Doctoral dissertations

Recent Submissions

  • Sun, Yan (Helsingin yliopisto, 2021)
    Soil pollution is one of the world’s biggest challenges. The most common soil pollutants include heavy metals and petroleum hydrocarbons. A great number of studies have developed strategies for pollutant remediation. For the removal of heavy metals including cadmium (Cd) in the soil, electrokinetic remediation has been rapidly developed in the recent decades as a both remediation and metal resource recovery method. However, field and full-scale applications of electrokinetic remediation in the removal of soil heavy metals are rare. As for organic pollutants including petroleum hydrocarbons, biostimulation with fertilization has been widely done and highly appreciated over physical and chemical methods ecologically and economically. Due to different soil physico-chemical properties and climates, fertilizers should be chosen carefully for the best outcome. Remediation strategies are often initially validated in the laboratory, which can still fail in the field tests or application usually due to soil heterogeneity that exists even within millimeters. A false conclusion may result from an improper experimental design in the laboratory, such as insufficient true replication (pseudoreplication) that fails to represent the sampling site, and composite sampling or randomized complete block design (RCBD) that only presents the average performance of the sampling site and can result in false positive or negative results for the component samples. This doctoral thesis presents three strategies in soil remediation, i.e. electrokinetic remediation of soil heavy metal Cd (paper I), biodegradation of soil gasoline aromatics stimulated by fertilization (paper II), and optimization of experimental design (paper III). Electrokinetic remediation of Cd was monitored for 14 days, in a pilot (4 m2) test and a full-scale (200 m2) application in paddy agricultural soil, at soil layers 0-10 cm, 10-20 cm, and 40-50 cm. A voltage of 20 V was applied at both scales. In the biostimulation study, three nitrogen fertilizers, i.e. inorganic NPK, urea, and methylene urea were compared in the biostimulation of gasoline aromatics removal in the soil collected from the high Arctic permafrost active layer and experimented in the laboratory at 10 °C for 28 days. Finally, the experimental design study that was conducted in the laboratory at 4 °C for 28 days illustrated how pseudoreplication and sole use of plot averages, would affect the conclusions drawn in biodegradation studies. In the experimental design study, three ecologically independent plots of soil were collected and processed independently in parallel. The soil was spiked with gasoline and divided for natural attenuation and biostimulation with methylene urea fertilization. Biodegradation results were analyzed individually within each plot of soil (pseudoreplication) as well as in a between-plot comparison by using the mean values of the three plots (plot averages). In 14 days, electrokinetic remediation showed a successful application at both scales, especially for the soil total Cd in the surface 0-10 cm layer, with a higher removal efficiency in the pilot test (87%) than the full-scale application (74%). The final concentration of soil total Cd was below the hazard threshold set for paddy agricultural soils in China. The higher removal efficiency in the pilot test can be due to the higher voltage gradient between the electrodes. The removal efficiency of the plant available Cd was lower than the soil total Cd, which can be due to the enhanced desorption of Cd cations through cation exchange and/or dissolution by lactic acid during electrokinetic remediation. In 28 days, biostimulation with urea fertilization managed to lower the concentration of the total gasoline aromatics below the initial level (by 47%). On day 7, the observed concentration of the total gasoline aromatics was higher than the initial level in the NPK and urea fertilized treatments, which indicated an enhanced desorption and extractability of soil gasoline aromatics. The enhanced desorption and thereafter bioaccessibility of gasoline aromatics in the NPK and urea fertilized treatments could be related to the enhanced biodegradation activity compared to natural attenuation and methylene urea fertilized treatment, mainly shown between day 7 and day 28. In contrast to the successful application of electrokinetic remediation and biostimulation with urea fertilization, the effect of methylene urea in biostimulation showed positive, negative, and negligible results. The random results of natural attenuation and biostimulation with methylene urea fertilization indicated the patchiness of biodegraders even within one plot of soil. Additionally, the results based on the between-plot comparison showed a dilution effect and could pose false positive and negative results for the component soil. Although electrokinetic remediation of heavy metal Cd and biodegradation of gasoline aromatics stimulated by urea fertilization showed success in the cases studied herein, the success of these remediation strategies cannot be generalized to other soil pollution cases due to soil heterogeneity at least, according to the third study. The results suggest that ecologically independent replication be adopted in the between-plot comparison and that parallel experiments and statistical analysis with within-plot replication for each replicate plot be performed to guide a more successful practical application of remediation strategies.
  • Lundell, Richard (Helsingin yliopisto, 2021)
    In the Arctic diving occurs in cold water throughout the year. At a depth of 20 meters sea/fresh water (msw/mfw) temperatures are 4°C even in the warmest summer. Cold is not only a discomfort factor for divers. It also impairs physical and cognitive performance, which in turn may jeopardize diving safety, and is one of the major risk factors for decompression illness (DCI). In our study we looked for factors that influence diving safety in Arctic water temperatures and searched for possible ways to reduce the risks. Based on the results from our three studies we aimed to suggest improvements for cold water diving procedures. First, we studied special features of DCI in the Finnish diving population, and different factors associated with DCI. Second, we investigated different thermal protection properties by comparing argon and air used as drysuit inflation gas. Argon is a widely-used passive method to reduce heat loss in cold water diving. Third, we studied the autonomic nervous system (ANS) responses to cold water diving with heart rate variability (HRV) measures. With results from these studies we aimed to give recommendations to make diving in Arctic conditions safer. We carried out a retrospective study to evaluate DCI treated in Finland over a time period of 20 years (1999-2018). The study included by estimation over 95% of all hyperbaric oxygen- treated DCI patients (n = 571) during the years studied. We divided cases into technical divers (n = 200) and non-technical divers (n = 371) and examined differences between the groups. Technical diving was defined as the usage of mixed breathing gases, closed circuit rebreather diving or planned decompression diving. The mean annual number of treated DCI cases in Finland was 29 (range 16– 38). The number of divers treated seemed to show a shift towards technical diving. Technical dives were deeper and longer and were mainly performed in cold water or in an overhead environment. Technical divers were more likely to utilize first aid 100% oxygen (FAO2) and sought medical attention earlier than non-technical divers. The symptom profiles were similar in both groups. Recompression was performed using US Navy Treatment Table Six (USN TT6) in the majority of the cases and resulted in good final outcomes. Eighty two percent of the patients were asymptomatic on completion of all recompression treatment(s). To study the difference in thermal insulation properties of argon compared to air we measured the rectal temperature and eight standardized skin temperatures during tests for navy drysuit diving equipment development in Arctic water conditions. Four divers completed 14 dives, each lasting 45 minutes: seven dives used air insulation and seven used argon insulation. From the measured temperatures, changes in the calculated mean body temperature (MBT) were assessed. There was a significant reduction in the area weighted skin temperature over time (0-45min) during air dives (ΔTskin = -4.16°, SE = 0.445, p<0.001). During argon dives the reduction was significantly smaller compared to the air dives (difference between groups = 2.26°C, SE = 0.358, P<0.001). There were no significant changes in rectal temperatures, nor was a significant difference seen between groups in rectal temperatures. We investigated the human diving responses in cold water temperatures by retrospectively analyzing repeated 5-minute HRV measures and mean body temperature measurements from dives at regular intervals using naval diving equipment measurement tests in 0°C water. The human body reacts to cold through ANS-mediated thermoregulatory mechanisms. Diving also induces ANS responses as a result of the diving reflex. Three divers performed seven dives without engaging in physical activity (dive time 81–91 min), and two divers performed four dives with physical activity after 10 min of diving (0–10 min HRV recordings were included in the study). Based on changes in the root mean square of successive RR interval differences (RMSSD) an increase in parasympathetic nervous system (PNS) activity could be seen at the beginning of the dive. First from the measure at rest to the measure 0 to 5 min showed a significant increase of 14.67 ms (SE = 6.09, p = 0.02). After this PNS activity decreased: the measure from 0 to 5 min to the measure at 5 to 10 min had a significant decrease of 12.92 ms (SE = 6.09, p = 0.04). The remaining measures showed an increase in PNS activity over time: the measure from 5 to 10 min until the measure at 75 to 80 min (n = 7), showed a significant increase of 97.86 ms (SE = 2.28, p < 0.001). As a conclusion there has been a shift towards technical diving in the Finnish diving population, and hence a more demanding types of diving. The number of diagnosed DCI cases in Finland has been quite constant over the last 20 years (1999 to 2018), estimated from a mean incidence of 29 primary decompression treatments annually. Fortunately, the majority of divers recovered well and could continue diving after successful treatment. The use of FAO2 was relatively uncommon in the treatment of DCI symptoms. Compared to air, argon seemed to have better thermal insulation properties when used as drysuit inflation gas, suggesting it would be beneficial when diving in Arctic conditions. Using argon could make diving safer and reduce the risks of fatal diving accidents. The results of the HRV measures suggested a rapid decrease in parasympathetic activity (PNS) after an initial PNS increase at the beginning of the dive. This decrease in PNS activity has not been described in previous studies. To avoid concurrent sympathetic (SNS) and PNS activity at the beginning of dives, which in turn could increase the risk of malign arrhythmia, we suggest a short adaptation phase before physical activity. Moreover, we suggest it is prudent to pay special attention to cardiovascular risk factors during fit-to-dive evaluations for cold water divers.
