Genetic variation in the LDL receptor-related protein 5 (LRP5) gene : Association with bone health and metabolic parameters

Bone mass accrual and maintenance are regulated by a complex interplay between genetic and environmental factors. Recent studies have revealed an important role for the low-density lipoprotein receptor-related protein 5 (LRP5) in this process. The aim of this thesis study was to identify novel variants in the LRP5 gene and to further elucidate the association of LRP5 and its variants with various bone health related clinical characteristics. The results of our studies show that loss-of-function mutations in LRP5 cause severe osteoporosis not only in homozygous subjects but also in the carriers of these mutations, who have significantly reduced bone mineral density (BMD) and increased susceptibility to fractures. In addition, we demonstrated for the first time that a common polymorphic LRP5 variant (p.A1330V) was associated with reduced peak bone mass, an important determinant of BMD and osteoporosis in later life. The results from these two studies are concordant with results seen in other studies on LRP5 mutations and in association studies linking genetic variation in LRP5 with BMD and osteoporosis. Several rare LRP5 variants were identified in children with recurrent fractures. Sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses revealed no disease-causing mutations or whole-exon deletions. Our findings from clinical assessments and family-based genotype-phenotype studies suggested that the rare LRP5 variants identified are not the definite cause of fractures in these children. Clinical assessments of our study subjects with LPR5 mutations revealed an unexpectedly high prevalence of impaired glucose tolerance and dyslipidaemia. Moreover, in subsequent studies we discovered that common polymorphic LRP5 variants are associated with unfavorable metabolic characteristics. Changes in lipid profile were already apparent in pre-pubertal children. These results, together with the findings from other studies, suggest an important role for LRP5 also in glucose and lipid metabolism. Our results underscore the important role of LRP5 not only in bone mass accrual and maintenance of skeletal health but also in glucose and lipid metabolism. The role of LRP5 in bone metabolism has long been studied, but further studies with larger study cohorts are still needed to evaluate the specific role of LRP5 variants as metabolic risk factors.

Technology-related peso problems in stock returns

Although empirical evidence suggests the contrary, many asset pricing models assume stock returns to be symmetrically distributed. In this paper it is argued that the occurrence of negative jumps in a firm's future earnings and, consequently, in its stock price, is positively related to the level of network externalities in the firm's product market. If the ex post frequency of these negative jumps in a sample does not equal the ex ante assessed probability of occurrence, the sample is subject to a peso problem. The hypothesis is tested for by regressing the skewness coefficient of a firm’s realised stock return distribution on the firm’s R&D intensity, i.e. the ratio of the firm’s research and development expenditure to its net sales. The empirical results support the technology-related peso problem hypothesis. In samples subject to such a peso problem, the returns are biased up and the variance is biased down.

Assessment of In-House Natural Product and Synthetic Compound Libraries Based on In vitro Inhibition of Cholinesterases

The first line medication for mild to moderate Alzheimer s disease (AD) is based on cholinesterase inhibitors which prolong the effect of the neurotransmitter acetylcholine in cholinergic nerve synapses which relieves the symptoms of the disease. Implications of cholinesterases involvement in disease modifying processes has increased interest in this research area. The drug discovery and development process is a long and expensive process that takes on average 13.5 years and costs approximately 0.9 billion US dollars. Drug attritions in the clinical phases are common due to several reasons, e.g., poor bioavailability of compounds leading to low efficacy or toxic effects. Thus, improvements in the early drug discovery process are needed to create highly potent non-toxic compounds with predicted drug-like properties. Nature has been a good source for the discovery of new medicines accounting for around half of the new drugs approved to market during the last three decades. These compounds are direct isolates from the nature, their synthetic derivatives or natural mimics. Synthetic chemistry is an alternative way to produce compounds for drug discovery purposes. Both sources have pros and cons. The screening of new bioactive compounds in vitro is based on assaying compound libraries against targets. Assay set-up has to be adapted and validated for each screen to produce high quality data. Depending on the size of the library, miniaturization and automation are often requirements to reduce solvent and compound amounts and fasten the process. In this contribution, natural extract, natural pure compound and synthetic compound libraries were assessed as sources for new bioactive compounds. The libraries were screened primarily for acetylcholinesterase inhibitory effect and secondarily for butyrylcholinesterase inhibitory effect. To be able to screen the libraries, two assays were evaluated as screening tools and adapted to be compatible with special features of each library. The assays were validated to create high quality data. Cholinesterase inhibitors with various potencies and selectivity were found in natural product and synthetic compound libraries which indicates that the two sources complement each other. It is acknowledged that natural compounds differ structurally from compounds in synthetic compound libraries which further support the view of complementation especially if a high diversity of structures is the criterion for selection of compounds in a library.

