Väitöskirjat

Recent Submissions

  • Bollepalli, Sailalitha Spurthy (Helsingin yliopisto, 2020)
    Obesity and smoking are the two major preventable causes of global mortality associated with a multitude of comorbidities, inflicting greater public health and economic burden. Complex interactions between genetic and environmental factors influence susceptibility to obesity and smoking. Epigenetic modifications provide a mechanistic link between genetic and non-genetic factors causing complex diseases or traits. Epigenetic modifications also function as an additional layer of gene regulation by modifying the structure and accessibility of DNA and chromatin. The fundamental objective of this thesis is to elucidate the role of epigenetic and transcriptomic markers in obesity and smoking. Hence, this thesis focuses on identifying epigenetic and transcriptomic markers associated with weight loss and smoking behavior using different study designs and by applying computational and statistical approaches. Genome-wide transcriptome and methylome were assessed in an unbiased, hypothesis-free setting to identify weight-loss and smoking-associated signals in Study I and II, respectively. Validation of the main findings from the discovery analyses and integration of transcriptomic and methylation data were performed to assess the validity and biological significance of the identified markers. A machine learning approach was employed in Study III to develop a robust smoking status classifier based on DNA methylation profiles. The performance of the classifier was tested in three different test datasets and also in comparison with two other existing approaches. Therefore, this thesis encompasses both application and method development aspects to achieve the corresponding aims of the studies. In Study I, clinical parameters, genome-wide transcriptome, and methylome analyses were assessed longitudinally at three time points during a one-year weight loss intervention study, to understand the temporal changes in transcriptome and methylome of subcutaneous adipose tissue (SAT) in response to weight-loss. Results from the discovery analyses were validated using monozygotic (MZ) twin pairs discordant for acquired obesity, to examine whether weight loss and acquired obesity exhibit reciprocal transcriptome and methylome profiles. Gene expression and methylation profiles of the SAT at the three time points were also integrated to enhance our understanding of their interaction and thereby their contribution in weight loss. Based on the weight loss trajectory of the participants, three comparisons were performed: short-term (baseline to the fifth month), continuous (fifth to twelfth month), and long-term weight loss (baseline to twelfth month). Clinical parameters were improved with the weight loss (e.g. from baseline to fifth month, total and low-density lipoprotein cholesterol; triglycerides; and systolic blood pressure decreased and insulin sensitivity increased) and several significant transcriptome profiles were identified in response to weight loss at the three comparisons. No genome-wide significant methylation profiles were identified for the three comparisons. However, several significant correlations were observed between expression and methylation, indicating a potential regulatory role of DNA methylation in weight loss -associated transcriptome profiles. At the pathway level, short-term weight loss was implicated in lipoprotein metabolism and long-term weight loss associated with various pathways associated with multiple functions of the SAT. Furthermore, several weight loss -associated genes exhibited opposite direction of expression in acquired obesity in the validation cohort of MZ twins, validating the robustness of identified associations. In Study II, discovery analyses focused on understanding the widespread effects of smoking on SAT by simultaneous assessment of genome-wide transcriptome and methylome of SAT. Discovery analyses performed on the current (n=54) and never (n=291) smokers in the TwinsUK cohort identified 42 significantly differentially methylated signals and 42 significant differentially expressed genes (DEG) indicating a substantial impact of smoking on metabolically important SAT. Integration of these results revealed an overlap at five genes (AHRR, CYP1A1, CYP1B1, CYTL1, and F2RL3) comprising 14 CpG sites. To further characterize the widespread effects of smoking on metabolic disease risk three adiposity phenotypes (total fat mass [TFM], android-to-gynoid fat ratio [AGR] and visceral fat mass [VFM]) were assessed with regards to the identified smoking-associated methylation and expression signals. Three CpG sites in CYP1A1 showed significant associations with VFM and AGR, and an inverse association was identified between methylation levels of cg14120703 (NOTCH1) and AGR. To validate these associations, a subset of younger Finnish twins (n=69, 21 current smokers) was used as a replication cohort. The overall inverse association between cg10009577 (CYP1A1) and AGR was replicated and exhibited a similar direction for interaction effects between smoking status and AGR. However, this association did not reach the genome-wide significance level. Expression levels of F2RL3 showed a significant association with all three adiposity phenotypes. While OR51E1 expression levels were significantly associated with AGR and VFM. Our results show that smoking affects both the methylome and transcriptome of the SAT with overlapping signals. Furthermore, smoking-associated methylation and transcriptome profiles are also associated with adiposity phenotypes indicating a broader impact of smoking on human metabolic health. In Study III, I developed a methylation-based smoking status classifier using a machine learning approach to overcome the limitations of cotinine and carbon monoxide biomarkers (i.e. limited to measuring recent exposure to smoking due to their short half-lives in body fluids) and the existing DNA methylation score-based approaches and to advance the practical applicability of smoking-associated methylation signals. I considered three smoking status categories (current, former and never) and used multinomial LASSO regression coupled with internal cross-validation to build the classifier. I demonstrated the global applicability and robustness of our classifier by evaluation of its performance in three independent test datasets from different populations and also compared the performance with two existing approaches. Our classifier differs from the existing approaches by curtailing the need to compute a threshold value specific to each dataset to predict smoking status. Our classifier showed good discriminative ability in identifying current and never smokers compared to other approaches. I also performed an extensive phenotypic evaluation to understand the results of our classifier. Accurate classification of former smokers is challenging as their classification is affected by cessation time and smoking intensity prior to quitting. I provide the functionalities of our classifier including other the two methods as an R package EpiSmokEr (Epigenetic Smoking status Estimator), facilitating prediction of smoking status in future studies. In conclusion, this doctoral thesis (1) enhances our understanding of obesity and smoking by integrating methylation and transcriptome data and identifying several weight-loss and smoking-associated signals, (2) shows wide-spread impact of smoking on metabolic health risk by evaluating the associations between smoking-associated signals and adiposity measures, and (3) demonstrates the role of DNA methylation profiles as a robust biomarker to predict smoking status by developing a smoking-status classifier.
  • Häkkinen, Riina (Helsingin yliopisto, 2020)
    The utilization of renewable biomass and development of greener technologies are in high demand. Especially, cellulose is a desired component in many applications, but the insolubility in most solvents limits its use. The currently used methods have also environmental issues and other concerns. To overcome these problems, ionic liquids were discovered to be able to dissolve cellulose and other renewable biomass fairly effectively. However, ionic liquids cannot be considered as “innocent” solvents, as their synthesis is not green, and they are often toxic and expensive. Deep eutectic solvents are recognized as promising green alternatives for ionic liquids and petroleum-based solvents, and are now widely used in biomass processing. Generally, deep eutectic solvents are binary mixtures formed by mixing cheap components together: a hydrogen bond donor with a hydrogen bond acceptor. The strong hydrogen bonding between the components is believed to be responsible of the reduced melting point of the mixture. As deep eutectic solvents were introduced quite recently, these novel solvents are still lacking the knowledge and understanding of their fundamentals. In this thesis, the introduction section covers the background on basic carbohydrate chemistry, ionic liquids which are able to dissolve cellulose, and deep eutectic solvents with their applications in biomass treatment. The characteristics of ionic liquids and deep eutectic solvents are compared. Generally, ionic liquids have better dissolution capability towards polysaccharides than deep eutectic solvents, but very little research has been done to explain why. The aim of this thesis is to understand and explain the fundamentals of deep eutectic solvents. Therefore, the properties affecting carbohydrate solubility, including cellulose (publication I), physicochemical properties of a new DES (publication III), solvent-solute interactions (publication I, II) and phase behavior of different alcoholic solutes in a DES (publication II) are studied in more detail. Furthermore, the unique properties of DESs are utilized in a novel way: as a green binder for Lithium-ion batteries (publication IV).
