Transcription factor GATA4 and apoptotic TRAIL pathway in granulosa cell function and tumors

Normal growth and development require the precise control of gene expression. Transcription factors are proteins that regulate gene expression by binding specific sequences of DNA. Abnormalities in transcription are implicated in a variety of human diseases, including cancer, endocrine disorders and birth defects. Transcription factor GATA4 has emerged as an important regulator of normal development and function in a variety of endoderm- and mesoderm- derived tissues, including gut, heart and several endocrine organs, such as gonads. Mice harboring a null mutation of Gata4 gene die during embryogenesis due to failure in heart formation, complicating the study of functional role of GATA4 in other organs. However, the expression pattern of GATA4 suggests it may play a role in the regulation of ovarian granulosa cell development, function and apoptosis. This premise is supported by in vitro studies showing that GATA4 regulates several steroidogenic enzymes as well as auto-, para- and endocrine signaling molecules important for granulosa cell function. This study assessed the in vivo role of GATA4 for granulosa cell function by utilizing two genetically modified mouse strains. The findings in the GATA4 deficient mice included delayed puberty, impaired fertility and signs of diminished estrogen production. At the molecular level, the GATA4 deficiency leads to attenuated expression of central steroidogenic genes, Steroidogenic acute regulatory protein (StAR), Side-chain cleavage (SCC), and aromatase as a response to stimulations with exogenous gonadotropins. Taken together, these suggest GATA4 is necessary for the normal ovarian function and female fertility. Programmed cell death, apoptosis, is a crucial part of normal ovarian development and function. In addition, disturbances in apoptosis have been implicated to pathogenesis of human granulosa cell tumors (GCTs). Apoptosis is controlled by extrinsic and intrinsic pathways. The intrinsic pathway is regulated by members of Bcl-2 family, and its founding member, the anti-apoptotic Bcl-2, is known to be important for granulosa cell survival. This study showed that the expression levels of GATA4 and Bcl-2 correlate in the human GCTs and that GATA4 regulates Bcl-2 expression, presumably by directly binding to its promoter. In addition, disturbing GATA4 function was sufficient to induce apoptosis in cultured GCT- derived cell line. Taken together, these results suggest GATA4 functions as an anti-apoptotic factor in GCTs. The extrinsic apoptotic pathway is controlled by the members of tumor necrosis factor (TNF) superfamily. An interesting ligand of this family is TNF-related apoptosis-inducing ligand (TRAIL), possessing a unique ability to selectively induce apoptosis in malignant cells. This study characterized the previously unknown expression of TRAIL and its receptors in both developing and adult human ovary, as well as in malignant granulosa cell tumors. TRAIL pathway was shown to be active in GCTs suggesting it may be a useful tool in treating these malignancies. However, more studies are required to assess the function of TRAIL pathway in normal ovaries. In addition to its ability to induce apoptosis in GCTs, this study revealed that GATA4 protects these malignancies from TRAIL-induced apoptosis. GATA4 presumably exerts this effect by regulating the expression of anti-apoptotic Bcl-2. This is of particular interest as high expression of GATA4 is known to correlate to aggressive GCT behavior. Thus, GATA4 seems to protect GCTs from endogenous TRAIL by upregulating anti-apoptotic factors such as Bcl-2.

What should I think; How should I feel? : The balancing of personal experiences and social norms in the outgroup attitude formation of youth

The present study focused on the associations between the personal experiences of intergroup contact, perceived social norms and the outgroup attitudes of Finnish majority and Russian-speaking minority youth living in Finland. The theoretical background of the study was derived from Allport s (1954) theory of intergroup contact (i.e., the contact hypothesis), social psychological research on normative influences on outgroup attitudes (e.g., Rutland, 2004; Stangor and Leary, 2006) and developmental psychological research on the formation of explicit (deliberate) and implicit (automatically activated) outgroup attitudes in adolescence (e.g., Barrett, 2007; Killen, McGlothlin and Henning, 2008). The main objective of the study was to shed light on the role of perceived social norms in the formation of outgroup attitudes among adolescents. First, the study showed that perceived normative pressure to hold positive attitudes towards immigrants regulated the relationship between the explicit and implicit expression of outgroup attitudes among majority youth. Second, perceived social norms concerning outgroup attitudes (i.e., the perceived outgroup attitudes of parents and peers) affected the relationship between intergroup contact and explicit outgroup attitudes depending on gender and group status. Positive social norms seem to be especially important for majority boys, who need both pleasant contact experiences and normative support to develop outgroup attitudes that are as positive as girls attitudes. The role of social norms is accentuated also among minority youth, who, contrary to majority youth with their more powerful and independent status position, need to reflect upon their attitudes and experiences of negative intergroup encounters in relation to the experiences and attitudes of their ingroup members. Third, the results are indicative of the independent effects of social norms and intergroup anxiety on outgroup attitudes: the effect of perceived social norms on the outgroup attitudes of youth seems to be at least as strong as the effect of intergroup anxiety. Finally, it was shown that youth evaluate intergroup contact from the viewpoint of their ingroup and society as a whole, not just based on their own experiences. In conclusion, the outgroup attitudes of youth are formed in a close relationship with their social environment. On the basis of this study, the importance of perceived social norms for research on intergroup contact effects among youth cannot be overlooked. Positive normative influences have the potential to break the strong link between rare and/or negative personal contact experiences and negative outgroup attitudes, and norms also influence the relationship between implicit and explicit attitude expression.

