Väitöstiivistelmät

Recent Submissions

  • Heo, Jungok (Helsingin yliopisto, 2020)
    The Arabidopsis root meristem consists of concentrically arranged tissues that surround the central vasculature. While the outer cell layers, the epidermis and ground tissue (GT), contribute to the radial symmetry of the entire root, the internal vasculature displays bilateral symmetry. These spatial patterns are established by the activity of stem cells located at defined positions within the stem cell niche. Daughter cells undergo cell expansion and differentiation to form shootward files along the longitudinal axis of the root. In the first part of this thesis, I describe GT specification and maturation. GT comprises the endodermis and cortex, and their lineages bifurcate following the asymmetric cell division (ACD) of the cortex-endodermis initial. The ACD requires the function of SHORT-ROOT (SHR) and its downstream regulator SCARECROW (SCR), which both belong to the GRAS transcription factor (TF) family. GA in the endodermis modulates the timing of GT maturation by promoting a second periclinal cell division which gives rise to an additional cortical layer between the endodermis and cortex. This additional cortex layer is named the middle cortex, and this process also requires SHR/SCR activity. Here, we have genetically and molecularly demonstrated that another GRAS member, SCARECROW-LIKE 3 (SCL3), is a direct downstream target of SHR/SCR, and its expression is also under the direct control of REPRESSOR OF ga1-3 (RGA), one of the DELLA proteins that are Gibberellin (GA) signaling inhibitors. SCL3 is expressed exclusively in the endodermis, where it integrates the SHR/SCR-mediated developmental signal and the GA-mediated hormonal signal to fine-tune the timing of middle cortex formation. The second part of my thesis investigates phloem sieve element (SE) development. SEs form a conductive tissue in the phloem that mediates the long-distance transport of sucrose. In Arabidopsis roots, protophloem SEs (PSE) comprise 20-25 cells from the stem cell to the enucleating cell. This cell file can serve as a model system to study tissue morphogenesis at single-cell resolution. Using confocal time lapse imaging technology, we monitored single-cell behaviors along the PSE lineage and defined five discernible stages: quiescent (stem cell), active division (transit amplifying cells), transition, differentiation and nuclear degradation (enucleation). We then focused on PSE differentiation, which involves dynamic cellular rearrangement ending with enucleation. We discovered a regulatory cascade in which ALTERED PHLOEM DEVELOPMENT (APL) and two closely related NAC-domain containing TFs – NAC45 and NAC86 – play major roles. We also identified NAC45/86-DEPENDENT EXONUCLEASE-DOMAIN PROTEINs (NENs) that is involved in nuclear degradation downstream of the APL-NAC pathway. In order to comprehensively understand PSE development, we carried out phloem-specific transcriptome profiling by performing fluorescence activated cell sorting of various phloem reporter lines followed by RNA-seq. By analyzing the transcriptome data, we identified 925 phloem-abundant genes. We focused on a cluster of genes which initiate their expression early in the protophloem sieve element (PSE) lineage. Interestingly, this cluster includes six DOF transcription factor family members. Knocking out all six genes resulted in a very narrow vasculature and impaired phloem transport, indicating that these DOFs are required for phloem differentiation as well as specification. We also determined that these DOFs promote PSE differentiation by directly activating the APL pathway. As part of the root meristem, the PSE must differentiate in coordination with the surrounding tissues. In fact, defects in vascular tissue development often lead to systemic growth inhibition and even seedling lethality in extreme cases. In the final part of this thesis, I demonstrate that the global root meristem regulator PLETHORA (PLT) overrides DOF function in the early stages of phloem development by suppressing the expression of APL, thereby preventing premature PSE differentiation.
  • Collin, Jesse (Alma Talent Oy, 2020)
    Osake ja modernit arvopaperimarkkinat on yhtiö- ja arvopaperimarkkinaoikeudellinen väitöskirja pörssiyhtiön osakkeen omistuksen sisällöstä suhteessa tiettyihin rahoitusvälineisiin. Osakkeenomistajilla on keskeinen rooli osakeyhtiön hallinnossa (corporate governancessa), sillä heille on annettu viimekätinen valta päättää yhtiön asioista äänestämällä yhtiökokouksessa. Perinteisesti suhteessa osakeyhtiöön osakkeen on katsottu muodostavan jakamattomana pidetyn oikeuksien ja velvollisuuksien summan. Lisäksi osakkeenomistajille annettuja oikeuksia on perusteltu oman pääoman ehtoisen sijoituksen riskillä, sillä yhtiön rahoittajien keskuudessa osakkeenomistajien sijoitusta on pidetty kaikkein riskipitoisimpana. Finanssiteknologian ja arvopaperimarkkinoiden kehityksen myötä perinteinen käsitys osakeomistuksen sisällöstä on murentumassa. Esimerkiksi eurooppalaiset aktivistiosakkeenomistajat ovat kyenneet pilkkomaan osakkeen tuottamia oikeuksia irti toisistansa ja muokkaamaan osakeomistuksen riskiä hyödyntämällä moderneja rahoitusvälineitä ja markkinakäytäntöjä, kuten johdannaisinstrumentteja ja lyhyeksimyyntiä. Tämä niin kutsuttu osakeoikeuksien pilkkominen on vaikuttanut eurooppalaiseen yhtiö- ja arvopaperimarkkinasääntelyä koskevaan sääntelypoliittiseen keskusteluun sekä muovannut pörssiyhtiöitä koskettavaa viimeaikaista EU-sääntelyä. Tutkimuksessa perehdytään syvällisesti pörssiyhtiön osakeomistusta määrittäviin taustateorioihin ja nykyaikaiseen osakkeenomistaja-aktivismiin. Toisaalta teoksessa tarkastellaan kattavasti käytännönläheisellä otteella osakkeenomistajan oikeuksia ja velvollisuuksia määrittävää yhtiö- ja arvopaperimarkkinaoikeudellista sääntelyä. Tutkimuksessa on huomioitu kattavasti pörssiyhtiöiden osakeomistusta koskettava kansallinen sääntely erityispiirteineen kuten myös viime aikoina merkittäviä muutoksia läpikäynyt EU-sääntely.
