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  • Ahlqvist, Kati (Helsingin yliopisto, 2015)
    Somatic stem cell (SSC) dysfunction is a common feature of mouse models of premature ageing, most of which are created by disturbing nuclear DNA repair, damage recognition or ROS defence. The SSC dysfunction leads to decline in SSCs ability to maintain tissue homeostasis resulting in degeneration and ageing. The role of mitochondria or mitochondrial DNA (mtDNA) integrity in SSC homeostasis is unknown. Mutator mice, which harbour proof-reading deficient mitochondrial DNA polymerase gamma, accumulate mtDNA point mutations and develop a premature ageing phenotype, whereas Deletor mice, a model for adult-onset mitochondrial myopathy, accumulate mtDNA deletions and have a normal lifespan. Accumulation of mtDNA mutations and respiratory chain (RC) defect are thought to contribute to ageing process, and the Mutator mouse was the first experimental evidence supporting this theory. The aim of this thesis work was to elucidate somatic stem cell function in both Mutator and Deletor models, to investigate whether SSC dysfunction might explain the premature ageing phenotype. Our results show that the Mutator mouse accumulates mtDNA point mutations in SSC compartments, leading to changes in SSC function already during embryonal development. Deletors do not accumulate mtDNA deletions in SSCs and have normal SSC function. This suggests that premature ageing of Mutators is due to disrupted SSC homeostasis. Hematopoietic progenitors are especially sensitive to mtDNA mutagenesis, which may partly explain the high prevalence of anemia without iron deficiency seen in elderly humans. In this thesis, a novel mechanism for mitochondrial anemias is presented. MtDNA mutagenesis in hematopoietic precursors modifies signaling which causes aberrant iron loading and delayed mitochondrial clearance from maturing erythrocytes. In consequence, Mutator mice have abnormal circulating erythrocytes carrying mitochondria, which are prematurely captured and destructed by splenic macrophages, leading to iron accumulation in spleen. Enhanced destruction of newly-born erythrocytes and concurrently depleted iron stores in the bone marrow make compensatory reticulocytosis inefficient. Delayed mitochondrial clearance was also detected in a human patient with Pearson s syndrome, a rare disorder caused by a sporadic single large mtDNA deletion and causing life-threatening anemia. Treatment with N-acetyl-L-cysteine (NAC), a glutathione precursor and a ROS scavenger, was able to rescue the SSC phenotype during embryogenesis and to normalize iron loading in vitro, suggesting that mtDNA mutagenesis affects ROS signaling. However, NAC could not prevent anemia in vivo, nor rescue delayed mitochondrial clearance in vitro. This indicates that signaling in the SSC compartment is different during embryogenesis than in adulthood. This thesis shows that mtDNA integrity is essential for SSC function. Further, a new and essential role is proposed for mitochondria in regulating their own removal from maturing reticulocytes.
  • Itkonen, Juha (Bank of Finland, 2015)
    Climate change is one of the greatest market failures of our time. This thesis consists of three essays in which we study the economics of climate change using networks as a theoretical framework. In the first essay, we discover flaws in the foundations of a recent strand of literature estimating the carbon Kuznets curve (CKC). The CKC hypothesizes that carbon dioxide emissions initially increase with economic growth but that the relationship is eventually reversed. The recent literature attempts to estimate the CKC by adding energy consumption as a control variable. Due to model misspecifications related to the econometric methodology and database definitions, the results are biased to support the existence of a CKC. Consequently, the literature underestimates the need for climate policies. In the second essay, we study how social networks might help to explain why differences of opinion about climate change persist across segments of the lay public despite the scientific consensus. To do this, we programmed a Facebook application that collected survey data on concerns about climate change and network data on friendships. We found that respondents tend to have friends with similar concerns as their own, the unconcerned respondents have fewer friends, and any two respondents who disagreed about the seriousness of global warming were less than half as likely to be friends. The results indicate that the structure of the social network may hinder changes in opinions, explaining why opinions persist despite the scientific consensus. The results suggest that the communication of climate science could be improved by strategies that aim to overcome these network effects. In the third essay, we study permit markets which are connected by a network of links. A link allows participants of one emissions trading system to use permits of other systems. In a linked network of markets, foreign regulators can influence domestic policy outcomes even without a direct link. We apply graph theory to study these dependencies between markets to determine who exactly can affect domestic emissions and prices. We characterize the equilibrium's dependency structure assuming perfect competition and an exogenous trading network. The results help to avoid unexpected foreign interference with domestic policy outcomes and to secure the effectiveness of climate change policies.
  • Kerola, Anne (Helsingin yliopisto, 2015)
    Rheumatoid arthritis (RA) is associated with a substantially increased risk for cardiovascular (CV) morbidity and mortality. Along with their CV burden, RA patients are at increased risk for other comorbidities such as hypothyroidism and depressive symptoms. The aim of this work was to evaluate the prevalence of CV comorbidities and hypothyroidism among RA patients in comparison to those of the general population at the time of RA diagnosis. We also aimed to determine, among patients with early RA, the contribution of psychiatric and CV comorbidities as causes of long-term work disability (WD). Lastly, we assessed CV mortality rates in early RA. Between 2000 and 2007, all patients diagnosed with RA in Finland were possible to identify from a Finnish nationwide register on special reimbursements for medicine expenses. The same register provided information on the presence of comorbidities antedating RA diagnosis. From the pension registers, we retrieved data on permanent or temporary disability pensions. Causes of death were obtainable until the end of 2008. We compared the main outcomes, that is, the prevalence of comorbidities at RA diagnosis, the incidence of comorbidity-related disability pensions, and CV mortality rates to those of the age- and sex-specific Finnish population, and calculated standardized rate, incidence and mortality ratios (SRRs, SIRs, and SMRs). In a population of 7,209 RA patients, the risk of having coronary heart disease (CHD) at RA diagnosis was slightly elevated, the SRR (95% CI) being 1.10 (1.01 1.20). The SRR for levothyroxine-treated hypothyroidism at RA diagnosis was 1.51 (1.35 to 1.67). SRR was highest, almost 2.5, among women with RA aged 20 to 49, the excess prevalence of hypothyroidism decreasing steadily and fading in older age groups. From 2000 to 2008, of 7,831 RA patients, 1,095 were granted a disability pension. The 9-year cumulative incidence of WD resulting from RA was 11.9%, from a psychiatric comorbidity 1.3%, and from a CV disease 0.5%. SIR of WD resulting from CV disease was 1.75 (1.23 to 2.51) and SIR of WD resulting from psychiatric disorders was 0.99 (0.80 to 1.23). By the end of 2008, of 14,878 RA patients, 1,157 had died, 501 (43%) from CV causes. The SMR in the entire RA cohort was 0.57 (0.52 0.62). To conclude, the risks for CHD and hypothyroidism were already higher among RA patients at RA diagnosis, highlighting the importance of CV risk detection and management and of vigilance for hypothyroidism. Psychiatric and CV comorbidities were the primary causes of long-term WD much less frequently than was RA itself; the risk for WD due to CV disease, however, was higher in RA than in the general population. During the era of modern treatment regimens for RA, the risk of CV death during the early years of RA was not elevated. All these findings together stress the importance of recognizing, preventing, and targeting comorbidities in RA, already in the early years of the disease.