  • Westberg, Anna (Helsingin yliopisto, 2021)
    The prevalence of obesity is increasing globally both in the general population and in women of a reproductive age. Maternal obesity is a well-known risk factor for acute adverse pregnancy outcomes. Furthermore, accumulating evidence suggests that maternal obesity may impact offspring health later in life. The finding is supported by the Developmental Origins of Health and Disease (DOHaD) paradigm, which suggests that adverse environmental influences during early development, such as maternal obesity, may have an unfavorable impact on later health through the mechanisms of developmental programming. Previous observational studies have found associations of maternal obesity and a number of offspring long-term health outcomes, including obesity, diabetes and asthma. While most preceding research in the field have focused on offspring health outcomes in childhood and adolescence, the associations of maternal obesity and offspring health in adulthood are less studied. The aim of this thesis was to examine the associations between maternal body mass index (BMI) in pregnancy and offspring health in late adulthood. The main offspring health outcomes in the thesis are physical and psychosocial functioning (study I), asthma (study II), glucose metabolism (study III) and physical activity (study IV). Study IV also examine associations between a change in participants’ weight status from childhood to late adulthood and physical activity in older age. This thesis is a part of the Helsinki Birth Cohort Study (HBCS). HBCS includes 13,345 individuals who were born in Helsinki between 1934 and 1944. In 2001- 2004, a subset of 2003 cohort members participated in a baseline clinical examination and in 2011-2013, 1094 participants attended a follow-up clinical examination. The 4 articles of the thesis produced several findings. Higher maternal BMI predicted a poorer physical and psychosocial functioning (study I) and an increased risk of asthma (study II) in men in late adulthood, whereas no similar associations were observed in women. In participants without diabetes, maternal BMI was associated with a favorable glucose metabolism in non-obese men (study III). Overweight in childhood, especially in women, and overweight in adulthood were associated with lower levels of physical activity in older age. In participants with childhood overweight, reaching normal weight by adulthood was associated with higher physical activity levels in older age. There was a slightly U-shaped association of maternal BMI and physical activity levels in older aged women, whereas there was no association on men (study IV). This thesis provides further insight into maternal obesity as a risk factor for offspring health later in life. Findings from this thesis support the evidence that maternal BMI may affect offspring later health in a sex-dependent way and suggest that the associations can still be observed in the offspring in late adulthood. Strategies to reduce overweight and obesity in young women should be implemented in order to improve the long-term health of their offspring.
  • Alyukov, Maxim (Helsingin yliopisto, 2021)
    This dissertation focuses on how Russian TV viewers make sense of the news in the context of the Russia-Ukraine conflict. It is based on focus groups with TV viewers and borrows the conceptual apparatus of political communication, psychology, and political science to analyze three separate domains of news processing under an electoral authoritarian regime: the formation of political opinions based on television news, the use of heuristics to evaluate the credibility of TV news, and the use of a range of information sources, both offline and online, in a high-choice media environment. Based on the existing literature, this study relies on the premise that citizens under authoritarian regimes lack incentives, cognitive tools, and opportunities to substantively process news and investigates how these three features are reflected in the political psychology and news processing of TV viewers. First, this study contributes to the literature on news processing under electoral authoritarian regimes. While scholars have identified numerous factors which affect how citizens (dis)trust news in authoritarian contexts, the role of political engagement in news processing is rarely taken into account in the analysis of electoral authoritarian regimes. My findings suggest that crucially affects how citizens make sense of the news. I find that a minority of focus group participants are politically engaged and rely on consistent political schemas to make sense of the news and demonstrate signs of consistency bias. Most participants are politically disengaged. They rely on the ideas which are more accessible in memory, contain both criticism and approval of state policies, and support the authoritarian equilibrium by being unable to articulate consistent opinions. Second, this study contributes to a better understanding of the functioning of low-information rationality under an electoral authoritarian regime. Scholars assume that in dealing with the news and political information, TV viewers rely on a wide variety of heuristics which are drawn from both daily life and the political environment. However, the literature on how citizens use heuristics outside democratic contexts is limited. I find that in dealing with the news, TV viewers prefer to rely on common sense and cultural stereotypes because political and media institutions under an electoral authoritarian regime are not seen as independent and authoritative. Finally, the study contributes to a better understanding of how the development of high-choice media environments affects news processing outside of democratic contexts. I find that politically engaged participants often find information which fits their pre-existing preferences demonstrating signs of selective exposure. Participants who are less politically engaged participants rely on TV news in combination with news aggregators to simplify information search. Since Russian news aggregators include information which is not different from TV news, this synchronization verifies the credibility of TV news. While the original concept of the personalized filter bubble is based on the complex interaction between individuals’ preferences and algorithms, I identify the orchestrated filter bubble effect which is based on the agenda of state-controlled television. Imposed in top-down fashion by the state, this filter bubble effect is used to reinforce the messages of the state-controlled television rather than citizens’ individual preferences under an electoral authoritarian regime.
  • Casado, Julia (Helsingin yliopisto, 2021)
    Cancer continues to be a major clinical and societal challenge. Globally, the cancer burden rises every year with a new record of 18.1 million new cases and 9.6 million cancer deaths, as reported by the World Health Organization. Despite the increased financial efforts of western countries to cure this disease, it is expected that in the year 2040, over one-third of the population will be diagnosed with cancer. The gap in translating basic research into clinical benefit requires cross-disciplinary approaches to harness large data from the complex molecular systems and cellular organization within the tumor. The main obstacles in current cancer care are late detection and therapy resistance. While high-throughput and single-cell methodologies have become an advisable tool to analyze molecular profiles, their use for clinical decision-making is still missing. This thesis aims to propose efficient methodologies to connect molecular and cellular profiling research to cancer therapy outcomes. In the first and second publications, we made available software to rapidly analyze large mass cytometry data with high resolution and interaction-assisted interpretation steps for the analysis. These methods allow the rapid profiling of tumor cell populations and their association with therapy response. As part of the third project, we developed new image analysis methods to identify therapy response predictors from highly multiplexed images. We found that spatial organization within the tumor microenvironment was highly associated with DNA damage genome scarring. In the fourth study, we designed a new method to identify epigenetically reversible drug resistance mechanisms in tumor cells. The application of novel methodologies contributed to a better understanding of the roles of genomic and proteomic features in the tumor-immune microenvironment in response to modern anti-cancer therapies.