  • Novakovic, Dunja (2020)
    Active pharmaceutical ingredients can assume a diverse spectrum of solid-state forms. These forms differ in properties that are of utmost importance for pharmaceutical performance, such as solubility, dissolution rate and bioavailability. Thus, selection of a suitable solid-state form is highly important, particularly for the growing number of poorly water-soluble drug molecules. The amorphous (i.e. non-crystalline) form offers an often much needed solubility advantage at the price of thermodynamic physical instability and possible recrystallization. As the number of poorly water-soluble molecules in drug development is growing, so is the interest in the amorphous form and strategies for its stabilization. Formation of amorphous polymeric solid dispersions is the most common answer. However, issues with recrystallization, particularly at the surface, still remain, as well as high polymeric loadings. The importance of differentiating between the surface and bulk properties of pharmaceutical materials is becoming increasingly recognized. Processes such as dissolution or chemical reactions with surrounding materials start from surfaces. For drugs in the amorphous form, inevitable recrystallization starts at the surface. This transformed (partly) crystalline surface thus dictates dissolution (or lack thereof), as well as other properties relevant for manufacturing, shelf-life or administration. This is why understanding, monitoring and manipulating superficial phenomena is of such importance. Most established solid-state analytical methods show no or limited surface specificity. Nonlinear imaging (sum frequency generation (SFG) and coherent anti-Stokes Raman scattering (CARS)) are relatively new solid-state and surface specific methods. Moreover, as imaging methods, they can visualize solid-state distribution at the surface. Therefore, this thesis utilized novel nonlinear imaging approaches to better understand surface solid-state behavior. Further, the importance of surfaces in the crystallization, stabilization and dissolution of amorphous drugs was investigated. The first part of the thesis established surface and solid-state specific non-linear imaging methods capable of distinguishing multiple solid state forms. SFG imaging proved to be an excellent tool in detecting low levels of surface crystallization (undetectable with other analytical methods employed), in particular amorphous transformation to a single crystalline solid-state form. Additionally, multimodal nonlinear imaging (SFG and CARS modalities, each with their own benefits) was used for the first time in pharmaceutical samples to simultaneously differentiate up to three different solid-state forms. The second part of the thesis compared surface versus bulk crystallization and investigated surface crystallization (change in the solid-state form) during storage, as one of the key indicators of pharmaceutical performance. Both the cross-sectional SFG imaging of compressed powders, as well as the SEM morphology of continuous particle tablets allowed visualization of the surface-biased crystallization during storage. Further, the addition of different excipients physically mixed with the drug affected the crystallization of the amorphous drug in the bulk, however, their inability to stabilize the crystallization at the surface was demonstrated. In contrast, thin polymer coatings were successful in delaying the onset of surface crystallization at high humidity and elevated temperature during storage. The final part of the thesis investigated the implications of storage-induced surface crystallization and its stabilization with polymer coatings on pharmaceutical performance during dissolution, as a further necessary step in drug development. It was shown that different extents and natures of surface crystallinity affect drug dissolution. Multimodal nonlinear imaging revealed up to five solid-state forms simultaneously present at the surface, and aided the interpretation of the dissolution profiles. The initial dissolution rates of the short-term stored polymer coated samples were equivalent to those of the unaged uncoated samples. In summary, this thesis demonstrated the importance of surface solid-state properties, and their surface-specific analysis, for understanding the pharmaceutical performance of amorphous formulations during storage and dissolution. With further developments in amorphous drug formulations, the interest in surface crystallization and its prevention in the future will likely increase, together with the demand for surface-specific solid-state analysis. Altogether, it can be expected that in the future the understanding and utilization of surface phenomena will evolve from superficial to comprehensive.
  • Talus, Anu (2019)
    In essence, the transparency and data protection regimes draw from different grounds. The aim of the research was to first identify and analyze the different requirements of the transparency and data protection regimes and thereafter seek the solution for balancing the said requirements. The rules examined in this research regulate the disclosure of information and processing of personal data by the EU´institutions. However, the solution for the tension is sought from the European law in a wider perspective. The analysis of the colliding rules draws from normative legal analysis. Critical legal positivism considers the rules only examples of issues pertaining to the surface level of law and this research draws essentially from the separation of rules and principles based on the doctrines elaborated by such scholars as Ronald Dworkin and Robert Alexy. The requirements drawing from the data protection legislation and the transparency legislation are contradictory to a certain extent and the tension on the level of rules is apparent. The most apparent contradiction relates to the purpose limitation principle, which closely relates to the further processing of personal data and the requirements to reason the disclosure of personal data. Simultaneously, the public access regime builds on a basis where applications for the requests of information do not need to be reasoned. However, the collision of rules does not necessarily reflect a collision of the underlying principles and the research will seek the balance between the examined rules by reconciling the underlying principles of the data protection and public access to documents regimes. After the essence of the examined rights has been identified, it will become clear that the collision does not exist on the level of principles. Besides privacy and self-determination, the requirement to have legal basis is considered to form the hard core of protection of personal data. This element also separates it from privacy. It follows that the right to protection of personal data can be reconciled with the right to public access to documents while the essence of both rights are preserved. A suggestion how to reconcile the examined rights will be given and the concluding analysis will also provide tools for balancing the said rights in the current legal framework by interpretation. There has been earlier study in this field of law. However, this study dates from 2007 and significant changes have taken place after that. A recast process on the Regulation 1049/2001 on public access to documents has been launched and a vast EU data protection reform was finished in the spring 2016. Also, the Court of Justice of the European Union has delivered significant decisions concerning the relationship between protection of personal data and transparency after 2007. Besides providing a new angle for seeking the solution by balancing the underlying principles, this research also provides first analysis of the relationship between protection of personal data and transparency in the current legal framework. Keywords data protection, privacy, personal data, transparency, purpose limitation, further processing, block exemption, democracy
  • Raju, Sajan (Painosalama, 2019)