  • Liu, Chang (Helsingin yliopisto, 2020)
    Faba bean is a legume that is not only rich in proteins but also is well adapted to the short growing seasons in the Nordic and Baltic countries. Considering the economic cost and sustainability issues, growing interests are focused on plant proteins. In this study, the potential applications of modified faba bean protein isolate (FBPI) in oil-in-water (O/W) emulsions were investigated. The overall aim of the research was to study how different modifications of FBPI affected the physical and oxidative stability of O/W emulsions. Modification of FBPI by microbial transglutaminase (MTG) induced protein cross-linking. MTG treatments for longer time (120 and 240 min) induced excessive surface hydrophobicity, resulting in decreased emulsifying activity and physical stability of emulsions. On the other hand, a short time (60 min) MTG treatment improved FBPI’s potential to maintain the physical stability while improving lipid oxidative stability of the emulsion. This might be attributed to thicker interfacial layer, larger droplet size, and protective effect of protein. Alcalase hydrolysis of FBPI to a degree of hydrolysis (DH) of 4% produced an emulsion with improved physical stability and least of lipid oxidation while maintaining protein oxidative stability as compared to emulsions prepared with native and extensively hydrolyzed (DHs of 9 and 15%) FBPI. FBPI hydrolysates with DH of 4% exhibited molecular weight better applicable to interfacial layer stability, increased surface net charge for more repulsive electrostatic force, and increased hydrophobicity. Considering the important role of interfacial layer thickness in emulsion stability, FBPI and chitosan (CH) were associated in different ways to construct different types of interfacial layer. Emulsions with layer-by-layer (LBL) interfacial structure not only showed better physical stability, but also had superior oxidative stability. This might be attributed to that CH assisted in forming LBL interface, which increased the interfacial layer thickness/compactness and maintained the interfacial protein adsorption. In conclusion, the emulsifying functionality of FBPI, and thereby the stability of FBPI containing O/W emulsions can be improved by different ways of modifications via several mechanisms.
  • Danilova, Tatiana (Helsingin yliopisto, 2020)
    Neurotrophic factors are small secretory proteins with essential roles in neuronal and non-neuronal tissues. Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) form a distinct family of unconventional neurotrophic factors. MANF and CDNF are endoplasmic reticulum (ER) located, but also secreted proteins. Initially, MANF was discovered as a trophic factor for dopamine neurons in vitro. Further studies revealed its protective and restorative properties in different animal disease models such as Parkinson´s disease, spinocerebellar ataxia, brain- and heart-ischemia. MANF is also identified as a protein upregulated in unfolded protein response (UPR) and protecting against ER stress-induced cell death. CDNF was identified based on its homology to MANF and characterized for its ability to protect and restore dopamine neurons in rodent models of Parkinson´s disease. However, the physiological roles of MANF and CDNF in mammals have remained unclear. The main objective of this thesis was, therefore, to study the biological roles of MANF in vivo by characterizing the phenotypes of MANF conventional and conditional knockout mice as well as analyzing MANF and CDNF expression in mouse tissues. Comprehensive expression analysis of MANF mRNA and protein revealed that MANF is widely expressed in most mouse tissues. It is highly expressed in neurons regulating energy homeostasis within the hypothalamus and neurons of other appetite-regulating areas including the brainstem structures and mesolimbic/mesocortical dopamine system. Exceptionally high levels of MANF was observed on peripheral mouse tissues with metabolic function, especially in cells with secretory functions within the endocrine and exocrine glands, suggesting essential roles for MANF in cells with high protein synthesis and secretion. Highest levels of CDNF protein was observed in tissues with high energy production and oxidative function including skeletal muscle, heart, testis and brown adipose tissue. In order to study the roles of MANF in mammals, we deloped MANF conventional knockout mice (Manf-/-), that showed severe growth retardation, poor survival and a progressive postnatal reduction of beta-cell mass resulting in severe insulin-deficient hyperglycemia and diabetes mellitus caused by decreased beta-cell proliferation and increased beta-cell apoptosis. In our further studies, we verified that diabetic phenotype of the Manf-/- mice was caused by a lack of MANF in the insulin-producing beta-cells in the pancreas and not in other organs by generating pancreas- and beta-cell-specific conditional Manf-/- mice. We found that pancreatic islets of conventional and conditional MANF deficient mice displayed chronic activation of the UPR, preceding downregulation of beta-cell markers, indicating unresolved ER stress as one possible cause of beta-cell failure in these mice. Thus, this work shows that MANF is an essential regulator of beta-cell maintenance and UPR in mice. We discovered that MANF protein increased beta-cell proliferation in vitro in islets isolated from young and even old mice. MANF protein also rescued mouse beta-cells from thapsigargin-induced apoptosis and ER stress-induced glucotoxicity in culture. Importantly, we found that MANF overexpression in the mouse pancreases mediated by adeno-associated virus vector was able to regenerate beta-cells in vivo in a mild low-dose streptozotocin mouse model of diabetes. Hence, these results indicate that MANF is a vital mitogen and protective protein for mouse beta-cells and can thus serve as a potential new regenerative drug for the diabetes therapy. Furthermore, we identified the decreased number of growth hormone (GH) and prolactin (PRL) expressing cells in the anterior pituitary gland of Manf-/- knockout mice associated with increased expression of UPR markers and decreased expression of Gh and Prl genes. Thus, reduced GH production could be one of the reasons for the growth retardation in Manf-/- mice. Taken together, the results in this thesis provide new critical biological functions of MANF in mouse in vivo which can be used to exploit the roles of MANF in human beta-cells and diabetes as well as in endocrine somatotropic cells and growth failure in human.
