Novel Roles of HCG/LH Signalling in the Mouse Mammary Gland and its Tumorigenesis.

Breast cancer is the most common cancer in women, and its development is intimately related to hormonal factors, but how hormones affect breast physiology and tumorigenesis is not sufficiently known. Pregnancy elicits long-term protection from breast cancer, but during the first ten years after pregnancy, breast cancer risk is increased. In previous studies, there has been conflicting data on the role of human chorionic gonadotropin (HCG) and the functionality of its receptor in extragonadal tissues. The aim of this study was to elucidate the role of chronically elevated HCG in mouse physiology. We have created a transgenic (TG) mouse model that overexpresses HCG. HCG is similar to lutenizing hormone (LH), but is secreted almost solely by the placenta during pregnancy. HCG and LH both bind to the LH receptor (LHR). In the current study, mammary gland tumors were observed in HCG TG mice. We elucidated the role of HCG in mammary gland signalling and the effects of LHR mediated signalling in mouse mammary gland gene expression. We also studied the effects of HCG in human breast epithelial cell cultures. Several endocrine disturbances were observed in HCGβ TG female mice, resulting in precocious puberty, infertility, obesity and pituitary and mammary gland tumors. The histology of the mammary gland tumors of HCGβ TG females resembled those observed in mouse models with activated Wnt/β-catenin signalling pathway. Wnts are involved in stem cell regulation and tumorigenesis, and are hormonally regulated in the mammary gland. We observed activated β-catenin signalling and elevated expression of Wnt5b and Wnt7b in TG tumors and mammary glands. Furthermore, we discovered that HCG directly regulates the expression of Wnt5b and Wnt7b in the mouse mammary gland. Pharmacological treatment with HCG also caused upregulation of several Wnt-pathway target genes in ovariectomized wild type (WT) mice in the presence of physiological concentrations of estradiol and progesterone. In addition, differential expression of several metabolic genes was observed, suggesting that HCG affects adipocyte function or glucose metabolism. When WT mice were transplanted with LHR deficient or wild type WT mammary epithelium, differential expression of several genes affecting the Wnt-signalling pathway was observed in microarray analysis. Diminished expression of several genes associated with LHR function in other tissues, such as the ovary, was observed in mammary glands deficient of epithelial LHR. In cultured human mammary epithelial cells HCG upregulated the expression of WNT5B, WNT7B similar to mouse, suggesting that the observations found are relevant in human physiology. These studies suggest that HCG/LHR signalling affects gene expression in non-gonadal tissues, and that Wnt-signalling is regulated by HCG/LH in human and mouse mammary glands.