Atmospheric particle formation in spatially and temporally varying conditions

Atmospheric particles affect the radiation balance of the Earth and thus the climate. New particle formation from nucleation has been observed in diverse atmospheric conditions but the actual formation path is still unknown. The prevailing conditions can be exploited to evaluate proposed formation mechanisms. This study aims to improve our understanding of new particle formation from the view of atmospheric conditions. The role of atmospheric conditions on particle formation was studied by atmospheric measurements, theoretical model simulations and simulations based on observations. Two separate column models were further developed for aerosol and chemical simulations. Model simulations allowed us to expand the study from local conditions to varying conditions in the atmospheric boundary layer, while the long-term measurements described especially characteristic mean conditions associated with new particle formation. The observations show statistically significant difference in meteorological and back-ground aerosol conditions between observed event and non-event days. New particle formation above boreal forest is associated with strong convective activity, low humidity and low condensation sink. The probability of a particle formation event is predicted by an equation formulated for upper boundary layer conditions. The model simulations call into question if kinetic sulphuric acid induced nucleation is the primary particle formation mechanism in the presence of organic vapours. Simultaneously the simulations show that ignoring spatial and temporal variation in new particle formation studies may lead to faulty conclusions. On the other hand, the theoretical simulations indicate that short-scale variations in temperature and humidity unlikely have a significant effect on mean binary water sulphuric acid nucleation rate. The study emphasizes the significance of mixing and fluxes in particle formation studies, especially in the atmospheric boundary layer. The further developed models allow extensive aerosol physical and chemical studies in the future.

Customer Value Formation in Practice: A Practice-Theoretical Approach

This thesis introduces a practice-theoretical approach to understanding customer value formation to be used in the field of service marketing and management. In contrast to current studies trying to understand value formation by analysing customers as independent actors and thinkers, it is in this work suggested that customer value formation can be better understood by analysing how value is formed in the practices and contexts of the customers. The theoretical approach developed in this thesis is applied in an empirical study of family cruises. The theoretical analysis in this thesis results in a new approach for understanding customer value formation. Customer value is, according to this new approach, something that is formed in practice, meaning that value is formed in constellations of the customer and contextual elements like tools, physical spaces and contextually embedded images and know-how. This view is different from the current views that tend to see value as subjectively created, co-created, perceived or experienced by the customer. The new approach has implications on how we view customer value, but also on the methods and techniques we can use to understand customer value in empirical studies. It is also suggested that services could in fact be reconceptualised as practices. According to the stance presented in this thesis the empirical analysis of customer value should not focus on individual customers, but should instead take the contextual entity of practices as its unit of analysis. Therefore, ethnography is chosen as a method for exploring how customer value is formed in practice in the case of family cruises on a specific cruise vessel. The researcher has studied six families, as well as the context of the cruise vessel with various techniques including non-participant observation, participant observation and interviews in order to create an ethnographic understanding of the practices carried out on board. Twenty-one different practices are reported and discussed in order to provide necessary insight to customer value formation that can be used as input for service development.