  • Abera, Temesgen (Helsingin yliopisto, 2020)
    The climate system responds to changes in the structure and physiology of vegetation. These changes can be induced by seasonal growing cycles, anthropogenic land cover changes (LCCs), and precipitation extremes. The extent to which vegetation changes impact the climate depends on the type of ecosystem, the season, and the intensity of perturbations from LCCs and precipitation extremes. Under the growing impacts of climate change and human modification of natural vegetation cover, understanding and monitoring the underlying biogeophysical processes through which vegetation affects the climate are central to the development and implementation of effective land use plans and mitigation measures. In Eastern Africa (EA) the vegetation is characterized by multiple growing cycles and affected by agricultural expansion as well as recurrent and severe drought events. Nonetheless, the degrees to which vegetation changes affect the surface energy budget and land surface temperature (LST) remain uncertain. Moreover, the relative contributions of various biogeophysical mechanisms to land surface warming or cooling across biomes, seasons, and scales (regional to local) are unknown. The objective of this thesis was to analyze and quantify the climatic impacts of land changes induced by vegetation seasonal dynamics, agricultural expansion, and precipitation extremes in EA. In particular, this thesis investigated these impacts across biomes and spatio-temporal scales. To address this objective, satellite observation and meteorological data were utilized along with empirical models, observation-based metrics, and statistical methods. The results showed that rainfall–vegetation interaction had a strong impact on LST seasonality across ecoregions and rainfall modality patterns. Furthermore, seasonal LST dynamics were largely controlled by evapotranspiration (ET) changes that offset the albedo impact on the surface radiation balance. Forest loss disturbed the LST dynamics and increased local LST consistently and notably during dry seasons, whereas during the wet season its impact was limited because of strong rainfall–vegetation interaction. Moreover, drought events affected LST anomalies; however, the impact of droughts on temperature anomalies was highly regulated by vegetation greening. In addition, the conversion of forest to cropland generated the highest net warming (1.3 K) compared with other conversion types (savanna, shrubland, grassland, and cropland). Warming from the reduction of ET and surface roughness was up to ~10 times stronger than the cooling effect from albedo increases (−0.12 K). Furthermore, large scale analysis revealed a comparable warming magnitude during bushland-to-cropland conversion associated with the dominant impact of latent heat (LE) flux reduction, which outweighed the albedo effect by up to ~5 times. A similar mechanism dominated the surface feedback during precipitation extremes; where LE flux anomalies dominated the energy exchange causing the strongest LST anomaly in grassland, followed by savanna. By contrast, the impact was negligible in forest ecosystems. In conclusion, the results of this thesis clarify the mechanics and magnitude of the impacts of vegetation dynamics on LST across biomes and seasons. These results are crucial for guiding land use planning and climate change mitigation efforts in EA. The methods and results of this thesis can assist in the development of ecosystem-based mitigation strategies that are tailored to EA biomes. Moreover, they can be used for assessing the performance of climate models and observation-based global scale studies that focus on the biogeophysical impacts of LCCs. Keywords: LST seasonality; Land cover change; Bushland (Acacia-Commiphora); Biophysical effects; Precipitation extremes; Satellite observation.
  • Pennonen, Anne-Maria (Helsingin yliopisto, 2020)
    This study examines the relationship between landscape painting in Düsseldorf and the natural sciences in the nineteenth century. The natural sciences here comprise meteorology, geology, geography and botany. The point of view provided by these fields offers an approach to the subject that has not been considered in Finnish art-historical discourse to date. The main focus is on the artworks of Finnish artists Werner Holmberg and Fanny Churberg, as well as those by Victoria Åberg, Magnus and Ferdinand von Wright, with essential comparison material provided by studying works by German artists Johann Wilhelm Schirmer and Carl Friedrich Lessing, and by Norwegian artists Hans Gude and August Cappelen. The primary material consists of sketches, studies and finished works of art. I reflect on the developments of the natural sciences in Germany, Norway and Finland in the 19th century, and how these affected the works of art, using the history of ideas and discourse analysis. The main temporal scope of this study falls between the years 1853 and 1880. The time period should not be understood too strictly, because it is not possible to talk about the relationship between landscape painting and natural sciences within these decades alone. During the first decades of the 19th century, artists in Dresden were interested in natural sciences, as well as drawing and painting studies from nature. The same trend continued in Düsseldorf, starting in the 1820s, where it was considered essential to observe the landscape in a ‘proper fashion’, and expressions such as ‘the new naturalism’ and ‘the truth of nature’ were widely used. Thanks to the activities of Johann Wilhelm Schirmer and Carl Friedrich Lessing in the field of open-air painting, the notion of naturalism gained the dimension it has been granted in this investigation. It was their example that encouraged younger artists to go out into nature in pursuit of depicting different landscape phenomena. When researching open-air painting, the travels these artists made also gained more importance. The idea of discovery in connection with travelling led me to follow in the footsteps of Alexander von Humboldt. His work as a naturalist and his expedition to South and Central America helped me to connect landscape painting with the development of different fields of natural sciences. Humboldt was a representative of Romantic science, and in his work he regarded landscape painting as an essential way of studying nature. He also co-operated with several artists. The artistic process of composing a landscape recalls the work of a naturalist, as described by Humboldt. Likewise, Humboldt reverted to landscape aesthetics in his writings. In the case of Finnish landscapes, many artists were guided by the work and writings of Zacharias Topelius. Being one of the leading cultural figures in Finland at the time, Topelius worked as an author, journalist, Secretary of the Finnish Art Society and as a teacher lecturing on geography at the University of Helsinki.
  • Soini, Sirpa (Helsingin yliopisto, 2020)
    BACKGROUND AND OBJECTIVES Weight loss is often successful in the short-term but long-term results are often difficult to maintain. Therefore, a study focusing on previously obese people who have successfully lost weight and maintained it for a longer time period is of major importance from a public health point of view. Several changes in lifestyle-related factors are required and the aim of this study was to identify the and other success factors, including the personality traits of the participants. METHODS This study was based upon findings from the FWCR, a web-based registry. A total of 316 people were recruited through articles in newspapers all over Finland and of these 184 met the inclusion criteria: age of 18-60 years, body mass index (BMI) of ≥30 kg/m2 before weight loss, a weight loss of at least 10%, and successful maintenance of this weight loss for a minimum of two years. The exclusion criteria was medication for weight loss and bariatric surgery. In total 158 (100 women and 58 men) formerly obese participants filled in an electronic questionnaire that included questions on sociodemographic factors, lifestyle habits, weight loss methods, self-weighing, motivational factors, experienced difficulties and need for support in weight management. The personality trait sections in the questionnaire used the Five Factor Model (FFM) which is based on the Finnish version of the Ten-item personality inventory (TIPI). RESULTS A total of 158 participants were included in the final analyses. The mean age was 44.5 years, average BMI before weight loss was 35.9 kg/m2 and after weight loss 26.1 kg/m2, and average weight loss was 26.5% (32.4 kg). Compared with the general Finnish population the participants were less often smokers (P=0.009), consumed less alcohol (P≤0.001), and were physically more active (P≤0.001). The weigh loss method varied: about half of the participants (48%) reported that they lost weight slowly primarily through dietary changes. Self-weighing frequency was high, 92% weighed themselves at least once a week during the weight loss phase, and 75% during the maintenance phase. Reported success factors related to diet included an increase in intake of vegetables, a reduction in the frequency of eating candies and fast food, regular meal frequency and application of the Plate model. The motivational factors for weight loss were either health- or appearance-related and varied by gender. The women reported dissatisfaction with their body more commonly than the men (P=0.023) and the men reported health-related reasons (P=0.008) as the main motivational factor more often than the women. Gender differences were also found in support during weight loss: the men more often reported losing weight alone without any outside support than the women (P=0.006). Difficulties during the weight maintenance phase were significantly less than those during weight loss phase. Personality traits of neuroticism, agreeableness and conscientiousness were associated with several factors such as; motivational factors, self-weighing frequency, dietary habits, support and difficulties during the weight loss process. We also found gender differences in these factors. CONCLUSIONS Those who were successful in long-term weight loss had a healthier lifestyle than the general Finnish population. Both slow and fast weight loss may lead to success along with significant decrease in the intake of energy-dense foods. Frequent self-weighing, applying the Plate model, and regular meal frequency were also factors that contributed to successful weight loss and maintenance. Motivational factors varied by gender as did difficulties and need for support. Personality traits may also be important in successful long-term weight maintenance after weight loss and should be taken into account in guidelines for the treatment of obesity. Generalization of our results should take into account the small sample size. Larger studies are needed. KEYWORDS: obesity, successful weight loss and weight maintenance, lifestyle changes, dietary habits, personality traits, motivational factors, gender
  • Marila, Marko (Helsingin yliopisto, 2020)
    In philosophical metaphysics, speculation is often seen to have value as an ontological concept referring to rational contemplation on the fundamental but unobservable nature of reality. In philosophy of science, on the other hand, speculation is commonly taken as an epistemological notion to mean that a proposition regarding the nature of reality can be possibly either true or false, and that the veracity of a proposition can be tested against empirically observed facts. This simplistic division into speculation as a matter of metaphysics and a matter of empirics also pertains to archaeology where speculation, as an ontological concept pertaining to the unobservable, has had little value. Instead, speculation, as well as the ambiguity and uncertainty introduced with it, have been treated as provisional resorts and epistemological points of elimination. In reviewing the history of archaeology in terms of the common views of the form and constituents of archaeological inference, and in drawing philosophical inspiration from a range of speculative philosophies and contemporary archaeological theorising, this thesis argues that the desirable strategy in the epistemology of archaeology is not the systematic elimination of speculation. In contrast, the thesis takes speculation seriously and contends that it has significance in the epistemology of archaeology as both an epistemological and an ontological notion. The thesis holds that in order to develop an empirically sensitive, ontologically considerate, and ethically sustainable epistemology of archaeology, speculation should be cultivated and cared for as a systematic consideration of the multiplicity of experience. In other words, speculation is to be preserved as a method of thinking otherwise; a countermeasure to the methodological (and the ensuing ontological) simplification risked by adhering to the eliminationist strategies. The practical possibilities towards a speculative epistemology of archaeology are discussed in terms of methodological and theoretical deceleration, a matter that has become increasingly relevant with the recent natural scientific revolution in archaeology. Slowing down, in this context, aims towards a historical understanding of the discipline as a community of practitioners with possibly conflicting concerns and objectives. In this way, the principle of speculative epistemology becomes the perpetual anticipation of the possible practical effects of pursuing truths and realities on epistemologies that entertain different understandings of those concepts.
  • Hakanpää, Laura (Helsingin yliopisto, 2020)
    Vascular integrity is essential for proper vessel function, and for the maintenance of tissue and organ homeostasis. Endothelial cells (ECs) in the inner lining of the blood vessels form a barrier that dynamically regulates permeability across the vessel wall. Permeability via EC-EC junctions is transiently increased during inflammation, whereas abnormally or persistently elevated EC permeability promotes disease pathogenesis. For example, in sepsis, systemic capillary leakage compromises blood perfusion, and may lead to hypovolemic shock and multiorgan failure. Despite the significant amount of research on the mechanisms that control the EC barrier, no targeted therapies currently exist to seal the leaky vessels and maintain tissue perfusion. The aim of this study was to investigate how vascular permeability is controlled via an EC-derived growth factor angiopoietin-2 (ANGPT2), which is upregulated in various human diseases, including sepsis. ANGPT2 was found to signal via 1-integrin, and therefore the function of endothelial 1-integrin in vascular permeability was investigated. The results identified a novel signaling pathway, where ANGPT2–1-integrin signaling promotes EC permeability. 1-integrin was found to play a previously uncharacterized role in inflammation-induced vascular permeability, and an antibody against 1-integrin inhibited vascular leakage, improved EC junction integrity and protected from cardiac failure in LPS-induced murine endotoxemia. Earlier studies have shown that ANGPT2 destabilizes blood vessel integrity in a context-dependent manner via its classical receptor TEK receptor tyrosine kinase (TIE2) on ECs. These studies have raised interest on ANGPT2 as a potential target in various diseases, including cancer and ocular neovascular diseases. This study revealed that ANGPT2 can promote EC destabilization independently of TIE2, which is downregulated during inflammation. These results suggest that a better understanding of the signaling function of ANGPT2 is necessary, in order to optimally target ANGPT2 in disease. This study also highlights the crucial role of endothelial 1-integrin in controlling inflammation-induced EC permeability. The results showed that various inflammatory agents induced EC monolayer destabilization via 1-integrin, manifested by the loss of junctional VE-cadherin, the formation of actin stress fibers, and altered EC-extracellular matrix (ECM) adhesions. The EC-ECM adhesions that formed in inflammation were elongated fibrillar adhesions that can be distinguished from focal adhesions by the presence of the adapter protein tensin-1. Furthermore, 1-integrin promoted inflammation-induced EC contractility and reduced the EC barrier function. Importantly, targeting 1-integrin using a monoclonal antibody, or via a heterozygous genetic deletion in the endothelium of gene-targeted mice decreased vascular leakage in LPS-induced murine endotoxemia. Notably, the 1-integrin antibody was effective both as a prophylactic and as an intervention therapy, administered after the onset of systemic inflammation and vascular leakage, and its mechanism of action was independent of attenuating systemic inflammation, and of the vascular stabilizing function of TIE receptors. In summary, this thesis provides new knowledge on the mechanisms that lead to vascular leakage via ANGPT2 and 1-integrin. 1-integrin was identified as a potentially universal regulator of EC permeability. A major finding was that targeting the EC 1-integrin in a preclinical model of sepsis decreased vascular leakage, thereby improving cardiac function. The results of this thesis call for further studies in evaluating the translational potential of 1-integrin mediated vascular permeability.
