes the enzyme fumarase from mitochondrial citric acid cycle. Fumarase enzyme activity or type or site of the FH mutation are unassociated with disease phenotype. The strongest evidence for tumourigenesis mechanism in HLRCC supports a hypoxia inducible factor driven process called pseudohypoxia resulting from accumulation of the fumarase substrate fumarate. In this study, to assess the importance of gene- or exon-level deletions or amplifications of FH in patients with HLRCC-associated phenotypes, multiplex ligation-dependent probe amplification (MLPA) method was used. One novel FH mutation, deletion of exon 1, was found in a Swedish male patient with an evident HLRCC phenotype with CLM, RCC, and a family history of ULM and RCC. Six other patients with CLM and 12 patients with only RCC or uterine leiomyosarcoma (ULMS) remained FH mutation-negative. These results suggest that copy number aberrations of FH or its exons are an infrequent cause of HLRCC and that only co-occurrence of benign tumour types justifies FH-mutation screening in RCC or ULMS patients. Determination of the genomic profile of 11 HLRCC-associated RCCs from Finnish patients was performed by array comparative genomic hybridization. The most common copy number aberrations were gains of 2, 7, and 17 and losses of 13q12.3-q21.1, 14, 18, and X. When compared to aberrations of sporadic papillary RCCs, HLRCC-associated RCCs harboured a distinct DNA copy number profile and lacked many of the changes characterizing the sporadic RCCs. The findings suggest a divergent molecular pathway for tumourigenesis of papillary RCCs in HLRCC. In order to find a genetic modifier of RCC risk in HLRCC, genome-wide linkage and identical by descent (IBD) analysis studies were performed in Finnish HLRCC families with microsatellite marker mapping and SNP-array platforms. The linkage analysis identified only one locus of interest, the FH gene locus in 1q43, but no mutations were found in the genes of the region. IBD analysis yielded no convincing haplotypes shared by RCC patients. Although these results do not exclude the existence of a genetic modifier for RCC risk in HLRCC, they emphasize the role of FH mutations in the malignant tumourigenesis of HLRCC. To study the benign tumours in HLRCC, genome-wide DNA copy number and gene expression profiles of sporadic and HLRCC ULMs were defined with modern SNP- and gene-expression array platforms. The gene expression array suggests novel genes involved in FH-deficient ULM tumourigenesis and novel genes with putative roles in propagation of sporadic ULM. Both the gene expression and copy number profiles of HLRCC ULMs differed from those of sporadic ULMs indicating distinct molecular basis of the FH-deficient HLRCC tumours.

Halun häilyvät rajat : Magnus Enckellin maalausten maskuliinisuuksien ja feminiinisyyksien representaatioista ja itsen luomisesta

My PhD-thesis The uneasy borders of desire Magnus Enckell's representations of masculinities and femininities and the question how to create the self concentrates on the works of Finnish fin-de-siècle artist Magnus Enckell (1870-1925). My thesis deals with representations of masculinities, femininities, sexualities and different identity-positions. My research is about questions concerning representational ways of melancholy, androgyny, narcissism, themes of Golden Age and Double in Enckell s ouvre. These themes are analyzed by contextualizing them with different, but intersecting, discourses of varied scientific, artistic and occult ideas in the fin-de-siècle. The main point is analyze how the subject is constructed in both Foucauldian and Freudian sense and what one has to know about oneself. My approaches are based on ideas expressed in different discourses as queer-theory, Michel Foucault s genealogical epistemology and knowledge-power theory, psychoanalysis, art history and visual culture studies. My starting point lays is Foucault s idea expressed in his The History of Sexuality that the constitution of homosexual or as well as heterosexual subject inaugurates possibilities for transgressive activities e.g. by giving own voice to the sexualized subject. My main thesis is to suggest that Enckell s works in their multiple and ambiguous ways construct a phantasmatic position for viewer who may identify oneself to different desires, may construct or deconstruct a sexual identity for oneself or try to define the truth about oneself. Enckell s works should be considered as a contradictory processes which both seduce person to construct an identity and as well as lure person to pursue for the deconstruction of specific and permanent identity by celebrating the ambiguousness and discontinuity in one s identity. I m suggesting that the gazing subject feels pleasure in finding one s identity but the one must face the exposure of the melancholic structure which forms the basis of sexual desire. The subject may try to resolve one s melancholy by creating a phantasy about the original and unisexual being where desires, sexualities, phantasies and identities haven t been diverged. This can be fantasized in terms of art which forms a double for the melancholic subject who is in this limited and imaginary way able to forget for a while one s existential solitude.

