Väitöskirjat

Recent Submissions

  • Robciuc, Alexandra (Helsingin yliopisto, 2017)
    The cornea is the first optical element of the eye and, together with the eyelids, eye socket, tears, and sclera, shares an important part in ocular protection. It is a thin, transparent, avascular tissue with a rigorous layered structure. The continuous contact with the outside environment exposes the ocular surface tissues, such as the corneal epithelium, to pathogens, mechanical traumas, irritants, toxins, allergens, or radiation from the sun. The cellular stress response represents an adaptive reaction to environmental stimuli and defines the health-state of the tissue, the absence/presence of clinical manifestations. We have aimed in this thesis project to study the stress response of the corneal epithelium to environmental stimuli and to determine its contribution to ocular surface diseases such as climatic droplet keratopathy (CDK), infection, or dry eye disease. A cell culture model of the corneal epithelium was exposed to environmental stress – UV radiation, LPS, or hyperosmolarity (HO) – to identify macromolecular alterations: mRNA expression, protein localization, enzyme activation, lipid conversions. CDK is a degenerative disease of the cornea with increased prevalence in warm, dry climate. Examination of corneal tissue and tears from patients with CDK suggested an involvement of metalloproteinases (MMPs) in the disease-associated tissue degradation. Our cellular model helped reveal the connexion between UV radiation and the unbalanced secretion of gelatinases (MMP-2 and MMP-9) and thus explain in part the pathogenesis of this rare disease. The evaluation of the inflammatory response to UV, initially, and then to LPS, or HO, highlighted IL-8 secretion as an acute stress marker and followed throughout the studies. Human corneal epithelial cells were found also to release lipid-modifying enzymes into the cell culture medium as a response to stress. Of particular importance to us were the enzymes of the sphingolipid metabolism, a lipid signalling pathway of great importance in the stress response. These enzymes were released as part of cell-derived extracellular vesicles, the vesicle-lipids, however, were the mediators of a significant decrease in IL-8 levels. The same sphingolipid enzymes appeared responsible for the intracellular response to HO, controlling the IL-8 production but also the stress-induced neutral lipid loading. We have therefore succeeded to establish a causative link between UV radiation and tissue degeneration in CDK, to determine the role of the sphingolipid signalling pathway in ocular surface stress and to discover more about HO consequences in the corneal epithelium. The stress response at the ocular surface is a thin balance between tissue protection and maintenance of function. Inflammation represents one of the most relevant clinical signs of distress and we aimed to identify targets for therapies that seek to restore tissue homeostasis.
  • Pyykönen, Aura (Helsingin yliopisto, 2017)
    Optimal care of pregnant women and newborn babies has an immeasurable effect on the well-being of a family, but it also significantly impacts society overall. In Finland, the quality of obstetric and perinatal care is high, but in order to further improve it, sensitive and commonly agreed quality indicators are required. The aim of the thesis was to validate different potential quality indicators for obstetric care, and to assess differences between different hospital size-categories in Finland. To facilitate reliable comparisons for benchmarking, we evaluated the usability of the Robson classification, a system for grouping the parturient population. This was done as an international comparison between the Nordic countries. The thesis also aims to contribute to more unified and high-quality obstetric care by examining the optimal time of labor induction in prolonged pregnancies. This thesis is based on data from the medical birth registries in Finland and in the other Nordic countries. The findings of this thesis indicate true differences in the obstetric management and treatment culture between the Nordic countries and between different-sized birth units in Finland. However, it should be acknowledged that part of the differences may be explained by confounding background factors. The results enforce the existing evidence on the effect of birth centralization on neonatal outcomes, e.g. lower neonatal mortality in large units, but indicate a higher risk for instrumental delivery. Obstetric trauma, a potentially preventable complication of vaginal delivery, showed substantial size-dependent variation between the Finnish birth units; the risk was the lowest in mid-sized birth units. The Robson classification proved to bed usable in the Nordic setting, facilitating more accurate comparisons, but comprehensive interpretations require experience and expertise. In our study on the effect of labor induction in prolonged pregnancy, we found an increased risk for Cesarean section around 41 gestational weeks, but no longer when the gestational age approached 42 weeks. From a neonatal perspective, labor induction resulted in a decreased risk for meconium aspiration syndrome, but only when the intervention took place before 41+5 weeks. Labor induction did not have a significant effect on neonatal mortality. International and inter-unit benchmarking pinpoints the areas needing improvement; e.g. prevention of obstetric trauma or induction protocols among nulliparous women. Some indicators, such as Cesarean section rates within Robson groups, show potential for readily directing obstetric practices, and are therefore of special interest. Like our neighboring countries Denmark and Sweden, we should establish a national quality monitoring program for obstetric care in Finland, to ensure its high-quality care also in the future.