'... the walls fell down but the blokes just coded ...' - Varieties of stability in software product development during organizational restructurings

Many Finnish IT companies have gone through numerous organizational changes over the past decades. This book draws attention to how stability may be central to software product development experts and IT workers more generally, who continuously have to cope with such change in their workplaces. It does so by analyzing and theorizing change and stability as intertwined and co-existent, thus throwing light on how it is possible that, for example, even if ‘the walls fall down the blokes just code’ and maintain a sense of stability in their daily work. Rather than reproducing the picture of software product development as exciting cutting edge activities and organizational change as dramatic episodes, the study takes the reader beyond the myths surrounding these phenomena to the mundane practices, routines and organizings in product development during organizational change. An analysis of these ordinary practices offers insights into how software product development experts actively engage in constructing stability during organizational change through a variety of practices, including solidarity, homosociality, close relations to products, instrumental or functional views on products, preoccupations with certain tasks and humble obedience. Consequently, the study shows that it may be more appropriate to talk about varieties of stability, characterized by a multitude of practices of stabilizing rather than states of stagnation. Looking at different practices of stability in depth shows the creation of software as an arena for micro-politics, power relations and increasing pressures for order and formalization. The thesis gives particular attention to power relations and processes of positioning following organizational change: how social actors come to understand themselves in the context of ongoing organizational change, how they comply with and/or contest dominant meanings, how they identify and dis-identify with formalization, and how power relations often are reproduced despite dis-identification. Related to processes of positioning, the reader is also given a glimpse into what being at work in a male-dominated and relatively homogeneous work environment looks like. It shows how the strong presence of men or “blokes” of a particular age and education seems to become invisible in workplace talk that appears ‘non-conscious’ of gender.

Plant communities of field margins : the effects of management and environmental factors on species composition and diversity

Agri-environmental schemes have so far resulted in only minor positive implications for the biodiversity of agricultural environments, in contrast to what has been expected. Land-use intensification has decreased landscape heterogeneity and the amount of semi-natural habitats. Field margins are uncultivated areas of permanent vegetation located adjacent to fields. Since the number of these habitats is high, investing in their quality may result in more diverse agricultural landscapes. Field margins can be considered as multifunctional habitats providing agronomic, environmental and wildlife services. This thesis aimed at examining the plant communities of different types of field margin habitats and the factors affecting their species diversity and composition. The importance of edaphic, spatial and management factors was studied on regional, landscape and habitat scales. Vegetation surveys were conducted on regional and landscape scales and a field experiment on cutting management was conducted on a habitat scale. In field margin plant communities, species appeared to be indicators of high or intermediate soil fertility and moist soil conditions. The plant species diversity found was rather low, compared with most species-rich agricultural habitats in Finland, such as dry meadows. Among regions, land-use history, main production line, natural species and human induced distribution, climate and edaphic factors were elements inducing differences in species composition. The lowest regional species diversity of field margins was related to intensive and long-term cereal production. Management by cutting and removal or grazing had a positive effect on plant species diversity. The positive effect of cutting and removal on species richness was also dependent on the adjacent source of colonizing species. Therefore, in species-poor habitats and landscapes, establishment of margins with diverse seed mixtures can be recommended for enhancing the development of species richness. However, seed mixtures should include only native species preferably local origin. Management by cutting once a year for 5 years did not result in a decline in dominance of a harmful weed species, Elymus repens, showing that E. repens probably needs cutting more frequently than once per year. Agri-environmental schemes should include long-term contracts with farmers for the establishment, and management by cutting and removal or grazing, of field margins that are several metres wide. In such schemes, the timing and frequency of management should be planned so as not to harm other taxa, such as the insects and birds that are dependent on these habitats. All accidental herbicide drifts to field margins should be avoided when spraying the cultivated area to minimize the negative effects of sprayings on vegetation. The harmful effects of herbicides can be avoided by organic farming methods.