  • Hakala, Anna-Riina (Helsingin yliopisto, 2021)
    This study analyzes the structure and meaning of gendered imagery in Bernard of Clairvaux’s letter collection through a selection of letters that have been dated to the first decade of his career as an abbot. The main question is how Bernard talks about the monastic man living in a monastic community, using gendered imagery in his letters to abbots and monks, and which meanings are given to manhood and womanhood in the context of the collection of letters. During his first decade as an abbot, Bernard had a growing network of influence, which among other things was kept up and expanded through the writing of letters. These letters and their role as an instrument of constructing and promoting a monastic ideal are the point of interest of this dissertation. The focus is on the gendered theology presented in the text and the cultural and historical context in which it was produced. Medieval reality was pronouncedly tied to images: faith and images were indistinguishable from each other, with salvation being directly linked to the symbolic system of iconography. Bernard exemplifies the blurred lines of image, material reality, text and thought in his letters. The gendered imagery of the letters is built around the situation that the letter concerns. In his usage of gendered imagery, he focuses on influencing the reader in a way that would result in the desired interior sensual experience, which then would convert the reader on the path desired by Bernard. In previous research on Bernard’s other texts, it has been proposed that he envisions salvation as participation in divine masculinized transcendence. Based on the gendered theology in the letters, this is only half of the picture. The road to salvation that the letters propose equally involves participation in the divinized feminine flesh of the incarnated Christ. Masculinized transcendence and divinized feminine flesh both need to be present simultaneously in the right order and without mixing in the ideal monk aiming at eternity with God. At times, Bernard transmits gendered theological views that seem undecided but have been chosen for him by the earlier authors he relies on. This results in self-contradicting views in the letters. Womanhood does not solely stand for worldliness or fleshliness in the negative sense and manhood does not signify only goodness of spiritual heights: womanhood and manhood frequently alternate places between these positions without any definite outcome or fixed position in the reversals of the gender binary. Human gendered reality is inherently behind the rhetorical use of gendered imagery. Belief in the incarnation and the resurrection changes the meaning of imperfect and mutable corporality in relation to the supernatural and immutable perfect God into a redemptive affirmation of fleshliness and womanhood. This results in the figures used to express the monastic ideal simultaneously having both masculinity and femininity, forming a differentiated unity of the two. These figures make visible the mystery of the marital union of humanity and divinity in Christ, the unity of the Christ-head and Church-body, which the monk should realize in his life as a monastic man.
  • Pulkka, Ville-Veikko (Helsingin yliopisto, 2021)
    In the 2010s, advances in digital technologies and artificial intelligence (AI) have sparked a wide-ranging debate on how social policy should be reformed so that the Fourth Industrial Revolution can benefit both people and the economy. The aim of this thesis is to contribute to a deeper understanding of the future of social policy by examining how socio-economic conditions, public opinion and ideas may drive social policy change in the digital economy. Sub-study I utilised the EUROMOD microsimulation model and EU-SILC-based microdata to examine the socio-economic implications of technology-induced hypothetical employment scenarios for the EU-28 countries. The microsimulations of hypothetical employment scenarios showed that the Nordic and Benelux countries in particular, but also France, are clearly more resilient to technological unemployment than the countries of Southern and Eastern Europe. In an optimistic employment scenario, the biggest beneficiaries would be Belgium, Croatia, Finland and Slovenia. Sub-study II explored the Finnish view on the future of work and preferred policy ideas utilising unique population-level survey data collected for this thesis. The survey results indicate that the vast majority of Finns are not worried about permanent technological unemployment, although most assume volatility will increase in the labour market. The results also suggest that Finns are not in favour of a significant change in the guiding principles of social policy. Due to unprecedented interest in universal basic income (UBI) in recent social policy debates, three sub-studies of this thesis focused specifically on the feasibility of the idea. While sub-study III examined public support for basic income in Finland based on seven population-level surveys conducted in the past decade, sub-study IV extended the analysis to an international context, with a focus on Finland and the UK. The economic feasibility of providing a basic income was analysed in sub-study V, exploiting microsimulation calculations conducted in Finland. Content analysis of basic income surveys showed that the divergent frames used in the surveys explain the great variation in measured support. Regression analysis exploiting the Finnish and British survey data also indicated that the socio-economic determinants of support for basic income are dependent on the frames used in the surveys. The feasibility of basic income can also be questioned from the perspective of economic efficiency, as analysed in sub-study V. The results from all five sub-studies of this thesis suggest that under current circumstances, the likelihood of a radical social policy change resulting from digital transformation is relatively small.
  • Mattila, Simo (Helsingin yliopisto, 2021)
    A variety of surgical techniques have been described to treat trapeziometacarpal (TMC) osteoarthritis (OA). The simple removal of the trapezium and partial trapeziectomy are traditional techniques. As an alternative treatment, the poly-L/D-lactide 96/4 implant RegJoint™, has shown positive results in small joint arthroplasty of the rheumatic hand and foot. The purpose of this study was to investigate the clinical results and biocompatibility of the RegJoint™ implant in partial and total trapeziectomy for TMC OA. The retrospective patient cohort for Studies I-II comprised 23 patients (23 hands) operated on for isolated TMC OA by partial trapeziectomy and interposition of the RegJoint™ implant. Subjective Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), Patient Evaluation Measure (PEM), pain Visual Analog Score (VAS), objective strength and range of motion, and radiographic evaluation were done preoperatively and at follow-up visits up to 3 years postoperatively. Overall, the results showed an unacceptable rate of complications related to clinically manifested foreign body reactions resulting in three revision procedures. The findings were unacceptable due to the high incidence of tissue reactions and revision surgery. The implant should not be used as an interpositional implant in partial trapeziectomy for TMC OA. In retrospective Study III, 34 patients (38 hands) were operated on for TMC OA by total trapeziectomy and interposition of the RegJoint™ implant. Subjective (QuickDASH, PEM, pain VAS), objective (strength and range of motion) and radiographic evaluation were done preoperatively and at follow-up visits up to 33 months postoperatively. The results showed better biocompatibility of the implant than in partial trapeziectomy with only three of 34 patients having signs of a clinically manifested foreign-body reaction. One patient was scheduled for revision surgery. Osteolysis was present in most cases. Strength and subjective outcomes improved and pain decreased during the follow-up. The clinical results were more favorable than in partial trapeziectomy. However, the high incidence of osteolysis casts doubt on the safety of the implant and there is a small risk of clinically manifested foreign-body reactions. The RegJoint™ implant cannot be recommended for use in the treatment of TMC OA in total trapeziectomy. Revision surgery is sometimes required after primary surgery for TMC OA. In Study IV, a single-center retrospective cohort of 1142 TMC arthroplasties performed on 930 patients was evaluated for risk factors for revision and possible factors affecting the final outcome of revision. There were 121 male and 809 female patients (mean age 61 years). Fifty patients (65 revision surgeries) were identified and invited for a follow-up visit. The revision rate was 5%. Patients ≤ 55 years had a revision rate of 9% and age ≤ 55 was identified as a risk factor for revision. Surgery on both thumbs at some point during the follow-up was a negative risk factor for revision. No difference was identified in revision risk between primary surgical techniques, and no difference in final outcome was found between patients having had one versus several revision procedures. The outcome measures QuickDASH and pain VAS were in the same range as previously reported for TMC OA revision surgery. The majority of patients exhibited residual symptoms after revision surgery. However, most patients felt subjectively that they had benefited from the treatment.