  • Ikonen, Jussi (Helsingin yliopisto, 2017)
    The geological disposal of spent nuclear fuel may represent a good solution after a thorough risk assessment. In Finland and Sweden, the host rock for geological disposal is crystalline rock and the repository is based on the Swedish KBS-3 multi-barrier design. When radionuclides from spent nuclear fuel are potentially released into the bedrock, they are then transported by advection along water-conducting fractures. The retardation of radionuclides can occur via molecular diffusion into stagnant pore water and/or via chemical retardation onto mineral surfaces in the rock matrix. When assessing the risk of spent nuclear fuel deposition, it is important to understand the transport behaviour of radionuclides in the bedrock, that is, at the rock–groundwater interface. Most parameters, such as the diffusion coefficient, the distribution coefficient and the rock porosity, associated with radionuclide migration in the rock are obtained from laboratory scale experiments. In order to apply results from laboratory experiments to the full-scale nuclear fuel deposition, in-situ experiments are performed. For example, the Swiss National Cooperative for the Disposal of Radioactive Waste (Nagra) have been conducting extensive in-situ experiments at the Grimsel Test Site (GTS). During the first in-situ test, tritiated water (HTO), 22Na, 134Cs and 131I, as well as non-radioactive isotopes 127I and 23Na, were circulated in a borehole interval isolated by packers 70 cm apart from each other. The second ongoing Long Term Diffusion (LTD) experiment primarily uses the same radionuclides as well as the non-radioactive element selenium. This thesis presents the laboratory analysis of HTO and iodine from an in-situ diffusion experiment and supporting laboratory studies aimed at determining the sorption and diffusion of caesium and selenium on Grimsel granodiorite (GG). Caesium sorption was studied through batch sorption experiments using crushed rock, while selenium diffusion and sorption relied on batch and block scale experiments using Kuru grey granite (KGG) and GG rock blocks. HTO and iodine diffusion was modelled using the time domain diffusion (TDD) method among in in-situ rock blocks as well as selenium in a laboratory using rock blocks. The outleaching method proved successful for analysing non-sorbing radionuclides from the connected pore network of the GG. TDD modelling of the results lead to an apparent diffusion coefficient of 3 × 10-10 m2/s for both HTO and iodine. No significant difference between the in-situ and laboratory diffusion coefficient was detected. Caesium sorption stood at 0.107 ± 0.003 m3/kg on GG at a 10−8 M Cs concentration. Sorption was highest on biotite at Kd = 0.304 ± 0.005 m3/kg, explaining the in-situ diffusion results of caesium which followed the biotite veins in GG. The sorption of selenium was significantly overestimated when the determination was conducted on crushed rock using the batch sorption method compared to studies conducted on intact rock. The outleaching method proved successful in the analysis of non-sorbing radionuclides, while flexible TDD modelling proved to be a quite useful tool in handling measured data from both block scale experiments and in-situ experiments of weakly and non-sorbing tracers.
  • Ajo, Martti (Helsingin yliopisto, 2017)
    Sigfrid Sirenius (1877–1961), Doctor of Theology, was a pioneer of the modern social Christian ideas and the founder of the Finnish Settlement movement. The link between God’s kingdom and the labour movement was essential both in Sirenius’ theologic-ideological thinking and in his Christian values based civic activity. Sirenius’ God’s kingdom ideology was a result of a multiphase process. It grew from the soil of both German Württembergian and Anglo-Saxon Pietism. The aiming point of Sirenius’ ideology was to strengthen the connection between the Church and the labour movement and to repress secularism. On the threshold of the General Strike (1905) Sirenius left for seamen’s mission to Antwerp and later to London. In England a cosmopolite seamen’s minister increasingly applied himself to labour question and received heavy influence from the British labour movement. While studying Anglican Church, Sirenius got familiar with the settlement movement, which drew ideas from Christian socialism. Sirenius radical Christian values based civic activity began in 1913, after F. Herbert Stead had paid a visit to Finland. The purpose of visit was to further labourizing SDP. On the factory areas Sirenius agitated on behalf of Christian socialism. He preached for the labourer about earthly God’s kingdom, which could be built by means of Social Democrats. The outbreak of the Civil War meant a setback for his endeavours to labourize the SDP. After the War he was one of the few ministers who stayed in touch with the SDP. In 1918 Sirenius found Finnish Settlement Movement. After the Civil War SDP had their suspicions about the Christian values based civic activity made by Sirenius. Due to his situation, he approached the Agrarian League and the party’s leading figure, Santeri Alkio. In the Northern Finland Sirenius teamed up with the Lapland Trio. Their goal was to spread social Christian ideology among log floaters in Lapland and to fight against materialistic Communism. The international conference of the religious socialists, held in Barchem 1924, became revolutionary to the development of Sirenius’ God’s kingdom ideology. In the conference Sirenius met L. Ragaz. And via Ragaz, Sirenius got familiar with the chiliastic God’s kingdom ideology and apokatastasis-yearning formed by Johann Christoph and Christoph Blumhardt. Blumhardt Jr. was a Social Democrat.