  • Paalanen, Tommi (Sexpo-säätiö, 2015)
    The topic of the dissertation is applying of liberal sexual ethics to sexological work with clients, sexual politics and jurisprudential problems. The work consists of an introduction and six articles that look into 1) ethical challenges and tools in therapeutic practice concerning sexuality, 2) the ethical basis of sexuality counselling and utilizing ethics in working with clients, 3) societal and ethical dimensions of women s sexual power, 4) the meaning of objectification to the ethics of pornography, 5) legislative problems and consequent ethical questions caused by child pornography, and 6) the ethical justification of criminalizing sadomasochistic sex and violent pornography. The introduction presents philosophical background for the articles: John Stuart Mill s ethical liberalism and the liberal tradition built on it, including the concepts of liberties and rights, which compose the most central ethos of modern sexual culture. The philosophical basis of liberal sexual ethics is built on egalitarian social philosophy, ethical neutrality of sexual acticity and rejection of paternalism and moralism as liberty-limiting principles. The articles are concerned with questions about supporting freedom and autonomy in helping professions and justifying limiting them in the society. Each article looks into the questions within their own context and thus expands into necessary theoretical backgrounds, arguments, questions and consequences in legal philosophy, criminalization theory, ethical basis of helping professions and sexual politics. The articles share a question about, how liberal sexual ethics support sexual wellbeing of individuals in different contexts. A shared result emerges: prevailing practices should be consistently liberalized in professional ethics and policies concerning equality, sexuality and criminal issues. All of these fields nurture practices that are illiberal, inconsistent and moralist due to their historical and cultural contexts, and thus impede the highest possible realization of sexual rights and well-being.
  • Hirvilammi, Tuuli (Kelan tutkimusosasto, 2015)
    The starting point of this study is a paradoxical situation: the wellbeing of average Finns is very high but simultaneously their environmental impacts threaten the carrying capacity of the earth. The paradox raises the question of what would sustainable wellbeing be and how is it to be studied. This study aims to develop a theory of sustainable wellbeing that recognizes the interaction between people and nature, as well as the goals of sustainability. In this interdisciplinary study the ecological issues are integrated into wellbeing research both in theory and in the empirical research settings. The empirical substudies are based on data that explores the wellbeing, standard of living and natural resource use (material footprints) of minimum income receivers. Material footprints were measured with the MIPS method.The results present a theory of sustainable wellbeing that is based on a relational conception of man. It enables us to see the connections between people and ecosystems, and humans as a part of nature. Sustainable wellbeing is defined as an entity that consists of a sufficient and sustainable standard of living, purposeful and responsible behavior, significant relations and an alert presence. The study develops a dynamic framework that can be used to explain the relations between capabilities, functionings and natural resource use. In order to be sustainable, wellbeing should be eco-efficient, which means satisfying needs with a minimal load on the environment. The results also present an interdisciplinary methodological setting, which can be used to assess the limits of a socially and ecologically sustainable standard of living. The aim of the sustainable standard of living is to secure all people with necessary resources within the carrying capacity of nature.
  • Törnroos, Maria (Helsingin yliopisto, 2015)
    The role of individual differences in perceptions of stress has long been recognized. Despite this, the models that are used to measure stress at the workplace the job strain model and the effort-reward imbalance model were developed to assess strenuous work characteristics and their health effects, regardless of the individual. Because work characteristics are usually measured using self-reports the measures cannot be completely objective. The present study examined the susceptibility of the job strain model and the effort-reward imbalance model to Five-Factor personality traits and cynicism. In addition, this study tested the longitudinal measurement invariance of the effort-reward imbalance scales. This study was part of the ongoing prospective, population-based Young Finns study. The measurements for the present study were carried out in 2001, 2007, and 2012. Five-Factor personality traits were assessed with a questionnaire on the Five-Factor model, and cynicism was assessed with a scale derived from the Minnesota Multiphasic Personality Inventory. Work characteristics were measured with questionnaires on the job strain model and the effort-reward imbalance model. The results showed that high neuroticism was associated with higher job strain and higher effort-reward imbalance and that high agreeableness was associated with lower job strain and lower effort-reward imbalance. High extraversion, high openness, and high conscientiousness were associated with lower job strain. Furthermore, high conscientiousness was related to lower effort-reward imbalance only in men. High job strain prospectively predicted higher cynicism six years later. The effort-reward imbalance scales achieved strict longitudinal measurement invariance and showed adequate criterion validity. Although developed to measure the structural work environment, the job strain model and the effort-reward imbalance model seem to be susceptible to Five-Factor personality traits especially to neuroticism and agreeableness. In addition, high job strain seems to have far reaching consequences on cynical attitudes. Furthermore, the results show that scores on effort-reward imbalance from different time points can reliably be compared with each other. This study shows that organizations and occupational health services should apply a more person-oriented approach to increasing wellbeing at work.