Exploring Customer Value Formation: A Customer Dominant Logic Perspective

This paper extends current discussions about value creation and proposes a customer dominant value perspective. A customer-dominant marketing logic positions the customer in the center, rather than the service provider/producer or the interaction or the system. The focus is shifted from the company´s service processes involving the customer, to the customer´s multi-contextual value formation, involving the company. It is argued that value is not always an active process of creation; instead value is embedded and formed in the highly dynamic and multi-contextual reality and life of the customer. This leads to a need to look beyond the current line of visibility where visible customer-company interactions are focused to the invisible and mental life of the customer. From this follows a need to extend the temporal scope, from exchange and use even further to accumulated experiences in the customer´s life. The aim of this paper is to explore value formation from a customer dominant logic perspective. This is done in three steps: first, value formation is contrasted to earlier views on the company’s role in value creation by using a broad ontologically driven framework discussing what, how, when, where and who. Next, implications of the proposed characteristics of value formation compared to earlier approaches are put forward. Finally, some tentative suggestions of how this perspective would affect marketing in service companies are presented. As value formation in a CDL perspective has a different focus and scope than earlier views on value it leads to posing questions about the customer that reveals earlier hidden aspects of the role of a service for the customer. This insight might be used in service development and innovation.

Direct detection of atmospheric particle formation using the Neutral cluster and Air Ion Spectrometer

Aerosol particles play an important role in the Earth s atmosphere and in the climate system: they scatter and absorb solar radiation, facilitate chemical processes, and serve as seeds for cloud formation. Secondary new particle formation (NPF) is a globally important source of these particles. Currently, the mechanisms of particle formation and the vapors participating in this process are, however, not truly understood. In order to fully explain atmospheric NPF and subsequent growth, we need to measure directly the very initial steps of the formation processes. This thesis investigates the possibility to study atmospheric particle formation using a recently developed Neutral cluster and Air Ion Spectrometer (NAIS). First, the NAIS was calibrated and intercompared, and found to be in good agreement with the reference instruments both in the laboratory and in the field. It was concluded that NAIS can be reliably used to measure small atmospheric ions and particles directly at the sizes where NPF begins. Second, several NAIS systems were deployed simultaneously at 12 European measurement sites to quantify the spatial and temporal distribution of particle formation events. The sites represented a variety of geographical and atmospheric conditions. The NPF events were detected using NAIS systems at all of the sites during the year-long measurement period. Various particle formation characteristics, such as formation and growth rates, were used as indicators of the relevant processes and participating compounds in the initial formation. In a case of parallel ion and neutral cluster measurements, we also estimated the relative contribution of ion-induced and neutral nucleation to the total particle formation. At most sites, the particle growth rate increased with the increasing particle size indicating that different condensing vapors are participating in the growth of different-sized particles. The results suggest that, in addition to sulfuric acid, organic vapors contribute to the initial steps of NPF and to the subsequent growth, not just later steps of the particle growth. As a significant new result, we found out that the total particle formation rate varied much more between the different sites than the formation rate of charged particles. The results infer that the ion-induced nucleation has a minor contribution to particle formation in the boundary layer in most of the environments. These results give tools to better quantify the aerosol source provided by secondary NPF in various environments. The particle formation characteristics determined in this thesis can be used in global models to assess NPF s climatic effects.

The effects of organic environmental toxicants on hard tissue formation in developing tooth : An in vitro study in mice

Dioxins are organic toxicants that are known to impair tooth development, especially dental hard tissue formation. The most toxic dioxin congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Further, clinical studies suggest that maternal smoking during pregnancy can affect child s tooth development. One of the main components of tobacco smoke is the group of non-halogenated polycyclic aromatic hydrocarbons (PAHs), a representative of which is 7,12-dimethylbenz[a]anthracene (DMBA). Tributyltin (TBT), an organic tin compound, has been shown to impair bone mineralization in experimental animals. In addition to exposure to organic toxicants, a well-established cause for enamel hypomineralization is excess fluoride intake. The principal aim of this thesis project was to examine in vitro if, in addition to dioxins, other organic environmental toxicants, like PAHs and organic tin compounds, have adverse effects on tooth development, specifically on formation and mineralization of the major dental hard tissues, the dentin and the enamel. The second aim was to investigate in vitro if fluoride could intensify the manifestation of the detrimental developmental dental effects elicited by TCDD. The study was conducted by culturing mandibular first and second molar tooth germs of E18 NMRI mouse embryos in a Trowell-type organ culture and exposing them to DMBA, TBT, and sodium fluoride (NaF) and/or TCDD at various concentrations during the secretory and mineralization stages of development. Specific methods used were HE-staining for studying cell and tissue morphology, BrdU-staining for cell proliferation, TUNEL-staining for apoptosis, and QPCR, in situ hybridization and immunohistochemistry for the expressions of selected genes associated with mineralization. This thesis work showed that DMBA, TBT, TCDD and NaF interfere with dentin and enamel formation of embryonic mouse tooth in vitro, and that fluoride can potentiate the harmful effect of TCDD. The results suggested that adverse effects of TBT involve altered expression of genes associated with mineralization, and that DMBA and TBT as well as NaF and TCDD together primarily affect dentin mineralization. Since amelogenesis does not start until mineralization of dentin begins, impaired enamel matrix secretion could be a secondary effect. Dioxins, PAHs and organotins are all liposoluble and can be transferred to the infant by breast-feeding. Since doses are usually very low, developmental toxicity on most of the organs is difficult to indentify clinically. However, tooth may act as an indicator of exposure, since the major dental hard tissues, the dentin and the enamel, are not replaced once they have been formed. Thus, disturbed dental hard tissue formation raises the question of more extensive developmental toxicity.

