Väitöskirjat

Recent Submissions

  • Ghahramani, Abolfazl (Unigrafia, 2017)
    Occupational injuries are a major problem worldwide and affect all countries, particularly developing ones. In recent decades, the application of approaches such as the Occupational Health and Safety Management System (OHSMS) has led to the successful control of workplace injuries in high-income countries. The Occupational Health and Safety Assessment Series (OHSAS) 18001 as a world-recognized OHSMS has gained considerable acceptance by a large number of organizations. However, few studies have examined the effectiveness of OHSAS 18001 on safety performance in certified organizations. This study consisted of four sub-studies, and was conducted to explore the effect of OHSAS 18001 on the occupational injury, safety climate, and Occupational Health and Safety (OHS)practices in OHSAS 18001-certified companies compared with a control group in Iran. OHSAS 18001 practices were also examined in the certified companies, where interviews were conducted to explore the influencing factors on the effectiveness of OHSAS 18001. A negative binomial regression indicated no significant effect of OHSAS 18001 certification on the occupational injury rate. The second sub-study applied a new safety climate questionnaire, and a hierarchical regression indicated that the safety climate was influenced by the implementation of OHSAS 18001 and safety training. The third sub-study pointed to the better OHS practices of the certified companies compared with the control ones. The results also showed that adopting the OHSAS 18001 standard improved the documentation for the management of OHS, but did not lead to continuous improvement in the required practices. The evaluation of the collected evidence revealed the main reasons for a poor safety culture. The interviewees emphasized the internal and external influencing factors in the effectiveness of OHSAS including commitment of top management and the enforcement of OHS legal requirements. It can be concluded that the implementation of OHSAS 18001 in an organization is not a guarantee of improved safety performance and of the existence of a high-quality management system. This study suggests that certified companies should focus on proper improvement and maintenance of the implemented management systems by escalating their commitment to the requirements of the established management systems and by participating their employees in OHSAS 18001 practices. This study also emphasized the importance of providing safety training for employees who work in the certified companies. These efforts may help the companies in the creation of a good safety culture and the transforming the paper systems into effective management systems to make improvement in OHS performance.
  • Hautamäki, Asta (Helsingin yliopisto, 2017)
    Age-related macular degeneration (AMD) is the leading cause of visual impairment in developed countries. Geographic atrophy and exudative AMD, the advanced forms of AMD account for the majority of visual impairment. No evidence-based medical treatment exists for geographic atrophy, but the choroidal neovascularization (CNV) forming exudative AMD lesion can be targeted with therapy. Vascular endothelial growth factor (VEGF) has a crucial role in ocular neovessel formation. VEGF-inhibitors form the mainstay of present-day treatment of exudative AMD. Although response to anti-VEGF agents is usually good, marked individual variations exist in treatment outcomes. The reasons behind the variations are largely unknown. The aim of this study was to identify factors that predict treatment response during anti-VEGF therapy and affect activity of exudative AMD lesion. We analyzed the effects of CNV lesion characteristics, the effects of potential genetic predictors: variants of interleukin-8 (IL-8), VEGF, and erythropoietin genes, the effects of well-known risk factors for AMD: tobacco smoking, risk variants of complement factor H (CFH), ARMS2, and complement component 3 (C3) genes, and the variations in anterior chamber protein concentration (flare). Initial treatment response after the first injections of anti-VEGF agent bevacizumab was analyzed retrospectively in a material of 96 patients. Long-term treatment response and flare was studied in a prospective two-year follow-up of 50 patients treated with bevacizumab. Association of the genetic variant of IL-8 with earlier onset of exudative AMD was analyzed retrospectively using the medical records of 301 patients with exudative AMD, 72 patients with dry AMD, and 119 control subjects. The IL-8 (rs4073) promoter polymorphism has been associated with regulation of the production of IL-8, a potent mediator of inflammation and neovascularization. It was the only genetic factor in the analyses that had an association with the initial anatomic treatment response. It also had a marked cumulative effect on the long-term anatomic response together with the risk variants of VEGF and CFH genes. CNV lesion characteristics affected both functional and anatomic outcomes of initial treatment, but were less important in predicting long-term response. In the long term follow-up also the genetic variant of ARMS2 was associated with functional outcome. Flare reflected poorly the lesion activity and did not predict treatment response. However, the fellow eyes that developed exudative AMD later had higher flare values at the beginning of follow-up compared with the eyes that remained free of exudative AMD features. An association was also found between the variant of IL-8 and age of onset of exudative AMD. These findings support the hypothesis that IL-8 has a role in the process leading to CNV growth in exudative AMD and in the regulation of activity of exudative AMD lesion during anti-VEGF treatment.