  • Rantanen, Ville (Helsingin yliopisto, 2015)
    Images provide invaluable information to Biomedicine. Especially, microscopy as an information source has been providing knowledge for research and clinical diagnostics. We have moved away from simply looking at the images to quantifiable computerized image analysis. Over the last decades, image analysis developers have prepared algorithms and software to address various scientific enquiries using images. These software are often created for a single purpose. Naturally, not even the most generic software can include all the algorithms ever created. From an image analysis developer point of view, the choice of software creates limitations. It limits the developer to the algorithms included and to the language it was developed in. Even if the software is modular and extendable, a specific language is required and the earlier algorithm implementations would have to be ported. This thesis presents an integration platform for image analysis: Anima. It is capable of using existing software and including them in analysis workflows. Since image analysis is very case specific, custom processing commands are frequently needed. Anima comes with a large number of data and image analysis components developed directly for the platform, as well as components that send custom commands to the integrated software. All of the components can be executed in a single analysis pipeline. Anima itself is built on top of Anduril, another software, inheriting its software architecture. Anduril gives Anima the power of parallel processing and rerun prevention mechanism, speeding up the development cycle of new algorithms. The usability of Anima for method development is shown by implementing new segmentation algorithms and visualization tools. The tools and methods are all suited to large data sets. To display the modularity, the tools are published as separate programs that are then integrated in Anima. The usefulness of the platform is shown by applying it in different biomedical research settings. The settings include different organisms: human, rat and nematode; different sample material: brain tissue, lymphatic nodes and serum; and different medical interests: cerebral ischemia, cancer and allergy. Anima is a versatile open-source image analysis platform, that encourages the use of best practices of programming habits. It makes the development of analysis workflows and individual algorithms more efficient.
  • Häkkinen, Margareeta (Helsingin yliopisto, 2015)
    Opioids are the most important drugs causing fatal poisonings. Determining whether an opioid death was poisoning may, however, be difficult even if involving appropriate toxicological laboratory investigation. Apart from heroin, little statistically significant data-analysis is available for interpretation of blood concentrations of opioids from various types of post-mortem cases. Tolerance, route of administration, and delay of death after drug administration all influence postmortem drug concentrations. In this thesis, quantitative blood concentration data extracted from the high-quality Finnish postmortem toxicology database was the investigative tool to overcome this problem. Opioid deaths typically involve drug abuse, and suspected drug-abuser deaths must, by Finnish law, undergo medico-legal examination. Medico-legal autopsy in these cases includes comprehensive drug screening and, based on its results, more specific drug quantification. This thesis combined concentration data stored in the postmortem toxicology database with information from death certificates issued by forensic pathologists to allow statistical comparisons between drug poisonings and other deaths, as well as between drug abusers and other users. Concentration data mainly involved drug concentrations in postmortem femoral blood, but drug concentrations in urine and parent drug/metabolite concentration ratios also allowed assessment of buprenorphine, codeine, and tramadol deaths. Opioid poisonings proved to be mainly unintentional polydrug poisonings, regularly involving benzodiazepines, gabapentinoids, and other psycholeptics. Buprenorphine and methadone blood concentrations in fatal poisonings remained within their therapeutic ranges, and these two opioids involved mostly abuse. Concentrations of the weak opioids tramadol and codeine were above their therapeutic ranges both in abuser cases and in fatal poisonings. Tramadol abuse was common but abuse of oxycodone, fentanyl, and codeine was rather low compared to their therapeutic use. Abuse of the gabapentinoids pregabalin and gabapentin was strongly associated with opioid abuse, and compared to gabapentin abuse, pregabalin abuse was proportionally more frequent. To prevent parenteral buprenorphine abuse, opioid maintenance treatment applied a combination product of buprenorphine-naloxone. This combination product is, however, abused as well, and monitoring its abuse is challenging. In this study, urine samples collected from living patients at different phases of opioid maintenance treatment supplemented the postmortem data. Based on the criteria established with these patients, combined with postmortem data and proper background information, a urine concentration limit was estimated for suspected parenteral abuse of the buprenorphine-naloxone product in postmortem cases. Deaths and fatal poisonings due to parenteral buprenorphine-naloxone abuse occurred frequently, and abuse of the combination product was proportionally even more fatal than was abuse of buprenorphine. The results of this study will assist in medico-legal cause-of-death investigations through providing quantitative reference concentrations for the interpretation of opioid-related deaths. Further, estimating the proportion attributable to prescription opioid abuse compared to that of other opioid use and creating abuser profiles for various opioids can promote public health through proper drug policy. In a clinical context, results may be helpful in evaluating possible drug abuse and compliance among prescription-drug users. Detecting abuse of these important yet addictive medications is vital in promoting welfare and drug safety.
  • Nordman, Nina (Helsingin yliopisto, 2015)
    Analytical microsystems are attractive in modern bioanalysis where sample amounts often are low and fast analyses are required. Microsystems also provide the prospect of integrating several functional elements on a single platform. The aim of this work was to develop analytical microsystems for fast analysis of bio- and drug molecules. For this, microchips with separation- and injection channels and monolithically integrated electrospray ionization (ESI) emitter were fabricated of epoxy photoresist SU-8 by photolithography and adhesive bonding. For peptide mass fingerprinting and protein sequencing characteristic tryptic peptides were fast and easily separated and detected by microchip capillary electrophoresis (MCE)-ESI/mass spectrometry (MS). Additionally, protein identification based on tandem MS fragmentation data of a single tryptic peptide was achieved. Finally, this rapid (total analysis time below ten minutes) microchip method permitted analysis of human muscle cell lysates. For online coupling of microchip capillary isoelectric focusing (cIEF) to ESI/MS a bilateral sheath flow interface or a two-dimensional separation unit was integrated on-chip. Rapid focusing of peptides by their isoelectric points (pI) was achieved without pretreatment of the SU-8 surface. After focusing the peptides were electrokinetically mobilized toward ESI/MS. The two-dimensional chip design enabled unique separation selectivity for peptides based on both pI values and intrinsic electrophoretic mobilities by multiplex-cIEF-transient-isotachophoresis. Rapid metabolic profiling was demonstrated from urine after intake of tramadol or paracetamol. Both phase I- and II metabolites were separated and detected by MCE-ESI/MS within 35 s. In addition, Michaelis-Menten kinetics was successfully determined for the CYP450-mediated oxidation of bufuralol to 1-hydroxybufuralol. Sample preconcentration (pretreatment) was integrated on-chip by solid-phase extraction (SPE) and liquid-phase microextraction (LPME). For SPE, a monolith zone was firmly anchored at the injection cross of the MCE-ESI/MS microchip by laser induced photopolymerization. The monolith was selective toward hydrophobic and hydrophilic sample molecules and enrichment factors as high as 23-fold was achieved with a loading time as short as 25 s. In addition, LPME was easily downscaled to low volume applications and offered selectivity in the analysis of phase I metabolites compared to SPE. In contrast to previous research in the same field this work offers bioanalysis with several on-chip integrated steps (preconcentration, injection, separation, and analysis) without considerably increasing the short analysis times characteristic of microchip assays.