On formation, growth and concentrations of air ions

Aerosol particles have effect on climate, visibility, air quality and human health. However, the strength of which aerosol particles affect our everyday life is not well described or entirely understood. Therefore, investigations of different processes and phenomena including e.g. primary particle sources, initial steps of secondary particle formation and growth, significance of charged particles in particle formation, as well as redistribution mechanisms in the atmosphere are required. In this work sources, sinks and concentrations of air ions (charged molecules, cluster and particles) were investigated directly by measuring air molecule ionising components (i.e. radon activity concentrations and external radiation dose rates) and charged particle size distributions, as well as based on literature review. The obtained results gave comprehensive and valuable picture of the spatial and temporal variation of the air ion sources, sinks and concentrations to use as input parameters in local and global scale climate models. Newly developed air ion spectrometers (Airel Ltd.) offered a possibility to investigate atmospheric (charged) particle formation and growth at sub-3 nm sizes. Therefore, new visual classification schemes for charged particle formation events were developed, and a newly developed particle growth rate method was tested with over one year dataset. These data analysis methods have been widely utilised by other researchers since introducing them. This thesis resulted interesting characteristics of atmospheric particle formation and growth: e.g. particle growth may sometimes be suppressed before detection limit (~ 3 nm) of traditional aerosol instruments, particle formation may take place during daytime as well as in the evening, growth rates of sub-3 nm particles were quite constant throughout the year while growth rates of larger particles (3-20 nm in diameter) were higher during summer compared to winter. These observations were thought to be a consequence of availability of condensing vapours. The observations of this thesis offered new understanding of the particle formation in the atmosphere. However, the role of ions in particle formation, which is not well understood with current knowledge, requires further research in future.

Hantavirus glycoprotein GN in virion assembly and regulation of interferon response