  • Kyllönen, Simo (Helsingin yliopisto, 2017)
    The thesis explores critically some of the theoretical suggestions offered in the literature of environmental political philosophy to overcome the ecological challenges and suggests some promising ways forward. According to the thesis, complexity of the ecological problems, uncertainty related to them, and vulnerability to disagreements because of this, speak in favour of democratic justification of the authority: no other way of resolving the disagreements in the uncertain and complex world can be claimed to be epistemically and morally superior to democracy. Moreover, because appropriately democratic processes are able to show publicly that the (possibly) disputing interests of people are treated in equal and fair manner, the democratic outcomes are able to gain more legitimacy than those resorting solely to the environmentally grounded epistemic (eco)-authority. While democratic processes remain an essential way to produce legitimately authoritative environmental outcomes, the global and intergenerational scope of the problems requires a justification that transcends the democratic processes themselves. Here the thesis defends a Rawlsian kind of contractualism as a way to justify the authority of some global and intergenerational principles and argues that even in the existing non-ideal circumstances the Rawlsian principle of fairness gives us some guidance about the limits within which our societal institutions, laws, and policies deserve our compliance. In addition, the thesis defends the common sense no-harm principle that holds irrespective of the institutional arrangements between people. ¬Due to vast dispersion of causes and effects, a growing number of environmental ethicists have doubted its applicability in the context of large-scale environmental problems at all. Some others have proposed its application at the collective level. Contrary to these authors, the thesis provides a defence of the individualistic no-harm principle as a common-sense way to justify individuals’ duties to change their environmentally harmful behaviour and to promote more effective collective and institutional ways to prevent environmental harm. Finally, the thesis defends a sufficientarian understanding of social justice as the most plausible and coherent way to connect local, global and intergenerational demands. It is also suggested that the sufficientarian approach is capable of overcoming some theoretical challenges that rise at the intergenerational context, in which our choices have an influence not only on how well- or badly-off people in the future are, but also on who those future people are.
  • Mayer, Minna (Helsingin yliopisto, 2017)
    Finnish development cooperation in the field of meteorology has continued for nearly 50 years and over 100 countries have been beneficiaries of this aid. Cooperation in this field is complex, it brings together public and private sector actors and experts from different backgrounds. Projects have succeeded in capacity development, but have struggled with sustainability. Local capacity often lowers after projects ends. Data includes interviews (n=56) with experts from the Finnish Meteorological Institute, Vaisala, Ministry for Foreign Affairs and 8 recipient countries. Archive material and policy documents are also included in analysis. Exploratory case study method applying conventional content analysis is used. The objective of the study is to explore the underlying issues influencing the challenge of sustainability. Theoretical framework includes a combination of concepts and theories: governmentality (Foucault) and analytics of government (Dean), power theories (Lukes, Clegg and French & Raven) and approaches regarding patterns of aid behavior (Hydén and Mease, Gibson et al., Burnell and Mosse). Historical analysis shows the various phases of these projects, and reflects them to the history of Finnish aid from the late 1960s to the 2010s. Experts’ experiences from the grass-roots level form an important basis for the analysis. Policy analysis shows that projects have been well-fitting with development policies up until the 2000s, after which the gap between policy and practice has widened. Cooperation is focused more on technology and less to the societal aspects of meteorology. The Ministry is not involved in practice, allowing projects to be driven towards more technology-oriented goals by the experts of meteorology, many of which who have adopted an “apolitical” strategy. This weakens connections between projects and local people. Private sector experts have adopted an opposing strategy, and engage actively with politicians, who are able to make decisions regarding purchasing of meteorological equipment. Analysis shows that all important decisions within the aid system "come from above", bureaucracy is heavy and control is tight. Lack of flexibility and trust within the system lowers the influence of the projects. Differences between the donor stakeholders are found in general approaches to key issues. Power analysis shows that the Ministry holds the most influential forms of power, while FMI and Vaisala hold mainly dispositional power. Recipients of aid lack access to important forms of power, yet they are expected to sustain capacity after projects ends. Several “donor traps” are also found to actualize, which influence outcomes of aid. In order to make projects truly sustainable for the aid recipients, the donor would have to give up some power and through that, also some accountability. This is nearly an impossible choice, since both are highly important for the donor. This study finds that within the current system, there is no one actor who has both motive and power to change aid. For the sake of the future, this is a significant challenge to overcome regarding the role of the developing nations, as well as the renewal of the aid system.