  • Lehto, Hanna (Helsingin yliopisto, 2015)
    Objective: Aneurysms of the vertebral artery (VA) and its branch posterior inferior cerebellar artery (PICA) are rare, comprising only about 1 to 3% of all intracranial aneurysms. The series published thus far on these lesions are small. We aim to describe the special anatomical and morphological features of these aneurysms compared to aneurysms in other locations, and to describe the variety of symptoms they cause. We describe their treatment and analyze the outcome. Additionally, we describe their anatomy imaged with computed tomography angiography. Patients and methods: We reviewed retrospectively 9 709 consecutive patients with intracranial aneurysms treated in the Department of Neurosurgery at Helsinki University Central Hospital, Finland, between 1934 and 2011. The study population included 268 patients with 284 VA or PICA aneurysms or both. Follow-up data came from the Population Registry Centre (dates of death), Statistics Finland (causes of death), from written questionnaires to patients still alive, medical records of the Department of Neurosurgery, and for those deceased, medical records from all public health services. Results: Among all the aneurysm patients, 5.1% had an aneurysm in the VA or PICA. Most aneurysms, 51%, were located at the VA PICA junction. The proportion of fusiform aneurysms was 28%. Compared to patients with ruptured aneurysms at other locations, patients with a ruptured VA or PICA aneurysm were older and had a higher Fisher grade. Ruptured distal PICA aneurysms also re-bled more regularly. Compared to other ruptured aneurysms, ruptured VA and PICA aneurysms were smaller and more often fusiform. At least one VA or PICA aneurysm was treated in 209 (78%) patients. The most common technique for aneurysm occlusion was clipping, used in 107 aneurysms. Total occlusion of the aneurysm was achieved among saccular aneurysms in 90%, and among fusiform aneurysms in 61%. Within one year of aneurysm diagnosis, 26% of the patients were dead. Among those who survived a minimum one year and in whom the VA or PICA aneurysm received active treatment; those returning to an independent or their previous stage of life amounted to 92%. Conclusion: In treatment of VA and PICA aneurysms, their special anatomical and morphological features are challenge. Despite this, and often severe hemorrhage, most patients surviving the initial stage make a good recovery.
  • Cousminer, Diana (Helsingin yliopisto, 2015)
    Puberty is a highly variable developmental stage marked by the development of secondary sex characteristics and the attainment of reproductive maturity. Variation during childhood developmental phases correlates with altered disease risk in adulthood; variation in pubertal growth and timing, in particular, correlates with adult risk for type 2 diabetes, obesity, adverse cardiovascular heath, and hormone-dependent cancers. While normal variation in age at menarche (AAM) has recently been investigated in large-scale genome-wide association (GWA) studies, the genetic regulation of male puberty remains less understood. Moreover, extreme variation in pubertal timing is a common cause for referral to pediatric specialists, while the underlying genetic factors are largely unknown. This work aimed to identify both common and rare genetic variants influencing pubertal growth and timing in both sexes. Utilizing Finnish population-based samples with frequent height measurements across puberty, we ran GWA of growth during late puberty and uncovered an association for variants near LIN28B, the most robust menarche-associated locus. Investigation of the longitudinal effects of two partly-correlated markers, one tagging a pubertal timing effect and one tagging an effect on adult stature, revealed distinct sex-specific association patterns with height growth from birth until adulthood. Thus, the LIN28B locus tags an important developmental regulator of both growth and maturational development. We then expanded to include European-wide samples within the Early Growth Genetics (EGG) Consortium. Genetic mapping of three pubertal growth traits revealed 9 novel pubertal growth variants in addition to LIN28B, 5 of which also associated with pubertal timing, and one which associated with childhood and adult body mass index (BMI). Longitudinal investigation of these variants showed diverse patterns of association with height growth, some of which contradicted epidemiological correlations between rapid prepubertal growth, advanced puberty, and reduced final adult stature. Given the complex relationships between these traits, tracking individual unique effects across multiple periods of growth may help uncover the pathways linking childhood development with adult health outcomes. Also within the EGG Consortium, GWA meta-analysis of Tanner genital and breast staging data uncovered the first robust male puberty locus on chromosome 16 near MKL2, a locus which also associates with advanced menarche, decreased pubertal growth, and shorter adult stature. Furthermore, part of the genetic architecture underlying the onset of puberty is shared between males and females, evidenced by the high correlation between menarche-advancing alleles and earlier male genital development. However, while BMI-increasing alleles strongly correlate with advanced breast development in girls, our data shows that these variants play a more complex role in male puberty. Finally, we performed targeted sequencing of the pericentromeric region of chromosome 2 previously robustly linked with constitutional delay of growth and puberty (CDGP), an extreme delay in normal pubertal timing, in multiply affected Finnish families. Analysis of shared low-frequency variation in genes and regulatory regions of the best functional candidate genes revealed 6 protein-altering variants in a single gene, DNAH6, in 10 of the families. However, follow-up sequencing in an additional 135 Finnish CDGP cases failed to provide evidence for enrichment of DNAH6 mutations compared to a large, unique set of SISu Finnish population controls. DNAH6 is potentially an appropriate candidate gene that may be involved in the regulation of steroid hormone biosynthesis by the cytoskeleton. This study highlights the difficulties of detecting susceptibility variants under a linkage signal for complex traits. Taken together, these results advance our understanding of the genetics of pubertal timing and development in both sexes. However, more work is needed to understand how each genetic locus functions in the biology of puberty and childhood growth, and further study of the genetic loci highlighted in this work may help pinpoint the mechanisms that link the timing of this important developmental stage with adult health and risk for common diseases. Keywords: puberty, development, growth, genome-wide association studies (GWAS), targeted sequencing, constitutional delay of growth and puberty (CDGP)