  • Yan, Xu (Helsingin yliopisto, 2017)
    Progressive development of pathology in neuroanatomically connected brain regions is a common feature of many neurodegenerative diseases. The spread of disease pathology is suggested to be dependent on the transmissibility of disease-associated proteins, particularly soluble aggregates of misfolded proteins. Emerging evidence suggests that many disease-associated proteins such as α-synuclein (aSyn) and tau, in certain misfolded and aggregated states convert from physiologically normal proteins into forms that lead to progression of disease pathology in a template-dependent manner, which is also known as seeding . The propagation and the proteinopathy have been suggested to occur via cell-to-cell transmission. The exact mechanisms involved in the seeding and spreading process are incompletely understood. In this thesis work, three critical steps of the seeding pathway (a process involves multiple steps), the intracellular aggregation, cellular release and uptake of aSyn and tau, were carefully studied primarily via a newly developed platform based on protein-fragment complementation assay. The main findings of this thesis are: a)Prolyl oligopeptidase (PREP) is a serine peptidase that was previously known to accelerate the process of aSyn aggregation and suppress autophagy clearance in cells and transgenic aSyn mice. The results of this thesis show that PREP directly interacts with aSyn in neuro2A cells and cell-free environment, and enhances aSyn dimerization, which is an early event in aSyn aggregation pathway. In addition, the PREP-mediated aSyn dimerization can be antagonized by KYP-2047, a small-molecule PREP inhibitor. b) Late-onset Alzheimer s disease (LOAD) susceptibility genes affect the individual risk of developing Alzheimer s disease, which is one of the common tauopathies. In this work, the functional connection between selected LOAD susceptibility genes and cell-to-cell transmission of tau was studied in vitro. We observed that RNAi knockdown of CD2AP and FRMD4A reduced tau secretion, and knockdown of APOE reduced tau uptake in HEK293T cells. Further mechanistic studies revealed that FRMD4A modulates tau secretion via the FRMD4A-cytohesin-Arf6 signalling pathway and the Par6/aPKC polarity signalling complex. This data, for the first time, demonstrates a functional connection between LOAD risk genes and cell-to-cell propagation of tau. c) Following internalization, extracellular, hyperphosphorylated tau was found to be recruited to stress granules, transient non-membraneous cytosolic structures composed of RNA and self-aggregating RNA-binding proteins. Tau recruitment was dependent on TIA-1, an RNA-binding stress granule protein. Importantly, the stress granules induced by and containing internalized tau were resistant to normal clearance and associated with increased sensitivity of cells to other stresses. This data describe a previously unrecognized mechanism and pathological consequence of cell-to-cell propagation of tau-mediated by stress granules, which have previously been associated with the pathophysiology of various neurodegenerative diseases. Overall, the work described in this thesis provides several novel findings that improve our understanding of cellular mechanisms underlying the development and spreading of aSyn and tau-related neurodegenerative pathologies. These pieces of knowledge may be potential avenues towards the development of crucial therapeutics against aSyn and tau-related neurodegenerative diseases.
  • Votsis, Athanasios (Helsingin yliopisto, 2017)
    As the adaptation of cities to climate change is increasingly overlapping sustainable urban development, the necessity to harmonize climate-proofing with economic objectives becomes ever clearer. Climate-sensitive ecological risks and amenities, and their role in markets and urban planning, are central in this issue. This research explores the reaction of urban housing markets to changes related to green amenities and flood risks; deepens the understanding of complex spatial processes, in housing markets and urban growth, that relate to the implementation of sustainable adaptation strategies; and develops advanced spatial modelling methodology that renders urban economic analysis better suitable to address questions of sustainable and climate-proof urban planning. The results demonstrate that physical or behavioral planning interventions surrounding climate-sensitive ecological risks and amenities generate economic benefits via multiple channels, when attuned with market mechanisms. This is an important building block in synchronizing climate-proofing with economic development objectives, therefore facilitating urban adaptation that is also sustainable. The synchronization requires an evidence-based understanding of the effects linked to particular interventions, at concrete locations and spatiotemporal scales. The overall message is that, while trade-offs are unavoidable, if green cities maintain agglomeration benefits, ensure increased information flows about ecological risks and amenities, while implementing amenities in a spatially parameterized manner, they are able to achieve both climate-proofing and sustainability objectives. The thesis consists of five quantitative analysis articles, while the introductory chapter synthesizes the results in the context of urban planning, spatial economics, and climate change adaptation. The first three articles apply empirical microeconometric methodologies (spatial hedonic and difference-in-differences analysis) to explore the response of housing markets to changes in green infrastructure and to policy instruments related to flood risk information. The fourth and fifth articles apply spatial complexity methods (cellular automata, fractal geometry) to extend the intuitions of microeconometric estimations into dynamic spatial processes in housing prices and urban growth. The five articles use environmental-economic datasets developed by this dissertation research, covering the urban region of Helsinki (Helsinki, Espoo, and Vantaa) and the cities of Pori and Rovaniemi.