  • Kilpi, Fanny (Helsingin yliopisto, 2017)
    Social inequalities in coronary heart disease (CHD) are a notable feature of modern societies, and create a major population health burden. Though CHD incidence and mortality have been in decline in past decades, the absolute and relative inequalities by socioeconomic position (SEP) remain substantial. This thesis investigates the influence of different social determinants on MI incidence and fatality amongst ageing Finnish cohorts. The focus lies on the interdependent and independent effects of several dimensions of SEP (education, occupation, income and wealth), living arrangements and partner characteristics. The study used longitudinal study designs with large nationally representative samples derived from Finnish registers. Education, occupation, income and wealth may all serve as indicators of SEP, yet denote different types of resources with varying health consequences. The findings demonstrated that distinct relationships with MI incidence and survival were observed when comparing their independent effects. Education and occupation strongly predict MI incidence, in contrast to the more robust connection between material resources and MI fatality. Wealth, however, differed from income in that it appears to play a role at both stages of disease. In addition, the effects of education and income were observed as independent from early socioeconomic circumstances, while childhood factors such as parental education, occupation and household crowding showed modest persisting associations with MI incidence. The findings from this study support the notion that living arrangements are important factors for MI survival. Amongst men, cohabiting with a marital or non-marital partner was associated with better outcomes than living alone. Amongst women, however, marital benefits depended on material resources, while cohabiting with a non-marital partner was associated with an elevated fatality risk. The results also indicate that the partner’s education substantially impacted women in the long-term aftermath of MI, providing further evidence that the health benefits of relationships may be at least partly contingent upon the socioeconomic resources of one’s partner. For both men and women, the partner’s education appeared to serve as an additional socioeconomic resource influencing cardiac health outcomes. The findings underscore the importance of both individual and household-level socioeconomic resources for health and mortality, and demonstrate how the health consequences of social relationships and socioeconomic resources have significant overlap. In light of the attempts to reduce inequalities in CHD mortality, more attention needs to focus on the distinct influences operating at different stages of disease, using a life course perspective on the upstream determinants of risk factors in the CHD aetiology.
  • Kuuluvainen, Emilia (Helsingin yliopisto, 2017)
    Precise control of transcription, the copying of the genetic DNA code to an expressed RNA molecule, is fundamental for all processes of an organism. Transcriptional regulation is dependent on the activity of proteins and protein complexes including general and cell specific transcription factors and co-activators. Studying how these transcriptional regulators function is crucial for understanding processes such as development and disease. This PhD thesis focuses on the function of one evolutionarily conserved transcriptional co-activator, called the Mediator complex, and in particular on the role of its kinase module. This kinase module consists of four proteins: Cdk8, cyclin C, Med12 and Med13 in lower metazoans and CDK8 or CDK19, cyclin C, MED12 or MED12L and MED13 or MED13L in vertebrates. The Mediator kinase module regulates transcription through various mechanisms, including association with transcription factors and regulation of enhancer-dependent transcription. Kinase module deregulation is implicated in developmental disorders and cancer, but the molecular mechanisms underlying these diseases remain poorly understood. CDK8 was found to be dispensable for cell-autonomous survival but required for mouse embryonic development at the pre-implantation stage. Cdk8-CycC-mediated regulation of transcription was dependent on Med12-Med13 while Cdk8 and CycC depletion caused distinct and even opposite effects on gene expression as compared to Med12 and Med13 depletion in fruit fly cells. This work identified highly similar effects on transcription after depletion of fruit fly Med12 or Med13, suggesting limited Med12-independent functions for Med13. Kinase module subunit hierarchy was conserved in human colon cancer cells where depletion of MED12 or double depletion of the redundant MED13 and MED13L also resulted in highly similar transcriptional responses. Med12 and Med13 were found to be activators of innate immunity genes that are dependent on the serpent/GATA transcription factor in fruit fly cells and larvae. In human colon cancer cells, MED12, MED13 and MED13L were disproportionally required for the expression of genes associated with cancer-acquired super-enhancers. MED12 or MED13 and MED13L depletion caused a dramatic decrease in the expression of the super-enhancer associated MYC oncogene and impaired proliferation of colon cancer cells, suggesting that targeting of these kinase module subunits is a possible future therapeutic opportunity. This thesis extends the present understanding of the relationships between Mediator kinase module subunits in metazoan species and identifies kinase module-dependent functions in development, immunity and cancer-acquired transcription. Further research should be directed at studying the molecular mechanisms of kinase module functions in vivo and at the potential to target this complex with the goal of treating human diseases such as cancer.