  • Ortiz-Nieminen, Oscar (Helsingin yliopisto, 2021)
    This dissertation examines changes in the perceptions and practices of architectural space in the context of the Lutheran sacral building in Finland from the 1900s to the mid-1960s. The topic was approached by studying multifunctional churches completed in Helsinki and its surrounding areas. In addition to a chapel, these hybrid buildings also contain other types of facilities, such as parish halls, club rooms, gyms, offices and employees' apartments. Nearly 40 Lutheran multifunctional churches were built in the Helsinki metropolitan area between 1900 and 1965. Both the temporal evolution and the development efforts associated with the building type have been examined in the light of six main case studies: the Betania (‘Bethany’) City Mission House (now known as the Betania Community Center) in Punavuori and the Kallio evangelical meeting house (now known as the Chapel of the Sacred Heart), both completed in the early 1900s; the Töölö Parish Hall (nowadays Church) and Saint Paul’s Church in Vallila, both built in the early 1930s; and the parish centers of Munkkivuori and Tapiola, both erected by the mid-1960s. The methodology used in this study is based on a close comparative reading of various research materials, such as buildings, drawings, written documents, newspaper clippings, memoirs and photographs. The research method was harnessed to closely reconstruct contemporary perspectives on the definition, design, execution, and everyday use of multifunctional church buildings. Theoretically, the dissertation relies on French theories of space, where the societal dimensions of spatial production are emphasized. Thus, space is defined as a physically, mentally, and socially conceived process. The analysis highlights the interconnections of the functional-structural goals of the multipurpose church building and categories of gender, class, age and language group. One of the key concepts used in the dissertation is that of heterotopia, developed by Michel Foucault. With this term, Foucault refers to a lived utopia, a special site or place where the prevailing social orders are reflected either directly or inversely. From the point of view of the Evangelical Lutheran Church of Finland, the multifunctional church building became a transformative instrument of internal renewal denoting the ability of Christianity to adapt to the ideological challenges and utilitarian requirements of the modern world. From the users’ perspective, the building type expanded and diversified the spectrum of religious practice. Architects, who relied on modernist design principals that emphasized the functional separation of spaces, were generally resistant to the concept of the multipurpose church building.
  • Leigh, Robert (Helsingin yliopisto, 2021)
    Disruption of chamber-specific gene regulatory networks underlies malformation of the heart and results in congenital heart disease. Re-activation of fetal gene regulatory networks in adults occurs during cardiac injury, and transcription factors composing these networks represent candidate therapeutic targets to impede heart failure progression. The identification of molecular markers and underlying regulators of cardiac chamber specification is thus an important step in understanding the aetiology of cardiovascular disease. Moreover, the examination of chemical modulation of molecular processes occurring during development allows for a more detailed understanding of the teratogenic effects of chemical compounds and could lead to the development of small molecule-based strategies for stimulating or impeding well-characterized developmental processes in the adult heart. To this end, this thesis is comprised of three studies related to the differentiation of atrial and ventricular cardiomyocytes and the selective modulation of this process. Study I led to the generation of an in vitro model of cardiomyocyte subtype specification of pluripotent stem cells for the use in studies II-III. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of native embryonic atrial and ventricular tissue confirmed the robust ventricular-specific expression of myosin light chain 2 (Myl2) and also indicated the lack of an endogenous atrial-specific marker during early embryogenesis. Genome editing was used to integrate a fluorescent reporter into the endogenous Myl2 locus to mark cells of the ventricular lineage, whereas atrial cells were traced by an atrial-specific transgene driven by the slow myosin heavy chain 3 (SMyHC3) promoter. Atrial and ventricular reporter expression were confirmed in vivo by laser-assisted morula injection of reporter mouse embryonic stem cells (mESCs) and microscopy of chimeric embryos. In addition to this in vivo validation, spontaneous differentiation of reporter mESCs was characterized by qRT-PCR, indicating dynamic expression of retinoic acid signalling components. Differentiation assays were developed based on chemical perturbation of undifferentiated progenitor cells and differentiated cardiomyocytes, respectively. Members of the retinoid family, known teratogens and modulators of anterior-posterior patterning, were tested for effects on the activation of atrial and ventricular reporter genes. Additionally, a directed-differentiation assay was developed based on highly pure multipotent progenitor cells and differentiation assessment in a 384-well format. In this assay, chemical inhibitors of Wnt and Transforming growth factor β (Tgfβ) pathways led to promotion of ventricular reporter expression when added at the multipotent progenitor stage, but not after the onset of spontaneous beating. Additionally, exogenous all-trans retinoic acid added to undifferentiated progenitors led to an inhibition of ventricular differentiation, whereas addition following the onset of spontaneous beating led to activation of the ventricular reporter gene. In addition to chemical probes described in study I, novel compounds targeting the protein-protein interaction of core cardiac transcription factors Gata transcription factor 4 (Gata4) and NK2 homeobox 5 (Nkx2-5) were examined in study II. Specifically, the effects of GATA-targeted compounds on the differentiation of atrial and ventricular cardiomyoyctes were explored. Lead compound 3i-1000 increased the proportion of atrial and ventricular reporter cells after 10-day treatment in the spontaneous differentiation assay. Further exploration of the effects of GATA4 targeted compounds revealed that a shorter treatment (2-day) of cells prior to the onset of spontaneous beating led to an upregulation of ventricular reporter genes in a directed differentiation assay. An acetyl-lysine like domain among active compounds, in addition to analysis of the GATA4 interactome by Bio-ID revealed the potential association of bromodomain-containing proteins with chamber-specific gene expression. This was further investigated by combinatorial treatment with the Bromo- and Extra- Terminal domain family (BET) bromodomain inhibitor JQ1 and GATA-targeted compounds in reporter gene assays. Finally, the effects of GATA compounds on cardiomyocyte maturation were explored by compound treatment and global run-on sequencing (GRO-seq) in primary cardiomyocytes, revealing the upregulation of several targets previously identified as regulators of cell fate determination and regeneration. Study III detailed the embryonic/cardiac expression of proCholecystokinin (proCCK), a classical gut and neuropeptide. Analysis of mRNA-seq data suggested that proCCK is a transcriptional target of the TBX5 transcription factor in mESC-derived cardiomyocytes. Native, endogenous mRNA levels were characterized in embryonic hearts by whole mount in situ hybridization and optical projection tomography, revealing that proCck mRNA is present prior to the linear heart tube stage and that it is upregulated in the ventricles compared to the atria in the newly formed embryonic heart. Interestingly, mRNA of proCck and its receptors Cckar/Cckbr is mostly restricted to the atrial chambers in neonatal stages, in line with its potential role in regulating cardiac rhythm. In silico analysis implicated both TBX5 and MEF2C as regulators of proCck transcription, and this regulation was confirmed by conducting in vitro reporter gene assays. Additionally, proCCK was induced by endothelin-1 (ET-1), another peptide associated with maladaptive remodelling during heart failure. Furthermore, proCck mRNA levels declined in the left ventricles of rats following myocardial infarction (MI). Finally, exogenous cholecystokinin octapeptide (CCK-8) exerted no effects on the differentiation process of pluripotent stem cells (PSCs) to the cardiomyocyte fate. Collectively, these studies led to the generation of new methodology for the study of chamber-specific cardiac gene regulatory networks. Additionally, they led to an improved understanding of the dynamics of chamber-specific marker localization and upstream transcription factors governing their expression, potentially important to biomarker development. Finally, these studies have indicated that specific chemical compounds are capable of influencing chamber-specific gene regulatory networks. This knowledge might be utilized to develop novel therapeutic strategies for the treatment of heart failure.