  • Viuhko, Minna (2020)
    This study takes a look at human trafficking and related exploitation in Finland in the 2000s. The term “human trafficking” is used to denote a serious crime against the individual and their freedom in which the perpetrator exploits the victim for benefit. Here, the exploitation is considered in the contexts of different job sectors and prostitution. The study takes a look at different cases of sexual exploitation and exploitation of migrant labour which fall under the category of human trafficking or which have included characteristics of human trafficking. The study yields an analysis of the human trafficking situation in Finland during the first 15 years of the 2000s. It comprises four sub-studies dealing with the overall theme of the control perpetrators impose on victims. The sub-studies analyse the violence, coercion and control imposed on the victims from different perspectives and, to a certain extent, in different contexts. The study asks how do exploitation and control manifest themselves in the human trafficking of the 21st-century Finland, what forms of control imposed on the victims can be identified, and how does the control restrict the agency of the victims. The study is interdisciplinary and falls within the disciplines of sociology, criminology, gender studies and, to a lesser extent, migration studies. The central concepts used in the study are agency, control, vulnerability, ideal victim, ideal offender and intersectionality. The central theoretical concept throughout is “agency”, and the concept of “restricted agency” has been developed further as part of the study. Sub-study I examines control in the context of prostitution and organised procuring in Finland at the beginning of the 2000s. It analyses the structure of criminal organisations and the different ways in which the perpetrators have acted. The sub-study sheds light on the circumstances in which the procurers operated at the turn of the millennium before human trafficking was criminalised in Finland and slightly after. The conclusion is that the women involved in prostitution under various criminal organisations had to act under different variations of control and in accordance with strict rules. In Sub-study II, exploitation and control are analysed from the victims’ point of view, especially in the context of labour exploitation. The sub-study shows that the victims of human trafficking face different kinds of physical, psychological and financial control. The analysis also touches upon the agency of victims, yielding the concept of “restricted agency”, which is used to describe the agency of victims of human trafficking and the framework of exploitation and control under which the victims act. The focus in Sub-study III is on the perpetrators and the stereotypical conceptions that are formed of them − here the concept “ideal offender” comes to fore. The sub-study calls the central role of organised criminal groups in human trafficking into question and asserts that human trafficking crimes are often organised by individuals rather than by organised criminal groups and that the parties involved in the exploitative situations often know each other beforehand. Nevertheless, the crimes can be profitable for the perpetrator and the exploitation can be very severe. Sub-study IV analyses the different relationships between the victims and perpetrators of human trafficking. The intersectional approach was used for this sub-study, looking into what exposes potential victims to exploitation on the one hand and what keeps them from leaving the exploitative situation on the other hand. The sub-study illuminates the power relations between the victims and the perpetrators, and it also shows that there is a plethora of intersecting factors which affect both the victimisation and the imbalanced power relations between the perpetrators and the victims. The dissertation moves from the analysis of the criminal organisations to that of close relationships and from the descriptive study of the phenomenon to intersectional analysis. The study makes use of different materials: official documents (court judgments and pre-trial investigation records), interviews with victims of human trafficking and related exploitation, and expert interviews. The study is a qualitative one and the methods of analysis used are thematic and analytical coding, close-reading and intersectional analysis. The study shows that the identified cases of human trafficking and related exploitation have changed their forms in certain ways between the period from the late 1990s to the beginning of the 2010s. Instead of large-scale pandering operations, exploitation between individuals and, at times, in close relationships is nowadays better identified in Finland in the contexts of working and private life. At the centre of the study lies the control perpetrators impose on victims and how this control restricts the agency of the victims. According to the study, the agency of the victims is restricted by the perpetrators, exploitative situations and social structures. The restrictions set by physical, psychological, sexual and financial control define the scope for the victim’s action. In addition, the intertwined individual and structural factors have an influence on how one might become exposed to exploitation and on the fact that disentangling oneself from an exploitative relationship is not possible or easy. For instance, gender, age, ethnic background and poverty can be connected to whether an individual is exposed to exploitation, and, on the other hand, lack of money, lack of language skills and the residence permit status can create obstacles to leaving the exploitative situation and the exploitative relationship. These restrictive factors on the victims’ agency do not mean, however, that the victims are merely passive objects who cannot make any decisions about their own lives. Instead, the victims act within the limits set by the control that has been imposed on them. Keywords: Agency, control, exploitation, human trafficking, offender, victim
  • Heikkilä, Maria (Helsingin yliopisto, 2020)
    Nutrition plays an important role in athletic performance. Its full potential is rarely realized due to limited nutrition knowledge among athletes and their coaches. Misunderstandings and gaps in knowledge can lead to food choices that do not support athletic development. This thesis study was undertaken to gain further insight into the nutrition knowledge of young Finnish endurance athletes. Another aim was to evaluate how athletes’ knowledge and nutritional skills can be improved. Study I created and validated a questionnaire measuring knowledge in different areas of sports nutrition. This questionnaire was then used in Study II, which aimed to measure the nutrition knowledge of young Finnish endurance athletes and their coaches. The results of Study II were used to develop an education intervention, aiming to improve athletes’ nutrition knowledge and dietary intake, in Study III. The intervention compared the effects of participatory nutrition sessions alone to those enhanced by a mobile app. In Study II, a total of 312 athletes and 94 coaches completed the questionnaire. The athletes were 17.9±1.2 and the coaches 44.3±12.3 years old. Half of the athletes were women and half men; of the coaches 27% were women. Of the athletes 36% were cross country skiers, 35% orienteers and the rest other endurance athletes. Seventy-nine athletes took part in the intervention in Study III. Their mean age was 18.0±1.4 years, 56% of them were men and 44% were women, and 42% were cross-country skiers. The education in the intervention was based on the Self-Determination Theory and the concept of meaningful learning processes. The education sessions included discussions, tasks and goal setting, which were all intended to increase the athletes’ intrinsic motivation. This motivation in turn is a prerequisite for effective learning. The three sessions lasted 90 minutes each and were held fortnightly. The athletes filled in the questionnaire at baseline and a week and three months after the last session. The athletes in the mobile app group used the app for four days after each session and took photos of everything they ate or drank. Both groups completed a three-day food diary at baseline and three months after the last session and received personal feedback on it. On average, the athletes in Study II answered 73% and the coaches 81% of the items correctly. However, over a half of the athletes and 44% of the coaches scored below the mean knowledge score, at worst answering only 47% of the items correctly. The coaches scored better in all sections of the questionnaire. The questions in the ‘Dietary supplements’ section proved to be the most difficult for the athletes, and those in the ‘Nutrition recommendations for endurance athletes’ section for the coaches. The older the athletes were, the higher was their mean nutrition knowledge score. Among the coaches, the situation was the opposite. On average, the female athletes and coaches scored better than the men. The athletes who were part of a national team had higher knowledge scores than those who were not. The athletes’ nutrition knowledge improved significantly during the intervention. At baseline, their knowledge score was 78%. A week after the education sessions, the athletes in the mobile app group answered on average 87% of the questions correctly and three months later, 86%. In the group without the mobile app, the scores were 85% and 84%, respectively. There was no significant difference between the groups in any sections of the questionnaire. The mean energy intake of the athletes was below the estimated energy expenditure during Study III. The intake of protein and fat met the recommendations for endurance athletes, but the intake of carbohydrates was below them (6–10 g·kg-1·day-1) throughout the study, even though it slightly improved. At the end of the intervention, the athletes in the mobile app group consumed 5.4 g·kg-1·day-1 of carbohydrates and the athletes in the other group 5.0 g·kg-1·day-1. Many psychological, social and economic factors affect what we eat. Improved knowledge does not automatically lead to better food choices if the intention to perform the behavioural change is lacking. The duration of the intervention may also have been too short for notable behavioural changes. In addition, already at the beginning of the study the diet of the athletes was better than that of the general Finnish population, thus leaving less room for dietary improvements. Nutrition knowledge improved after only three education sessions and food diary feedback, but the mobile app did not further improve this learning. Thus, if sport clubs and other sport organizations dedicated even a relatively small amount of time and other resources to structured, targeted, motivational and science-based nutrition education, it may promote positive changes in nutrition knowledge. As athletes make use of the skills they learn during their sports careers in their everyday lives as well as when training other athletes, receiving influential nutrition education could also benefit their performance and health in the future.