Proportionality and Party Success in Europe

This thesis consists of four articles and an introductory section. The main research questions in all the articles are about proportionality and party success in Europe, at European, national or district levels. Proportionality in this thesis denotes the proximity of seat shares parties receive compared to their respective vote shares, after the electoral system’s allocation process. This proportionality can be measured through numerous indices that illustrate either the overall proportionality of an electoral system or a particular election. The correspondence of a single party’s seat shares to its vote shares can also be measured. The overall proportionality is essential in three of the articles (1, 2 and 4), where the system’s performance is studied by means of plots. In article 3, minority party success is measured by advantage-ratios that reveal single party’s winnings or losses in the votes to seat allocation process. The first article asks how proportional are the European parliamentary (EP) electoral systems, how do they compare with results gained from earlier studies and how do the EP electoral systems treat different sized parties. The reasons for different outcomes are looked for in explanations given by traditional electoral studies i.e. electoral system variables. The countries studied (EU15) apply electoral systems that vary in many important aspects, even though a certain amount of uniformity has been aspired to for decades. Since the electoral systems of the EP elections closely resemble the national elections, the same kinds of profiles emerge as in the national elections. The electoral systems indeed treat the parties differentially and six different profile types can be found. The counting method seems to somewhat determine the profile group, but the strongest variables determining the shape of a countries’ profile appears to be the average district magnitude and number of seats allocated to each country. The second article also focuses on overall proportionality performance of an electoral system, but here the focus is on the impact of electoral system changes. I have developed a new method of visualizing some previously used indices and some new indices for this purpose. The aim is to draw a comparable picture of these electoral systems’ changes and their effects. The cases, which illustrate this method, are four elections systems, where a change has occurred in one of the system variables, while the rest remained unchanged. The studied cases include the French, Greek and British European parliamentary systems and the Swedish national parliamentary system. The changed variables are electoral type (plurality changed to PR in the UK), magnitude (France splitting the nationwide district into eight smaller districts), legal threshold (Greece introducing a three percent threshold) and counting method (d’Hondt was changed to modified Sainte-Laguë in Sweden). The radar plots from elections after and before the changes are drawn for all country cases. When quantifying the change, the change in the plots area that is created has also been calculated. Using these radar plots we can observe that the change in electoral system type, magnitude, and also to some extent legal threshold had an effect on overall proportionality and accessibility for small parties, while the change between the two highest averages counting method had none. The third article studies the success minority parties have had in nine electoral systems in European heterogeneous countries. This article aims to add more motivation as to why we should care how different sized parties are treated by the electoral systems. Since many of the parties that aspire to represent minorities in European countries are small, the possibilities for small parties are highlighted. The theory of consociational (or power-sharing) democracy suggests that, in heterogeneous societies, a proportional electoral system will provide the fairest treatment of minority parties. The OSCE Lund Recommendations propose a number of electoral system features, which would improve minority representation. In this article some party variables, namely the unity of the minority parties and the geographical concentration of the minorities were included among possible explanations. The conclusions are that the central points affecting minority success were indeed these non-electoral system variables rather than the electoral system itself. Moreover, the size of the party was a major factor governing success in all the systems investigated; large parties benefited in all the studied electoral systems. In the fourth article the proportionality profiles are again applied, but this time to district level results in Finnish parliamentary elections. The level of proportionality distortion is also studied by way of indices. The average magnitudes during the studied periodrange from 7.5 to 26.2 in the Finnish electoral districts and this opens up unequal opportunities for parties in different districts and affects the shape of the profiles. The intra-country case allows the focus to be placed on the effect of district magnitude, since all other electoral systems are kept constant in an intra-country study. The time span in the study is from 1962 to 2007, i.e. the time that the districts have largely been the same geographically. The plots and indices tell the same story, district magnitude and electoral alliances matter. The district magnitude is connected to the overall proportionality of the electoral districts according to both indices, and the profiles are, as expected, also closer to perfect proportionality in large districts. Alliances have helped some small parties to gain a much higher seat share than their respective vote share and these successes affect some of the profiles. The profiles also show a consistent pattern of benefits for the small parties who ally with the larger parties.

Cultural Diversity, Social Cohesion, Religion: Core Values and Educational Policies in Four European Nations

In my doctoral thesis I evaluate strategies designed to cope with the multicultural nature of four European nations: Great Britain, The Netherlands, Sweden, and Denmark. I also analyse and clarify the question of the place of religion in present-day Europe. The empirical material analysed in the study consists of politicians’ statements and policy documents dealing with immigration policy and religious and values education in the four countries. In addition, I analyse statements issued by the Council of Europe regarding religious education, along with all cases relevant to religious education brought before the United Nations Human Rights Committee or the European Court of Human Rights. The theoretical framework is formed by the scholarly debate – among philosophers, sociologists and scholars of religion in education – concerning the question of a just society. Special emphasis is given to philosophical theories that are in favour of granting special group rights to religious minorities in the name of equal treatment. With regard to the question of the appropriate place of religion, I apply Kim Knott’s methodological model for locating religion in secular contexts, and Émile Durkheim’s theory as to the significance of religion and collective sentiments in uniting adherents or members of a group into a single moral community. The study shows that even when the positive side of immigration, as a potential force for the enrichment of the public culture, is acknowledged, there is anxiety as to the successful integration of immigrants. The premises and goals of immigration policies have also been questioned. One central problem is the incommensurability between the values upheld by Western liberal democracies and certain religious traditions, above all those of Islam. Great Britain, The Netherlands, Sweden, and Denmark have tightened control over their citizens’ ethical attitudes and want to regulate these as well. In coping with cultural diversity, the significance of education, especially religious education, plays a significant role; as future citizens, pupils are expected to internalise the society’s core values as well as gaining an understanding of different cultures and ways of life. It is also worth noting that both the Council of Europe and the European Court of Human Rights have recently expressed the view that one important goal of religious education is to enable pupils to be critical and autonomous with regard to different religions and moral positions. The study shows that religion is not seen as purely a personal matter. Religion is closely linked to individual and national identity, and religious traditions thus have a place in the public domain. It should be noted, however, that a religious tradition – more precisely, an interpretation of religious tradition – qualifies as a legitimate partner in the democratic decision-making process only if it shares similar values with Western European nations.