  • Kulashekhar, Shrikanth (2017)
    Working memory is used to maintain information for cognitive operations, and its deficits are associated with several neuropsychological disorders. Human functional magnetic resonance imaging (fMRI) f isolated key brain areas associated with the maintenance of sensory and duration information. However, the systems-level mechanisms coordinating the collective neuronal activity in these brain areas have remained elusive. It has been suggested that synchronized oscillations could regulate communication in neuronal networks and could hence serve such coordination, but their role in the maintenance of sensory and duration information has remained largely unknown. In this thesis, combined magnetoencephalography (MEG) and electroencephalography (EEG) together with minimum norm estimate (MNE) based source modelling was used to study the oscillatory dynamics underlying visual and temporal working memory. In Publication I, we developed a neuro-informatics approach to understand the anatomical and dynamic structures of network synchrony supporting visual working memory (VWM). VWM was associated with a sustained and stable inter-areal phase synchrony among frontoparietal and visual areas in alpha- (10 13 Hz), beta- (18 24 Hz), and gamma- (30 40 Hz) frequency bands. In this study, the subjects' individual behavioural VWM capacity was predicted by synchrony in a network in which the intraparietal sulcus was the most central hub. In Publication II, we characterised the oscillatory amplitude dynamics associated with the VWM maintenance. Increasing VWM load was associated with strengthened oscillation amplitudes in the occipital and occipitotemporal cortical areas, in the alpha (8 14 Hz) beta- (15 30 Hz), gamma- (30-50 Hz), and high-gamma- (50 150 Hz) frequency bands. In Publication III, we addressed the functional significance of local neuronal synchronization, as indexed by the amplitudes of cortical oscillations, in the estimation and maintenance of duration information. The estimation of durations in the seconds range was associated with stronger beta-band (14 30 Hz) oscillations in cortical regions that have earlier been associated with temporal processing. The encoding of duration information was associated with strengthened gamma- (30 120 Hz), and the retrieval and comparison with alpha-band (8 14 Hz) oscillations. Further, the maintenance of stimulus duration was associated with stronger theta- and alpha-band (5 14Hz) frequencies. These data suggested that both local and large-scale phase synchrony in the alpha-, beta-, and gamma-frequency bands in the frontoparietal and visual regions could be a systems level mechanism for coordinating and regulating the maintenance of visual information in VWM. In addition, it suggested that beta-band oscillations may provide a mechanism for estimating short temporal durations, while gamma, alpha and theta-alpha oscillations support their encoding, retrieval, and maintenance in working memory, respectively.
  • Massinen, Satu (Helsingin yliopisto, 2017)
    Specific reading disorder (SRD), or developmental dyslexia, is defined as an unexpected difficulty in learning to read and write when intelligence and senses are normal. Hereditary factors are estimated to play a substantial role in the etiology of SRD, although the exact neurobiological mechanisms involved are rather poorly understood. In this thesis we have investigated the function of three SRD susceptibility candidate genes, DYX1C1, DCDC2 and ROBO1, with the aim of finding neurodevelopmental and molecular pathways that might shed light on the etiology of SRD. When research for this thesis began, knockdown of the rodent orthologs of DYX1C1 and DCDC2 had been shown to disturb radial neuronal migration in the developing cerebral cortex, but the function of human DYX1C1 and DCDC2 at the cellular level was still unclear. We discovered that both DYX1C1 and DCDC2 are involved in signalling pathways that are important in brain development; DYX1C1 is involved in estrogen signalling and DCDC2 is involved in ciliary signalling. We found that the effect of DYX1C1 on estrogen signalling was concerted through its interaction with estrogen receptors (ERs) in in the presence of the endogenous ligand, 17β-estradiol. We observed that DYX1C1 regulates the degradation of ERs, resulting in decreased transcriptional responses to 17β-estradiol. Our findings suggest that the effects of DYX1C1 on brain development may be at least partially mediated by ERs and that hormonal factors may play a role in SRD. We also observed DYX1C1 and ERα complexes in the neurites of primary rat hippocampal neurons, which suggests a role for DYX1C1 in rapid non-genomic ER signalling. The effect of DCDC2 on the ciliary signalling was such that the overexpression of DCDC2 was found to activate SHH signalling, whereas the downregulation of DCDC2 expression was found to enhance WNT signalling. We also observed that the DCDC2 protein localizes to the primary cilium in primary rat hippocampal neurons and is involved in regulating the length of the cilium through its role in stabilizing microtubules. DCDC2 was also found to interact with the ciliary kinesin-2 subunit KIF3A, a key molecule in function and maintenance of cilia. Consistent with a role in ciliary function, the overexpression of DCDC2 in C. elegans resulted in an abnormal neuronal phenotype that could only be observed in ciliated neurons. Our results were the first to suggest a role for DCDC2 in the structure and function of primary cilia. Later, others have reported more links between ciliary function and SRD candidate genes, most notably the putative role of DYX1C1 as a cytoplasmic assembly factor for ciliary dynein. ROBO1 has been discovered as a SRD susceptibility gene in a large multi-generation family, in whom a rare haplotype in the broad genomic area of ROBO1 is co-segregated with SRD. The expression of ROBO1 has been shown to be reduced from the SRD-associated haplotype, but the causal factor for the reduced expression was not known. In this thesis we have characterized genetic variation within the SRD-susceptibility haplotype by whole genome sequencing, aiming to identify variants that would increase our understanding of the altered expression of ROBO1. We found several novel variants in the SRD susceptibility haplotype and tested transcription factor binding to four of the variants by EMSA. We did not detect transcription factor binding to three of the variants. However, one of the variants was bound by the LIM homeobox 2 (LHX2) transcription factor with increased binding affinity to the non-reference allele. Knockdown of LHX2 in lymphoblast cell lines extracted