  • Tienhaara, Annika (Helsingin yliopisto, 2020)
    The diversity of agricultural genetic resources (AgGR) is the foundation of food security. A diverse gene pool enables adaptation to changing conditions and is therefore essential, for example, to responding to climate change. However, during the past decades, intensification of agriculture has led to genetic erosion. Previously common animal breeds and plant varieties are becoming rare or extinct throughout the world as they are being replaced with small ranges of more productive specialized breeds and varieties. Yet, indigenous breeds and varieties have a wide range of socio-economic, cultural, ecological and genetic values and, in fact, the importance of conserving genetic resources has been acknowledged in global agreements and national policy programs. Nonetheless, as the resources available for conservation are limited, information on the value of AgGR is needed in order to compare the costs and benefits of conservation and to support decision making. Benefits from the conservation of AgGR can be measured from citizens’ and consumers’ preferences. This dissertation provides new, policy-relevant information on citizens’ and consumers’ willingness to pay for conservation and sustainable use of AgGR. Three stated preference methods were used to examine the value that citizens and consumers place on AgGR. Consumers’ willingness to purchase Finncattle meat and their willingness to pay for it was studied with contingent behavior and contingent valuation methods. In turn, willingness to support a conservation program for AgGR was examined with contingent valuation and choice experiment methods. In addition, heterogeneity in preferences and the effect of information use were analyzed. The results show strong support for the conservation of AgGR. There is a high will-ingness to purchase Finncattle meat among Finnish consumers, and a share of respondents is willing to pay +20-26% more for Finncattle meat compared to conventional meat. Studies also revealed that over 70% of the respondents supported an AgGR conservation program despite the increased cost related to it. Average willingness to pay for the program was €50-170 depending on the method of calculation. However, there was significant heterogeneity among respondents’ preferences. This is important to take into account, as ignoring the heterogeneity can lead to overestimation of benefit estimates. This dissertation provides new information on the benefit estimates of the AgGR conservation in Finland, which has not been studied before. It also contributes to the globally scarce literature on citizens’ and consumers’ preferences related to AgGR. The results of this dissertation can be used in cost–benefit analysis and they can assist in designing optimal AgGR conservation policies.
  • Niemeläinen, Julia (Helsingin yliopisto, 2020)
    This dissertation consists of an introduction and three essays on the determination of external imbalances and the real interest rate. In particular, the objective of the dissertation is to analyze the reasons behind the long-lasting current account imbalances observed over the past decades in large open economies, such as the current account deficit of the United States and the current account surplus of China, as well as the concurrent long-term decline in the world real interest rate. In the first two essays, I focus on demographic change, social security and fiscal policy as potential drivers of households’ consumption-saving decisions, the current account and the world real interest rate. The analysis is based on a dynamic general equilibrium model with an embedded life-cycle structure, which allows me to study the role of life-cycle savings and intergenerational transfers in the consumption-saving decisions, and in which fiscal policy is non-Ricardian. In the first essay I analyze how permanent differences in demographics, social security and fiscal policy affect the external sector and the world real interest rate in the long run, and compare the effects under fixed and variable labour supply, which the literature on demographic change and external imbalances often abstracts from. I find that, relatively high life expectancy and low social security are associated with a positive net foreign asset position in the two-country world. Because the impact of social security is quantitatively large, a country with relatively low life expectancy may become a net creditor if its social security is low enough. This result suggests that analyzing the effects of social security could help us understand the observed low-frequency capital flows from fast-growing emerging economies to industrialized countries. High life expectancy is, in the model, associated with a low international real interest rate, but endogenizing labour supply results in a higher real interest rate for a given level of life expectancy. This indicates that the negative effect of population ageing on the real interest rate might not be as strong as suggested by several earlier studies. The objective of the second essay is to analyze whether it is possible to replicate the dynamics of China’s trade surplus vis-a-vis the United States over the period 1980-2015, by taking into account the differences in demographic factors and social security between the countries. Productivity growth in China has been approximately twice as rapid as in the United States during this period, which, according to traditional neoclassical models, should imply high investment and consumption rates, and result in a trade deficit. In my model, China’s relatively rapid population ageing and low social security result in high and increasing savings by Chinese households, so that even when China’s high productivity growth is taken into account, the model produces a trade surplus for China during the sample period. In the third essay, I analyze the impact of the Chinese government’s macroeconomic policies on the observed trade balance dynamics and the transmission of these policies to the United States in the 2000s. The analysis is based on a life-cycle model, which includes features that describe the behavior of the Chinese policymakers. In particular, I assume that private agents are excluded from the international financial market, and that the public authorities can directly control the domestic real interest rate and the real exchange rate. I find that macroeconomic policies, especially the undervaluation of China’s real exchange rate, and the growth in government expenditures and fiscal deficits run by China and the United States, have had a positive impact on China’s trade balance, and raised the international interest rate. However, the overall effect of the policies depends qualitatively on the assumption of the elasticity of intertemporal substitution.
  • Mäkelä, Jarmo (Helsingin yliopisto, 2020)
    How important are different uncertainty sources when simulating the future state of the forest ecosystem in Finland? In this thesis, we examine this question and provide some answers to this broad topic by simulating 21st century ecosystem conditions with a land-ecosystem model called JSBACH and compare the results to similar simulations performed by another model called PREBAS. We consider four different sources of uncertainty that are related to 1) the model that is used to generate the future ecosystem conditions; 2) climate used to drive the model, represented by an ensemble of CMIP5 simulations; 3) RCP scenarios that depict the rising atmospheric CO2 concentration and; 4) forest management actions. Before running the simulations described above, we calibrated and validated the JSBACH model extensively on different temporal resolutions and with multiple model modifications in order to improve the site-level model representation of transpiration, evaporation and carbon assimilation of boreal forests. These hindcasting calibrations were performed with two Bayesian approaches: the adaptive Metropolis algorithm and the adaptive population importance sampler. The resulting parameter values were compared to literature and the model performance was validated with distinct data sets and independent validation sites. We then generated a suitable model setup and parameter distributions to represent the JSBACH model uncertainty in the 21st century simulations. Canonical correlation analysis and redundancy indices were used to gleam the impact of the different uncertainty sources on multiple groups of ecosystem variables. Overall, forest management actions and RCP scenarios tend to dominate the uncertainties towards the end of the century, but the effect of climate models and parameters should not be overlooked especially since a more detailed examination revealed that their impact was not fully captured.