    The human microbiota, i.e. the microbes living in or on humans, plays an important role in health and disease. Lifestyle factors, such as diet and physical activity as well as environmental factors, and exposure to antimicrobials (AMs) are likely among the important factors shaping the microbiota. Several studies have reported that the gut microbiota may be associated with overweight and obesity. Fewer studies have investigated associations between body mass index (BMI) and the salivary microbiota. There is a worldwide epidemic of obesity and the number of overweight and obese people reached 1.9 billion in 2016. Overweight and obese children are likely to stay obese into adulthood and tend to develop diseases more frequently and at a younger age. Thus, identification of the associations between microbiota and body size in young individuals are of great importance. The increased use of AMs rises concern of increasing antibiotic resistance resulting in lack of treatment options for many diseases. Exposure to AMs affects the microbial diversity and composition in the gut microbiota, but less is known about salivary microbiota. Since AM use is frequent in children, it is vital to study its associations with saliva microbiota at this age. The objectives of this doctoral thesis were to develop cost effective protocols to assess the salivary microbiota profiles for large-scale epidemiological studies and, with the new protocol, to determine its association with body size and lifetime antimicrobial use in children. In this thesis, all in-house 16S amplicon assays produced similar salivary microbiota profiles for the individual samples, i.e. there was no superior protocol. Salivary microbiota profiles of Finnish children were gender-specific in terms of alpha- and beta-diversity and relative abundances of bacteria. A prominent finding was the decrease in the core bacteria in overweight and obese children. Lifetime AM exposure to saliva microbiota showed that Azithromycin use was associated with alpha-diversity in all children, and in girls. Microbiota dissimilarities were significant between children with low, medium and high number of AM user groups in all children with all AMs combined. Similar trend was significant with Azithromycin use, whereas Amoxicillin use affected the dissimilarity only in boys. This thesis suggests that the saliva microbiota is significantly associated with body size, antimicrobial use and gender in Finnish children. Thus, saliva microbiota profiles open new possibilities to study the potential roles of microbiota in weight development and management in children. In addition, the involuntary consequences of lifetime AM use are a concern and the importance of microbiota in the development of new therapeutic strategies should be emphasized in order to limit the use of AMs wisely. Studies have shown that the saliva microbiota is more resilient and stable than gut microbiota when exposed to antibiotics. Thus, the saliva-based screening of microbial biomarkers in health surveillance, and the associations with oral and general health status, may be considered feasible, simple, economical and easy to collect with high compliance for all age groups compared to faecal samples. However, further research on metabolic and functional potential of saliva microbiota is needed to fully understand the saliva microbiota – host relationship.
  • Kärrylä, Ilkka (Valtiotieteellinen tiedekunta, 2019)
    This study analyzes the contested and changing relation of democracy and the economy in Finnish and Swedish political thought and rhetoric from the 1960s until the 1990s. More specifically, it investigates how composite concepts such as ‘economic democracy,’ ‘industrial democracy’ and ‘enterprise democracy’ have been used in past political debates, what kinds of beliefs and concrete practices they have been related to, how they have been legitimized and criticized, and how their role has changed in political thought and rhetoric. The study utilizes theories and methods of conceptual history, combined with a broader approach to ‘history of thought.’ Concepts are analyzed as parts of semantic fields or ideational constellations, where their meaning, reference and valuation are shaped in relation to other concepts and beliefs. These constellations are reproduced, challenged and changed in everyday language use. The study’s empirical focus in Sweden and Finland allows contrasting political thought and the use of concepts as well as reflecting on possible conceptual transfers. The source material consists of books, articles and governmental documents dealing with economic and industrial democracy. Special attention is paid to the programs, manifestos and statements of political parties and labor market organizations. The main focus is on Social Democrats and Conservatives, as well as employer and trade union confederations. For most of the 20th century, ‘economic democracy’ was a key political concept in Finland and Sweden. Most groups agreed on the goal of giving citizens more power over economic decisions, but the concrete meaning of economic democracy was deeply contested. For the left, the concept meant societal planning and steering of the economy, as well as the power of employees in the workplace. For the right, economic democracy referred to the dispersion of private ownership to wider ranks of people, and consultative cooperation between employees and employers. In the 1990s, economic democracy practically vanished from the Finnish and Swedish political language. This is explained with dilemmas, such as economic crises, which challenged the existing beliefs and concepts of historical agents. Instead of democratization, national economies were to be liberalized and marketized in order to survive in global competition. In the new world of free capital flows, old ideas of economic democracy were set aside from mainstream political rhetoric. For advocates of the free market economy, it was safer to emphasize people’s economic role as free consumers and to separate this from their role as democratic citizens in the political sphere.
  • Kaukonen, Maria (Helsingin yliopisto, 2019)
    The genetic background of three canine hereditary eye diseases, namely microphthalmia, open-angle glaucoma and progressive retinal atrophy, were addressed in this thesis. Currently, no standardized curative treatment options are available for these diseases. Gene defects behind each of them were identified using modern genome-wide approaches followed by functional validations. In study I, the genetic analyses revealed that a 3-bp deletion in the RBP4 gene is associated with microphthalmia in Irish Soft-Coated Wheaten Terriers. Simultaneously, a new mode of maternal inheritance was discovered as the disease manifests only if both the dam and the offspring were homozygous for the variant. During gestation, RBP4 transfers vitamin A from maternal liver stores to the developing puppy. The defective protein is not secreted into serum, causing vitamin A deficiency, a known risk factor for microphthalmia. In study II, a recessive missense variant in ADAMTS10 was associated with open-angle glaucoma in Norwegian Elkhounds. The disease was found to be bilateral, unresponsive to medical treatment and led to irreversible blindness by the age of six years. In study III, a recessive variant in a putative silencer region fully segregated with progressive retinal atrophy in Miniature Schnauzers. The breed was also found to suffer from another genetic form of the disease, for which a tentative locus was identified. The results of this study have led to novel scientific insights and practical applications and have translational implication to human medicine with similar conditions and gene associations. Three gene tests have been developed to aid veterinary diagnostics and breeding programs. The new mode of maternal inheritance discovered in study I could be a more common phenomenon in developmental disorders across species and should be taken into consideration in all genetic studies.