Hantaviruses have a tri-segmented negative-stranded RNA genome. The S segment encodes the nucleocapsid protein (N), M segment two glycoproteins, Gn and Gc, and the L segment the RNA polymerase. Gn and Gc are co-translationally cleaved from a precursor and targeted to the cis-Golgi compartment. The Gn glycoprotein consists of an external domain, a transmembrane domain and a C-terminal cytoplasmic domain. In addition, the S segment of some hantaviruses, including Tula and Puumala virus, have an open reading frame (ORF) encoding a nonstructural potein NSs that can function as a weak interferon antagonist. The mechanisms of hantavirus-induced pathogenesis are not fully understood but it is known that both hemorrhagic fever with renal syndrome (HFRS) and hantavirus (cardio) pulmonary syndrome (HCPS) share various features such as increased capillary permeability, thrombocytopenia and upregulation of TNF-. Several hantaviruses have been reported to induce programmed cell death (apoptosis), such as TULV-infected Vero E6 cells which is known to be defective in interferon signaling. Recently reports describing properties of the hantavirus Gn cytoplasmic tail (Gn-CT) have appeared. The Gn-CT of hantaviruses contains animmunoreceptor tyrosine-based activation motif (ITAM) which directs receptor signaling in immune and endothelial cells; and contain highly conserved classical zinc finger domains which may have a role in the interaction with N protein. More functions of Gn protein have been discovered, but much still remains unknown. Our aim was to study the functions of Gn protein from several aspects: synthesis, degradation and interaction with N protein. Gn protein was reported to inhibit interferon induction and amplication. For this reason, we also carried out projects studying the mechanisms of IFN induction and evasion by hantavirus. We first showed degradation and aggresome formation of the Gn-CT of the apathogenic TULV. It was reported earlier that the degradation of Gn-CT is related to the pathogenicity of hantavirus. We found that the Gn-CT of the apathogenic hantaviruses (TULV, Prospect Hill virus) was degraded through the ubiquitin-proteasome pathway, and TULV Gn-CT formed aggresomes upon treatment with proteasomal inhibitor. Thus the results suggest that degradation and aggregation of the Gn-CT may be a general property of most hantaviruses, unrelated to pathogenicity. Second, we investigated the interaction of TULV N protein and the TULV Gn-CT. The Gn protein is located on the Golgi membrane and its interaction with N protein has been thought to determine the cargo of the hantaviral ribonucleoprotein which is an important step in virus assembly, but direct evidence has not been reported. We found that TULV Gn-CT fused with GST tag expressed in bacteria can pull-down the N protein expressed in mammalian cells; a mutagenesis assay was carried out, in which we found that the zinc finger motif in Gn-CT and RNA-binding motif in N protein are indispensable for the interaction. For the study of mechanisms of IFN induction and evasion by Old World hantavirus, we found that Old World hantaviruses do not produce detectable amounts of dsRNA in infected cells and the 5 -termini of their genomic RNAs are monophosphorylated. DsRNA and tri-phosphorylated RNA are considered to be critical activators of innate immnity response by interacting with PRRs (pattern recognition receptors). We examined systematically the 5´-termini of hantavirus genomic RNAs and the dsRNA production by different species of hantaviruses. We found that no detectable dsRNA was produced in cells infected by the two groups of the old world hantaviruses: Seoul, Dobrava, Saaremaa, Puumala and Tula. We also found that the genomic RNAs of these Old World hantaviruses carry 5´-monophosphate and are unable to trigger interferon induction. The antiviral response is mainly mediated by alpha/beta interferon. Recently the glycoproteins of the pathogenic hantaviruses Sin Nombre and New York-1 viruses were reported to regulate cellular interferon. We found that Gn-CT can inhibit the induction of IFN activation through Toll-like receptor (TLR) and retinoic acid-inducible gene I-like RNA helicases (RLH) pathway and that the inhibition target lies at the level of TANK-binding kinase 1 (TBK-1)/ IKK epislon complex and myeloid differentiation primary response gene (88) (MyD88) / interferon regulatory factor 7 (IRF-7) complex.

Tetrahydrofuran Clathrate Hydrate Formation

We report on the formation of tetrahydrofuran clathrate hydrate studied by x-ray Raman scattering measurements at the oxygen K edge. A comparison of x-ray Raman spectra measured from water-tetrahydrofuran mixtures and tetrahydrofuran hydrate at different temperatures supports stochastic hydrate formation models rather than models assuming hydrate precursors. This is confirmed by molecular dynamics simulations and density functional theory calculations of x-ray Raman spectra. In addition, changes in the spectra of tetrahydrofuran hydrate with temperatures close to the hydrate's dissociation temperature were observed and may be connected to changes in hydrate's local structure due to the formation of hydrogen bonds between guest and water molecules.

Genomic alterations in Myeloproliferative Neoplasms and Myelodysplastic Syndromes

Myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders whose etiology and molecular pathogenesis are poorly understood. During the past decade, enormous developments in microarray technology and bioinformatics methods have made it possible to mine novel molecular alterations in a large number of malignancies, including MPN and MDS, which has facilitated the detection of new prognostic, predictive and therapeutic biomarkers for disease stratification. By applying novel microarray techniques, we profiled copy number alterations and microRNA (miRNA) expression changes in bone marrow aspirate and blood samples. In addition, we set up and validated an miRNA expression test for bone marrow core biopsies in order to utilize the large archive material available in many laboratories. We also tested JAK2 mutation status and compare it with the in vitro growth pattern of hematologic progenitors cells. In the study focusing on 100 MPN cases, we detected a Janus kinase 2 (JAK2) mutation in 71 cases. We observed spontaneous erythroid colony growth in all mutation-positive cases in addition to nine mutation negative cases. Interestingly, seven JAK2V167F negative ET cases showed spontaneous megakaryocyte colony formation, one case of which also harbored a myeloproliferative leukemia virus oncogene (MPL) mutation. We studied copy number alterations in 35 MPN and 37 MDS cases by using oligonucleotide-based array comparative hybridization (array CGH). Only one essential thrombocythemia (ET) case presented copy number alterations in chromosomes 1q and 13q. In contrast, MDS cases were characterized by numerous novel cryptic chromosomal aberrations with the most common copy number losses at 5q21.3q33.1 and 7q22.1q33, while the most common copy number gain was trisomy 8. As for the study of the bone marrow core biopsy samples, we showed that even though these samples were embedded in paraffin and underwent decalcification, they were reliable sources of miRNA and suitable for array expression analysis. Further, when studying the miRNA expression profiles of the 19 MDS cases, we found that, compared to controls, two miRNAs (one human Epstein-Barr virus (miR-BART13) miRNA and one human (has-miR-671-5p) miRNA) were downregulated, whereas two other miRNAs (hsa-miR-720 and hsa-miR-21) were upregulated. However, we could find no correlation between copy number alterations and microRNA expression when integrating these two data. This thesis brings to light new information about genomic changes implicated in the development of MPN and MDS, and also underlines the power of applying genome-wide array screening techniques in neoplasias. Rapid advances in molecular techniques and the integration of different genomic data will enable the discovery of the biological contexts of many complex disorders, including myeloid neoplasias.