  • Andersen, Claus Elholm (University of Helsinki, 2015)
    You have to be on your guard On Literariness in Karl Ove Knausgård s My Struggle This dissertation is a discussion of literariness in Karl Ove Knausgård s novel My Struggle (2009-2011). I argue that My Struggle first and foremost is a novel and should be read accordingly. Though Knausgård might challenge the genre of the novel as we know it, I show how he does so within the framework of one of the strongest traditions in the 20th century. This tradition includes writers such as Proust, Joyce, and Thomas Mann, all of whom, like Knausgård, have sought to challenge the novel as such. Thus, Knausgård is stretching the limits of what a novel can be by taking his point of departure in the challenge that already exists in the genre. Read this way, Knausgård expands the limits of what a novel is and can do, so it becomes impossible to ignore him as a novelist. The dissertation is based on five articles published, or accepted for publication, in peer-reviewed academic journals. Combined, these articles show how Knausgård as a writer belongs to a literary tradition that can be seen as an extension of literary modernism. In each article, I identify what I have named the central paradox of the novel that Knausgård wants to write honestly about his life, but can only do so in the form of a novel and by using the literary devices from the world of fiction. It is through the analysis of this central paradox that I portray the literariness of the novel. Aside from the five articles, the dissertation also consists of a cap or a summarizing report where I place the articles in relation to the existing scholarship on Knausgård and explain my theoretical framework and why I consider it important to read My Struggle as novel. Here, I argue that the dissertation is in clear opposition to the majority of what has previously been written on Knausgård, where the focus has been on how Knausgård plays with reality and fiction instead of striving to understand what the novel is trying to say.
  • Valtanen, Marjo (Helsingin yliopisto, 2015)
    Urbanization is causing a substantial increase in impervious surfaces and thereby alterations in the hydrological cycle, e.g. by increasing runoff volumes and intensities that can lead to urban flooding. Furthermore, urban runoff is considered as one of the most important surface water pollutant sources. The characteristics of urban runoff are known to vary greatly between land use types and climates. However, in cold climates, only a few studies have tackled urban runoff phenomena and these studies rarely include catchment-based and long-term monitoring on both runoff quantity and quality. Yet, to develop successful urban runoff management practices, knowledge on runoff characteristics from various urban sites that are monitored for several pollutants throughout the year is required. The aim of this thesis was to fill gaps in our knowledge on the effects of urbanization on runoff characteristics and to study the mechanisms affecting runoff generation and pollutant transport during vastly divergent seasons in cold climates. This research was conducted in the city of Lahti, southern Finland, and comprised three urban catchments of varying imperviousness: High catchment (city centre, total impervious area [TIA], 89%), Intermediate catchment (city centre, 62%) and Low catchment (residential, 19%). At each catchment, continuous measurements on runoff flow rate and precipitation were carried out for a period of two years. In addition, runoff samples were taken to determine concentrations for total nitrogen (tot-N), total phosphorus (tot-P), total suspended solids (TSS), total and dissolved heavy metals (Zn, Cu, Cr, Mn, Al, Co, Ni, Pb) and total organic carbon (TOC). I showed that in cold climates, annual runoff volumes, most pollutant loads and some of the pollutant concentrations increased with increasing imperviousness. Furthermore, urbanization altered runoff generation (volume, intensity, duration, number of events) more strongly during the warm than the cold period. However, when the summer was dry and the winter wet, the effects of urbanization on annual runoff volumes diminished most likely due to snow removal. The spring snowmelt period began earlier and occurred as several events at the city centres in comparison to the low-development catchment. In contrast with patterns observed during warm periods, cumulative runoff volumes during cold periods decreased with increasing urbanization when TIA reached about 60%. Nevertheless, urbanization increased both warm and cold period loads for most pollutants. However, the mechanisms controlling runoff event quality were distinct between seasons: during cold periods event loads and concentrations were mainly increased by long event durations, yet, during warm periods the peak intensity of runoff was the main increasing factor whereas concentrations tended to decrease as event durations increased. Because of snow removal in the High catchment with TIA of 89%, snowmelt volumes during spring were not affected by the amount of precipitation. In addition, at the High catchment, warm periods contributed more to annual volumes than cold periods, contrary to the pattern observed at the Low catchment. Irrespective of land use, the largest seasonal pollutant loads and concentrations for several pollutants occurred during spring. However, the importance of the warm season in annual pollutant load generation increased with increasing urbanization. This study provides updated data on pollutant unit loads, especially for city centres and for heavy metals. This thesis - applying a catchment-based approach - also showed, for the first time how the seasonality of runoff volumes and loads change at highly impervious city centres.