Kansallisvaltion teräsmiehestä valtakunnan sovittelijaksi : Poliisikulttuurin psykohistorialliset solmukohdat 1930-1997

From Steely Nation-State Superman to Conciliator of Economical Global Empire – A Psychohistory of Finnish Police Culture 1930-1997 My study concerns the way police culture has changed within the societal changes in Finnish society between 1930 and 1997. The method of my study was psycho-historical and post-structural analysis. The research was conducted by examining the psycho-historical plateaus traceable within Finnish police culture. I made a social diagnosis of the autopoietic relationship between the power-holders of Finnish society and the police (at various levels of hierarchical organization). According to police researcher John P. Crank, police culture should be understood as the cognitive processes behind the actions of the police. Among these processes are the values, beliefs, rituals, customs and advice which standardize their work and the common sense of policemen. According to Crank, police culture is defined by a mindset which thinks, judges and acts according to its evaluations filtered by its own preliminary comprehension. Police culture consists of all the unsaid assumptions of being a policeman, the organizational structures of police, official policies, unofficial ways of behaviour, forms of arrest, procedures of practice and different kinds of training habits, attitudes towards suspects and citizens, and also possible corruption. Police culture channels its members’ feelings and emotions. Crank says that police culture can be seen in how policemen express their feelings. He advises police researchers to ask themselves how it feels to be a member of the police. Ethos has been described as a communal frame for thought that guides one’s actions. According to sociologist Martti Grönfors, the Finnish mentality of the Protestant ethic is accentuated among Finnish policemen. The concept of ethos expresses very well the self-made mentality as an ethical tension which prevails in police work between communal belonging and individual freedom of choice. However, it is significant that it is a matter of the quality of relationships, and that the relationship is always tied to the context of the cultural history of dealing with one’s anxiety. According to criminologist Clifford Shearing, the values of police culture act as subterranean processes of the maintenance of social power in society. Policemen have been called microcosmic mediators, or street corner politicians. Robert Reiner argues that at the level of self-comprehension, policemen disparage the dimension of politics in their work. Reiner points out that all relationships which hold a dimension of power are political. Police culture has also been called a canteen culture. This idea expresses the day-to-day basis of the mentality of taking care of business which policing produces as a necessity for dealing with everyday hardships. According to police researcher Timo Korander, this figurative expression embodies the nature of police culture as a crew culture which is partly hidden from police chiefs who are at a different level. This multitude of standpoints depicts the diversity of police cultures. According to Reiner, one should not see police culture as one monolithic whole; instead one should assess it as the interplay of individuals negotiating with their environment and societal power networks. The cases analyzed formed different plateaus of study. The first plateau was the so-called ‘Rovaniemi arson’ case in the summer of 1930. The second plateau consisted of the examinations of alleged police assaults towards the Communists during the Finnish Continuation War of 1941 to 1944 and the threats that societal change after the war posed to Finnish Society. The third plateau was thematic. Here I investigated how using force towards police clients has changed culturally from the 1930s to the 1980s. The fourth plateau concerned with the material produced by the Security Police detectives traced the interaction between Soviet KGB agents and Finnish politicians during the long 1970s. The fifth plateau of larger changes in Finnish police culture then occurred during the 1980s as an aftermath of the former decade. The last, sixth plateau of changing relationships between policing and the national logic of action can be seen in the murder of two policemen in the autumn of 1997. My study shows that police culture has transformed from a “stone cold” steely fixed identity towards a more relational identity that tries to solve problems by negotiating with clients instead of using excessive force. However, in this process of change there is a traceable paradox in Finnish policing and police culture. On the one hand, policemen have, at the practical level, constructed their policing identity by protecting their inner self in their organizational role at work against the projections of anger and fear in society. On the other hand, however, they have had to safeguard themselves at the emotional level against the predominance of this same organizational role. Because of this dilemma they must simultaneously construct both a distance from their own role as police officers and the role of the police itself. This makes the task of policing susceptible to the political pressures of society. In an era of globalization, and after the heyday of the welfare state, this can produce heightened challenges for Finnish police culture.

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.