from subjects of the DYX5-linked family showed decreased expression of ROBO1 supporting the idea that LHX2 regulates ROBO1. Because the regulation of ROBO1 is likely to be complex and the effect of the novel variants was at the most very subtle in our experiments, it remains unknown if any of them are causal factors for the SRD susceptibility. The mouse ortholog of ROBO1 has been shown to have many functions in brain development: it is involved in neuronal migration of interneurons and pyramidal cells and in axonal guidance of major nerve tracts. The role of ROBO1 in mouse brain led us to test two hypotheses on two human populations: 1) We tested whether ROBO1 controls midline crossing of auditory pathways in the family with reduced expression of ROBO1 and 2) we tested whether in the normal population ROBO1 is involved in the development of the corpus callosum, the major axon tract connecting the cerebral hemispheres. The axonal crossing of the auditory pathways was studied using a functional approach, based on magnetoencephalography and frequency tagging. We found impaired interaural interaction in the subjects that had reduced ROBO1 expression supporting a defect in midline crossing of auditory pathways. Moreover, the deficit in interaural interaction depended on the ROBO1 in a dose-dependent manner. Our results suggest that ROBO1 controls midline crossing of the auditory pathways and were the first evidence of a SRD susceptibility gene being linked to a specific sensory function in the human brain. The role of ROBO1 in callosal development was assessed by studying whether polymorphisms in ROBO1 correlate with variation in the white matter structure in the corpus callosum. By using data acquired by both structural magnetic resonance imaging and diffusion tensor imaging we found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections from the body of the corpus callosum to the parietal cortical regions. Our results suggest that the human ROBO1 may be involved in the regulation of the structure and connectivity of the posterior part of the corpus callosum. Overall, our results support the idea that similarly as in mice, the human ROBO1 is likely to play many different roles in brain development. In conclusion, the results of this study have advanced the field of SRD research by suggesting new functions for SRD candidate susceptibility genes in cellular and developmental pathways that are highly relevant in the context of brain development. More studies will be needed to clarify the role of genes in the etiology of SRD and in the neurobiology of reading, but our results have provided clues that may be worthwhile to be investigated.
  • Kieloaho, Antti-Jussi (Helsingin yliopisto, 2017)
    Low-molecular-weight alkyl amines are reactive organic nitrogen compounds that are im- portant precursors in secondary aerosol formation. Atmospheric aerosols have direct and indirect effects on Earth's climate system. Alkyl amines are emitted from marine and terrestrial ecosystems, agricultural activities and other anthropogenic sources. In terrestrial ecosystems, the quantities in the different parts of an ecosystem and formation processes are not well understood. Alkyl amine soil concentration and biosphere atmosphere exchange measurements are scarce. The main focus of this thesis is to determine concentrations of alkyl amines in ambient air in boreal forest and urban area, and further identify possible sources and reservoirs of alkyl amines in boreal forest. The main results presented in the thesis consist of a timeseries of gas- phase concentrations of alkyl amines measured over several months, concentrations of alkyl amines in the soil and fungal biomass, and an emission estimation based on the measured concentrations. Alkyl amines were studied in two northern latitude environments: in a boreal Scots pine (Pinus sylvestris L.) forest at the SMEAR II station in Hyytiälä and in an urban background area at the SMEAR III station in Helsinki. To quantify ambient air concentrations of alkyl amines in these environments, sample collection and analytical methods were developed. Ambient air concentrations of alkyl amines were measured from May to October 2011 in the forest site and from May to August 2011 in the urban site. The effect of the measured ambient air concentrations of alkyl amines on the local air chemistry was also assessed together with aromatic hydrocarbons and terpenoids. To assess boreal forest soil as a source of alkyl amines, a pot-scale experiment was set up. In the experiment Scots pine seedlings were grown on humus soil collected from the forest site, and the effects of Scots pine and soil organic matter (SOM) degrading enzymes on alkyl amine soil concentrations were studied. In addition, fungal strains common in boreal forest soils were cultured, and the alkyl amine concentrations in the grown fungal biomass were quanti- fied. The role of boreal forest soil as a source or as a sink of atmospheric alkyl amines was studied using a gradient-diffusion approach. In the approach, the soil atmosphere exchange of selected alkyl amines was estimated. This was done by describing dissolution/volatilisation on water and transport processes, and utilizing the quantified soil and ambient air gas-phase concentrations of the selected alkyl amines found in the studied boreal forest. The gas-phase concentrations of alkyl amines in ambient air were found to be higher in the forest site than in the urban site. In the forest site, the atmospheric concentrations appeared to be linked to soil and vegetation activity based on the seasonal course of the measured alkyl amines. Litterfall, a phenological event, coincides with the concentration maxima of some of the measured alkyl amines. In the pot-scale experiment, the SOM degrading enzymes were found to have no effect on the soil concentrations of alkyl amine while the presence of Scots pine was found to have an effect on the concentrations of some of the measured alkyl amines. The soil concentrations of alkyl amines were found to be lower than those measured from the fungal biomass. The most abundant fungal groups (ectomycorrhizal and saprotrhopic fungi) in the forest soil contained the highest quantities of alkyl amines revealing that fungal biomass may be an important reservoir of alkyl amines in boreal forest soil. Based on the flux estimate, the boreal forest soil was found to act as both a source and a sink of alkyl amines. The direction of the flux was dependent on the studied alkyl amines and environmental conditions in the forest site. Soil pH was found to be one of the most critical factors determining the direction of the flux between the soil and the atmosphere.