  • Ito, Sanae (Helsingin yliopisto, 2015)
    Assurbanipal, the last great king of the Assyrian Empire (934-609 BC), ruled from 668 BC until at least 630 BC. He had to spend four years suppressing a revolt by ama - umu-ukīn, his older brother and the king of Babylon (667-648 BC), but his reign was much longer than his predecessors and he controlled almost all the area of the Ancient Near East. One of the essential bodies of research material on his reign is his correspondence, which has never before been studied in detail because much of it has been published in cuneiform copies only. His extant correspondence consists of 359 letters: 72 letters from him (the so-called royal letters) and 287 letters to him. Royal letters are particularly rare in the Assyrian correspondence and Assurbanipal s royal letters outnumber those of his predecessors, hence this dissertation focuses on them. The letters deal with political, military, and diplomatic matters through the king s point of view and in his words. The aim of this research has been to find out what image of himself Assurbanipal tried to convey in his letters and how he utilized the image in order to further Assyrian policies. The dissertation uses philological method and also takes advantage of the electronic database of the Neo-Assyrian Text Corpus Project (Helsinki), which contains the majority of texts of the Neo-Assyrian period in transliteration. Most of Assurbanipal s royal letters were written during the revolt and its aftermath, and sent to Babylonia, Elam, and the Sealand, which were deeply involved in the revolt. Since the most common recipients of the missives were citizens, Assurbanipal clearly considered it particularly important to address the population at large when the revolt shook the foundation of the empire. As the royal letters originate in the state archives in the capital of Assyria, Nineveh, most of them are archival copies or drafts. Two languages and two scripts (Neo-Assyrian, Neo-Babylonian) were used in them, but the drafts would have first been drawn up in Neo-Assyrian, and later translated into Neo-Babylonian, perhaps first in Assyrian script and only later in Babylonian script. Assurbanipal had dialogue with both adversaries and adherents, emphasized the favours he had done, and described himself as a benevolent and merciful king who was capable of establishing justice, peace, and equality in the realm. He involved Nippur and Uruk in Assyrian military activities against rebels and settled a sibling rivalry between the governor of Ur and his predecessor. He continued a conciliatory policy towards Babylon even during the revolt in order to resolve the conflict peacefully. He tried to incorporate foreign countries into Assyrian control by treaties and sometimes exerted direct pressure on them with thinly veiled threats. Some countries came under Assyrian rule at their own initiative in order to acquire military and political gains from Assyria. Throughout the royal letters, he stressed his devotion to the gods and their support for his rule. Especially A ur, supreme god of Assyria, was an important figure in the letters.
  • Kareinen, Ilona (Helsingin yliopisto, 2015)
    Atherosclerosis is an inflammatory disease characterized by the accumulation of cholesterol in the arterial intima and consequently the formation of atherosclerotic plaques. Formation of these plaques is initiated by the appearance of macrophage foam cell in the arterial intima. Foam cells are formed as excessive cholesterol accumulates in the cytosol of macrophages and finally the net influx exceeds the efflux of cholesterol. Excessive accumulation of chemically modified cholesterol in foam cells finally leads to apoptosis and contributes to the formation of the lipid core in atherosclerotic plaques. The efflux of cholesterol from foam cells is essential for preventing the progression of atherosclerosis. The only unidirectional transporters ABCA1 and ABCG1, expressed on macrophages, transport intracellular cholesterol actively to distinct subpopulations of HDL. ApoA-I, the most important structural and functional component of nascent preβ-migrating HDL particles, receives cholesterol from ABCA1. Lipid-free HDL and apoA-I are sensitive to proteolytic modification leading to loss of function of these molecules. Functional apoA-I is essential for removal of cellular cholesterol and for cholesterol homeostasis. Cholesterol efflux initiates reverse cholesterol transport (RCT) which is the pathway for removal of cholesterol from the periphery for its final excretion into feces. The tiny fraction of total body-RCT that originates from the cholesterol-loaded macrophage foam cells located in the intima, is considered the only RCT component directly involved in atherosclerosis. Mast cells are bone marrow-derived inflammatory cells that are able to activate and secrete various mast cell mediators. Mast cells infiltrate the inflamed arterial intima where they can be activated through several stimuli present in the atherosclerotic intima. Mast cells release several inflammatory compounds of which histamine is probably the best known for its notorious effects in anaphylaxis. In addition to histamine and other vasoactive compounds, such as serotonin and bradykinin, mast cells release upon activation their unique serine proteases, tryptase and chymase. Chymase involvement in the progression of atherosclerosis has been suggested in a number of studies. Chymase is an enzyme capable of degrading LDL and HDL components leading to increased uptake of the modified LDL by macrophage foam cells or resulting in diminished cholesterol efflux, respectively. The purpose of this study was to evaluate whether mast cell-dependent HDL and apoA-I proteolysis would occur in vivo and whether such modification would alter the cholesterol efflux capacities of these cholesterol acceptors and finally affect the macrophage-specific RCT (mRCT). In the present study it was demonstrated for the first time that mast cell activation in vivo resulted in HDL proteolysis. Systemic mast cell activation led to the degradation of lipoprotein particles present in HDL and the entire preβ-HDL and α-HDL subpopulations were reduced in mouse serum following systemic mast cell activation. Systemic activation of mast cells in mice blunted the ability of serum and intraperitoneal fluid to promote cholesterol efflux from macrophage foam cells in vitro. Rat cardiac mast cell activation ex vivo led to the production of truncated apoA-I. ApoA-I was cleaved at the carboxyl-terminal region at Phe229 and Tyr192 or only at Tyr192 depending on the mast cell stimulus. Local peritoneal mast cell activation led to decreased ability of intraperitoneally injected apoA-I to promote macrophage cholesterol efflux in vitro. Furthermore treatment with intact lipid-free apoA-I but not chymase-treated apoA-I increased the overall mRCT from the peritoneal cavity to the intestinal contents within 3 hours. Importantly such an increase was fully blocked by the mast cell-specific degranulating compound 48/80 in mast cell-competent mice but not in mast cell-deficient mice. Interestingly local mast cell activation in the skin was able to promote mRCT from skin to feces. This was due to increased vascular permeability and influx of plasma HDL particles to skin consequently leading to increased mRCT. This stimulatory effect could be reproduced by the sole administration of the mast cell mediators, histamine, serotonin, and bradykinin. Importantly histamine treatment in apoA-I deficient mice was unable to promote mRCT. In conclusion, mast cell chymase is able to proteolyze HDL and lipid-free apoA-I reducing their abilities to promote cellular cholesterol efflux. Proteolysis of lipid-free apoA-I by rat cardiac mast cell chymase can occur within minutes and results in the formation of carboxyl-terminally truncated apoA-I. ApoA-I proteolysis in vivo results in reduced mRCT. Local mast cell activation in the skin results in increased mRCT due to increased availability of cholesterol acceptors in the vicinity of macrophage foam cells. These two seemingly opposite results underline the pleiotropic role of mast cells in the development of atherosclerosis
  • Konttori, Johanna (2015)