  • Ahtiainen, Raisa (Helsingin yliopisto, 2017)
    Change-theories and theoretical conceptualizations of educational development are the primary focal points of this investigation. Michael Fullan’s and Andy Hargreaves’s change theories are examined for their breadth and depth. Then the Finnish special educational reform measures (2005–2012) are investigated. The research questions concern 1) what are the key characteristics of selected Fullan’s and Hargreaves’s works? 2) What are the most compelling similarities and differences in the theoretical models of educational change? 3) To what extent is the construction of a synthesized Fullan-Hargreavesian change model of value and even possible? 4) How well does a Fullan-Hargreavesian model apply to Finnish special education reform? Three data sets undergird the research: 1) Interview data. Fullan was interviewed in 2013 and Hargreaves in 2011; 2) Selected works from Fullan (n=4) and Hargreaves (n=4), and 3) Finnish policy documents (n=19) representing different phases of the entire reform process in 2005–2012. The examination of Fullan’s and Hargreaves’s theories resulted in two lines of thought about educational change. Alongside theoretical aspects lie an assortment of professional practice pathways. They were gleaned through interview data and substantiated through analysis of their literature. By combining their change-theoretical approaches a Fullan-Hargreavesian model was constructed consisting of four categories: Entry, Objective, Dissemination, and Impact. Through the conceptual framework of change the nature and content of political eloquence in the policy documents became visible, the process explicated upper and lower level reasons for the reform, visiting the means for disseminating the new policy, and reflected the means for evaluating the impact of the reform measures in Finland. The contributions to the field of educational change are multifold, including the examination and comparison, and the incorporation of Fullan’s and Hargreaves’s change-theories. The quest is to deliver an innovative theoretical approach to policy analysis. The analysis of the Finnish reform process points toward a new phase in the theoretical model, Preparation, as a type of understanding of long-term pre-reform happenings, and a dimension that is absent in Fullan’s and Hargreaves’s theories included in this study. The field of special education benefits from the thorough description of the reform process, and the analytical approach to the reform process brings new insights to the research in that field. The Finnish education system, and no doubt many other systems, could benefit from a more systematic and well-structured theory-oriented approach to educational change that would be applied in the early stages of the process.
  • Mikula, Kornelia (Helsingin yliopisto, 2017)
    During host invasion, pathogenic bacteria express a variety of virulence factors that facilitate their escape from the immune system and thus enable propagation of the infection. The trimeric autotransporter adhesins (TAAs) are one example of a specialised virulence factors expressed by many Gram- negative bacteria, such as Yersinia spp, Escherichia coli, Moraxella catarrhalis, and others. TAAs are highly modular proteins consisting of passenger and translocation domain. Passenger domains are variable domains, constructed of repetitive, structurally homologous subdomains: heads, connectors and stalks. In contrast, the translocation domain is a highly conserved β-barrel anchoring the passenger into the outer membrane of bacteria. TAAs are a key part of Gram-negative bacterial virulence, and as such could be potential drug targets. However, to develop novel drugs, we need to understand the nature of TAAs as well as the molecular details of their interactions with host molecules. In my thesis, I showed that the intact TAA translocation domain is essential and capable of translocating heterologous passengers to the bacterial cell surface. Additionally, heterotrimeric passenger domains have the functionality of the individual monomers, which can generate an extra diversity on the bacterial cell surface to combat immune attack, especially as multiple TAA genes are present in one bacterium. In addition, I have solved the structure of a fragment of the ubiquitous surface protein A (UspA1) from M. catarrhalis, revealing the C3d-binding surface. C3d binding by UspAs is essential in serum resistance preventing formation of the membrane attack complex. Finally, I studied interactions between E. coli immunoglobulin binding protein D (EibD) and IgG Fc. Eibs bind to the Fc region of IgG and IgA in a non-immune manner, which appears to mask the bacterium from the immune system. Attempts to solve crystallographic structure of the EibD-Fc complex were not successful, but they resulted in the another binding. I showed that a single mutation within the linker region between CH2 and CH3 domains of IgG Fc could drastically change the relative structural arrangement of constant heavy chains 2 and 3.