  • von Ossowski, Lotta (Helsingin yliopisto, 2017)
    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors are glutamate-gated cation channels and mediators of fast excitatory neurotransmission in the mammalian central nervous system. Trafficking and functional regulation of AMPA receptors GluA1-4 is carried out through numerous intracellular protein interactions and post-translational modifications. The aim of this thesis work was to study the selective interaction between AMPA receptor subunit GluA1 and synapse-associated protein 97 (SAP97), a protein scaffold belonging to the protein family of membrane associated guanylate kinase homologs. The interaction between SAP97 and GluA1 has been implicated in AMPA receptor trafficking, neuronal development and synaptic plasticity, while disturbances in normal levels of both GluA1 and SAP97 have been linked to neuropathologies such as Alzheimer s disease and schizophrenia. In the present study, a combination of biochemical and structural work was employed to gain detailed information on the selective interaction of GluA1 with SAP97 identifying molecular determinants involved in and regulating the interaction. X-ray crystallization screens of the second PDZ domain of SAP97 (SAP97PDZ2) yielded well-diffracting crystals both for the apo and ligand bound form. The solved crystal structure of the SAP97PDZ2-GluA1 peptide complex conformed to a conventional class I PDZ interaction with hydrogen bonds forming between the carboxylate group of the ultimate C-terminal residue of the peptide and main chain nitrogens in the carboxylate binding loop of the PDZ domain, and a hydrogen bond between the antepenultimate residue of the peptide and a conserved histidine in the αB helix lining the peptide binding groove. Beside these typical PDZ interactions, as a novel finding we observed contacts within the PDZ domain reorganizing upon peptide binding leading to a slight opening of the peptide binding groove facilitating better accommodation of the ligand. In vitro binding analysis of isolated PDZ domains and short GluA1 peptides showed that, in addition to the prototypic PDZ interaction, a C-terminal cysteine, C893 located upstream from the short PDZ binding motif on GluA1 participated in the interaction through a disulfide bond formed with cysteine C378 of SAP97 under in vitro conditions. Streptavidin pull-down experiments with full-length molecules expressed in cultured cells showed that the C893S mutation leads to a substantial reduction in binding of GluA1 to SAP97, confirming the involvement of C893 in the regulation of the interaction in live cells. Reactive cysteines, like C893, can in addition to disulfide bonds participate in other thiol modifications. In our work we constructed several deletion and cysteine replacement mutants of GluA1 and tested their sensitivity to S-nitrosylating agents nitrosoglutathione and nitrosocysteine. Out of the three C-terminal cysteine residues in GluA1, we identified C893 as the sole cysteine residue sensitive to a post-translational modification by nitric oxide (NO). Furthermore, we found evidence of a physical link between GluA1 and the NO generating neuronal enzyme nitric oxide synthase nNOS via SAP97. The results of the present study provide, for the first time, detailed structural information on the interaction between GluA1 AMPA receptor and SAP97. In addition to a canonical PDZ interaction, the association with SAP97 involves a reactive cysteine residue, C893, in GluA1 C-terminal tail, a potential regulatory target for nitric oxide and oxidative conditions.
  • Kaila, Eero (Faculty of Social Sciences, 2017)
    This dissertation is aimed at clarifying the concept of moral responsibility within Anglophone, analytic ethics broadly defined, as well as looking at the concept of character to inquire about its role embedded within these theories. In this work, it is claimed that considerations of character matter when moral responsibility is assessed. Two families of theories of moral responsibility are compared with each other starting with Peter F. Strawson s'sentimentalist theory, originated in his influential article Freedom and Resentment (Strawson, 1962) and followed by work of others including R. Jay Wallace (1994). Scholarship on Aristotle's theory provides the basis for a similar framework of responsibility for action (NE III.1). Other aspects of Aristotle's work provide additional depth to his concept of moral responsibility however. Character differs greatly in emphasis in Aristotle's theory from that of Strawson. It is claimed here that character is an essential part of human agency, and is thus a defining factor for actions taken. It is also claimed since that character is not a precise concept, taking it fully into account presents a formidable challenge to all theories attempting to explain responsibility exhaustively. In Strawson's case, the further claim is made that what is traditionally discussed in terms of character is rephrased in terms of pleas and special conditions, which amount together into excuses instead. One common concept that both of these doctrines utilize is blame. Blame (usually accompanied with praise) is identified as a crucial component of responsibility by a majority of thinkers writing on the subject, and this reasoning is followed here as well. An aporetic conclusion supporting critical sources is reached in terms of a common understanding of moral responsibility in Part I. The Aristotelian notion of character and the Strawsonian notion of excuse will be re-visited as examples of blame mitigation within the context of these theories in the systematic section of Part II. Analysis is conducted based on Bernard Williams's (1993 and 1997) explication of elements of responsibility, where a comparison is done between character and excuses appearing in the two families of theories of responsibility. Based on the findings it is concluded that the two theoretical families share similarity of structure regardless of the difference in their age, in a way that no matter whether character or excuses are used to describe the alteration of initial judgment, in terms of the end results blame mitigation appears to happen identically in all cases. Examination of character in the context of philosophy of responsibility shows that there is room for expansion in the narrower attempts to define the concept. Comparisons of both of these theoretical alternatives are illustrated with examples and further discussion is called for.