The molecular basis of Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia due to cerebellar cortical atrophy, infantile- or childhood-onset bilateral cataracts, progressive myopathy, and mild to severe mental retardation. Additional features include hypergonadotropic hypogonadism, various skeletal abnormalities, short stature, and strabismus. The neuroradiologic hallmarks are hypoplasia of both the vermis and cerebellar hemispheres. The histopathologic findings include severe cerebellar atrophy and loss of Purkinje and granule cells. The common pathologic findings in muscle biopsy are variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation. The presence of marked cerebellar atrophy with myopathy distinguishes MSS from another rare syndrome, the congenital cataracts, facial dysmorphism, and neuropathy syndrome (CCFDN). Previously, work by others had resulted in the identification of an MSS locus on chromosome 5q31. A subtype of MSS with myoglobinuria and neuropathy had been linked to the CCFDN locus on chromosome 18qter, at which mutations in the CTDP1 gene had been identified. We confirmed linkage to the previously identified locus on chromosome 5q31 in two Finnish families with eight affected individuals, reduced the critical region by fine-mapping, and identified SIL1 as a gene underlying MSS. We found a common homozygous founder mutation in all Finnish patients. The same mutation was also present in patient samples from Norway and Sweden. Altogether, we identified eight mutations in SIL1, including nonsense, frameshift, splice site alterations, and one missense mutation. SIL1 encodes a nucleotide exchange factor for the endoplasmic reticulum (ER) resident heat-shock protein 70 chaperone GRP78. GRP78 functions in protein synthesis and quality control of the newly synthesized polypeptides. It senses and responds to stressful cellular conditions. We showed that in mice, SIL1 and GRP78 show highly similar spatial and temporal tissue expression in developing and mature brain, eye, and muscle. Studying endogenous proteins in mouse primary hippocampal neurons, we found that SIL1 and GRP78 colocalize and that SIL1 localizes to the ER. We studied the subcellular localization of two mutant proteins, a missense mutant found in two patients and an artificial mutant lacking the ER retrieval signal, and found that both mutant proteins formed aggregates within the ER. Well in line with our findings and the clinical features of MSS, recent work by Zhao et al. showed that a truncation of SIL1 causes ataxia and cerebellar Purkinje cell loss in the naturally occurring woozy mutant mouse. Prior to Purkinje cell degeneration, the unfolded protein response is initiated and abnormal protein accumulations are present. MSS thus joins the group of protein misfolding and accumulation diseases. These findings highlight the importance of SIL1 and the role of the ER in neuronal function and survival. The results presented in this thesis provide tools for the molecular genetic diagnostics of MSS and give a basis for future studies on the molecular pathogenesis of MSS. Understanding the mechanisms behind this pleiotropic syndrome may provide insights into more common forms of ataxia, myopathy, and neurodegeneration.

Spatial and temporal determinants of Finnish farmland bird populations

During the past decades agricultural intensification has caused dramatic population declines in a wide range of taxa related to farmland habitats, including farmland birds. In this thesis, I studied how boreal farmland landscape characteristics and agricultural land use affect the abundance and diversity of farmland birds using extensive field data collected by territory mapping of breeding farmland birds in various parts of Finland. My results show that the area and openness of agricultural areas are key determinants of farmland bird abundance and distribution. A landscape composition with enough open farmland combined with key habitats such as farmyards and wetland is likely to provide essential prerequisites for the occurrence of a rich farmland avifauna. In Finland, the majority of large areas suitable for open habitat specialists are located in southern and western parts of the country. However, the diversity of the species with an unfavourable conservation status in Europe (SPECs) had notable hotspot areas in northern and north-western agricultural areas. I found that in boreal agroecosystems farmland birds favour fields with springtime vegetative cover, especially agricultural grasslands and set-asides. Hence, in the spring cereal dominated Finnish agroecosystems it is the absence of field vegetation that may limit populations of many farmland bird species. It is likely that the decrease of crops providing vegetative cover in the spring, such as permanent grasslands, cultivated grass, and autumn-sown cereals, has greatly contributed to the declines of Finnish farmland birds. Grass crops have persistently declined in Finland as a consequence of specialization in crop production and the large-scale decline in livestock husbandry. Small-scale non-crop habitats, especially ditches and ditch margins, are also important for many bird species in the Finnish agroecosystems, but have dramatically declined during the last decades. A major problem for farmland bird conservation in Finland is the conflict between landscape structure and agricultural management. Areas with mixed and cattle farming are virtually absent from the large agricultural plains of southern and south-western Finland, where the landscape structure is more likely to be favourable for rich farmland bird assemblages. On the other hand, mixed and cattle farming is still rather frequent in northern and central parts of the country, where the landscape structure is not suitable for many farmland specialist birds requiring open landscapes. My results provide useful guidelines for farmland bird conservation, and imply that considerable attention needs to be paid to landscape factors when selecting areas for various conservational management actions, such as agri-environment schemes. Actions promoting the abundance of set-asides, grass crops, and ditches would markedly benefit Finnish farmland bird populations. Organic farming may benefit farmland birds, but it is not clear how general its beneficial effect is in boreal agroecosystems. The most urgent action aiming to preserve farmland biodiversity would be to support re-introducing and sustaining cattle farming by environmental subsidies. This would be especially beneficial in the southern parts of Finland, where the landscape characteristics and abundance of agricultural areas are most suitable for farmland birds and where cattle farming is currently rare.