  • Nyrhinen, Hannu (Helsingin yliopisto, 2017)
    For a hundred years Einstein's general relativity (GR) has persisted as the standard model of gravity. To date, no observations conflict it. Moreover, GR has predicted effects that have been later confirmed, such as the deflection of light, the redshift of light in gravitational field, and gravitational waves. Modifications to GR have been studied since the early days of relativistic gravity. In this thesis, we present three projects on different modified gravity models. These include Palatini f(R), bimetric variational principle, and scalar-tensor theories. In Palatini f(R) theories, a function of the Ricci scalar, f(R), acts as the gravitational Lagrangian. The connection is independent of the metric. In GR, the function f(R) = R, and the Einstein equations follow regardless of whether or not the connection is independent. We show that for a system of compact objects, the difference between Palatini f(R) and GR is the scaling of masses. However, without complementary measurement of masses, such systems are observationally indistinguishable. In bimetric variational principle, the independent spacetime connection is constructed of a tensor apart from the physical metric. The physical metric and this new tensor then give the field equations. We study Einstein-Hilbert and f(R) actions of the Ricci scalar of the connection. We use ADM formalism to show that without further constraints the resulting Hamiltonian contains a dynamical variable without a lower bound. This leads to decaying to lower energy states by radiating energy ad infinitum. Hence, these theories are physically unviable. We also study scalar-tensor theories with disformally coupled matter. In these theories matter couples to the scalar field and its derivatives. We focus on a system of disformally coupled matter surrounding a black hole. In Brans-Dicke-type theories such systems suffer from the so called spontaneous scalarisation. In it, the scalar field develops stable scalar hair around the black hole. This conflicts the no-hair theorem according to which the only observable properties of a black hole are its mass, angular momentum, and electric charge. We show that disformal coupling can further destabilise the system. We find a range of disformal coupling strengths where the coupling enhances the scalarisation. Outside this range, the effect of the disformal coupling is stabilising.
  • Laos, Maarja (Helsingin yliopisto, 2017)
    Supporting cells (SCs) of the mammalian inner ear are differentiated, postmitotic cells that hold promise as a platform in therapeutic interventions to replace lost sensory cells, the hair cells (HCs). However, SCs exhibit an age-dependent decline in their responsiveness to regenerative manipulations that aim to trigger cell cycle re-activation or to stimulate transdifferentiation into HCs. The aim of this PhD thesis project was to identify barriers restricting the therapeutic potential of auditory and vestibular SCs. Using viral-mediated ectopic expression of cyclin D1 (cD1) in organotypic cultures to force postmitotic SCs to re-enter the cell cycle, the efficiency of the cells to complete cell cycles was shown to decrease with maturation. Unscheduled cell cycle re-activation was found to be associated with accumulation of DNA double-strand breaks (DSBs), indicated by the upregulation of the serine 139 phosphorylated form of histone H2AX (γH2AX). By studying the dynamics of the DNA repair protein Rad51, the underlying reason for age-related restrictions in proliferative plasticity was shown to be delayed or inefficient DNA repair. Furthermore, delayed repair of DNA damage was found to lead to SC death. To study the possible involvement of DNA damage in stimulated SC-to-HC transdifferentiation, the pharmacological inhibitor of Notch signaling that triggers SC transdifferentiation into HCs was applied to inner ear explant cultures. It was shown that unlike forced cell cycle re-activation, stimulated transdifferentiation does not trigger DNA damage, suggesting that it might be a “safe” way generate HCs. p53 has been shown to antagonize cell proliferation and regenerative events in other contexts. Thus, it was investigated here whether this is the case also in the inner ear. Using a loss-of-function mutant mouse model, p53 was shown to be dispensable for inner ear development. By applying various growth-promoting manipulations on cochlear explants from these mutant mice in vitro, inactivation of p53 was shown to not confer regenerative potential to SCs. Excess levels of p53 that are generally associated with cellular stress response have been shown to direct cells to cell death. Thus, p53 levels are under a tight control. The significance of controlled levels of p53 in different developmental situations and in a tissue context is poorly understood. Thus, inner ear was used here as a model to study the consequences of p53 overexpression in various developmental contexts: proliferation; differentiation; and homeostasis. Mutant mouse models in which the interaction between p53 and its negative regulator Mouse double minute 2 (Mdm2) was abolished demonstrated that p53 accumulation is lethal to both proliferating HC, SC and neuronal progenitors, and quiescent, differentiating SCs and HCs. More thorough analysis that focused on SCs showed that their sensitivity to p53 decreases with postnatal maturation. The data presented here thus suggests that epigenetic signaling and maturation-related mechanisms that regulate chromatin conformation might limit p53´s pro-apoptotic functions in maturing SCs. This PhD work has revealed DNA damage signaling and inefficient DNA repair as important barriers restricting the proliferative potential of mammalian SCs. This work also demonstrates the importance of controlled levels of p53 for the survival of cells of the auditory organ. Furthermore, the data obtained from this work can be extrapolated to other postmitotic, differentiated cell types when evaluating their potential for regenerative therapies.