  • Reuter, Lauri (Helsingin yliopisto, 2016)
    Recombinant proteins are used as pharmaceuticals, enzymes and components of nanotechnology. The exceptional properties of fungal hydrophobins make them interesting for many of those uses. They also transfer some of their functionalities to fusion proteins enabling completely new applications. In general, plants are a potential platform for manufacturing recombinant proteins even in agricultural scale. This work explores production of hydrophobin fusion proteins in a plant cell factory: the tobacco bright yellow 2 cells (BY-2). The hydrophobin fusion technology has been mainly based on a single hydrophobin molecule the Trichoderma reesei HFBI. This work expanded the toolkit with several new molecules. When expressed in plants the hydrophobin fusion partners induced formation of protein bodies, in relation to the accumulation levels. In addition to HFBI, only HFBII and HFBIV interacted with non-ionic surfactant to selectively separate fusion proteins in surfactant based two phase separation. In Nicotiana benthamiana HFBII improved accumulation of green fluorescent protein (GFP) and Protein A in comparison to both HFBI-fused and non-fused proteins. However, HFBI, HFBII and HFBIV fusion partners all slightly reduced the yield of transferrin. Both HFBI-Protein A and transferrin-HFBIV were produced in BY-2 suspension cells with good yields. Furthermore, continuous selection resulted also in a cell line yielding 1.1 g/l GFP-HFBI. This is the first report on a plant cell culture reaching gram per litre yields. The BY-2 propagation was successfully scaled-up to 600 litre culture volume in classical stirred tank bioreactors. The aqueous two phase separation from plant cell extract was successfully scaled to 20 l volume. The fusion proteins retained functional properties from both fusion partners. The HFBI-Protein A enabled harvesting of antibodies in solution using aqueous two phase separation. The HFBIV fused transferring retained its capability to bind iron and interact with the transferrin receptor. Coating with transferrin-HFBIV resulted in uptake of the silicon nanoparticles in human cancer cells. This work builds foundation for utilization of BY-2 suspension cells in industrial manufacturing of recombinant proteins and on the other hand opens interesting new applications for bi-functional hydrophobin fusion proteins.
  • Puonti, Helena (Helsingin yliopisto, 2017)
    A beautiful, naturally-shaped and symmetrical breast mound will be created for a breast cancer patient after mastectomy using a free abdominal flap. The disadvantage with the breast reconstructed with this method is its lack of sensation, even some spontaneous reinnervation takes place from the surrounding tissues. The objective of the present study was to find and develope a method of dissecting and reconnecting nerves of the abdominal flap and the chest area in order to reconstruct a breast with sensation for the breast cancer patient. The first aim was to find out, which nerves in the chest and the flap, when coapted, would provide the best sensation to the reconstructed breast. The second aim was to investigate whether the dissecting of the nerves causes additional complications in the abdominal flap donor site. The third aim was to develop a better neurorrhaphy technique, using two nerve pedicles. The fourth aim was to assess and qualify the methods of sensory assessment employed in the study. Breast reconstruction with a free muscle-sparing transverse rectus abdominis myocutaneous flap (ms-TRAM flap) was performed in this study for 96 breast cancer patients in Savonlinna Central Hospital between 2001 and 2013. The reinnervation of the flap was performed in 44 patients with the novel dual neurorrhaphy technique and in 32 with single neurorrhaphy, and 20 breast reconstruction patients without flap reinnervation functioned as a control group. The contralateral healthy breasts of 38 breast reconstruction patients were used as the reference site, and 20 healthy volunteer women participated sensory testing of healthy abdominal skin. Skin sensation of the reconstructed breast was assessed two years after the surgery. In addition, between 2006 and 2013, sensory testing of the skin of the mastectomized breast was performed prospectively before the reconstruction surgery, and the healthy breast, abdominal skin and the reconstructed breast skin were also tested one year after the surgery. Sensory tests included clinical sensory examinations, quantitative sensory tests (QST), skin samples, and neurophysiological somatosensory evoked potentials (SEP). Additionally, a patient questionnaire of patients subjective sensory changes was carried out. Both neurorrhaphy techniques provided the reconstructed breast with better skin sensation than without neurorrhaphy, and dual neurorrhaphy resulted in better sensory recovery than innervation with single neurorrhaphy. All available tactile nerves in the chest area proved to be capable of restoring sensation to the ms-TRAM flap breast. No significant complications occurred in the abdominal wall in the flap donor site with either of the neurorrhaphy techniques. Nerve coaptations did not cause pain symptoms, and the increase in the operative time was insignificant. The function of large myelinated sensory fibres (i.e. vibration and tactile detection) recovered best. The poorest recovery took place in small unmyelinated sensory fibres (i.e. thermal detection and sharp-blunt discrimination). As a result of breast cancer treatment, tactile and thermal sensitivity of the mastectomized skin was reduced already before breast reconstruction surgery. All methods of sensory assessment employed in the study could detect the nerve damage caused by the surgery and measure nerve regeneration, with the exception of epithelial nerve fibre density (ENFD) testing, which could not identify nerve regeneration in the comparison of innervated and non-innervated breast reconstructions. Additionally objective SEP proved to be quite an insensitive method in diagnosing nerve damage, they might be suitable for follow-up of its recovery. QST and the clinical sharp-blunt discrimination test were the most sensitive tests both for the identification of sensory damage and nerve regeneration. Based on this study, we recommend dual neurorrhaphy of the ms-TRAM flap in breast reconstruction for use in clinical practice.