  • Wasastjerna, Maria (Unigrafia, 2019)
    This doctoral thesis examines the role of privacy in competition law in the age of digitalization and big data. It explores the growing significance of data protection and looks at the interlinkage between privacy and competition policy, thereby testing conventional boundaries and expanding horizons. With the transition to the data-driven economy, our society has grown to rely on products and services that are free of charge to consumers, but because they have no monetary price, there is hesitation whether, and how, action should follow. The thesis questions whether competition policy is too fixated on the idea that the only real harm to consumers consists of rising prices. Consumers pay for online services with time and data. When many products and services seem free in today’s online markets, with user data as the invisible cost, looking only at price effects in competition analysis is misleading. The thesis asserts that an overly price-centered approach to competition policy risks overlooking welfare harms that relate to significant non-price dimensions, such as privacy and consumer choice. The research objectives and questions explored in the thesis can be summarized by way of sub-questions, namely what is the role (if any) of personal data and privacy in competition law? Should competition policy protect privacy among its objectives, and if so - how? The findings point to current shortcomings in competition law and propose a rethinking of competition policy for the data economy. This includes a proposal to expand horizons beyond a static price-centric approach, incorporating a privacy dimension to competition law and exploring a conjoined policy approach. Here, competition law is examined not only from a strictly legal perspective, but in a wider context, including elements that are societal, political, economic, historical and cultural. The thesis emphasizes that over time, many different values have been advocated in the name of competition law and depending on the interests that are being promoted, different objectives are put forward as a driver for law enforcement. This is all the more true today when observing the public discussion and politics around competition in digital markets and companies’ use of data as market power, think only of the Cambridge-Analytica scandal and Facebook’s handling of personal information. The topic of the thesis is timely and highly relevant. By providing a comprehensive insight into competition policy in the digital economy, and especially the role of personal data in this context, the thesis offers important contributions and policy considerations to the current debate. Readers are provided with an overview of the contemporary interplay between competition, data and privacy in the digital economy, including implications for business practice, reflections on the way forward and suggestions for future research.
  • Matilainen, Sanna (2019)
    Leigh syndrome is a progressive mitochondrial encephalopathy manifesting in early childhood, with characteristic symmetric lesions of the brainstem and basal ganglia, and a spectrum of clinical findings. Often multi-organ manifestation is known to occur. The genetic background of Leigh syndrome is exceptionally wide, with over 75 known disease genes affecting mitochondrial function, in both the mitochondrial and nuclear genomes. The molecular characteristics of this clinically and genetically heterogenetic disease, however, remain largely unknown. In this study genetic diagnoses were found for patients with Leigh syndrome and the underlying molecular pathomechamisms were studied. The disease found in two families was caused by a novel Scandinavian founder mutation in SUCLA2, causing deficiency of succinyl-CoA ligase (SCL) of the TCA cycle, a central metabolic pathway. The substrate for the reaction catalyzed by SCL is succinyl-CoA, also serving as the substrate for succinylation, a recently characterized post-translational modification with yet unknown biological significance. These results show SCL deficiency to lead to increased protein succinylation via accumulation of succinyl-CoA in cell lines of patients. Metabolic disturbances caused by the succinylation of hundreds of target lysine residues, found on a wide range of metabolic proteins in nearly all cell compartments, propose succinylation as a mechanism for the simultaneous control of several metabolic pathways. Also, defects of the mitochondrial polynucleotide phosphorylase (PNPase) caused by PNPT1 mutations were established among the causative mechanisms of Leigh syndrome with next-generation sequencing in one patient with a progressive Leigh encephalomyopathy. Defective mitochondrial RNA metabolism due to loss of RNA degradation activity of PNPase is shown as a novel mechanism for mitochondrial disease. The paths to molecular diagnoses for the patients in this study portray the recent advancements of molecular and genetic diagnostics, which have developed dramatically with the era of next-generation sequencing methods. Genetic diagnoses were provided for patients with Leigh syndrome of unknown molecular etiology, crucial for the well-being of the families and treatment of the patients. Simultaneously, patient-derived cell lines and tissues with a disarrangement of mitochondrial metabolism were utilized to increase our understanding of the related metabolic pathways and mitochondrial metabolism.
  • Scherleitner, Moritz (2019)
    In many different circumstances, hybrid financial instruments (HFIs) can be an appealing source of finance. At the same time, however, such instruments may also be used in tax planning. Its differential treatment in the affected jurisdictions can give rise to double non-taxation of a payment. Exploiting this allows for significant reductions in the corporate tax liability. In the aftermath of the recent financial crisis, such “tax arbitrage” has increasingly entered debate within the G20, OECD, EU and UN. As a result various concepts of how to engage with the problem were developed. Besides these, some states already rely on provisions that can be of relevance in this context. Starting from these developments, the objective of the monograph is to help those in charge of solving the problem to make a more educated decision. As such, it addresses tax policymakers around the world. For the sake of reaching its goals, the thesis applies a socio-legal method. This should acknowledge that tax policymakers design rules in a context that is broader than existing tax law. They have to consider the traditional principles of tax policy, including tax competition constraints, as well as legal dogmatic restrictions – and does this thesis. Against this background, the dissertation is structured in the following way: In chapter 1, the reader is introduced into the topic and the design of the research. In chapter 2, HFIs are shed light on from the perspective of tax law, corporate finance and economics. The goal is to understand their role in reality. In chapter 3, the guiding principles for company taxation are reviewed. Contemporary tax research relies on the triumvirate: (i) equity, (ii) efficiency and (iii) administrability. So does this thesis. The literature on these issues is considered in sufficient depth, but with a strong focus on the research objectives. Chapter 4 builds the bridge between the above preparatory part and the core research. This happens by working out the non-legal concerns attached to tax arbitrage with HFIs. They include three from an inter-taxpayer equity perspective, three from an inter-nation equity perspective and two from an efficiency perspective. This is the problem definition. Chapters 5¬8 investigate how four approaches address these concerns. These are the “OECD approach”, the “low tax approach”, the “UN approach” and the “recharacterisation approach”. The focus will be on tax arbitrage transactions with HFIs that rely on a qualification conflict and substitute transactions with financial instruments that reach the same, or a similar, result. The research on these approaches also takes into account their administrability and legal dogmatic considerations. In doing so, the collateral damage caused by the rules is assessed as well. Also this happens from a multi-disciplinary perspective. In chapter 9, the author presents his own thoughts on what developed and developing countries may want to consider in dealing with the problem of tax arbitrage with HFIs. The author is aware of tax arbitrage with HFIs only being a part of the challenges tax policymakers have to deal with. In an attempt to consider this, the discussion is put into a broader context. As a direct consequence thereof, the thesis also lacks a clear solution. Rather, it aims to provide information that should improve tax policymakers´ ability to address the issue. It is left up to them to trade-off equity, efficiency and administrability considerations, paying attention to what is possible de lege lata.