Psychologically-Based and Content-Oriented Experience in Entertainment Virtual Environments

In daily life, rich experiences evolve in every environmental and social interaction. Because experience has a strong impact on how people behave, scholars in different fields are interested in understanding what constitutes an experience. Yet even if interest in conscious experience is on the increase, there is no consensus on how such experience should be studied. Whatever approach is taken, the subjective and psychologically multidimensional nature of experience should be respected. This study endeavours to understand and evaluate conscious experiences. First I intro-duce a theoretical approach to psychologically-based and content-oriented experience. In the experiential cycle presented here, classical psychology and orienting-environmental content are connected. This generic approach is applicable to any human-environment interaction. Here I apply the approach to entertainment virtual environments (VEs) such as digital games and develop a framework with the potential for studying experiences in VEs. The development of the methodological framework included subjective and objective data from experiences in the Cave Automatic Virtual Environment (CAVE) and with numerous digital games (N=2,414). The final framework consisted of fifteen factor-analytically formed subcomponents of the sense of presence, involvement and flow. Together, these show the multidimensional experiential profile of VEs. The results present general experiential laws of VEs and show that the interface of a VE is related to (physical) presence, which psychologically means attention, perception and the cognitively evaluated realness and spatiality of the VE. The narrative of the VE elicits (social) presence and involvement and affects emotional outcomes. Psychologically, these outcomes are related to social cognition, motivation and emotion. The mechanics of a VE affect the cognitive evaluations and emotional outcomes related to flow. In addition, at the very least, user background, prior experience and use context affect the experiential variation. VEs are part of many peoples lives and many different outcomes are related to them, such as enjoyment, learning and addiction, depending on who is making the evalua-tion. This makes VEs societally important and psychologically fruitful to study. The approach and framework presented here contribute to our understanding of experiences in general and VEs in particular. The research can provide VE developers with a state-of-the art method (www.eveqgp.fi) that can be utilized whenever new product and service concepts are designed, prototyped and tested.

CSR in forest industry – Case study of reporting and implementation of social responsibility in three international companies

Corporate Social Responsibility (CSR) has become increasingly important topic in forest industries, and other global companies, in recent years. Globalisation, faster information delivery and demand for sustainable development have set new challenges for global companies in their business operations. Also the importance of stakeholder relations, and pressure to become more transparent has increased in the forest industries. Three dimensions of corporate responsibility economic, environmental and social, are often included in the concept of CSR. Global companies mostly claim that these dimensions are equally important. This study analyses CSR in forest industry and has focus on reporting and implementation of social responsibility in three international companies. These case-companies are Stora Enso, SCA and Sappi, and they have different geographical base, product portfolios and therefore present interesting differences about forest industry strategy and CSR. Global Reporting Initiative (GRI) has created the most known and used reporting framework in CSR reporting. GRI Guidelines have made CSR reporting a uniform function, which can also be measured between companies and different sectors. GRI Guidelines have also made it possible to record and control CSR data in the companies. In recent years the use of GRI Guidelines has increased substantially. Typically CSR reporting on economic and environmental responsibility have been systematic in the global companies and often driven by legistlation and other regulations. However the social responsibility has been less regulated and more difficult to compare. Therefore it has previously been often less focused in the CSR reporting of the global companies. The implementation and use of GRI Guidelines have also increased dialogue on social responsibility issues and stakeholder management in global companies. This study analyses the use of GRI´s framework in the forest industry companies´ CSR reporting. This is a qualitative study and the disclosure of data is empricially analysed using content analysis. Content analysis has been selected as a method for this study because it makes it possible to use different sources of information. The data of this study consists of existing academic literature of CSR, sustainability reports of thecase-companies during 2005-2009, and the semi-structured interviews with company representatives. Different sources provide the possibility to look at specific subject from more than one viewpoint. The results of the study show that all case-companies have relatively common themes in their CSR disclosure, and the differences rise mainly from their product-portfolios, and geographic base. Social impacts to local communities, in the CSR of the companies, were mainly dominated by issues concerning creating wealth to the society and impacting communities through creation of work. The comparability of the CSR reporting, and especially social indicators increased significally from 2007 onwards in all case-companies. Even though the companies claim that three dimensions of CSR economic, environmental and social are equally important economic issues and profit improvement still seem to drive most of the operations in the global companies. Many issues that are covered by laws and regulations are still essentially presented as social responsibility in CSR. However often the unwelcome issues in companies like closing operations are covered just briefly, and without adequate explanation. To make social responsibility equally important in the CSR it would demand more emphasis from all the case-companies. A lot of emphasis should be put especially on the detail and extensiveness of the social reponsibility content in the CSR.