  • Fahmi, Mustafa (Helsingin yliopisto, 2017)
    ABSTRACT Livelihoods are precarious in arid and semi-arid regions, such as Sudan, as the main food crops are often grown in production systems that heavily depend on climatic conditions and appear to be threatened by several factors. Over 70% of Sudanese are farmers who rely mainly on rain-fed agriculture to secure their livelihoods. Their crop cultivation is constrained by such factors as climate change and variability, as well as low soil fertility, which is aggravated by limited agricultural inputs. Indigenous legume trees, such as acacias, can potentially alleviate the vulnerability of these systems. In practice this is possible by integrating trees with agricultural crops on the same piece of land, thus forming an agroforestry system. Nevertheless, the adoption of agroforestry also remains constrained by several factors, including unclear tree tenure and small farm size. The main objectives of this research were: (I) To classify and compare various land-use systems so as to facilitate an analysis of the socio-economic impacts of farming practices in the semi-arid zone of Sudan; (II) To define the determinants and constraints for agroforestry based on the integration of natural acacia trees with agricultural crops, thus forming the agroforestry parkland system in Sudan; (III) To identify and analyse the main factors underlying the variability of crop yields during the period 2001–2010; and (IV) To characterize the impact of land-use changes between 1972 and 2010 on natural forests and land productivity. The research was conducted at two distinct sites, El Dali and El Mazmum in Sennar state, Sudan (latitudes 12° 5ʹ and 14° 7ʹ N and longitudes 32° 58ʹ and 34° 42ʹ E, respectively). Principal data on households and crop yields were collected from 281 randomly selected households in face-to-face interviews using a pre-structured questionnaire. Soil and rainfall data along with satellite images were obtained from associated institutions in Sudan. Qualitative and quantitative methods were used to analyse crop and household data, and the Excel template MAKESENS was used to study the rainfall data. GIS software applications and economic analysis were used in clarifying land-use changes and crop profitability with various land-use systems, respectively. Agroforestry parklands that consist of the integration of acacia trees with agricultural crops were found to financially be the most profitable system, offering higher crop yields than monoculture systems. The number of people in a household, agro-ecological location, incentives from agricultural associations, and land holding size were the main drivers for farmers to combine acacia trees with agricultural crops, forming an agroforestry parkland system. Constraints for practicing agroforestry included insecurity of tree ownership, poor interaction between farmers and extension agents, lack of tree planting materials (in cases where a farmer would have adopted tree planting as a method to increase the tree cover), uncontrollable livestock movements on farms, and land owners’ preference to rent their entire holding to landless farmers. The yields of most of the studied crops (sorghum, pearl millet and sesame) were affected by interannual variability in rainfall rather than agricultural practices. Land use and land cover have remarkably changed over time, resulting in a negative impact on soil properties and crop performance. This research concludes for the region now studied in Sudan that climatic variability, low soil fertility and inadequate agricultural inputs contribute to a decline in crop yields. The lack of an appropriate tree tenure regime constitutes the strongest disincentive factor inhibiting farmers from practicing agroforestry, obviously the best available land-use option for sustainable crop cultivation and securing rural livelihoods. Key words: Sudan, livelihoods, rain-fed agriculture, agroforestry parklands, crop yields, climate change and variability, tree tenure, acacia trees
  • Lim, Kean-Jin (Helsingin yliopisto, 2017)
    Scots pine is an ecologically and economically important tree species in Finland because of its heartwood (HW) quality traits that contributed by the pine HW extractives, which is mainly attributed to stilbenes. Pine stilbenes, pinosylvin (PS) and its monomethyl ether, are development and stress inducible metabolites. During HW formation, biosynthesis of pine stilbene takes place in a narrow zone between the HW and the sapwood (SW), namely the transition zone (TZ). Pine stilbenes can also be induced in SW or needles in response to stressors. Despite the importance of pine HW, studies on the molecular development of HW formation from its TZ are scarce. Besides, the timing and type of HW formation in Scots pine has not been satisfactorily described. Scots pine HW extractive content varies between individuals and is highly heritable, thus breeding for high extractives in pine is possible. However, traditional