Negotiating home and belonging. Young Kurds in Finland

This study looks at negotiation of belonging and understandings of home among a generation of young Kurdish adults who were born in Iraq, Iran, and Turkey and who reached adulthood in Finland. The young Kurds taking part in the study belong to the generation of migrants who moved to Finland in their childhood and early teenage years from the region of Kurdistan and elsewhere in the Middle East, then grew to adulthood in Finland. In theoretical terms, the study draws broadly from three approaches: transnationalism, intersectionality, and narrativity. Transnationalism refers to individuals’ cross-border ties and interaction extending beyond nationstates’ borders. Young people of migrant background, it has been suggested, are raised in a transnational space that entails cross-border contacts, ties, and visits to the societies of departure. How identities and feelings of belonging become formed in relation to the transnational space is approached with an intersectional frame, for examination of individuals’ positionings in terms of their intersecting attributes of gender, age/generation, and ethnicity, among others. Focus on the narrative approach allows untangling how individuals make sense of their place in the social world and how they narrate their belonging in terms of various mechanisms of inclusion and exclusion, including institutional arrangements and discursive categorisation schemes. The empirical data for this qualitative study come from 25 semi-structured thematic interviews that were conducted with 23 young Kurdish adults living in Turku and Helsinki between 2009 and 2011. The interviewees were aged between 19 and 28 years at the time of interviewing. Interview themes involved topics such as school and working life, family relations and language-learning, political activism and citizenship, transnational ties and attachments, belonging and identification, and plans for the future and aspirations. Furthermore, data were collected from observations during political demonstrations and meetings, along with cultural get-togethers. The data were analysed via thematic analysis. The findings from the study suggest that young Kurds express a strong sense of ‘Kurdishness’ that is based partially on knowing the Kurdish language and is informed by a sense of cultural continuity in the diaspora setting. Collective Kurdish identity narratives, particularly related to the consciousness of being a marginalised ‘other’ in the context of the Middle East, are resonant in young interviewees’ narrations of ‘Kurdishness’. Thus, a sense of ‘Kurdishness’ is drawn from lived experiences indexed to a particular politico-historical context of the Kurdish diaspora movements but also from the current situation of Kurdish minorities in the Middle East. On the other hand, young Kurds construct a sense of belonging in terms of the discursive constructions of ‘Finnishness’ and ‘otherness’ in the Finnish context. The racialised boundaries of ‘Finnishness’ are echoed in young Kurds’ narrations and position them as the ‘other’ – namely, the ‘immigrant’, ‘refugee’, or ‘foreigner’ – on the basis of embodied signifiers (specifically, their darker complexions). This study also indicates that young Kurds navigate between gendered expectations and norms at home and outside the home environment. They negotiate their positionings through linguistic repertoires – for instance, through mastery of the Finnish language – and by adjusting their behaviour in light of the context. This suggests that young Kurds adopt various forms of agency to display and enact their belonging in a transnational diaspora space. Young Kurds’ narrations display both territorially-bounded and non-territorially-bounded elements with regard to the relationship between identity and locality. ‘Home’ is located in Finland, and the future and aspirations are planned in relation to it. In contrast, the region of Kurdistan is viewed as ‘homeland’ and as the place of origins and roots, where temporary stays and visits are a possibility. The emotional attachments are forged in relation to the country (Finland) and not so much relative to ‘Finnishness’, which the interviewees considered an exclusionary identity category. Furthermore, identification with one’s immediate place of residence (city) or, in some cases, with a religious identity as ‘Muslim’ provides a more flexible venue for identification than does identifying oneself with the (Finnish) nation.

Political Legitimacy and Ethnocultural Justice. Essays on Public Reason, Democratic Citizenship, and the Rights of Cultural Minorities