    The aim of this study is to add a new perspective to the large body of scholarly work dealing with the debates on the use of headscarves and full veils in contemporary France. The study examines the discursive construction of national identity by members of the political and social elite as they discuss the use of headscarves in state schools, and the use of full veils in the public sphere more generally. The new perspective that the study presents is threefold. First, the study examines both headscarf and full veil debates, which have so far been mainly studied separately. Second, the data consists of the little-studied transcripts of the hearings organized by the two parliamentary commissions (the Debré and Gerin Commissions) that looked into the headscarf and full veil issues in 2003 and 2009, respectively. Third, even though it has been widely noted in the existing research literature that the headscarf and full veil debates were linked to national identity, it has not been common to draw theoretical insights from nationalism studies, as is done here. The analytical focus is on Muslims and Islam, headscarves and full veils, and their relation to the Republic, its identity and values (notably laïcité). Using analytical tools derived from the discourse-historical approach, the study shows the great variety of different perceptions of Islam and Muslims, but also laïcité, in the data. Even though headscarves and especially full veils are mostly regarded as problematic and even threatening to the Republic, this does not necessarily result in negative perceptions of Muslims and Islam. Finally, the study ponders the usefulness of binary categories. It is concluded that neither the Us vs Them categorization often linked to the construction of national identities nor the claim of Muslims as Others in France entirely fit the data. Instead, it is suggested that the concepts of stranger and national capital enable a more nuanced examination of the place of Muslims and Islam in France.
  • Savola, Pekka (Helsingin yliopisto, 2015)
    This article-based dissertation examines the involuntary role of Internet connectivity providers in copyright enforcement in the EU, and in particular injunctions ordering user-end providers to block access to websites facilitating infringement. The main method is doctrinal legal scholarship supplemented by a socio-legal study of legal policy, seeking answers to the why questions underlying the law. Copyright enforcement measures using providers include website blocking, disconnecting the website or the user, subscriber information disclosure, and notice or graduated response mechanisms. There are also dozens of other options for enforcement, and the IPR holder may select the optimal one(s). In international settings, this can be further optimised by the choice of jurisdiction, the applicable law, and characterisation of the infringement. These provide opportunities for gaming the system . Enforcement proceedings are problematic because typically only the copyright holder and possibly the provider are represented in court. Nobody is responsible for arguing for the users or website operators. The court should take their interests into account on its own motion. Unfortunately, many courts have not yet recognised this responsibility. Even this dual role as both the defender of unrepresented parties and judge is less than ideal and improvement is called for. All the enforcement mechanisms must be compatible with EU fundamental rights, as well as the national ones. A proportionality evaluation procedure is suggested, consisting of identifying the context, the interests of different parties, and applicable principles as well as formulating the evaluation criteria and applying them in a proportionality test. In the test, the legitimacy of the objective, suitability for the purpose, necessity and balancing need to be critically assessed. The underlying goal of copyright enforcement has implications for how the scale tilts. Ineffective enforcement mechanisms can be more easily accepted if the goal of symbolic, educational or politically motivated enforcement is deemed legitimate. However, if the goal is to decrease the impact of infringement, greater efficiency and economically quantifiable results may be required. A proportionate mechanism does not necessarily exist in any particular case. Current enforcement legislation is a product of heavy lobbying by the copyright industry. This has led to the legislators being inundated with copyright ideology and proprietarian bias. In consequence, the legislation fails to take the more general public policy interests and the rights of others into account adequately. The pressure is on rationalising rather than expanding the role of connectivity providers. This background context also calls for a critical approach to interpreting the law. Such an approach might help in achieving more rational and balanced justifications and conclusions.
  • Hokkanen, Ann-Helena (Helsingin yliopisto, 2015)
    Disbudding entails destroying calves horn buds, and in dairy farming is most often done with a hot-iron. Disbudding is routinely carried out because hornless cattle are considered to be safer for themselves and for humans. Hot-iron disbudding is very painful and causes severe pain-related distress and behavioural changes in calves. Options for treating disbudding-related pain during the procedure, and for 24 hours subsequently, are well known, but continued pain and its management are not much studied in calves after disbudding. Pain can cause restlessness and thus affect calves lying time. Pain in humans and rats also changes sleeping behaviour. Pain connected with disbudding often remains untreated. Reasons for this are unclear. Therefore, more knowledge and research are needed on the recognition of calves pain after hot-iron disbudding, on the duration of pain and on options to treat it in an effective, safe and practical way. Research is also needed on producer knowledge and attitudes towards pain in calves and their decision-making in connection with pain alleviation. The objectives of the work reported in this thesis were all connected with gaining an improved understanding of producer perceptions about pain caused to young calves by hot-iron disbudding, and with options available to increase the use of pain alleviation for this common and painful procedure. Initially we asked dairy producers for their perceptions towards disbudding pain in calves. Then, in order to be able to study the duration of pain after disbudding in the future, we attempted to develop a new device to measure calves lying and sleeping time: a small, neck-based, wireless accelerometer system. Because new methods and various options for pain alleviation are needed, we investigated if sublingual detomidine provided sufficient sedation in calves to allow administration of local anaesthetics prior to disbudding. Because the use of pain alleviation is often a choice faced by producers, we wanted to study Finnish dairy producers interests and motivation regarding pain alleviation in connection with disbudding. We studied Finnish dairy producers perceptions on disbudding-related pain and the need for pain alleviation, and how such perceptions affect the actual practice of pain alleviation. Finnish dairy producers estimated disbudding pain to be severe and producer estimation of pain severity caused by disbudding was correlated with their sensitivity to pain caused by different cattle diseases in general. We were able to develop an accurate device for measuring calves lying and sleeping time. Detomidine oromucosal gel was an effective sedative for calves before infiltration of local anaesthetics and disbudding. Finnish dairy producers who estimated the disbudding-related pain and need for pain alleviation to be high had a veterinarian medicate calves before disbudding more often than producers who ranked disbudding pain and need for pain alleviation lower. Because more studies on duration and alleviation of disbudding pain are needed, our new device for measuring lying and sleeping time in calves could make these studies easier in the future. A non-invasive and user-friendly oromucosal sedation method for calves could enhance the use of local anaesthetics before disbudding by making sedation easier. Our findings among dairy producers support the idea that persons who have knowledge of pain and who think pain alleviation is beneficial and important are also more prone to administer pain alleviation. Education of producers on disbudding-related pain could increase the use of pain alleviation in the future. It could also increase pain alleviation for other cattle diseases because producer perceptions on disbudding-related pain are likely to be connected with pain in cattle in general.