Farmland birds and habitat heterogeneity in intensively cultivated boreal agricultural landscapes

The biodiversity of farmland ecosystems has decreased remarkably during the latter half of the 20th century, and this development is due to intensive farming with its various environmental effects. In the countries of the EU the Common Agricultural Policy (CAP) is the main determinant affecting farmland biodiversity, since the agricultural policy defines guidelines of agricultural practices. In addition to policies promoting intensive farming, CAP also includes national agri-environment schemes (AES), in which a part of subsidies paid to farmers is directed to acts that are presumed to promote environmental protection and biodiversity. In order to shape AES into relevant and powerful tools for biodiversity protection, detailed studies on the effects of agriculture on species and species assemblages are needed. In my thesis I investigated the importance of habitat heterogeneity and effects of different habitat and landscape characteristics on farmland bird abundance and diversity in typical cereal cultivation-dominated southern Finnish agricultural environments. The extensive data used were collected by territory mapping. My two main study species were the drastically declined ortolan bunting (Emberiza hortulana) and the phenomenally increased tree sparrow (Passer montanus); in addition I studied assemblages of 20 species breeding in open arable and edge/bush habitats. In light of my results I discuss whether the Finnish AES take into account the habitat needs of farmland birds, and I provide suggestions for improvement of the future AES. My results show that heterogeneity of both uncultivated and cultivated habitats increases abundance and species richness among farmland birds, but in this respect the amount and diversity of uncultivated habitats are essential. Ditches in particular are a keystone structure for farmland birds in boreal landscapes. Ditches lined by trees or bushes increased ortolan bunting abundance. Loss of that kind of ditches (and clearance of forest and bush patches), reduced breeding ortolan buntings, mainly by decreasing availability of song-posts that are important for the breeding groups of the species. Heterogeneity of uncultivated habitats, most importantly open ditches and the habitat patch richness, increased densities and species richnesses of species assemblages of open arable and edge/bush habitats. Human impact (winter-feeding, nest-boxes) affected favourably the tree sparrow s rapid range expansion in southern Finland, but any habitat types had no significant effects. At the moment the Finnish agri-environmental policy does not conserve farmland ditches as a habitat type. Instead, sub-surface drainage is financially promoted. This is a fatal mistake as far as farmland biodiversity is concerned. In addition to the maintenance of ditches, at least the following aspects should be included more than is done previously in the measures of the future AES: 1) promotion of diverse crop rotation (especially by promoting animal husbandry), 2) maintenance of tree and bush vegetation in islets and along ditches, 3) promotion of organic farming.