In this thesis, I argue that there are public cultural reasons that can underpin public justifications of minority rights of indigenous and national minorities in a constitutionaldemocracy. I do so by tackling diverse issues facing a liberal theory of multiculturalism. In the first essay, I criticize Will Kymlicka’s comprehensive liberal theory of minority rights and propose a political liberal alternative. The main problem of Will Kymlicka’s theory is that it builds on the contestable liberal value of individual autonomy and thus fails to take diversity seriously. In the second essay, I elaborate on the Rawlsian political liberalism assumed here by criticizing Chandran Kukathas’s version of political liberalism as overly accommodating to diversity. In the third essay, I discuss questions of method that arise for a political liberal approach to the moral-political foundations of multiculturalism, and propose a certain understanding of the political liberal enterprise and its crucial standard of reasonableness. In the fourth essay, I dwell on the political liberal ethic of citizenship and propose a strongly inclusionist interpretation of the duty of civility. In the fifth and last essay, I introduce a certain understanding of ethnocultural justice and propose a view on certain cultural reasons as public cultural reasons. Cultural reasons are public when they are based on necessarily established cultural marks of a democratic polity, as specified by the cultural establishment view; and when they are crucial for the societal cultural bases of self-respect of citizens. The arguments in this thesis support, and help to spell out, moral-political rights of indigenous and national minorities as formulated in international legal documents, such as the Declaration on the Rights of Indigenous Peoples (United Nations 2007) or the International Covenant on Economic, Social and Cultural Rights (United Nations 1966).

Etnistä identiteettiä luomassa Euroopan rajoilla

Kirjallisuusarvostelu

Kansalliset vähemmistöt ja Weimarin perustuslain synty

Kirjallisuusarvostelu

Targeting oncogenic signaling proteins : new insights using a FRET-based chemical biology approach

Cancer affects more than 20 million people each year and this rate is increasing globally. The Ras/MAPK-pathway is one of the best-studied cancer signaling pathways. Ras proteins are mutated in almost 20% of all human cancers and despite numerous efforts, no effective therapy that specifically targets Ras is available to date. It is now well established that Ras proteins laterally segregate on the plasma membrane into transient nanoscale signaling complexes called nanoclusters. These Ras nanoclusters are essential for the high-fidelity signal transmission. Disruption of nanoclustering leads to reduction in Ras activity and signaling, therefore targeting nanoclusters opens up important new therapeutic possibilities in cancer. This work describes three different studies exploring the idea of membrane protein nanoclusters as novel anti-cancer drug targets. It is focused on the design and implementation of a simple, cell-based Förster Resonance Energy Transfer (FRET)-biosensor screening platform to identify compounds that affect Ras membrane organization and nanoclustering. Chemical libraries from different sources were tested and a number of potential hit molecules were validated on full-length oncogenic proteins using a combination of imaging, biochemical and transformation assays. In the first study, a small chemical library was screened using H-ras derived FRET-biosensors. Surprisingly from this screen, commonly used protein synthesis inhibitors (PSIs) were found to specifically increase H-ras nanoclustering and downstream signalling in a H-ras dependent manner. Using a representative PSI, increase in H-ras activity was shown to induce cancer stem cell (CSC)-enriched mammosphere formation and tumor growth of breast cancer cells. Moreover, PSIs do not increase K-ras nanoclustering, making this screening approach suitable for identifying Ras isoform-specific inhibitors. In the second study, a nanoncluster-directed screen using both H- and K-ras derived FRET biosensors identified CSC inhibitor salinomycin to specifically inhibit K-ras nanocluster organization and downstream signaling. A K-ras nanoclusteringassociated gene signature was established that predicts the drug sensitivity of cancer cells to CSC inhibitors. Interestingly, almost 8% of patient tumor samples in the The Cancer Genome Atlas (TCGA) database had the above gene signature and were associated with a significantly higher mortality. From this mechanistic insight, an additional microbial metabolite screen on H- and K-ras biosensors identified ophiobolin A and conglobatin A to specifically affect K-ras nanoclustering and to act as potential breast CSC inhibitors. In the third study, the Ras FRET-biosensor principle was used to investigate membrane anchorage and nanoclustering of myristoylated proteins such as heterotrimeric G-proteins, Yes- and Src-kinases. Furthermore, Yes-biosensor was validated to be a suitable platform for performing chemical and genetic screens to identify myristoylation inhibitors. The results of this thesis demonstrate the potential of the Ras-derived FRETbiosensor platform to differentiate and identify Ras-isoform specfic inhibitors. The results also highlight that most of the inhibitors identified predominantly perturb Ras subcellular distribution and membrane organization through some novel and yet unknown mechanisms. The results give new insights into the role of Ras nanoclusters as promising new molecular targets in cancer and in stem cells.

Slits in container wall improve root structure and stem straightness of outplanted Scots pine seedlings

Abstract

Stem straightness and compression wood in a 22-year-old stand of container-grown Scots pine trees

Abstract