Investigations of Noise-Related Tinnitus

Tinnitus is a frequent consequence of noise trauma. Usually, however, the main focus regarding the consequences of noise trauma is placed on hearing loss, instead of tinnitus. The objectives of the present study were to assess various aspects of noise-related tinnitus in Finland, such as to determine the main causes of conscript acute acoustic traumas (AAT) in the military, assess tinnitus prevalence after noise trauma, characterize long-term AAT-related tinnitus prevalence and characteristics, assess occupational tinnitus, and evaluate the efficacy of hearing protection regulations in preventing hearing loss and tinnitus. The study comprised several independent noise-exposed groups: conscripts performing their military duty, former conscripts who suffered an AAT over a decade earlier, bomb explosion victims, and retired army personnel. Tinnitus questionnaires were used to assess tinnitus prevalence and characteristics. For occupational tinnitus, occupational noise-induced hearing loss (NIHL) reports to the Finnish Institute of Occupational Health were reviewed. Tinnitus is a common result of AAT, blast exposure and long-term noise exposure. Despite hearing protection regulations, up to hundreds of AATs occur annually among conscripts in the Finnish Defence Forces (FDF). The most common cause is an accidental shot, accounting for approximately half of the cases. Conscript AATs are mainly due to accidental shots, while the ear is unprotected. Only seldom is an AAT due to negligence. The most common causative weapon of conscript AATs is the assault rifle, accounting for 81% of conscript AATs. After AAT, the majority of tinnitus cases resolve during military service and become asymptomatic. However, in one-fifth of the cases, tinnitus persists, causing problems such as sleeping and concentration difficulties in many. In Finland, occupational tinnitus often remains unreported in conjunction with NIHL reports. In a survey of occupational NIHL cases, tinnitus was mentioned in only four per cent. However, a subsequent inquiry revealed that almost 90% in fact had tinnitus, indicating that most cases remained undetected and unreported. The best way to prevent noise-related tinnitus is prevention of noise trauma. In the military, hearing protection guidelines have been revised several times over the years. These regulations have been effective in reducing hearing loss of professional soldiers. There has also been a reduction in cases with tinnitus, but the decrease was not significant. However, with improved hearing protection regulations, a significant reduction in the risk of more serious, disturbing tinnitus was observed.

Hostility: A prospective study of the genetic and environmental background and associations with cardiovascular risk

Hostility is a multidimensional construct having wide effects on society. In its different forms, hostility is related to a large array of social and health problems, such as criminality, substance abuse, depression, and cardiovascular risks. Identifying and tackling early-life factors that contribute to hostility may have public health significance. Although the variance in hostility is estimated to be 18-50 percent heritable, there are significant gaps in knowledge regarding the molecular genetics of hostility. It is known that a cold and unsupportive home atmosphere in childhood predicts a child s later hostility. However, the long-term effects of care-giving quality on hostility in adulthood and the role of genes in this association are unclear. The present dissertation is part of the ongoing population-based prospective Young Finns study, which commenced in 1980 with 3596 3-18-year-old boys and girls who were followed for 27 years. The specific aims of the dissertation were first to study the antecedents of hostility by looking at 1) the genetic background, 2) the early environmental predictors, and 3) the gene environment interplay behind hostility. As a second aim, the thesis endeavored to examine 4) the association between hostility and cardiovascular risks, and 5) the moderating effect of demographic factors, such as gender and socioeconomic status, on this association. The study found potential gene polymorphisms from chromosomes 7, 14, 17, and 22 suggestively associated with hostility. Of early environmental influences, breastfeeding and early care-giving were found to predict hostility in adulthood. In addition, a serotonin receptor 2A polymorphism rs6313 moderated the effect of early care-giving on later hostile attitudes. Furthermore, hostility was shown to predict cardiovascular risks, such as metabolic syndrome and inflammation. Finally, parental socioeconomic status was found to moderate the association between anger and early atherosclerosis. The new genetic and early environmental antecedents of hostility identified in this research may help in understanding the development of hostility and its health risks, and in planning appropriate prevention. The significance of early influences on this development is stressed. Although the markers studied are individual- and family-related factors, these may be influenced at the societal level by giving accurate information to all individuals concerned and by improving the societal circumstances.