Pelon ja toivon välissä : Pätkätyöläisen urakerronta

This study analyzes the forming of the occupational identity of the well-educated fixed-term employees. Fixed-term employment contracts amongst the well-educated labour force are exceptionally common in Finland as compared to other European countries. Two groups of modern fixed-term employees are distinguished. The first comprises well-educated women employed in the public sector whose fixed-term employment often consists of successive periods as temporary substitutes. The other group comprises well-educated, upper white-collar men aged over 40, whose fixed-term employment careers often consist of jobs of project nature or posts that are filled for a fixed period only. Method of the study For the empirical data I interviewed 35 persons (26 women and 9 men) in 33 interviews, one of which was conducted by e-mail and one was a group interview. All the interviews were electronically recorded and coded. All the interviewees have two things in common: fixed-term employment and formal high education. Thirteen (13) of them are researchers, four nurses, four midwives, four journalists, and ten project experts. I used the snowball method to get in touch the interviewees. The first interviewees were those who were recommended by the trade unions and by my personal acquaintances. These interviewees, in turn, recommended other potential interviewees. In addition, announcements on the internet pages of the trade unions were used to reach other interviewees. In analysing process I read the research material several times to find the turning points in the narrative the interviewees told. I also searched for the most meaningful stories told and the meaning the interviewees gave to these stories and to the whole narrative. In addition to that I paid attention to co-production of the narrative with the interviewees and analyzed the narrative as performance to be able to search for the preferred identities the interviewees perform. (Riesman 2001, 698-701). I do not pay much attention to the question of truth of a narrative in the sense of its correspondence with facts; rather I think a working life narrative has two tasks: On the one hand one has to tell the facts and on the other hand, he/she has to describe the meaning of these facts to herself/himself. To emphasize the double nature of the narrative about one’s working life I analyzed the empirical data both by categorizing it according to the cultural models of storytelling (heroic story, comedy, irony and tragedy) and by studying the themes most of the interviewees talked about. Ethics of the study I chose to use narrative within qualitative interviews on the grounds that in my opinion is more ethical and more empowering than the more traditional structured interview methods. During the research process I carefully followed the ethical rules of a qualitative research. The purpose of the interviews and the research was told to the interviewees by giving them a written description of the study. Oral permission to use the interview in this research was obtained from the interviewees. The names and places, which are mentioned in the study, are changed to conceal the actual identity of the interviewees. I shared the analysis with the interviewees by sending each of them the first analysis of their personal interview. This way I asked them to make sure that the identity was hidden well enough and hoped to give interviewees a chance to look at their narratives, to instigate new actions and sustain the present one (Smith 2001, 721). Also I hoped to enjoy a new possibility of joint authorship. Main results As a result of the study I introduce six models of telling a story. The four typical western cultural models that guide the telling are: heroic story, comedy, tragedy and satirical story (Hänninen 1999). In addition to these models I found two ways of telling a career filled with fixed-term employments that differ significantly from traditional career story telling. However, the story models in which the interviewees pour their experience locates the fixed term employers work career in an imagined life trajectory and reveals the meaning they give to it. I analyze the many sided heroic story that Liisa tells as an example of the strength of the fear of failing or losing the job the fixed term employee feels. By this structure it is also possible to show that success is felt to be entirely a matter of chance. Tragedy, the failure in one’s trial to get something, is a model I introduce with the help of Vilppu’s story. This narrative gets its meaning both from the sorrow of the failure in the past and the rise of something new the teller has found. Aino tells her story as a comedy. By introducing her narrative, I suggest that the purpose of the comedy, a stronger social consensus, gets deeper and darker shade by fixed-term employment: one who works as a fixed term employee has to take his/her place in his/her work community by him/herself without the support the community gives to those in permanent position. By studying the satiric model Rauno uses, I argue that using irony both turns the power structures to a carnival and builds free space to the teller of the story and to the listener. Irony also helps in building a consensus, mutual understanding, between the teller and the listener and it shows the distance the teller tells to exist between him and others. Irony, however, demands some kind of success in one’s occupational career but also at least a minor disappointment in the progress of it. Helmi tells her story merely as a detective story. By introducing Helmi’s narrative, I argue that this story model strengthens the trust in fairness of the society the teller and the listener share. The analysis also emphasizes the central position of identity work, which is caused by fixed-term employment. Most of the interviewees talked about getting along in working life. I introduced Sari’s narrative as an example of this. In both of these latter narratives one’s personal character and habits are lifted as permanent parts of the actual professional expertise, which in turn varies according to different situations. By introducing these models, I reveal that the fixed-term employees have different strategies to cope with their job situations and these strategies vary according to their personal motives and situations and the actual purpose of the interview. However, I argue that they feel the space between their hopes and fears narrow and unsecure. In the research report I also introduce pieces of the stories – themes – that the interviewees use to build these survival strategies. They use their personal curriculum vitae or portfolio, their position in work community and their work morals to build their professional identity. Professional identity is flexible and varies in time and place, but even then it offers a tool to fix one’s identity work into something. It offers a viewpoint to society and a tool to measure one’s position in surrounding social nets. As one result of the study I analyze the position the fixed-term employees share on the edge of their job communities. I summarize the hopes and fears the interviewees have concerning employers, trade unions, educational institutions and the whole society. In their opinion, the solidarity between people has been weakened by the short-sighted power of the economy. The impact the fixed-term employment has on one’s professional identity and social capital is a many-sided and versatile process. Fixed-term employment both strengthens and weakens the professional identity, social capital and the building of trust. Fixed-term employment also affects one’s day-to-day life by excluding her/him from the norm and by one’s difficulty in making long-term plans (Jokinen 2005). Regardless of the nature of the job contract, the workers themselves are experts in making the best of their sometimes less than satisfying work life and they also build their professional identity by using creatively their education, work experiences and interpersonal relations. However, a long career of short fixed-term employments may seriously change the perception of employee about his/her role. He/she may start concentrating only in coping in his/her unsatisfactory situation and leaves the active improvement of the lousy working conditions to other people. Keywords: narrative, fixed-tem employment, occupational identity, work, story model, social capital, career  

Dissection of the genetic background of childhood onset progressive myoclonic epilepsies