Tree mortality, fire scar formation and regeneration 8 years after low-intensity fire in managed Pinus sylvestris stands

Fire is an important driver of the boreal forest ecosystem, and a useful tool for the restoration of degraded forests. However, we lack knowledge on the ecological processes initiated by prescribed fires, and whether they bring about the desired restoration effects. The purpose of this study was to investigate the impacts of low-intensity experimental prescribed fires on four ecological processes in young commercial Scots pine (Pinus sylvestris) stands eight years after the burning. The processes of interest were tree mortality, dead wood creation, regeneration and fire scar formation. These were inventoried in twelve study plots, which were 30 m x 30 m in size. The plots belonged to two different stand age classes: 30-35 years or 45 years old at the time of burning. The study was partly a follow-up of study plots researched by Sidoroff et al. (2007) one year after burning in 2003. Tree mortality increased from 183 stems ha-1 in 2003 to 259 stems ha-1 in 2010, corresponding to 15 % and 21 % of stem number respectively. Most mortality was experienced in the stands of the younger age class, in smaller diameter classes and among species other than Scots pine. By 2010, the average mortality of Scots pine per plot was 18%, but varied greatly ranging from 0% to 63% of stem number. Delayed mortality, i.e. mortality that occurred between 2 and 8 years after fire, seemed to become more important with increasing diameter. The input of dead wood also varied greatly between plots, from none to 72 m3 ha-1, averaging at 12 m3 ha-1. The amount of fire scarred trees per plot ranged from none to 20 %. Four out of twelve plots (43 %) did not have any fire scars. Scars were on average small: 95% of scars were less than 4 cm in width, and 75% less than 40 cm in length. Owing to the light nature of the fire, the remaining overstorey and thick organic layer, regeneration was poor overall. The abundance of pine and other seedlings indicated a viable seed source existed, but the seedlings failed to establish under dense canopy. The number of saplings ranged from 0 to 12 333 stems ha-1. The results of this study indicate that a low intensity fire does not necessarily initiate the ecological processes of tree mortality, dead wood creation and regeneration in the desired scale. Fire scars, which form the basis of fire dating in fire history studies, did not form in all cases.

Essays on labour demand and wage formation

The first essay in this thesis is on gender wage differentials among manufacturing sector white-collar workers. The wage differential is decomposed into firm, job (within-firm) and individ-ual-level components. Job-level gender segregation explains over half of the gap, while firm-level segregation is not important. After controlling for firm, job and individual characteristics, the remaining unexplained wage cap to the advantage of men is six per cent of men s mean wage. In the second essay, I study how the business cycle and gender affect the distribution of the earnings losses of displaced workers. The negative effect of displacement is large, persistent and strongest in the lowest earnings deciles. The effect is larger in a recession than in a recov-ery period, and in all periods women s earnings drop more than men s earnings. The third essay shows that the transition from steady employment to disability pension de-pends on the stringency of medical screening and the degree of experience-rating of pension costs applied to the employer. The fact that firms have to bear part of the cost of employees disability pension costs lowers both the incidence of long sick leave periods and the probabil-ity that sick leave ends in a disability pension. The fourth and fifth essays are studies on the employment, wage and profit effects of a re-gional payroll tax cut experiment conducted in northern and eastern Finland. The results show no statistically significant effect on any of the response variables.