  • Översti, Sanni (Helsingin yliopisto, 2021)
    A mitochondrion is a cytoplasmic organelle responsible for the energy production of the eukaryotic cells. Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is a double-stranded circular molecule. Due to mitochondria’s essential role in metabolism, a cell can contain hundreds of thousands of copies of mitochondrial DNA, depending upon the cell’s energy requirements. In mammals, mtDNA is generally maternally inherited, meaning that it is transmitted from a mother to all of her descendants. Although mtDNA constitutes only a small fraction of the cell genome, it has several qualities which make it widely used in population genetic studies such as uniparental inheritance, and the fact that the mitochondrial genome does not recombine. Moreover, mtDNA has a mutation rate ten times higher than that of the nuclear genome and therefore allows us to trace back matrilineal lineages through generations and subsequently make inferences about maternal ancestors. The human mtDNA sequence consists of approximately 16,570 base pairs and also contains both a coding region and a non-coding control region, the latter constituting around 7% of the whole mtDNA genome. Since mtDNA does not undergo recombination, an individual’s mitochondrial haplotype can be determined simply by the direct sequencing of target amplicons. Haplotypes containing certain defining variants are considered to be descendants of a common ancestor and are classified into haplogroups. The geographical distribution of haplogroups among contemporary populations is well-known – for instance, the majority of Europeans exhibit mitochondrial lineages H, U, J, K, T and V. Ancient DNA research has uncovered that lineage U was already highly prevalent among the earliest hunter-gatherer settlers of Europe, whereas the gradual spread of agriculture from the Near East that started approximately 10,000 years ago brought along new people and hence also novel mitochondrial lineages (H, J, K and T). Previous studies have stated that compared with other European populations, contemporary Finns do not seem to be an exception in terms of mitochondrial genome pool. This is rather surprising, since other genetic markers have revealed that contemporary Finns are characterized by a strong Eastern genetic influence and are distinguishable from other Europeans. Moreover, the evident East-West distinction within Finland, apparent in Y-chromosomes and autosomes, has not been previously identified in the mtDNA. This thesis outlines the mitochondrial DNA variation among present-day Finns in a Bayesian framework. The aims were to evaluate if Finns display a homogeneous geographical distribution of haplogroups and if the mtDNA composition of Finns resembles that of other European populations, as previously suggested. While no spatial differences have previously been detected in the mitochondrial haplogroup frequencies within Finland, a clear geographical distinction arose when clustering haplogroups into ‘hunter-gatherer’ (U and V) and ‘farmer’ associated lineages (H, J, K and T). Whereas the farmer related haplogroups were notably more common in Southwestern Finland, the hunter-gatherer lineages had higher densities in the Northeastern parts compared to the Southwest. Furthermore, utilization of the complete mitochondrial genomes allowed for reassessing the Finnish mtDNA pool on a larger scale. One third of the subhaplogroups in Finland today were characteristic only of Finns, i.e. these lineages were virtually absent from other populations. When further partitioning the Finnish samples based on their inclusion in ‘local’ and ‘non-local’ lineages, two notably different demographic trajectories were obtained. The population history for Finn-characteristic lineages was more in accordance with what is known through other data types, such as Y-chromosomal and archaeological data. In general, the observed geographical within-country deviation in the Finnish mtDNA pool and the high proportion of Finn-characteristic lineages reflected the signals reported from other genetic markers. Alongside Finnish mtDNA, this thesis explores the molecular rate variation among the different subhaplogroups of lineage U. Unexpectedly, a noteworthy discrepancy emerged from the tip calibrated phylogenies: haplogroup U5b had a notably lower substitution rate when compared to U2, U4 and U5a. This lineage-specificity in the rates most likely arose, at least to some extent, from differences in past population dynamics. In particular, U4 and U5a have been associated with the rapid population expansion which occurred during the Bronze Age, whereas the frequency of U5b has remained rather stable. Subsequently, the observed rate of deviation influences the divergence estimates for subhaplogroups, suggesting that U5b emerged considerably earlier than U5a. Since molecular rates are fundamental to several population genetic analyses and the timing of divergence and demographic events relies heavily on the rate used, more attention should be paid to the interlineage molecular rate variation. The results of this thesis demonstrate not only the importance of using complete mtDNA genomes and the appropriate molecular rate, but also the relevance of approaching the data from new angles when assessing the demographic past of mitochondrial lineages.
  • Paananen, Riku (Helsingin yliopisto, 2021)
    The ocular surface is covered by the tear film that provides a smooth optical surface required for clear vision, offers lubrication necessary for eye movement, and maintains a suitable microenvironment for the ocular surface cells. The tear film can be divided into two separate layers: the aqueous layer, which makes up the bulk of the tear film, and a thin tear film lipid layer (TFLL), which covers the aqueous layer. The TFLL is considered to stabilize the tear film by slowing down evaporation of water from the aqueous tear film. The loss of this stabilizing function of the TFLL is believed to play a central role in the development of most cases of dry eye disease. However, the structure of the TFLL remains poorly characterized, and currently no consensus exists on the molecular level organization within the TFLL. Due to this lack of understanding of TFLL organization on a molecular level, the basis underlying the stabilizing mechanism has remained unclear. In this thesis, the aim was to gain insight into the molecular level structure of the TFLL by dissecting how different lipids in the TFLL organize at the aqueous interface. Further, the effects of interfacial organization of different lipid classes on the evaporation resistance was studied to understand how these structural characteristics are related to the evaporation resistance of the TFLL. The lipids studied in this work cover most of the lipid classes that are found in the TFLL, namely wax esters (WEs), cholesteryl esters (CEs), Type II diesters (DiE), and O-acyl-ω-hydroxy fatty acids (OAHFAs). For each lipid class, model compounds representing the most abundant lipids in the TFLL were used. The organization and evaporation resistance of each lipid class was studied experimentally using a Langmuir trough model system, and this work was complemented by molecular dynamics simulations. This thesis project identified OAHFAs and WEs as the most important lipid classes related to TFLL evaporation resistance. The evaporation resistance of both OAHFAs and WEs was related to the formation of solid monomolecular structures at the aqueous interface. WEs formed solid crystals of monomolecular thickness at the aqueous surface, which spread to cover the surface at a narrow temperature range below the melting point of the WE facilitated by coexistence with a disordered WE monolayer. Long-chained OAHFAs formed a solid monolayer phase on the aqueous interface that provided up to 5 s/cm of evaporation resistance, making OAHFAs even more effective in resisting evaporation than WEs. However, such condensed monolayers inhibited the spreading of nonpolar CE multilayers, which challenges the role of polar lipids in spreading and stabilizing the TFLL. Instead, these results suggest that polar TFLL lipids, mainly OAHFAs, form a condensed monolayer that is directly responsible for the evaporation resistance of the TFLL.