  • Räsänen, Markus (Helsingin yliopisto, 2019)
    Cardiovascular diseases are the leading cause of mortality worldwide, and they have become the most important and most significant cause of non-communicable diseases. In the Western world, they also rank first when listed by disability-adjusted life years (DALY). In particular, ischemic heart disease is still a major burden to the society, causing up to one third of the deaths of persons over 35 years. My aim in this thesis was to investigate the translational potential of vascular endothelial growth factor B (VEGF-B) and the downstream Bone marrow kinase X (Bmx) tyrosine kinase in the treatment of pathological cardiac conditions, such as myocardial ischemia, pathological cardiac hypertrophy and cardiotoxicity. Vascular endothelial growth factors (VEGFs) are major regulators of blood and lymphatic vessel development and growth. Based on earlier studies, VEGF-B appeared as a potential angiogenic growth factor because of its relative specificity to the heart and adipose tissue. Furthermore, I was interested in analyzing the Bmx tyrosine kinase, which has been shown to receive signals from VEGF receptors, and to be required for the development of cardiac hypertrophy. In the first study of my thesis, we showed that the expression of a VEGF-B transgene (TG) in the cardiomyocytes leads to an expansion of the coronary arterial tree. The VEGF-B transgenic hearts were also protected against myocardial ischemia. This opened further possibilities to study VEGF-B and its signaling in different pathological conditions in the heart. In the second publication of the thesis, we showed that angiotensin II (Ang II)-induced cardiac hypertrophy was significantly reduced in mice, which were either deleted for the Bmx gene or in which the tyrosine kinase activity of Bmx was inactivated. This suggests that a selective Bmx tyrosine kinase inhibitor could be used in the treatment of pathological cardiac hypertrophy. Cardiotoxicity and congestive heart failure are growing problems in cardio-oncology, due to decreased cancer mortality and associated increased long-term use of cytotoxic drugs. Doxorubicin (DOX) is an anthracycline antibiotic, which is associated with cardiotoxicity that may further develop into congestive heart failure. In the third paper of my thesis we showed that, in mice, VEGF-B gene therapy can be used to protect the endothelium and to inhibit cardiac atrophy and capillary rarefaction induced by DOX. In the fourth study of this thesis, we found that VEGF-B gene therapy can induce endocardium to venous endothelial cell (EC) transition, opening the possibility of a new pathway for coronary reperfusion. The sinus venosus and the endocardium are the major sources of the coronary vessels that support the expanding myocardium in the developing heart. The adult heart can no longer generate new blood vessels from the endocardium, because the endocardium-to-coronary vessel transition is inhibited after the neonatal stage. Importantly, in this study the subendocardial EC proliferation was obtained also in adult mice by VEGF-B gene delivery to the cardiomyocytes. Furthermore, we were able to induce the endocardial to EC transdifferentiation by VEGF-B gene delivery after myocardial infarction (MI). Thus, re-activation of the adult endocardium by growth factors could be a new therapeutic strategy for cardiac neovascularization after MI. Overall, these findings open translational therapeutic possibilities for the treatment of coronary artery disease, cardiac hypertrophy and anthracycline-induced cardiotoxicity.
  • Koskinen, Suvi (Picaset Oy, 2019)
    Tiivistelmä lähetetään erikseen.
  • Petäjä, Liisa (2019)
    Annually world-wide, 17.7 million people die of cardiovascular diseases. Cardiac surgery is performed to improve patients’ prognosis and alleviate their symptoms. However, these challenging procedures have inherent risks, including cardiac and renal injury. The objective of this study was to investigate, by biomarkers and risk models, cardiac surgery-related cardiac and renal morbidity, and their association with prognosis. A systematic search, review and meta-analysis were performed to find out the relationship of postoperative injury markers after coronary artery bypass grafting (CABG), and mortality. Additionally, two cohorts, 428 CABG and 220 other cardiac surgical patients, were enrolled to a prospective study. The associations of pre- and postoperative high-sensitivity troponin (hs-TnT) with postoperative major adverse events (MAE) and mortality were explored. Whether these biomarkers offer additive information for an established risk model, EuroSCORE II, was detected. Acute kidney injury (AKI) was defined by complete Kidney Disease: Improving Global Outcomes (KDIGO) criteria including serum creatinine and urine output (UO). The associations of AKI stages and the separate criteria with long-term mortality was assessed in the two cohorts as one. Finally, a recently published risk model predicting cardiac surgery-associated AKI (CSA-AKI), named AKI Risk Score, was validated in this cohort. The potential benefit of adding preoperative biomarkers, hs-TnT and N-terminal pro-B-type natriuretic peptide (NT-proBNP), to AKI Risk Score, was evaluated. Postoperative CK-MB releases after cardiac surgery were related to increased mortality until 3 years. Even though troponins seemed better predictors, the assays lack standardization, and this remains a problem in generalizing the results. Elevated preoperative hs-TnT determined the meaning of first postoperative day hs-TnT in all cardiac surgery. It was related to long-term mortality regardless of postoperative hs-TnT in cardiac surgery other than plain CABG. Adding hs-TnT to EuroSCORE II yielded to better prediction of MAE in all cardiac surgery, and to better prediction of half-a-year mortality in at least cardiac surgery other than plain CABG. AKIs, diagnosed by separate criteria of KDIGO, were all associated with 2.5-year mortality, even AKI diagnosed by only urine output. AKI by KDIGO stages was associated with increased mortality, related to severity. The excess mortality associated with AKI was not predicted by EuroSCORE-based risk of mortality or risk factors for AKI. AKI Risk Score performed acceptably in Finnish cardiac surgical patients. Adding preoperative biomarkers to the score yielded to no clear clinical benefit. A thorough analyses of the added value of the biomarkers, by risk assessment plot and estimation of net benefit, is warranted to reveal true potential of the biomarkers.