The progressive myoclonic epilepsies (PMEs) are a clinically and etiologically heterogeneous group of symptomatic epilepsies characterized by myoclonus, tonic-clonic seizures, psychomotor regression and ataxia. Different disorders have been classified as PMEs. Of these, the group of neuronal ceroid lipofuscinoses (NCLs) comprise an entity that has onset in childhood, being the most common cause of neurodegeneration in children. The primary aim of this thesis was to dissect the molecular genetic background of patients with childhood onset PME by studying candidate genes and attempting to identify novel PME-associated genes. Another specific aim was to study the primary protein properties of the most recently identified member of the NCL-causing proteins, MFSD8. To dissect the genetic background of a cohort of Turkish patients with childhood onset PME, a screen of the NCL-associated genes PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8 and CTSD was performed. Altogether 49 novel mutations were identified, which together with 56 mutations found by collaborators raised the total number of known NCL mutations to 364. Fourteen of the novel mutations affect the recently identified MFSD8 gene, which had originally been identified in a subset of mainly Turkish patients as the underlying cause of CLN7 disease. To investigate the distribution of MFSD8 defects, a total of 211 patients of different ethnic origins were evaluated for mutations in the gene. Altogether 45 patients from nine different countries were provided with a CLN7 molecular diagnosis, denoting the wide geographical occurrence of MFSD8 defects. The mutations are private with only one having been established by a founder-effect in the Roma population from the former Czechoslovakia. All mutations identified except one are associated with the typical clinical picture of variant late-infantile NCL. To address the trafficking properties of MFSD8, lysosomal targeting of the protein was confirmed in both neuronal and non-neuronal cells. The major determinant for this lysosomal sorting was identified to be an N-terminal dileucine based signal (9-EQEPLL-14), recognized by heterotetrameric AP-1 adaptor proteins, suggesting that MFSD8 takes the direct trafficking pathway en route to the lysosomes. Expression studies revealed the neurons as the primary cell-type and the hippocampus and cerebellar granular cell layer as the predominant regions in which MFSD8 is expressed. To identify novel genes associated with childhood onset PME, a single nucleotide polymorphism (SNP) genomewide scan was performed in three small families and 18 sporadic patients followed by homozygosity mapping to determine the candidate loci. One of the families and a sporadic patient were positive for mutations in PLA2G6, a gene that had previously been shown to cause infantile neuroaxonal dystrophy. Application of next-generation sequencing of candidate regions in the remaining two families led to identification of a homozygous missense mutation in USP19 for the first and TXNDC6 for the second family. Analysis of the 18 sporadic cases mapped the best candidate interval in a 1.5 Mb region on chromosome 7q21. Screening of the positional candidate KCTD7 revealed six mutations in seven unrelated families. All patients with mutations in KCTD7 were reported to have early onset PME, rapid disease progression leading to dementia and no pathologic hallmarks. The identification of KCTD7 mutations in nine patients and the clinical delineation of their phenotype establish KCTD7 as a gene for early onset PME. The findings presented in this thesis denote MFSD8 and KCTD7 as genes commonly associated with childhood onset symptomatic epilepsy. The disease-associated role of TXNDC6 awaits verification through identification of additional mutations in patients with similar phenotypes. Completion of the genetic spectrum underlying childhood onset PMEs and understanding of the gene products functions will comprise important steps towards understanding the underlying pathogenetic mechanisms, and will possibly shed light on the general processes of neurodegeneration and nervous system regulation, facilitating the diagnosis, classification and possibly treatment of the affected cases.

Modernity, postmodernity and identity of jazz in Chile : The cases of the generation of 1990 and Ángel Parra

This research is about jazz in Chile in relation to modernity and identity. Final chapters focus and detach latest jazz musician s generation in 1990 decade and composer guitarist Angel Parra. An historic and sociological approach is developed, which will be useful for modernity and identity analysis, and so on post modernity and globalization. Modernity has been studied in texts of Adorno, Baudrillard, Brünner, García Canclini, Habermas and Jameson. Identity has been studied in texts of Aharonián, Cordúa, Garretón, Gissi, Larraín and others. Chapter 3 is about Latin-American musicology and jazz investigations, in relation to approach developed in chapter 2. Chapters 4 and 5 are about history of jazz in Chile until beginning of XXI century. Chapter 6 focuses in Ángel Parra Orrego. Conclusions of this investigation detach the modernist mechanical that has conducted jazz development in Chile, which in Ángel Parra´s case has been overcame by a post modernist behaviour. This behaviour has solved in a creative way, subjects like modernity and identity in jazz practice in a Latin-American country.

Meän tapa puhua : Tornionlaakso pellolaisnuorten subjektiivisena paikkana ja murrealueena

This folk linguistic and human geographic study deals with dialect awareness, dialect use and place attachment. The study discusses theoretical and methodological issues current in sociolinguistics suggesting that the study of attitudes should be regarded as a core area in the study of variation and change. Furthermore, it is suggested that instead of putting effort into improving mental mapping methodology (adopted into folk linguistics from behavioural geography of the 1960 s), the more up-to-date thinking of space in geography should be adopted. The region and the dialect are treated as perceptual constructs in the study. The dialect perceptions of high school seniors in the Finnish Tornio Valley are examined trough a triangulation method involving a questionnaire, interviews and dialect recognition test as the research methods. The h in non-initial syllables (e.g. lähethä(ä)n, saunhaan ~ sauhnaan let s go into sauna ) turns out, expectedly, as the most salient feature in the dialect awareness of the locals and in terms of local identity construction. This feature is no longer heard in most of the present dialects of Finnish but is still thriving in the Tornio Valley in the cross-border dialect area. The metathetic variant (saunhaan > sauhnaan into sauna , käymhään > käyhmään to go ) is a characteristic feature of the Tornio Valley dialect. However, individual differences have long been found in the use of the h. This study challenges the essentialist variationist view of social categories (gender) by analysing variation from a quantitative but emic and human geographic point of view. The study shows that the variation of the h is statistically significantly patterned in terms of the degree of feeling of insideness vs. outsideness. New light is shed on the gender differences found in earlier sociolinguistic studies: differences in dialect use between and inside gender groups are illuminated by the fact that, in this case, it is young women who are generally less attached to the local community than young men, but this does not hold for all the individuals. The ideological motivation for preservation of the h seems to be based on the imagined community of Tornio Valley covering both the Swedish and the Finnish valley area. The general image of the dialect area and it s speakers, the shared cognitive dialect boundaries of the locals and the particularly deep level of awaress of the linguistic variation of the h are notable resources of the Tornio valley identity. Hyperdialectic forms analogical to the most frequently attested metathetic forms are found in the interview data, predicting that in this dialect the h will be maintained also in the future.