  • Helin, Noora (Helsingin yliopisto, 2021)
    Background: Small children often experience gastrointestinal (GI) symptoms such as regurgitation or abdominal pain. These are usually benign, functional symptoms. In infants, spilling or vomiting can also be suspected to be a symptom of food allergy. In children of developed countries, the most common organic disease in the upper GI tract is gastroesophageal reflux disease (GERD), which refers to troublesome symptoms caused by reflux and related complications such as esophagitis. Upper endoscopy has traditionally been used to verify or exclude esophagitis in patients with symptoms suggestive of GERD, or to exclude other diseases such as eosinophilic esophagitis. Distinguishing children with functional symptoms from those in whom symptoms are associated with disease is often challenging, although guidelines to facilitate differential diagnosis are available. Good availability of endoscopy and lack of data on the long-term prognosis of common upper GI symptoms may have increased the number of upper endoscopies in young children. However, clinical experience suggests that upper endoscopies performed on young patients with non-acute, non-specific symptoms seldom provide clinically relevant data.   Aim: This study aimed to evaluate the diagnostic role of upper endoscopy in children younger than 7 years presenting with non-acute, non-specific GI symptoms. The aim was also to estimate school-age outcomes of symptoms suggestive of GERD or cow’s milk protein allergy with GI symptoms (GI-CMPA) in early childhood.  Patients and methods: The first substudy included children who had undergone primary upper endoscopy at Helsinki University Children’s Hospital in 2006-2016. At an age younger than 7 years, these children had presented with non-specific, non-acute symptoms (n=1850). Patients with acute symptoms, a known disease, or a foreign body for which endoscopy was performed, and congenital malformations of the head, neck and respiratory tract or GI tract, as well as patients with antibody-positive suspected celiac disease were excluded from the study. The remaining patients’ records (n=666) were retrospectively searched for data on the symptoms leading to upper endoscopy, the use of anti-acid medication at the time of endoscopy, the endoscopy results, and the impact of the results on the follow-up or treatment plans.  In the second substudy, children who had undergone primary upper endoscopy due to suspicion of GERD (n=254) were further investigated by evaluating the effect of predisposing conditions to GER on endoscopy findings. Also, the current well-being and anti-acid medication use of children in whom the primary upper endoscopy had resulted in normal findings (n=199) was assessed using the Patient Data Repository and Prescription Service. Of these patients, those whose native language is Finnish (n=175) were invited to an electronic follow-up survey on current symptoms, medications, and GI health-related quality of life (QoL).  The third substudy investigated children who had in early childhood undergone a double-blind, placebo-controlled food challenge due to suspicion of GI-CMPA (n=57). The suspicion of GI-CMPA had not been confirmed in the majority (68%) of these patients. Mothers of both challenge-positive and challenge-negative children were invited to respond to an electronic follow-up questionnaire on children's current GI symptoms, diet, and QoL.    Results: In the majority (81%) of the 666 children who had undergone primary upper endoscopy to investigate non-acute, non-specific symptoms, the endoscopy results were completely normal. Especially in infants, the findings were minor. The most common symptoms leading to endoscopy were related to gastroesophageal reflux, and the most common cause of endoscopy was suspicion of GERD. None in the cohort had erosive esophagitis. The most common histological finding was mild to moderate histological esophagitis (9%). The number of histological findings increased significantly with age. The use of acid blocker medication at the time of endoscopy did not significantly affect the histological findings. There were no unsuspected celiac disease cases, and the number of histologically confirmed eosinophilic esophagitis in this group was low (0.3%). In children diagnosed with inflammatory bowel disease using concomitant colonoscopy, upper endoscopy findings (most often mild gastritis) did not require active treatment. Regardless of the original cause of the primary upper endoscopy, the results affected treatment or follow-up plans in less than 10% of the patients. In children with suspicion of GERD, the upper endoscopy findings were normal in 83%. Vomiting was the most common symptom associated with suspicion of GERD, but none of the symptoms leading to the endoscopy predicted positive findings. Some of the children (39%) had also undergone 24-hour pH- monitoring, but increased esophageal acid reflux did not predict positive endoscopy findings. Thirty-one patients had undergone more than one upper endoscopy. In these patients, the histological degree of changes in the esophageal biopsies remained unchanged or became less severe. Based on medical records, after a median of eight years of follow-up, the otherwise healthy children had seldom reported reflux-related complaints. However, 4% of children with initially normal primary upper endoscopy findings were currently using long-term acid blocker medication, with most of them having underlying conditions predisposing them to GER. Of the 175 Finnish-speaking families who were invited to the follow-up survey, 51 parents (29%) completed the questionnaire on their child’s current reflux symptoms and use of anti-acid medications. Current daily or weekly occurring reflux-related complaints were parentally reported by 24% of survey responders. The use of anti-acid medications was uncommon, but many parents described their child to use a restricted diet. The GI health-related QoL was reported as good by both parents and children older than 8 years of age who responded to the survey. Of the children who had previously undergone a double-blind, placebo-controlled food challenge for symptoms suggestive of GI-CMPA, all had a normal diet after an average of five follow-up years, and mothers reported their children's quality of life as good. After the food challenge, two challenge-negative children with on-going GI symptoms had also undergone an upper endoscopy with normal results.   Conclusions: Based on this study, the diagnostic role of upper endoscopy is minimal in young children presenting with non-specific, non-acute symptoms. There were only a few positive findings in the endoscopy, most non-specific, and the findings rarely led to changes in the child's treatment or follow-up plan. In children who had undergone more than one upper endoscopy, the histological changes either remained unchanged or became less severe. The suspicion of symptom-based diseases in early childhood was not associated with long-term morbidity at school age. Also, the early childhood symptoms leading to suspicion of GERD were not associated with long-term use of acid blocker medications at school age, especially if the child did not have underlying diseases predisposing to GERD. Moreover, no subsequent dietary restrictions occurred in children investigated due to an early childhood suspicion of GI-CMPA.  It is essential to educate clinicians referring children to upper endoscopy about the rarity of diagnostic findings in association with non-acute, non-specific GI symptoms in young children. Also, centers performing pediatric upper endoscopies should ensure that their endoscopy indications are in line with the scientifically approved data, reserving the endoscopy for those who most benefit from it.
  • Zafar, Sadia (Helsingin yliopisto, 2021)
    Dendritic cells (DCs) are the sentinels of the immune system and are specialized in initiating adaptive immune responses by presenting foreign antigens to T cells. Thus, dendritic cells are critical regulators of immune responses and accordingly have been a focus of cancer immunotherapy research. DC therapy is considered as a promising approach in cancer immunotherapy. However, DC-based vaccines have shown limited efficacy in clinical trials. Oncolytic adenovirus replicates and lyses only cancer cells. Virus-mediated lysis of cancer cells also induces danger signals and exposes tumor epitopes that promote immune system activation against cancer. This study investigated the oncolytic adenovirus 3 coding for CD40 Ligand: Ad3-hTERT-CMV-CD40L (also known as TILT-234) as an enhancer of DC therapy. In the first study, human cancer patient data suggested that intravenous adenovirus administration is able to transduce distant tumors and virally-produced CD40L can activate DCs in situ. Studies with mice suggested that the virus possesses potent antitumor activity. In the second study, treatment with Ad3-hTERT-CMV-CD40L and DCs showed 100% survival of humanized mice and resulted in greater antitumor efficacy than either approach as monotherapy. The third study focused on the treatment of prostate cancer. In this study, treatment with companion therapy (i.e. Ad3-hTERT-CMV-CD40L and DC therapy) was shown to induce greater antitumor immune responses in vivo and in established prostate cancer histocultures. In the fourth study, we focused on the interaction of a chimeric adenovirus Ad5/3 with human lymphocytes and erythrocytes. This study showed that the binding of Ad5/3 with human lymphocytes and erythrocytes occurs in a reversible manner, which enables the virus to transduce different tumors and to retain oncolytic potency both in vitro and in vivo, with or without neutralizing antibodies. In summary, the first three studies demonstrated the ability of Ad3-hTERT-CMV-CD40L to modulate the tumor microenvironment and that local delivery of CD40L is safe and efficient regarding DC therapy. In conclusion, Ad3-hTERT-CMV-CD40L was shown to be a potential enabler of DC therapy. The fourth study revealed the ability of a chimeric Ad5/3 adenovirus to transduce non-injected tumors through blood, even in the presence of neutralizing antibodies.