  • Antin, Katri (Helsingin yliopisto, 2019)
    This thesis examines how divine knowledge is understood to be transmitted from God to human beings in the seven sapiential Thanksgiving Psalms (1QHa 5:12‒6:33; 7:21‒8:41; 9:1‒10:4; 15:29‒36; 17:38‒19:5; 19:6–20:6; 20:7–22:42). A modern scholarly definition of divination is used as an aid to analysis, and how the transmission of divine knowledge is understood in the sapiential Thanksgiving Psalms is discussed in relation to previous theories about the divinatory practices of the Second Temple period. The demarcations and structure of each Thanksgiving Psalm are discussed by noting scribal practices. The sapiential Thanksgiving Psalms can be grouped together by their inclusion of various sapiential themes, forms, and vocabulary, but when it comes to the transmission of divine knowledge, they form a heterogenous group. Four sapiential out of the seven Thanksgiving Psalms (1QHa 5:12‒6:33; 7:21‒8:41; 9:1‒10:4; 20:7–22:42) depict a teacher of wisdom as the mediator of divine knowledge, the divine knowledge itself described as a mystery (רז) that concerns God’s deterministic plan for his creation. In 1QHa 5:12‒6:33 and 7:21‒8:41, God’s deterministic plan are described in terms of two diverse ways. Previously, several sapiential Thanksgiving Psalms have been studied in relation to either sapiential divination or inspired interpretation of earlier traditions; thus far, however, it has gone unnoticed that same psalms include features of both phenomena. In 1QHa 5:12‒6:33, 7:21‒8:41, and 9:1‒10:4, divine knowledge is acquired and transmitted through the implicit interpretation of earlier traditions, but, instead of making this process visible, the transmission of divine knowledge is described as a sapiential revelatory process. These earlier traditions concern especially the creation. Both “biblical” and “non-biblical” compositions are interpreted in the same psalms, indicating that the division to “biblical” and “non-biblical” arises more from modern conceptions of the Bible than from that of the late Second Temple sources themselves. Transmission of divine knowledge includes both inductive and intuitive aspects. The sapiential Thanksgiving Psalms relate similar intuitive elements of the transmission of divine knowledge as the classical prophetic books of the Hebrew Bible. Nonetheless, the transmission of divine knowledge requires also elements that are more at home with inductive than with intuitive divination. According to 1QHa 15:29‒36, 17:38‒19:5, and 19:6–20:6, no mediator is needed to have access to divine knowledge.One possible explanation for why these psalms do not depict any human mediator is that they lack didactic elements, unlike 1QHa 5:12‒6:33, 7:21‒8:41, and 9:1‒10:4. The psalms 1QHa 9:1‒10:4, 15:29‒36, 17:38‒19:5, and 19:6–20:6 contribute to our understanding of the role divine knowledge played in praising God as well as in eschatological beliefs. On the other hand, 1QHa 5:12‒6:33, 7:21‒8:41, and 9:1‒10:4 not only describe the transmission of divine knowledge; these psalms could themselves have functioned as vehicles in that transmission. The process of transmitting divine knowledge can be examined as part of the literary and oral transmission of these psalms.
  • Viljanen-Pihkala, Anna-Maija (Suomen kirkkohistoriallinen seura, 2019)
    The Impact of the Social and Church-Political Situation of Hungary on the Finnish-Hungarian Lutheran Relationship, 1956–1958 The aim of this study is to clarify the relationship between the Finnish Lutheran Church and the Lutheran Church of Hungary during the period 1956–1958. Between the world wars, the relationship had been lively, motivated by both Finno-Ugric kinship and revival movements. During the mid-1950s, the political conditions in Finland and Hungary were profoundly different, as these countries found themselves on different sides of the Iron Curtain. This study explores the Finnish-Hungarian relationship from different perspectives, including its socio-political grounds and the religious and emotional motives behind this activity. In addition, it presents the practical realization of interaction and the international Lutheran and ecumenical context for the Finnish-Hungarian Lutheran relationship. The study is based on archival material and newspaper articles, which is organized in chronological order. Moreover, this material was collected in Finland, Hungary and Switzerland (Geneva), where the main part is either in Finnish or Hungarian. Supplemented with the addition of (auto)biographies, this material is analysed in multiple ways with a special emphasis on motivational factors. Overall, this study revealed a great variety of motives for the interaction between the Churches. In addition to kinship and religious motives, the Finnish relief programmes initiated to help Hungarians, and the reciprocal visits these prompted, were also motivated by the curiosity of the Finns in crossing the Iron Curtain. Especially for the Finns, the relationship was emotionally charged. There were strong feelings of compassion and sympathy, but also disgust and fear of communism. On the Hungarian side, the relationship with the Lutheran Church of Finland was also used for (church-)political goals. The State Church Office of Hungary decided whether or not church people on each side could either go to Finland or visit Hungary, respectively. The same office controlled the Finnish relief programmes to help Hungarian Lutherans as well. One of the important results of the research is that the Finnish–Hungarian relationship was active in four dimensions simultaneously. First, the relationship was fed at the grass-roots level by the Hungarian and Finnish pastors, who had taken part in or had been affected by the exchange programme of theologians between the world wars. Second, many Finnish organizations took (economical) responsibility for the visits of Hungarian pastors in Finland. This organizational level did not exist in Hungary. Third, there were active church leaders and a central church government in both countries. However, the Finnish side that decided there was no reason to make the relationship more official. In Hungary, all the communication went through this level, i.e. bishops. Furthermore, all acting bishops of Hungary during 1956–1958 supported the interaction with the Church of Finland. Fourth, a connection was upheld in the international and ecumenical context, especially in the activities of the Lutheran World Federation (LWF) and the World Council of Churches (WCC). The relationships between Finns and Hungarians were well known, for instance, in LWF circles. The key figure of this study proved to be Bishop Lajos Ordass of Hungary. He was not ‘a friend of Finland’, like his colleague Bishop Zoltán Túróczy. Yet, because of his ecumenical and international Lutheran standing, he was trusted in Finland and demonstrated stable leadership in their relationship. Finally, the changes related to Ordass’s situation as an acting bishop were carefully followed in Finland, subsequently influencing the relationship between the Churches.