Expert Identity in Development of Core-Task-Oriented Working Practices for Mastering Demanding Situations

The point of departure in this dissertation was the practical safety problem of unanticipated, unfamiliar events and unexpected changes in the environment, the demanding situations which the operators should take care of in the complex socio-technical systems. The aim of this thesis was to increase the understanding of demanding situations and of the resources for coping with these situations by presenting a new construct, a conceptual model called Expert Identity (ExId) as a way to open up new solutions to the problem of demanding situations and by testing the model in empirical studies on operator work. The premises of the Core-Task Analysis (CTA) framework were adopted as a starting point: core-task oriented working practices promote the system efficiency (incl. safety, productivity and well-being targets) and that should be supported. The negative effects of stress were summarised and the possible countermeasures related to the operators' personal resources such as experience, expertise, sense of control, conceptions of work and self etc. were considered. ExId was proposed as a way to bring emotional-energetic depth into the work analysis and to supplement CTA-based practical methods to discover development challenges and to contribute to the development of complex socio-technical systems. The potential of ExId to promote understanding of operator work was demonstrated in the context of the six empirical studies on operator work. Each of these studies had its own practical objectives within the corresponding quite broad focuses of the studies. The concluding research questions were: 1) Are the assumptions made in ExId on the basis of the different theories and previous studies supported by the empirical findings? 2) Does the ExId construct promote understanding of the operator work in empirical studies? 3) What are the strengths and weaknesses of the ExId construct? The layers and the assumptions of the development of expert identity appeared to gain evidence. The new conceptual model worked as a part of an analysis of different kinds of data, as a part of different methods used for different purposes, in different work contexts. The results showed that the operators had problems in taking care of the core task resulting from the discrepancy between the demands and resources (either personal or external). The changes of work, the difficulties in reaching the real content of work in the organisation and the limits of the practical means of support had complicated the problem and limited the possibilities of the development actions within the case organisations. Personal resources seemed to be sensitive to the changes, adaptation is taking place, but not deeply or quickly enough. Furthermore, the results showed several characteristics of the studied contexts that complicated the operators' possibilities to grow into or with the demands and to develop practices, expertise and expert identity matching the core task. They were: discontinuation of the work demands, discrepancy between conceptions of work held in the other parts of organisation, visions and the reality faced by the operators, emphasis on the individual efforts and situational solutions. The potential of ExId to open up new paths to solving the problem of the demanding situations and its ability to enable studies on practices in the field was considered in the discussion. The results were interpreted as promising enough to encourage the conduction of further studies on ExId. This dissertation proposes especially contribution to supporting the workers in recognising the changing demands and their possibilities for growing with them when aiming to support human performance in complex socio-technical systems, both in designing the systems and solving the existing problems.

Becoming a teacher: emerging teacher identity in mathematics teacher education

This research examines three aspects of becoming a teacher, teacher identity formation in mathematics teacher education: the cognitive and affective aspect, the image of an ideal teacher directing the developmental process, and as an on-going process. The formation of emerging teacher identity was approached in a social psychological framework, in which individual development takes place in social interaction with the context through various experiences. Formation of teacher identity is seen as a dynamic, on-going developmental process, in which an individual intentionally aspires after the ideal image of being a teacher by developing his/her own competence as a teacher. The starting-point was that it is possible to examine formation of teacher identity through conceptualisation of observations that the individual and others have about teacher identity in different situations. The research uses the qualitative case study approach to formation of emerging teacher identity, the individual developmental process and the socially constructed image of an ideal mathematics teacher. Two student cases, John and Mary, and the collective case of teacher educators representing socially shared views of becoming and being a mathematics teacher are presented. The development of each student was examined based on three semi-structured interviews supplemented with written products. The data-gathering took place during the 2005 2006 academic year. The collective case about the ideal image provided during the programme was composed of separate case displays of each teacher educator, which were mainly based on semi-structured interviews in spring term 2006. The intentions and aims set for students were of special interest in the interviews with teacher educators. The interview data was analysed following the modified idea of analytic induction. The formation of teacher identity is elaborated through three themes emerging from theoretical considerations and the cases. First, the profile of one s present state as a teacher may be scrutinised through separate affective and cognitive aspects associated with the teaching profession. The differences between individuals arise through dif-ferent emphasis on these aspects. Similarly, the socially constructed image of an ideal teacher may be profiled through a combination of aspects associated with the teaching profession. Second, the ideal image directing the individual developmental process is the level at which individual and social processes meet. Third, formation of teacher identity is about becoming a teacher both in the eyes of the individual self as well as of others in the context. It is a challenge in academic mathematics teacher education to support the various cognitive and affective aspects associated with being a teacher in a way that being a professional and further development could have a coherent starting-point that an individual can internalise.