A proteomic view of probiotic Lactobacillus rhamnosus GG

Lactobacillus rhamnosus GG is a probiotic bacterium that is known worldwide. Since its discovery in 1985, the health effects and biology of this health-promoting strain have been researched at an increasing rate. However, knowledge of the molecular biology responsible for these health effects is limited, even though research in this area has continued to grow since the publication of the whole genome sequence of L. rhamnosus GG in 2009. In this thesis, the molecular biology of L. rhamnosus GG was explored by mapping the changes in protein levels in response to diverse stress factors and environmental conditions. The proteomics data were supplemented with transcriptome level mapping of gene expression. The harsh conditions of the gastro-intestinal tract, which involve acidic conditions and detergent-like bile acids, are a notable challenge to the survival of probiotic bacteria. To simulate these conditions, L. rhamnosus GG was exposed to a sudden bile stress, and several stress response mechanisms were revealed, among others various changes in the cell envelope properties. L. rhamnosus GG also responded in various ways to mild acid stress, which probiotic bacteria may face in dairy fermentations and product formulations. The acid stress response of L. rhamnosus GG included changes in central metabolism and specific responses related to the control of intracellular pH. Altogether, L. rhamnosus GG was shown to possess a large repertoire of mechanisms for responding to stress conditions, which is a beneficial character of a probiotic organism. Adaptation to different growth conditions was studied by comparing the proteome level responses of L. rhamnosus GG to divergent growth media and to different phases of growth. Comparing different growth phases revealed that the metabolism of L. rhamnosus GG is modified markedly during shift from the exponential to the stationary phase of growth. These changes were seen both at proteome and transcriptome levels and in various different cellular functions. When the growth of L. rhamnosus GG in a rich laboratory medium and in an industrial whey-based medium was compared, various differences in metabolism and in factors affecting the cell surface properties could be seen. These results led us to recommend that the industrial-type media should be used in laboratory studies of L. rhamnosus GG and other probiotic bacteria to achieve a similar physiological state for the bacteria as that found in industrial products, which would thus yield more relevant information about the bacteria. In addition, an interesting phenomenon of protein phosphorylation was observed in L. rhamnosus GG. Phosphorylation of several proteins of L. rhamnosus GG was detected, and there were hints that the degree of phosphorylation may be dependent on the growth pH.

Accessibility as a determinant of opportunities : A case study from Peruvian Amazonia