  • Semenova, Svetlana (2019)
    The neurotransmitter dopamine is involved in the regulation of diverse functions of the nervous system, from reward processing and motor control to cell proliferation. The zebrafish dopaminergic system is an outstanding research object for research on nervous system disorders, especially for neurodevelopmental and neurochemical studies. The present work was focused on the distinct roles of the tyrosine hydroxylase genes in the development of the zebrafish nervous system, and on the previously unexplored features of COMT enzymes and genes in the zebrafish. An antibody was generated to detect zebrafish TH2, a tyrosine hydroxylase that had remained overlooked for a long time. As the new antibody recognized both TH1 and TH2 proteins, it was used together with a validated commercial anti-TH1 antibody to map the entire dopaminergic network in the zebrafish brain and to characterize the responses of TH2-expressing cells to various stressful stimuli. TH2-expressing cell groups were found in the preoptic area (group 3b), paraventricular nucleus of the hypothalamus (group 8b) and nuclei of the lateral and posterior recesses of the caudal hypothalamus (groups 9b and 10b). Cells of groups 9b and 10b were intermingled with serotonin-containing cells, but no (serotonin+TH2)-immunopositive cells were detected. Chemical and social stress induced cell activation in distinct regions of the brain, including the caudal hypothalamus, as inferred from c-fos expression, but only a small fraction of TH2 cells was activated. Dopaminergic regulation of histaminergic neuron development was assessed in pharmacological and gene knockdown experiments. Knockdown of the th1 gene by morpholino oligonucleotide injection reduced histamine and orexin neuron numbers in zebrafish larvae, whereas th2 gene knockdown increased cell numbers in these populations. These opposite effects may be due to the different spatiotemporal expression patterns of the two th genes in the zebrafish.Wnt signaling was implicated in the regulation of cell numbers. Similar patterns of expression of zebrafish comt-a and comt-b genes and a broad distribution of COMT enzymatic activity in zebrafish tissues was demonstrated. High activity and expression levels were detected in the brain, liver, and kidney. Treatment with an inhibitor of COMT did not lead to increased dopamine concentrations in zebrafish larvae, but it shifted the balance of dopamine inactivation towards the oxidation pathway catalyzed by monoamine oxidase Dopamine degradation in the zebrafish was shown to have many features in common with that in other vertebrates. Anti-TH2 antibodies were developed and characterized as tools for imaging studies in zebrafish, and possibly in other fish species. Distinct roles of TH1- and TH2-producing cells in the regulation of brain development were revealed. The thesis demonstrated that enzymes with similar biochemical functions in dopamine synthesis but different spatiotemporal expression patterns may make fundamentally different contributions to the regulation of brain development.
  • Noparast, Zahra (Helsingin yliopisto, 2019)
    The UN peacekeeping missions have constituted a substantial part of international attempts for maintaining and restoring international peace and security. The missions have been deployed in almost every part of the world to control conflict situations and keep the adversaries apart. In some cases the operations held all the hallmarks of an enforcement action and did not observe the three pillars of the UN peacekeeping action. The deployment of forces in "peace enforcement", dominantly after the Cold War with questionable legal basis led to unfortunate outcomes. Furthermore, non-stop reports of alleged crimes committed by military, and civil peacekeeping personnel tarnished the image of the organization as a peace-broker. It seems that the organization is unable to solve the problems attached to the deployment and conduct of the operations. Having said that one has to acknowledge that during last seven decades the organization has set up many panels, committees, commissions which led to the publication of lengthy reports with different titles for overcoming those problems, but the recommendations fell on deaf ears, and the member states did not comply with them, because it was not legally binding. The best example was the Zied report, which was published after the widespread alleged atrocities of the peace personnel in Congo in the early 1990s. Since these political attempts did not yield any tangible results, the legal approach to remove the problems so as to have successful missions seems inevitable. According to paragraph 1(a) of article 13 of the UN Charter, The General Assembly is entrusted to encourage "…the progressive development of international law and its codification…" The organization has been successful in this field and sponsored the adoption of many legal instruments such as the four Geneva Conventions of 1949. Moreover, the UN General Assembly established a permanent subsidiary organ, namely; the International Law Commission to enhance the process of law-making, but all the attempts have been for bringing law and order only among member states. The organization itself is not a party to those legal instruments, and this situation caused many difficulties for the international community, specifically as far as legal successful conduct and command of UN peace operations are concerned. Since the UN peace operations under any title are the only mechanism at the service of the international community, revisiting the causes of the failure of the missions in number of cases is indispensable. Therefore, this dissertation presents a thorough research of the organization's record of observing international law in terms of establishing, conducting, commanding and financing the peace missions. The main question of this research is how to make the UN peacekeeping operation more successful while the rules of international law could be observed in every step of establishing a mission. In this research the connection between the major problems that the organization has experienced and the absence of UN conventional obligation is scrutinized to the point of conclusion that each problem could be overcome if the international community adopts a comprehensive legal convention on peacekeeping. To the author of this thesis, the suggested convention would comprise existing legal instruments such as the four Geneva Conventions, and adaptation of them to the status of the UN as an international organization. However, new codifications are necessary where there are no legal international instruments for removing the ever-lasting problems of deploying a peace operation. The main areas which require new codification are as follows: giving the peace enforcement action a proper legal basis; determining the effective command and control of forces by the organization, or establishing dual responsibility of force-contributing states; establishing an effective, and authentic accountability mechanism for the prosecution of the alleged criminal acts of peace personnel by either national states, or an international tribunal; setting up a proper mechanism for monitoring justifiable financial contribution of all member states to the cause in a way that no state, large or small could withhold their assessed share of contribution; and finally observing well-functioning of the Secretariat which has played a defining role in the outcome of every peace operation. The proposal in this dissertation may be materialized if some countries take the initiative and put it on the Agenda of the General Assembly for discussion. Let's hope there will be enough volunteers who consider the lawful and orderly manner of deploying peacekeeping missions as an urgent and vital step for having a peaceful world which would be beneficial for all member states. .