Neural stem cell characteristics affected by oncogenic pathways and in a human motoneuron disease

Neural stem cell characteristics affected by oncogenic pathways and in a human motoneuron disease Stem cells provide the self-renewing cell pool for developing or regenerating organs. The mechanisms underlying the decisions of a stem or progenitor cell to either self-renew and maintain multipotentiality or alternatively to differentiate are incompletely understood. In this thesis work, I have approached this question by investigating the role of the proto-oncogene Myc in the regulatory functions of neural progenitor cell (NPC) self-renewal, proliferation and differentiation. By using a retroviral transduction technique to create overexpression models in embryonic NPCs cultured as neurospheres, I show that activated levels of Myc increase NPC self-renewal. Furthermore, several mechanisms that regulate the activity of Myc were identified. Myc induced self-renewal is signalled through binding to the transcription factor Miz-1 as shown by the inhibited capacity of a Myc mutant (MycV394D), deficient in binding to Miz-1, to increase self-renewal in NPCs. Furthermore, overexpression of the newly identified proto-oncogene CIP2A recapitulates the effects of Myc overexpression in NPCs. Also the expression levels and in vivo expression patterns of Myc and CIP2A were linked together. CIP2A stabilizes Myc protein levels in several cancer types by inhibiting its degradation and our results suggest the same function for CIP2A in NPCs. Our results also support the conception of self-renewal and proliferation being two separately regulated cellular functions. Finally, I suggest that Myc regulates NPC self-renewal by influencing the way stem and progenitor cells react to the environmental cues that normally dictate the cellular identity of tissues containing self-renewing cells. Neurosphere cultures were also utilised in order to characterise functional defects in a human disease. Neural stem cell cultures obtained post-mortem from foetuses of lethal congenital contracture syndrome (LCCS) were used to reveal possible cell autonomous differentiation defects of patient NPCs. However, LCCS derived NPCs were able to differentiate normally in vitro although several transcriptional differences were identified by using microarray analysis. Proliferation rate of the patient NPCs was also increased as compared to NPCs of age-matched control foetuses.

Kidney Induction: control by Notch, Wnt and GDNF/Ret signalling

The permanent mammalian kidney (metanephros) develops as a result of complex reciprocal tissue interactions between a ureteric epithelium and the renal mesenchyme. The overall goal of the research in this thesis was to gain data that will eventually help in elucidating the formation of congenital renal malformations. The experiments in my thesis aimed to reveal the mechanisms by which Notch, Wnt and GDNF/Ret signalling pathways regulate the development of functional kidney. The function of Notch pathway was studied by a transgenic mouse model, where it was shown that overactivation of Notch signalling disturbs kidney development and alters the expression of Gdnf and Ret/GFRa1. This indicates that Notch signalling interplays with GDNF/Ret in the regulation of the primary ureteric budding and its subsequent branching. The data also suggested that strict spatio-temporal regulation of these two pathways is required for determination of ureteric tip-identity, which appeared to be crucial for the branch formation. The function of Wnt signalling in the ureteric morphogenesis was studied by in vivo and in vitro methods to show that a canonical pathway is required for ureteric branching. Stabilisation and deletion of the canonical pathway mediator, b-catenin specifically in the ureteric epithelium result in renal aplasia/hypodysplasia. These defects originate from severe blockage of ureteric branching due to the disrupted Ret signalling. Consequently, ureteric tip specific markers are lost and ureteric stalk identity is expanded throughout the whole epithelium. Thus, the data demonstrates that the Wnt/b-catenin pathway plays an essential role in the patterning and branching of the ureteric epithelium. A novel in vitro method was generated and utilised in nephron induction studies to reveal the mechanisms through which nephrogenesis is induced. Transient GSK3 inhibition results in stabilisation of b-catenin in the isolated renal mesenchyme, which efficiently triggers nephron formation. Also genetic stabilisation of b-catenin specifically in the mesenchyme results in spontaneous nephrogenesis. The results show that activation of the canonical Wnt pathway is sufficient to initiate nephrogenesis, and suggest that this pathway mediates the nephron induction in murine kidney mesenchymes. Taken together, this thesis demonstrates Notch and Wnt signalling pathways as novel regulators of ureteric branching morphogenesis, and that activation of the canonical Wnt pathway is sufficient for nephron induction. The studies also indicate that the Notch and Wnt pathways cross-talk with GDNF/Ret signalling in the patterning of ureteric epithelium.