  • Mönttinen, Heli (2015)
    The right-hand-shaped polymerases comprising the DNA/RNA polymerase superfamily represent at least six different protein families containing replicases, transcriptases and repair proteins from all three domains of life as well as from their viruses. All of these polymerases have at least three subdomains: fingers, palm and thumb, which form together a structure resembling a right-hand. The catalytic site is located in the palm subdomain, in which polymerization process is catalysed by two Mg2+ ions. There can also be additional ions such as the non-catalytic ion in the RNA-dependent RNA polymerase of phage φ6, which is located approximately 6 Ångströms from the catalytic site. The phylogeny and common regions of the right-hand-shaped polymerases have been previously studied mainly using amino acid sequence alignments. However, the sequence similarity between polymerases belonging into different protein families is low and therefore, the structure alignment provides a potential alternative because protein structures can retain similarity longer in evolution than amino acid sequences. In this thesis, the common structural features between and within the families of the right-hand-shaped polymerases are described, and based on the structural cores the phylogenetic trees are deduced. In addition, the phylogenetic relationships between the right-hand-shaped polymerases and other structurally related proteins are described. As results, it is shown that a phylogenetic tree following the established boundaries of protein families is possible to construct based on structural core sharing no sequence identity. This tree, illustrating long distance phylogenetic relationships suggests that the known right-hand-shaped polymerase families are not the closest relatives to each other. The phylogenies within polymerase families suggest that the relationships among the polymerases do not always follow the evolution of the corresponding organism, which implies horizontal gene transfer between cells, and cells and viruses. The phylogeny of RNA virus RNA polymerases seem to be dependent on the priming mechanism and it does not follow the virion architecture or the Baltimore classification. In addition, the viral RNA-dependent RNA polymerases seem to share a third ion binding site in the proximity of catalytic site.
  • Örmälä-Odegrip, Anni-Maria (Helsingin yliopisto, 2015)
    Bacterial viruses (i.e. phages) are ubiquitous intracellular parasites of bacteria, that along with protist grazers account for majority of bacterial mortality in nature. Phages impose strong selection for bacterial phage-resistance, which is often coupled with fitness costs on bacterial traits such as growth ability, virulence or motility. Traditionally phage-host interactions have been studied with two species systems in the laboratory, neglecting the complex web of interactions present in natural communities. The ability of phages to selectively kill bacteria has ignited an interest on phages as alternative antibacterials. However, in order to develop phage therapy, understanding of phage-host interactions in the eco-evolutionary context is essential. In this thesis I studied the implications of lytic phages on opportunistic pathogenic bacteria, as opportunists often have the ability reproduce and reside in outside-host environments, where they are predisposed to a variety of selection pressures. The role of phages in top-down control of bacterial biomass and the evolution of bacterial phage-resistance were studied in the presence of protist predators with differing feeding modes, in low-resource systems mimicking natural pond environment. Hypothesis of coincidental evolution suggests that virulence is a by-product of selection for traits that maximize bacterial fitness in environmental reservoirs. Yet, disease outbreaks by opportunists are relatively rare, suggesting that something constrains the selection for virulence. To assess the role of lytic phages on the evolution of virulence, bacteria were cultured in low-resource environment, accompanied with changes in temperature regime or changes in composition of the community of interacting bacterial enemy species, and the virulence of bacteria was measured in vivo. To study whether the potential phage-resistant bacteria surviving phage therapy would be coupled with lowered virulence, due to costs associated with phage-resistance, a clinical bacterial isolate was exposed to phage cocktails and the virulence of the phage-resistant bacteria was measured in vivo. given the strong selection for phage- resistance, the prospects of phage therapy depend a great deal on whether new phages infecting pathogenic bacteria can be readily isolated from environment. To address this, an attempt was made to isolate phages against clinical bacterial isolates harboring resistance genes to multiple antibiotics. A single lytic phage was shown to be a non- efficient top-down regulator of bacterial biomass. Rapidly emerging phage-resistant bacteria took over the bacterial populations after initial lysis by phages and protist grazers accounted for most of the long-term negative trophic effects on bacterial biomass. The presence of protist predators selected for bacteria that were less susceptible to infection by lytic phages, which suggests an overlap in the bacterial defense against a parasite and predatory protists. In general, the presence of lytic phages selected for lowered virulence in bacteria. High temperature selected for more virulent and more motile bacteria, but this was constrained by the presence of a lytic phage. In the multispecies communities the presence of all bacterial enemies led to decreased virulence in vivo. Altogether, these results contrast the hypothesis of coincidental evolution, and suggest that the presence of phages in natural reservoirs constrains the evolution of virulence, most likely through fitness costs associated with phage-resistance. Exposure to phage cocktails was also shown to be associated with decreased bacterial virulence in the phage-resistant bacteria. However, exposure to some individual phages resulted in more virulent bacteria, suggesting that the outcome of therapy could depend on the identity of the phage cocktail. Finally, a phage cocktail lysing a wide range of clinical strains was isolated from sewage. This, along with geographical patterns of phage infections suggest that new phages are available in environmental reservoirs for therapy, and the emergence of phage-resistance should not hinder the prospects of phage therapy in the global perspective.