forest tree breeding is time-consuming, particularly for a trait that can only be assessed in mature trees. A solution for early selection in forest tree breeding could be with a genomic approach coupled with bioinformatics analysis. In this work, the transcriptome changes during HW formation were studied in the TZ compared to the SW of mature pine trees. In addition, the stress response transcriptome changes were studied by wounding the stems of pine seedlings. The timing of Scots pine HW formation was investigated by studying the year-round expression profile of selected transcripts using quantitative RT-PCR. HW formation was initiated in spring and ceased in late autumn. The process was marked by programmed cell death. During HW formation, sucrose was metabolised for stilbene biosynthesis, indicating that pine stilbenes are biosynthesised in situ in the TZ. The pine stilbene biosynthetic pathway is upregulated both during HW formation and in response to stress. Interestingly, distinct transcripts encoding two enzymes acting at the beginning of the pathway were induced during development and stress. This work also showed that the previously characterised PS O-methyltransferase, PMT1, is probably not part of the stilbene pathway. A newly characterised O-methyltransferase, PMT2, turned out to be PS specific, and is strictly coexpressed with stilbene synthase. Unexpectedly, the resin acid biosynthetic transcripts were not induced in concert with stilbene biosynthesis. The year-round expression study showed that the expression of resin acid biosynthetic transcripts was induced in early spring and ceased later in spring. Resin acid biosynthesis was not induced in response to wounding. Single members of the MYB and NAC transcription factor families were upregulated in the TZ compared to SW, and closely followed the expression of stilbene biosynthesis and its upstream pathways. However, other members of the MYB and NAC families were transiently induced in response to wounding. Similarly, distinct transcripts associated with cell wall modification, water deficit stress and plant defence were induced during development and stress. This work demonstrated that only little similarity occurred in the transcriptome changes between HW formation and wounding response in pine. Despite stilbene synthase and PMT2 being commonly induced in both conditions, different sets of transcripts were induced, suggesting their physiological roles may be development and stress specific in Scots pine.
  • Meinilä, Jelena (Helsingin yliopisto, 2017)
    Gestational diabetes mellitus (GDM) is increasing globally and it causes pregnancy complications and later type 2 diabetes (T2D) for the mother and offspring. Studies of the association between diet in Nordic populations and GDM, as well as the effect of observed dietary change on the risk is scanty. The thesis was based on data from the Finnish Gestational Diabetes Prevention Study RADIEL, a randomized controlled trial with diet and physical-activity counselling. The participants were either obese (body mass index, BMI ≥30 kg/m2) or had a history of GDM, and they were recruited either before pregnancy or at early pregnancy. Based on 3-day diet records, at the 1st trimester of pregnancy the pregnant women had fat intake of 33 (standard deviation (SD) 6) % from total energy (E%), intake of saturated fatty acids higher than recommended (12, SD 3 E%), and low intake of carbohydrate (46, SD 6 E%). Average intakes of vitamins D (mean 7 µg, SD 4) and A (724 µg, SD 357), folate (282 µg, SD 85), and iron (12 mg, SD 3) from food sources were below the Nordic Nutrition Recommendations (NNR), but mean total intakes (from foods and supplements), excluding vitamin A, were above the recommended lower level. The proportion of users of any dietary supplements was 77%. The purpose of developing a diet quality index (Healthy Food Intake Index) was to study the level of adherence to the NNR in pregnant women at high risk of GDM. The 11 components of the HFII reflected the food guidelines of the NNR, intakes of relevant nutrients, and characteristics known to vary with diet quality. The HFII showed reproducibility. High scores in the HFII, and thus, high adherence to the NNR at 1st trimester was associated with 2nd trimester’s lower glucose concentrations 2 hours after 75 g oral glucose tolerance test. Dietary changes towards the food guidelines of the NNR during pregnancy were associated with a lower risk of GDM. A diet adherent to the NNR may lower the risk of GDM in high-risk women. This highlights the need for adequate NNR-based dietary intervention in early pregnancy of obese women and women with a history of GDM. Guidance should emphasize importance of quality of fats and safe sources of vitamin A. Vitamin A status of Finnish pregnant women warrants further investigations. With minor adjustments, the HFII is a promising instrument for maternity clinics for quick screening of pregnant women’s diet quality.