  • Bennett, Eleanor (Helsingin yliopisto, 2021)
    During the Neo-Assyrian period (approximately 934-612 BCE, based in modern Iraq) the annals and royal inscriptions of several kings mention women with a curious title: ‘Queen of the Arabs’. These women have been included in previous discussions regarding Assyrian interaction with the ‘Arabs’, but a full investigation into their roles as rulers has been lacking. This is what this dissertation seeks to answer: what were the roles of the ‘Queens of the Arabs’ during the Neo-Assyrian period? The reason for no prior traditional Assyriological research into these women is due to a very small number of texts. As Assyriology has traditionally been a text-based discipline, a corpus of just twenty-eight texts has not been seen as ‘worthy’ of a full investigation. This dissertation goes beyond the traditional approach, by incorporating gender theory and comparative methodology. A key heuristic tool in this dissertation is Michael Mann’s ‘IEMP’ model of power. This has identified three key areas where we can clealy see the roles of the ‘Queens of the Arabs’: military, economic, and religious roles. The most important finding was that the process of researching about ‘Arabs’ meant contending with two layers of misinterpretation. The first of which is the misunderstandings of modern scholars allowing modern stereotypes influence how they write about ‘Arabs’. The second is that the ancient sources themselves do not seem to know who or what they refer to when they discuss the ‘Arabs’. This has resulted in a discussion based on these women as individuals, not as a group. We do not know if they all ruled the same population group, and so they may have all been rulers of different cultures. We see Samsi, Teʾelḫunu, and Adiye in positions of military leadership, and Samsi was potentially even present on the battlefield. Zabibê, Samsi, and Tabūʾa all exhibited the ability to control either resources or access to the networks that transported these resources. And finally, Teʾelḫunu likely had a religious role of some sort as part of her leadership duties, but we do not know what that was. None of these women appear in all of the chapters, and as such should be discussed as individuals.
  • Saajasto, Mika (Helsingin yliopisto, 2021)
    How stars form is one of the most central issues in astrophysics. Many questions remain open, in particular regarding the roles of the gas dynamics and self-gravity in determining the location, mass, and multiplicity of the future stars as they form within molecular clouds. Moreover, what is the contribution of feedback processes, from outflows and intense ultraviolet radiation from newly-born stars to the dynamical processes? Combining observations at various wavelengths with numerical simulations, it is possible to address these questions by characterizing the energy balance of star-forming regions. In this thesis work, we have explored the possibilities and limitations of combining observations and modelling of star-forming regions. The first and third paper explore the correlations between the gas and dust through observations, analysing the dynamical and physical properties of star forming regions. The clouds studied in these papers are different in both morphology and environment, from a large filamentary structure to a compact star forming clump. However, in both clouds, several compact cores could be identified from the observations, showing clear signs of star formation. Changes in the properties of dust grains should be reflected in how the grains scatter light at near-infrared (NIR) wavelengths and in the thermal emission at far-infrared (FIR). Thus, in the second paper, a method to study dust properties with NIR scattering was developed. The method was shown to be able to provide relevant information on dust properties, but high-precision observation and further constraints on the strength of the radiation field are required. The radiation field can be constrained by observing the thermal emission from dust, and in the fourth and fifth papers constraints on the dust properties were derived with simultaneous modelling at NIR and FIR wavelengths. The models can reproduce the observed emission, while the scattered light can only be matched with dust models that include evolution of dust grains. However, the modelled scattered light in the diffuse regions is clearly overestimated. Thus further numerical work is required to provide a self-consistent model of the region.
  • Njoghomi, Elifuraha Elisha (Helsingin yliopisto, 2021)
    This research focuses on stand dynamics and ecological recovery in miombo woodlands, Morogoro, Tanzania. The study uses the Kitulangalo Permanent Sample Plots (PSPs) to analyse tree species’ site-specific growth, regeneration dynamics, and stand development using empirical and modeling approaches. The high number of tree species in miombo necessitated the formulation of three species groups involving 1) trees that grow relatively rapidly to be dominants in top canopy layers 2) trees that stay mainly in the lower and middle canopy levels and 3) trees that grow slowly but persistently and may eventually rise to dominant and codominant canopy positions applied in studies I and III. Study III also applies three harvesting alternatives, which align with the recommended harvesting practices for these woodlands. Diameter increment varied with the change in basal area growth across species groups, reaching a maximum of 3.2 cm (group 1) during 2008-2016. Density-dependent mortality and ingrowth also varied with species group as higher mortality rates dominated the lower and middle canopy layers due to asymmetrical competitions. Fencing the plots prompted thick grass cover. The drop in the total number of regeneration stems and the simultaneous increase in the number of main stems in fenced areas and dense plots indicated a self-thinning process induced by competition. This is linked to multi-stem regeneration undergoing a morphological transformation into single-stem saplings (main stems) and eventually becoming small trees. Harvesting intensity, density-dependent mortality, and ingrowth regulated stand basal area and therefore stand growth and development during the simulation. Stand structural development was dominated by species groups 1 and 2, indicating sustainability in species composition and structures. Stand development was affected by the addition of new stems of each species in each simulation year. Miombo stands have demonstrated the potential to attain a steady-state condition over the medium-term under-regulated stand conditions and silvicultural treatments. The developed models, treatments, and harvesting alternatives may be limited in application to Kitulangalo and similar lowland miombo woodlands in Tanzania. Future studies concerning stand conditions, silvicultural treatments, and harvesting alternatives are vital for a better understanding of stand dynamics in miombo woodlands in Tanzania. Keywords: Forest disturbance, tree growth and stand dynamics, regeneration dynamics, silvicultural treatment, harvesting alternative, miombo woodlands
  • Suojärvi, Nora (Helsingin yliopisto, 2021)
    The diagnosis and treatment of distal radius fractures (DRFs) are currently guided by the interpretation of findings in conventional radiographs. However, measurement of radiographic parameters has not been standardized. Cone-beam computed tomography (CBCT) is an alternative imaging technology that is increasingly applied in primary wrist imaging. The purpose of this thesis was to study the potential of CBCT in wrist imaging. Conventional radiographs and CBCT were compared with respect to the reliability of the measurements used in evaluation of DRFs. The potential of CBCT in diagnosing ligamentous and chondral lesions of the wrist was also assessed. CBCT arthrography and magnetic resonance arthrography findings were compared to wrist arthroscopic findings in a group of patients with wrist pain. To improve DRF analysis, a 3D image processing tool based on segmentation of CBCT images and mathematical modelling was developed. The first step was to analyse the osseous anatomy of the normal distal radius and to define the radiographic measurements in the 3D modality. Second, the reliability of computer-aided analysis in performing the measurements in normal radii was compared to physicians’ manual measurements on reformatted 2D wrist radiographs. CBCT images provided better reliability than radiographs for evaluation of intra-articular incongruency. Determining the angular parameters revealed variation in both imaging modalities. CBCT was similar to magnetic resonance imaging in assessment of ligament or triangular fibrocartilage complex tears and chondral lesions of the wrist. The location where the longitudinal axis of the distal radius is determined affects the measurements of the angular parameters used in fracture analysis. The volar tilt angle varies along the distal articular surface and the measurements of ulnar variance and radial inclination vary according to the ulnar reference point. The intraobserver reliability analysis of the new computer-aided analysis showed excellent reliability for the measurements, whereas physicians’ assessment of reformatted 2D radiographs demonstrated variable reliability, particularly for angular measurements. CBCT is a valuable imaging option in wrist imaging. For accurate DRF analysis, the reference points for the radiographic measurements should be standardized. Computer-aided 3D analysis of the radiographic measurements of the intact distal radius is very reliable.