  • Jokinen, Ewa (Helsingin yliopisto, 2020)
    During recent decades, gynecological surgery has changed considerably, and this development affects surgical training. In Finland, the total number of gynecological procedures has decreased by 30% during the last ten years. An increasing number of basic procedures are now done under local anesthesia at outpatient clinics where training is much more demanding than in the operating room. Laparotomies are frequently replaced by laparoscopic procedures that require more complex skills than open surgery. Furthermore, operating room efficiency causes time constraints, while patients in general have more co-morbidities and the surgical procedures needed are more complex. Thus, for trainees all these factors make training more challenging, and the traditional apprenticeship model alone no longer ensures that trainees learn the needed skills. In this dissertation study our aim was to assess developments in gynecological surgery in Finland and other Nordic countries by evaluating trends in hysterectomies. In addition, we investigated outcomes of traditional surgical training, as compared to systematic cognitive and manual pre-training on laparoscopic skills. We assessed separately the effect of pretraining on the trainee’s first operative laparoscopy, and on the other hand, on laparoscopic hysterectomy, which is the most demanding laparoscopic procedure trainees perform. In Study I, we assessed the numbers of different hysterectomies from the Nordic Medico-Statistical Committee and Finnish Institute for Health and Welfare databases. We compared outcomes of different hysterectomy methods between trainees and specialists collected from the FINHYST 2006 survey. In Finland, hysterectomy rates started to decline in 2003 and reached the rate of other Nordic countries in 2008. The rate of hysterectomy in Finland declined until 2017, and the laparoscopic method has been the most common method since 2013. In the outcome comparison, it was noted that the overall operative time was longer in trainees’ operations. In the vaginal method, blood loss was higher in the trainees’ group whereas in other hysterectomy methods or in total complication rates there were no differences between the groups. In Study II, we evaluated the effectiveness of a cognitive web-course ‘Basics in Gynecological Laparoscopy’ for trainees at various levels of experience. All trainees in Finland were invited to participate in this web-based anonymous study where the level of knowledge was evaluated before and after taking the course. Participants were allocated into three groups according to their experience. After the course, improvement in knowledge gain was detected in all three groups; the less experienced group reached the starting level of the middle group and the middle group reached the starting level of the most experienced group. In Studies III and IV, the effect of simulator training on operative skills was evaluated. Trainees with no experience in operative laparoscopy were recruited for Study III. Half of the group comprised the intervention group. They did the web-based course ‘Basics in Gynecological Laparoscopy’ and trained basic skills with a virtual reality simulator. The control group took part in the traditional training only. The first live laparoscopic salpingectomy was video-recorded and evaluated. We found no differences in the surgical outcomes between the groups. In Study IV, the participants recruited were more experienced, but had not done laparoscopic hysterectomy as a first surgeon. All participants did the basic training as the intervention group in Study III. Furthermore, the intervention group trained with the hysterectomy module in a virtual reality simulator. The intervention group performed significantly better as evaluated by the Objective Assessment of Technical Skills and Visual Analog scale. Our findings indicate that the traditional apprentice model alone is no longer sufficient in trainee education due to changes in gynecological surgery. In Study III, we did not detect differences in outcomes between the groups. However, in Study IV evaluating learning of a more advanced procedure, we demonstrated better performance after training with the procedural module in a simulator. Based on these studies, we suggest that simulator training should be mandatory, with allocated training time for the trainee and supervision time for the trainer for providing feedback. As innate skills are different, a proficiency-based curriculum results in more homogeneous skills. Less experienced trainees seem to benefit the most from simulator training, thus the training should be started in the earliest stage of training.
  • Hanzlíková, Martina (Helsingin yliopisto, 2020)
    Gene therapy provides a promising option for treatment of various diseases, but the fact remains that the large number of gene delivery systems has met with little therapeutic success. Viral gene delivery has a high degree of specificity and efficacy, but it does not provide sufficient safety for clinical applications. Therefore, the search for an efficient alternative, a synthetic gene delivery vector, has been active. Typically, non-viral delivery vectors are based on the use of cationic polymers which bind and compact DNA via electrostatic interactions into nanoparticles (polyplexes). The ability of a cationic polymer to bind and condense DNA is important for effective delivery because good packing not only protects DNA against degradation in the extracellular space, but also allows effective release of DNA inside cells. While cationic polymers are relatively nontoxic and safe, they lack significant efficacy. This major drawback of non-viral vectors is largely due to a poor understanding of the mechanism underlying the complexation and gene delivery process. Furthermore, the lack of reliable methods to study the binding between DNA and cationic polymers has hindered development in synthetic gene delivery systems. The aim of this study was to investigate the mechanisms of DNA complex formation and gene transfer mediated by cationic polymers with different structures (poly-L-lysine, PLL; polyethylenimines, PEIs; poly-β-amino esters, PBAEs) and transfection efficiencies. This thesis combines time-resolved fluorescence spectroscopy with cell transfection studies in order to elucidate how polymer structure can affect DNA binding and influence gene delivery outcomes. This method allows the quantitative determination of polymer–DNA interaction and binding. We showed that the mechanism of PEI–DNA and PLL–DNA complex formation was positively cooperative with a saturation limit near 100% at a polymer/DNA molar (N/P) ratio of 2, whereas most of PBAE–DNA complexes expressed negative cooperativity and reached a saturation level close to 80%. The polymer topology, the type of amines (primary, secondary and tertiary) and their density, and the environmental pH had a clear effect on the binding constants and the degree of cooperativity. The possible correlation between fluorescence parameters and transfection efficiency was investigated with a series of PBAEs. Their transfection efficiency showed an increasing trend in association with the relative efficiency of PBAE–DNA nanoparticle formation. The role of free polymer in polyplex formation and gene delivery was examined with PEI as a model vector. For PEI polyplexes, the formation of the polyplex core was completed at N/P 2 and the excess of polymer formed a protective shell around the core. Unlike PLL, PEI molecules were able to undergo an exchange between the core and shell of the polyplexes. Such differences in structural dynamics of these polyplexes may partly provide an explanation for the differences seen in their DNA release and transfection efficacy at the cellular level. The excess of PEI in the shell had no effect on the physical state of polyplexes, suggesting that the polyplex core retains its original structure during shell formation. However, the excess of PEI was a crucial factor in successful transfection. The role of free PEI in the gene transfection process was examined in cell cultures with modified cell-surface glycosaminoglycans content. This study showed that free PEI is essential for minimizing the undesirable binding of polyplexes to cell-surface glycosaminoglycans, which may otherwise pose a barrier in non-viral gene delivery. Lastly, we focused on the role of PEI structure in PEI–liposome–DNA delivery systems (lipopolyplexes). We found that the enhancement of lipopolyplex-mediated delivery by different types of PEI species is common and associated with PEI size rather than structure. In conclusion, the present study demonstrated that the fluorescence spectroscopy approach for the analysis of gene delivery systems can provide valuable quantitative information about the binding behaviour of various cationic polymers to DNA. The improved understanding of mechanisms behind formation of these complexes can contribute to the design of polymeric delivery vectors with improved properties. Furthermore, this study sheds light on the mechanisms by which free polymer enhances gene transfer. It explains why high N/P ratios are needed for effective transfection and how the interactions between free polymer and cell-surface GAGs lead to alterations in gene transfer by the polyplexes.