  • Obstbaum-Federley, Yaira (Helsingin yliopisto, 2017)
    Kriminologian ja oikeuspolitiikan instituutin Tutkimuksia
    This doctoral dissertation study analyzed changes in the division of labor between the main societal institutions that handle substance-abuse-related harm, the changes in substance-abuse problems among prisoners that occurred between 1985 and 2006, as well as current prison practices in the assessment and treatment of these problems. The study materials included registers from the social and health authorities, the police and the prisons, along with nationally representative medical studies - Finnish Prisoner Health investigations conducted in 1985, 1992 and 2006. The study shows that substance-abuse-related harm handled within institutions increasingly became a matter for the prison rather than the social-welfare institutions between 1985 and 2006. The number of prisoners with substance-abuse problems in Finnish prisons grew substantially between 1985 and 2006. Addiction to both alcohol and drugs increased. Drug dependence increased to a higher degree and drugs have heavily supplemented alcohol among prisoners. Substance abuse is currently seen as a risk factor that should be tackled in prison in order to reduce reoffending. The study further investigated the degree to which substance-abuse problems are recognized in prisons, comparing the prisoner s sentence plans and risk and need assessments to the independent prisoner health study of 2006. Furthermore the study analyzed interventions given to prisoners whose sentence plans or risk and needs assessments recognized problems related to intoxicant abuse, focusing on prisoners released in 2011 (N=3798). The study shows that longer sentences allow more thorough recognition of problems and leave time for interventions, whereas short sentences seem to warrant both less thorough recognition of problems and fewer interventions. This is a cause for concern given the prominent link between substance abuse and repeat offending among prisoners who receive short sentences. The study suggest that efforts should be made to notice misuse problems in prison and to provide support during the re-entry phase via the providers of social and other services if there is not time during the sentence.
  • Vaara, Satu (Helsingin yliopisto, 2017)
    Coronary artery disease (CAD), acute coronary syndromes (ACS), and other conditions related to atherosclerosis are leading causes of death in developed countries. The incidence of CAD cannot be explained only by clinical risk factors, such as hypertension, dyslipidemia, diabetes and smoking; the genetics also matters. Major findings concerning the genetics of CAD have emerged during the last decade with many CAD-related risk variants found. This study evaluated the characteristics of the Corogene cohort of Finnish consecutive patients who underwent coronary angiography between 2006 and 2008. Furthermore, it evaluated the importance of clinical risk factors and genetic risk scores (GRS) formed of known CAD risk variants in predicting the ACS prognosis and sought for genetic differences between patients with non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). The most common reason for coronary angiography in the Corogene Study during the study period was ACS. About half of all patients were finally revascularized either by percutaneous coronary intervention or coronary artery by-pass grafting. One-fourth of the patients had no signs of obstructive CAD in coronary angiography. GRS formed of 47 confirmed risk variants was found to be associated with recurrent ACS independent of clinical factors. Smoking and STEMI had an inverse association with the GRS. When compared to other studies evaluating GRS in recurrent ACS prediction, the GRS with 47 confirmed CAD variants included the greatest number of risk variants. As it did not improve the accuracy of prediction by clinical factors, the GRS has thus not yet proven useful in clinical practice. Smoking, having an inverse association with the GRS, may outweigh the genetic predisposition to CAD. Both clinical and genetic differences between STEMI and NSTEMI patients were studied and genome-wide association analysis revealed variants, including rs656843, at a locus near 1p13.3, to be associated nominally with NSTEMI. This finding could be replicated in another case-control sample of MI patients, but not in a prospective sample of FINRISK participants. The inverse correlation of the GRSs with STEMI, the finding of a genetic variant linked nominally to NSTEMI, and the fact that patients with NSTEMI and STEMI present with different clinical risk-factor profiles suggest that these two ACS subtypes may have somewhat different etiologies. The genetic variant conferring the risk for NSTEMI (rs656843) was also associated with peripheral artery disease (PAD) in ACS patients, but not in a general population sample of FINRISK individuals. The heterogeneity in PAD phenotypes and genetics may explain why the association could not be shown in a general population sample but only in a selected cohort of ACS patients.