Accessibility is a crucial factor for interaction between areas in economic, cultural, political and environmental terms. Therefore, information concerning accessibility is relevant for informed decision making, planning and research. The Loreto region in the Peruvian Amazonia provides an interesting scene for an accessibility study. Loreto is sparsely populated and because there are few roads in the region, in practice all movement and transportation happens along the river network. Due to the proximity of the Andes, river dynamics are strong and annual changes in water level combined with these dynamic processes constantly reshape accessibility patterns of the region. Selling non-timber forest products (NTFP) and agricultural products (AP) in regional centres is an important income source for local rain forest dwellers. Thus, accessibility to the centres is crucial for the livelihood of local population. -- In this thesis I studied how accessible the regional centre Iquitos is from other parts of Loreto. In addition, I studied the regional NTFP/AP trade patterns and compared them with patterns of accessibility. Based on GPS-measurements, using GIS, I created a time-distance surface covering Loreto. This surface describes the time-distance to Iquitos, along the river network. Based on interview material, I assessed annual changes to accessibility patterns in the region. The most common regional NTFP/AP were classified according to the amount of time they can be preserved, and based on the accessibility surface, I modelled a catchment area for each of these product classes. -- According to my results, navigation speeds vary considerably in different parts of the river network, depending on river types, vessels, flow direction and season. Navigating downstream is, generally, faster than upstream navigation. Thus, Iquitos is better accessible from areas situated south and south west of the city, like along the rivers Ucayali and Marañon. Differences in accessibility between different seasons are also substantial: during the dry season navigation is slower due to lower water levels and emerging sand bars. Regularly operating boats follow routes only along certain rivers and close to Iquitos transport facilities are more abundant than in more distant areas. Most of the products present in Iquitos market places are agricultural products, and the share of NTFP is significantly smaller. Most of the products were classified in product class 2, and the catchment area for these products is rather small. Many products also belonged to class 5, and the catchment area for these products reaches up to the edges of my study area, following the patterns of the river network. -- The accessibility model created in this study predicts travel times relatively well, although in some cases the modelled time-distances are substantially shorter than observed time-distances. This is partly caused by the fact that real-life navigation routes are more complicated than the modelled routes. Rain forest dwellers having easier access to Iquitos have more opportunities in terms of the products they decide to market. Thus, they can better take advantage of other factors affecting the market potential of different products. -- In all, understanding spatial variation in accessibility is important. In the Amazonian context it is difficult to combine the accessibility-related needs of the local dwellers with conservation purposes and the future challenge lies in finding solution that satisfy both of these needs.

The Effect of Food-Related Lifestyle on the Choices of Consumers of Five Food Products

The purpose of this study was to find out whether food-related lifestyle guides and explains product evaluations, specifically, consumer perceptions and choice evaluations of five different food product categories: lettuce, mincemeat, savoury sauce, goat cheese, and pudding. The opinions of consumers who shop in neighbourhood stores were considered most valuable. This study applies means-end chain (MEC) theory, according to which products are seen as means by which consumers attain meaningful goals. The food-related lifestyle (FRL) instrument was created to study lifestyles that reflect these goals. Further, this research has adopted the view that the FRL functions as a script which guides consumer behaviour. Two research methods were used in this study. The first was the laddering interview, the primary aim of which was to gather information for formulating the questionnaire of the main study. The survey consisted of two separate questionnaires. The first was the FRL questionnaire modified for this study. The aim of the other questionnaire was to determine the choice criteria for buying five different categories of food products. Before these analyses could be made, several data modifications were made following MEC analysis procedures. Beside forming FRL dimensions by counting sum-scores from the FRL statements, factor analysis was run in order to elicit latent factors underlying the dimensions. The lifestyle factors found were adventurous, conscientious, enthusiastic, snacking, moderate, and uninvolved lifestyles. The association analyses were done separately for each choice of product as well as for each attribute-consequence linkage with a non-parametric Mann-Whitney U test. The testing variables were FRL dimensions and the FRL lifestyle factors. In addition, the relation between the attribute-consequence linkages and the demographic variables were analysed. Results from this study showed that the choice of product is sequential, so that consumers first categorize products into groups based on specific criteria like health or convenience. It was attested that the food-related lifestyles function as a script in food choice and that the FRL instrument can be used to predict consumer buying behaviour. Certain lifestyles were associated with the choice of each product category. The actual product choice within a product category then appeared to be a different matter. In addition, this study proposes a modification to the FRL instrument. The positive towards advertising FRL dimension was modified to examine many kinds of information search including the internet, TV, magazines, and other people. This new dimension, which was designated as being open to additional information, proved to be very robust and reliable in finding differences in consumer choice behaviour. Active additional information search was linked to adventurous and snacking food-related lifestyles. The results of this study support the previous knowledge that consumers expect to get many benefits simultaneously when they buy food products. This study brought detailed information about the benefits sought, the combination of benefits differing between products and between respondents. Household economy, pleasure and quality were emphasized with the choice of lettuce. Quality was the most significant benefit in choosing mincemeat, but health related benefits were often evaluated as well. The dominant benefits linked to savoury sauce were household economic benefits, expected pleasurable experiences, and a lift in self-respect. The choice of goat cheese appeared not to be an economic decision, self-respect, pleasure, and quality being included in the choice criteria. In choosing pudding, the respondents considered the well-being of family members, and indulged their family members or themselves.