  • Pöhö, Päivi (Helsingin yliopisto, 2020)
    Metabolites are small molecules present in a biological system that have multiple important biological functions. Changes in metabolite levels reflect genetic and environmental alterations and play a role in multiple diseases. Metabolomics is a discipline that aims to analyze all the small molecules in a biological system simultaneously. Since metabolites represent a diverse group of compounds with varying chemical and physical properties with a wide concentration range, metabolomic analysis is technically challenging. Due to its high sensitivity and selectivity, mass spectrometry coupled with chromatographic separation is the most commonly used analytical tool. Currently, there is no comprehensive universal analytical tool to detect all metabolites simultaneously and multiple methods are required. The aim of this study was to develop and apply mass spectrometry-based analytical methods for metabolomics studies. Neonatal rodents can fully regenerate their hearts after an injury. However, this regenerative capacity is lost within 7 days after birth. The molecular mechanism behind this phenomenon is unknown and understanding the biology behind this loss of regeneration capacity is necessary for the development of regeneration-inducing therapies. To investigate this mechanism, changes in mouse heart metabolite, protein, and transcript levels during the early postnatal period were studied. Non-targeted metabolomics methods utilizing liquid chromatography-mass spectrometry (LC-MS) and two-dimensional gas chromatography-mass spectrometry (GCxGC-MS) were applied to detect the metabolic changes of neonatal mouse hearts. Two complementary techniques increased metabolite coverage. A total of 151 identified metabolites showed differences in the neonatal period, reflecting changes in multiple metabolic pathways. The most significant changes observed in all levels (metabolite, protein, and transcript) were branched chain amino acid (BCAA) catabolism, fatty acid metabolism, and the mevalonate and ketogenesis pathways, thus revealing possible associations with regeneration capacity or regulation of the cardiomyocyte cell cycle. Insulin resistance (IR), metabolic syndrome, and type 2 diabetes have been shown to induce metabolic changes; the origin of the changes is unknown. In this study, human serum metabolite profiles from non-diabetic individuals were associated with IR. Gut microbiota were identified as a possible origin of the metabolic changes. Serum metabolites were detected with GCxGC-MS and lipids with LC-MS method. In total, 19 serum metabolite clusters were significantly associated with the IR phenotype, including 26 polar metabolites from five separate clusters and 367 lipids from 14 clusters. IR and changed metabolites were further associated with gut microbiota metagenomics and gut microbiota functional modules, showing that gut microbiota impacts the human serum metabolites associated with IR. Individuals with the IR phenotype had increased BCAA levels, which was influenced by bacterial species with increased BCAA biosynthesis potential and the absence of species with active bacterial inward BCAA transport. Sample throughput is often limited when chromatographic separation is used in metabolomics applications; a short analysis time is of great importance in large metabolic studies. The feasibility of direct infusion electrospray microchip MS (chip-MS) for global non-targeted metabolomics to detect metabolic differences between two cell types was studied and was compared to the more traditional LC-MS method. We observed that chip-MS was a rapid and simple method that allowed high sample throughput from small sample volumes. The chip-MS method was capable of separating cells based on their metabolic profiles and could detect changes of several metabolites. However, the selectivity of chip-MS was limited compared to LC-MS and chip-MS suffers more from ion suppression. Many biologically important low-abundance metabolites are not detectable with non-targeted metabolomics methods and separate more sensitive targeted methods are required. An in-house developed capillary photoionization (CPI) source was shown to have high ion transmission efficacy and high sensitivity towards non-polar compounds such as steroids. In this study, the CPI prototype was developed to increase its sensitivity. The feasibility of the ion source for the quantitative analysis of biological samples was studied by analyzing 18 endogenous steroids in urine with gas chromatography capillary photoionization tandem mass spectrometry (GC-CPI-MS/MS). The GC-CPI-MS/MS method showed good chromatographic resolution, acceptable linearity and repeatability, and low limits of detection (2-100 pg mL-1). In total, 15 steroids were quantified either as a free steroid or glucuronide conjugate from the human urine samples. Additionally, the applicability of the CPI interface for LC applications was explored for the first time using low flow rates. The feasibility of the LC-CPI-MS/MS for the quantitative analysis of four steroids was studied in terms of linearity, repeatability, and limits of detection. The method showed good quantitative performance and high sensitivity at a low femtomole level.
  • Hiipakka, Janne (Helsingin yliopisto, 2020)
    This dissertation consists of six independent published papers or unpublished manuscripts. They treat metaphysics of modalities (necessity, possibility, contingency etc.) and how to distinguish different types of modalities from each other I try to distinguish between logical, analytic and metaphysical modalities. Sometimes philosophers also talk about genuine possibilities in distinction from mere conceivability (see the first chapter and especially references to D.M.Armstrong there). I approach the metaphysics of modalities through a version of combinatorial theory of modality that our research group has developed (Janne Hiipakka, Markku Keinänen, and Anssi Korhonen: "A Combinatorial Theory of Modality", Australasian Journal of Philosophy (AJP 77:4, 483-497). When treating demarcation problem of different types of modality, I take as my starting point Erik Stenius' writings on the subject. As my method, I have used used philosophical method which is basically thinking applied to questions held central in philosophical community. Most important results are the version of combinatorial theory of modality developed by us, my suggestion of how to demarcate between logical and analytic modalities, and to show that Per Martin-Löf´s type theory is incompatible with certain metaphysical theory about properties, so-called trope theory.
  • Kortekallio, Kaisa (Helsingin yliopisto, 2020)
    Reading Mutant Narratives explores how narratives of environmental and personal transformation in contemporary ecological science fiction can develop more-than-human modes of embodied experience. More specifically, it attends to the conflicted yet potentially transformative experientiality of "mutant narratives". Mutant narratives are viewed as uneasy hybrids of human-centered and posthumanist science fiction that contain potential for ecological understanding. Drawing on narrative studies and empirical reading studies, the dissertation begins from the premise that in suitable conditions, reading fiction may give rise to experiential change. The study traces and describes experiential changes that take place while reading works of science fiction. The bodily, subjective and historical conditions of reading are considered alongside the generic contexts and narrative features of the fictional works studied. As exemplary cases of mutant narratives, the study foregrounds the work of three American science fiction authors known for their critiques of anthropocentrism and for their articulations of more-than-human ecologies: Greg Bear, Paolo Bacigalupi, and Jeff VanderMeer. While much of contemporary fiction naturalizes embodied experience and hides their own narrative strategies, mutant narratives have the potential to defamiliarize readers’ notions of bodies and environments while also estranging their embodied experience of reading fiction. As a theoretical contribution to science fiction studies, the study considers such a readerly dynamic in terms of "embodied estrangement". Building on theoretical and practical work done in both embodied cognitive and posthumanist approaches to literature, the study shows how engagements with fictional narratives can, for their part, shape readers’ habitual patterns of feeling and perception. These approaches are synthesized into a method of close reading, "performative enactivism", that helps to articulate bodily, environmental, and more-than-human aspects of readerly engagement. Attending to such experiential aspects integrates ecological science fiction more deeply into the contemporary experiential situation of living with radical environmental transformation.
  • Meriläinen, Mikko (Helsingin yliopisto, 2020)
    Digital gaming has become an important pastime and phenomenon especially among adolescents and young adults, and the growth of the phenomenon has brought with it new challenges for parenting. The study looks at the requirements that Finnish youth’s (aged 13–30) gaming motives, experiences of adverse effects, and gaming-related parenting place on game education. The concept of pelisivistys (being gaming literate) is presented and serves as a lens through which key issues in game education are examined. The three substudies of the study explored young people’s experiences of their gaming: why they spent time gaming, what adverse consequences they had encountered and how they viewed gaming-related parenting. The results revealed a broad range of different game players, gaming experiences, and ways of gaming. While games provided important experiences of autonomy, relatedness, and competence, they also helped kill time and alleviate boredom. Respondents who spent the most time gaming reported more adverse consequences than other respondents, but the connection between time spent gaming and adverse consequences was not linear. Time spent gaming was not a reliable predictor of adverse consequences, as gaming motives and experiences of excessive gaming were related to experiencing gaming-related harm. Young game players were aware of risks related to gaming and sought to prevent them. Based on the results, gaming does not appear to pose a significant threat to the well-being of Finnish youth on a population level, but on an individual level the effects can be considerable, especially if gaming ties in with existing problems. Experiences of gaming-related parenting varied. Parents’ attitudes towards gaming ranged from very negative to highly positive, which was reflected in parenting practices. The need for parents to both understand gaming and prevent harm was prominent in respondents’ views on gaming-related parenting. The results of the study are examined in the light of previous research and public discourse. Based on the results, suggestions are presented for game education that acknowledges the diversity of both young game players and gaming and promotes youth agency.

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