  • Hokkanen, Marja (Hokkanen Marja, 2019)
    If derivatives are capable of destabilizing the world economy, they are too powerful a tool to be ignored in European value added tax (VAT). That said, while certain types of derivatives, such as gold derivatives and certain options, are currently regulated under the EU VAT Directive (2006/112/EC), the lack of regulation in respect of derivatives in general has led to individual EU Member States treating derivatives very differently. The distinct lack of regulation on an EU level brings uncertainty as to how these instruments should be treated and the resulting inconsistencies and lack of guidance at a national level has effectively jeopardized any prospect of achieving neutrality and equality of treatment across the EU derivatives market. The European Commission published its proposal for a Council Directive amending Directive 2006/112/EC on the common system of value added tax in 2007. These proposals also included regulation on derivatives. However, a final compromise was never reached and the proposals were finally withdrawn by the Commission in April 2016. The challenge to define derivatives in the scope of the European VAT System is not easy because of the diversity of derivatives. At the same time, the European VAT System sets challenges to the analyze phenomena as legal tender, consideration or reciprocal supplies which have a special role in the world of derivatives, just to name few. The aim of the research is to define the most common types of derivatives i.e. commodity and financial options, futures, forwards and swaps in terms of the European VAT system and to bring clarity to the EU area regarding their VAT treatment on the basis of the VAT Directive, the primary purpose being to give concrete answers as to how derivatives should be treated with specific reference to the scope of the VAT system as defined under Articles 1 and 2(1) of the Directive. In addition to the supply of commodities, interesting questions arise regarding whether derivative trading can be considered an economic activity as defined under Article 9(1) of the VAT Directive. Fundamental questions include whether the VAT system itself effectively conspires to exclude derivatives from its scope; whether derivatives traders effectively act as taxable persons under the VAT system; whether derivatives as financial instruments or contracts represent transactions in goods or services in VAT terms; or, whether the underlying transactions in goods and services should provide the sole focus for VAT. In addition, the nature of derivatives as financial instruments raises questions as to whether derivatives should also be entitled to the exemption afforded financial and insurance services under Article 135(1) of the VAT Directive. Other pertinent questions arising concern are what, if anything, constitutes consideration under a derivative as well as when VAT becomes due, i.e. when the chargeable event takes place. In addressing the research question, the doctrinal method is appropriate in bringing clarity to the definition of the scope of VAT as a key first step. The interpretation of Articles 2(1)(a) and (c), 9(1) and 135(1) of the VAT Directive are crucial in this regard and effectively forms the basis for the research. A testbed created from the key features (building blocks) of the VAT system forms the basis for the systems thinking. These key features are the role of VAT as a tax on consumption, the wide scope of VAT, the narrow interpretation of exempt supplies as well as the principle of neutrality in terms of similar supplies.
  • Junnilainen, Lotta (Vastapaino, 2019)
    This PhD thesis is an ethnographic study on social life in two public housing neighborhoods. It is a story from the inside, describing residents´ experiences of community and belonging as social practices. As such, it aims at challenging the one-dimensional approaches representing public housing neighborhoods as problem neighborhoods in need of correction. The research also shows how outsiders prejudices and preconceptions are not only related to these places and neighbourhoods, but also towards the people living in them. The research is based on ethnographic fieldwork conducted in two post-WWII housing estates built in the 1960s and 1970s located in two of the biggest cities in Finland. The areas were originally built for working-class families, but have since become neighborhoods of concentrated disadvantage and unemployment. For five years (2012-2016), I collected data on the social networks, residents´ everyday practices and interactions, their relations to local institutions, as well as narratives guiding their understanding of who they are and what their neighbourhood is. In addition, I used media archives for chasing the processes of stigmatization in public narratives that have made the areas “problem neighborhoods” of today. The data describes neighbourhood life in which social class is not an articulated identification, but an everyday experience manifesting in collective memory, place attachment, solidarity and misrecognition. The empirical contribution of the thesis lies in micro-level description of urban bonds, place-making and practices of community – such as story-telling, neighboring, gossiping, collective nostalgia and boundary making. The analysis of interaction between the residents and outsiders also highlights the processes, where the good and sincere intentions of individuals can end up renewing and strengthening forms of social inequality as an unintended consequence of their actions. Theoretically, the research builds on urban sociological theories and approaches that until now have been less applied to the Finnish context. Traditionally, urban scholars have approached neighborhoods of concentrated disadvantage either as “communal villages” based on strong social ties or “problem neighborhoods” of isolation and social disorganization. However, neither of these descriptions characterized the neighborhoods of this research. Instead, built through the everyday practices of local life, the residents were able to form and maintain patterns of mutual recognition, as well as a sense of belonging – all without the requirement of the close social ties usually related to the traditional idea of village life. For almost half a century outsiders from politicians to urban planners have tried to fix the neighbourhoods of my research by making their inhabitants more active and communal. The communality resulting from the social practices of the areas has not been recognized due to its´ failures to resemble the middle-class ideals of communal life. This PhD is a micro-level description of the paradox of communality and the power to define what type of communality and solidarity is preferred and welcome in society. Now at the turn of the decade Finland is not faced with problem neighborhoods, but rather a neighborhood problem reflecting first and foremost the middle-class presumptions concerning the types of people living in certain areas of the country.
  • Frisk, Matleena (Nuorisotutkimusverkosto/Nuorisotutkimusseura, 2019)
    This study investigates norms of young femaleness and maleness, from the perspective of consumer products and ideals concerning the body. The context of the study is the major increase in Finnish private consumption and change in views related to sexuality that took place during the 1960s and early 1970s. The study focuses on the gender perspective in the history of everyday life structured by consumption. The research subject is delineated using a concept, intimate bodily consumer products, which refers to products that are used to process the body in an intimate way. The study asks what connections there are between the use of intimate bodily consumer products and the norms of bodily young femaleness and maleness in the commercial popular culture directed at young people in Finland in the 1960s and at the beginning of the 1970s. The key source in the study is the widely read youth music magazine Suosikki, especially the advertisements in the magazine. The analysis is contextualized by utilizing household surveys and collections of oral history data. In the first part, the study analyses the norms that could be found in the Suosikki magazine regarding girls and boys, dating and sexuality. An ideal relationship emphasised being alike and belonging together, and the ideal couple often referred to themselves as ‘we’. In this research, this is characterised with the concept of we-ness. Though the magazine had portrayed itself ever since the end of the 1960s as having a modern, non-moralising attitude to sexuality, the issue of a girl’s sexual reputation continued to be evident in the articles of Suosikki. However, the girl’s sexual agency was given space within the ideal relationship characterised by we-ness. The latter part of the study takes a closer look at the way in which the intimate bodily products and their use were woven into the understanding of gender. Two cases are analysed: young men adopting the use of deodorant and the change in the type of menstrual products used by young women. In the early 1960s, deodorant was considered to be a feminine fragrance and first started to be used on a wider scale when both the understanding of young maleness and the meaning of deodorant as a product changed. The study of disposable menstrual products, on the other hand, focuses attention on the availability of products and rising living standards. The ideal of we-ness as well as changed attitudes to pre-marital sex were reflected in advertising: Advertisements for products related to especially a girl’s body often referred to dating and sexual relationships. The ideal body was constructed with the advertised products, but was represented as natural.

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