  • Paldánius, Päivi Maria (Helsingin yliopisto, 2017)
    Serum osteocalcin (OC) is an osteoblast-derived protein and an established biomarker of bone turnover and formation. Previous studies have focused on its role as a predictor of fractures and only recently, OC has been recognized as an endocrine factor potentially regulating glucose tolerance and energy metabolism. Uncarboxylated OC has been shown to induce expression of adiponectin, insulin, and markers of pancreatic islet cell proliferation in mice while only few studies have evaluated these interactions in humans. The association of OC and glucose homeostasis has been retrospectively explored, in multiple post hoc analyses and in cohorts impacted by multiple confounding factors including chronic metabolic conditions, cardiovascular (CV) co-morbidities, and diabetes. None of the studies have addressed the alleged association in apparently healthy young adults or those with early signs of insulin resistance but no diabetes. In addition, the timing, duration and magnitude of serum OC response to glucose loads in any population remain unknown. Adult subjects born with very low birth weight (VLBW) present with significant, simultaneous impairments in skeletal health such as lower bone mineral density (BMD), and progressively worsening glucose tolerance in early adulthood. This provides an opportunity to further explore the recently suggested bidirectional regulative pathway between glucose and bone metabolism. The thesis studies evaluated whether early signs of insulin resistance and impaired glucose tolerance in early adulthood in an apparently healthy VLBW cohort, in obese young adults without diabetes, or their controls, could demonstrate if and how the changes in bone and glucose metabolism are associated and whether these changes are reflected in serum OC concentrations and its degree of carboxylation. Furthermore, normal paediatric reference ranges and their independent determinants for serum total, carboxylated and urinary OC were to be established. No association between parameters of glucose homeostasis and OC were established at any time-point. Energy metabolism evidently influences the key parameters of bone turnover but the direct role of insulin as the mediator of these changes needs further investigations. Contradictory to the preclinical rodent data, serum OC appears to be associated with long-term glucose regulation, if any, whereas acute changes during OGTT may be mediated via other mechanisms. Age, height and weight, and parathyroid hormone (PTH) and puberty, are independent determinants of serum and urinary OC levels during childhood and adolescence. Circulating OC reflects more pubertal growth status than instant grade of bone mineralisation and thus its validity, similar to other bone turnover markers, as a determinant of bone status in healthy individuals is limited. With greater discrimination of the different forms of osteocalcin present in circulation and inclusion of multiple measures of bone turnover and glucose homeostasis, evidence currently does not support OC as a protein critical to the regulation of energy metabolism. OC is still a prodigious marker of bone turnover and for monitoring of the effect treatments targeting impaired bone metabolism, especially in adults.
  • Uotila, Karri (Helsingin yliopisto, 2017)
    The purpose of the work done for this thesis was to construct and develop the concept of cost-efficient Juvenile Stand Management (JSM) for planted Norway spruce (Picea abies L. Karst) stands. The principles of time based management were followed, by integrating regeneration activities as a cost-efficient value chain and by minimizing non-value-adding work with straightforward decision making based on Forest Management Plan (FMP) data. The effects of soil preparation and Early Cleaning (EC) on further development of the stands were studied in intensive field experiments. Extensive survey data from juvenile stands were used to develop methods applicable for efficient decision making in JSM. The survey data were used to model the effects of site and stand attributes on the need for EC and labor time consumption of PreCommercial Thinning (PCT). Timing of JSM had major effect on its costs; a delay in PCT increased the labor time needed to manage a stand by 8.3% annually. Moreover, 61 70% of the saplings in a typical Norway spruce stand were considered to need EC years before the need for PCT arose. EC was also found to be an effective release treatment as it subsequently increased the diameter growth of crop trees by 21 32%. However, a two-stage management regimen, which included EC and PCT, appeared to be somewhat more labor consuming than the PCT only option. The soil preparation method had a major effect on the number of trees to be removed in EC, and spot mounding led to a less labor consuming JSM program than disc trenching. Thus, spot mounding appeared to be a less costly activity overall even though it initially appeared a more expensive method than disc trenching. The results showed that interactions in regeneration chain activities are important for cost-effective wood production. Furthermore, a priori information can have practical implications in decision making for JSM. Several site or stand attributes were found to explain the need for EC or for labor consumption of PCT. However, the models developed in this study are rather inaccurate for reliable a priori estimation. The modeling data in further research should go beyond the data of traditional FMP. Big data offers promising opportunities, but data collection and storage need to include data with the relevant attributes.