  • Zhang, Chao (Helsingin yliopisto, 2021)
    Multi-Model DataBases (MMDBs) are database management systems that utilize a single platform to store, manipulate, and query data in various data models, e.g., relational, tree, and graph models. Numerous MMDBs have been developed to facilitate multi-model data management, but they differ fundamentally in data storage, query language, and query processing. Existing tools are not suitable for benchmarking MMDBs because they do not consider the multi-model data and workloads. Therefore, it is of paramount importance to provide a new benchmark to evaluate the performance of MMDBs. Furthermore, MMDBs bring new issues for query optimization as traditional techniques cannot properly optimize the queries due to the lack of consideration of multi-model operators and storage. Thus, it calls for new approaches to optimize multi-model queries. This thesis is divided into two parts to accomplish the above two goals, respectively. In the first part, we developed a new benchmark system for MMDBs in a scenario of social commerce with five data models, i.e., relational, JSON, XML, graph, and key-value. This benchmark system is an end-to-end tool that consists of various components, including synthetic data generation, workload specification, parameter curation, and execution client. Moreover, we leveraged the developed system to conduct a holistic experimental evaluation of the state-of-the-art MMDBs to compare their performance and identify their performance bottlenecks in handling multi-model workloads. In the second part, we proposed two query optimization techniques for MMDBs. Firstly, we proposed a kernel density estimation (KDE)-based model to estimate the selectivity of multi-model joins that involve predicates for relational and tree data models. The estimation method can serve as a building block for selecting an optimal joining order in a cross-model query execution plan. We also proposed two approaches, the max-min approximation (MMA) and grid-based approximation (GBA) models, to approximate the KDE contribution while improving the estimation efficiency for large data samples. Secondly, we studied the problem of view selection in the relational-based graph databases to avoid the costly joins in the relational engine. Particularly, we proposed an end-to-end system that can automatically create, evaluate, and select views for accelerating the query processing. We proposed an extended graph view that can answer the subgraph and supergraph queries simultaneously. We devised a filtering-and-verification framework that enables the verification of the query containment by graph views. We formalized the view selection problem as a 0-1 Knapsack problem, then we developed a view selection algorithm, named graph gene algorithm (GGA), which explores the graph view transformations to reduce the view space and optimize the view benefit. Overall, the present thesis advances MMDBs in three aspects, i.e., performance benchmarking, join selectivity estimation, and automatic view selection.
  • Voutilainen, Silja (Helsingin yliopisto, 2021)
    Subclinical fibrosis and inflammation are common findings in pediatric hepatic diseases and in liver grafts after liver transplantation (LT). The mechanisms of these histopathological changes are unclear. Biomarkers that would precede these changes and non-invasive ways to assess fibrosis are needed. The aim of this thesis was to investigate the molecular and cellular markers of subclinical graft fibrosis and non-invasive methods to determine the stage of fibrosis and varices. Study I included 99 pediatric patients with chronic liver disease who underwent liver biopsy sampling for histology and transient elastography (TE) study for liver stiffness (LS) between January 2012 to March 2015. In addition, data on spleen size, platelet count, and aspartate aminotransferase to platelet ratio index (APRI) were collected. Esophagogastroduodenoscopy (EGD) was performed for 61 patients to assess varices. LS had the best accuracy in the prediction of liver fibrosis stage, compared to APRI, spleen size, and platelets to spleen size score. For moderate fibrosis (≥F2) and cirrhosis (F4) the area under receiver curve (AUROC) values for LS were 0.831 (95%CI: 0.745-0.981, p<0.001) and 0.919 (95%CI: 0.861-0.977, p<0.001, respectively). APRI performed little better in the prediction of varices with AUROC 0.832 [95%CI: 0.730-0.934, p<0.001), compared to LS with AUROC 0.818 (95%CI: 0.706-0.930, p<0.001). Patients of studies II-IV consisted of pediatric LT patients who underwent LT in Finland between 1987-2007 and were available for the study in 2009-2011 (time point referred here as cross-section/first follow-up) (n=54). The median time from LT was 11 years. All patients underwent liver biopsy sampling for histological evaluation and blood sampling for liver biochemistry. In Study II, serum concentrations of matrix metalloproteinase-8 (MMP-8), MMP-9, and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were analyzed from 52 patients and 94 healthy controls. Also, hepatic gene expression of MMPs and TIMPS genes was measured from 29 patients and eight control liver samples. The findings were correlated with histological findings. Patients with graft fibrosis had significantly increased hepatic gene expression of MMP-2, MMP-9, MMP-14, TIMP-1, and TIMP-2, compared to those without fibrosis (Mann-Whitney U test p-values ranging from 0.001 to 0.031). However, serum concentrations of MMP-8, MMP-9 TIMP-1 were unrelated to the presence of graft fibrosis. In Study III, hepatic gene expression of 40 fibrosis-related genes was measured from 29 patients and eight healthy controls. Gene expression levels were correlated with histological findings. Compared to patients with normal histology, patients with fibrosis and no inflammation had higher hepatic gene expression of genes related to fibrosis: transforming growth factor-3 (TGF-3), connective tissue growth factor (CTGF), platelet-derived growth factor subunit- (PDGF-), PDGF-, integrin-subunit-1, -smooth muscle cell actin (-SMA), and type I collagen and lower gene expression of decorin and vascular endothelial growth factor A (VEGF A) (Mann-Whitney U test p-values ranging from 0.005 to 0.049). However, compared to patients with normal histology, patients with fibrosis and inflammation had much fewer differences in the gene expression of the fibrosis-related factors than patients with solely fibrosis. Study IV included 51 patients who had sufficient liver biopsy for immunohistochemical staining of six biomarkers; -SMA, type I collagen, decorin, vimentin, p-selectin glycoprotein-1 (PSGL-1), and CD34. Immunohistochemical staining was also performed on 29 patients' biopsy samples taken at the LT operation available from the biobank. Before November 2019, at the final assessment, data on patient (n=48, three deceased) liver status was evaluated. Second liver biopsies (taken after the first follow-up) were available from 24 patients for histological evaluation. The immunohistochemically assessed expression of the six biomarkers at the time of the operation was unrelated to the presence of graft fibrosis at the first follow-up. The expression -SMA, type I collagen, decorin and vimentin correlated with simultaneous graft fibrosis (r=0.693, p<0.001; r=0.612, p<0.001; r=0.464, p=0.003; and r=0.562, p<0.001, respectively). Increased portal expression of -SMA, decorin, and vimentin in liver grafts without fibrosis at the first follow-up were observed in patients who later developed fibrosis (second follow-up biopsies) (Fisher's exact test p-values: 0.014, 0.024, and 0.024 respectively). Moderate fibrosis (≥F2) and increased expression of -SMA, type I collagen, decorin, and vimentin at the first follow-up associated with suboptimal liver status at the final assessment (Fishers exact test p=0.002, p=0.003, p=0.003, p=0.003, p=0.042, p=0.014 and p=0.004 respectively). Our findings implicate that the hepatic gene expression of MMPs and TIMPs is altered in patients with fibrosis after LT. Still, the serum concentration of MMPs and TIMPs was unrelated to graft fibrosis or their gene expression. The genes related to fibrosis were mostly associated with graft fibrosis without inflammation after LT. The immunohistochemically assessed expression of -SMA, decorin, and vimentin might precede the development of later fibrosis and suboptimal liver status, but their expression at the time of LT seems to be unrelated to later graft fibrosis. LS and APRI could be used in some cases to rule out moderate fibrosis and varices and thus avoid invasive liver biopsy sampling and EGS.

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