New mechanisms regulating human Th1 and Th2 cell differentiation

Selective development of human T helper (Th) cells into functionally distinct Th1 and Th2 subtypes plays an essential role in the host immune response towards pathogens. However, abnormal function or differentiation of these cells can lead to development of various autoimmune diseases as well as asthma and allergy. Therefore, identification of key factors and the molecular mechanisms mediating Th1 and Th2 cell differentiation is important for understanding the molecular mechanisms of these diseases. The goal of this study was to identify novel factors involved in the regulation of Th1 and Th2 differentiation processes. A new method was optimized for enrichment of transiently transfected resting human primary T lymphocytes, that allowed the study of the influence of genes of interest in human Th1/Th2 cell differentiation and other primary Th cell functions. Functional characterization of PRELI, a novel activation-induced protein in human Th cells, identified it as a mitochondrial protein involved in the regulation of Th cell differentiation and apoptosis. By influencing the intracellular redox state, PRELI induces mitochondrial apoptosis pathway and downregulates STAT6 and Th2 differentiation. The data suggested that Calpain, an oxidative stress induced cysteine protease, is involved as a mediator in PRELI-induced downregulation of STAT6. PIM serine/threonine-specific kinases were identified as new regulators of human Th1 cell differentiation. PIM1 and PIM2 kinases were shown to be preferentially expressed in Th1 cells as compared to Th2 cells. RNA interference studies showed that PIM kinases enhance the production of IFN, the hallmark cytokine produced by Th1 cells. They also induce the expression of the key Th1-driving factor T-bet and the IL-12 signaling pathway during early phases of Th1 cell differentiation. Taken together, new regulators of human T helper cell differentiation were identified in this study, which provides new insights into the signaling mechanisms controlling the selective activation of human Th cell subsets.

The intrinsic mechanisms of softwood fiber damage in brown stock fiber line unit operations Lappeenranta 2010

The effects of pulp processing on softwood fiber properties strongly influence the properties of wet and dry paper webs. Pulp strength delivery studies have provided observations that much of the strength potential of long fibered pulp is lost during brown stock fiber line operations where the pulp is merely washed and transferred to the subsequent processing stages. The objective of this work was to study the intrinsic mechanisms which maycause fiber damage in the different unit operations of modern softwood brown stock processing. The work was conducted by studying the effects of industrial machinery on pulp properties with some actions of unit operations simulated in laboratory scale devices under controlled conditions. An optical imaging system was created and used to study the orientation of fibers in the internal flows during pulp fluidization in mixers and the passage of fibers through the screen openings during screening. The qualitative changes in fibers were evaluated with existing and standardized techniques. The results showed that each process stage has its characteristic effects on fiber properties: Pulp washing and mat formation in displacement washers introduced fiber deformations especially if the fibers entering the stage were intact, but it did not decrease the pulp strength properties. However, storage chests and pulp transfer after displacement washers contributed to strength deterioration. Pulp screening proved to be quite gentle, having the potential of slightly evening out fiber deformations from very deformed pulps and vice versa inflicting a marginal increase in the deformation indices if the fibers were previously intact. Pulp mixing in fluidizing industrial mixers did not have detrimental effects on pulp strength and had the potential of slightly evening out the deformations, provided that the intensity of fluidization was high enough to allow fiber orientation with the flow and that the time of mixing was short. The chemical and mechanical actions of oxygen delignification had two distinct effects on pulp properties: chemical treatment clearly reduced pulp strength with and without mechanical treatment, and the mechanical actions of process machinery introduced more conformability to pulp fibers, but did not clearly contribute to a further decrease in pulp strength. The chemical composition of fibers entering the oxygen stage was also found to affect the susceptibility of fibers to damage during oxygen delignification. Fibers with the smallest content of xylan were found to be more prone to irreversibledeformations accompanied with a lower tensile strength of the pulp. Fibers poor in glucomannan exhibited a lower fiber strength while wet after oxygen delignification as compared to the reference pulp. Pulps with the smallest lignin content on the other hand exhibited improved strength properties as compared to the references.

The molecular mechanisms and evolutionary significance of plumage colour variation in pied flycatchers (Ficedula hypoleuca)

A common feature of natural populations is that individuals differ in morphology, physiologyand behavior (i.e .phenotype). A thorough understanding of the molecular mechanisms and evolutionary forces behind this phenotypic variation is a prerequisite for understanding evolution.This thesis examines the molecular mechanism and the roles of the different evolutionary forces in plumage colour variation in pied flycatchers (Ficedulahypoleuca). Malepied flycatchers exhibit marked variation in both pigmentary and structural plumage colourand the trait has repeatedly been suggested to be of adaptive significance. An examination of plumage colour variation on reproductive output trevealed that structural colouration, and more specifically the degree of ultraviolet (UV) reflectance had an effect on number of young sired. Paternity analyses of breeding males revealed that males that had been cuckolded by their social mate tended to be less UV reflectant than males that had not been cuckolded.Neither pigment-based norstructural colouration was found to affect the probability of siring young in other nests. Phenotypic differentiation was found to be markedly greater than differentiation at neutralgenetic markers across the pied flycatcher breeding range. Furthermore patterns of differentiationin phenotypes and selectively neutral genes were not uniform. Outlier tests searching for genomic footprints of selection revealed elevated levels of genetic divergence in a gene associated with feather development (and thus potentially structural colouration) and ultraviolet vision. Th eobserved differentiation in allelic frequencies was particularly pronounced in the Spanish piedflycatcher populations. Examining gene expression during feather development indicated that the TYRP1 gene (known to be involved in the production of black pigment) may be relevant in generating phenotypic variation in pied flycatcher plumage. Also, energy homeostasis related genesfeatured prominently among the genes found to be expressed in one extreme phenotype but not the other. This is of particular interest in light of what is known about the pleiotropy ofthe melanocortin system which underlies brown-black pigment production. The melanocortinsystem is also associated with energy homeostasis (among a number of other physiological functions) and thus the results could be pointing to the signalling function of brown-blackplumage. Plumage colour variation in pied flycatchers, both structural and pigmentary, can thus beconcluded to be exhibiting signals of non-neutral evolution. Structural colouration was found to play a role in sexual selection and putative signals of selection were further detected in acandidate gene for this trait. Evidence for non-neutral evolution of pigmentary colouration was also detected. These findings, together with the fact that preliminary evidence for an energy balance associated signalling function for plumage was found, present good starting points for further investigations into the meaning and mechanisms of plumage colour variation in piedflycatchers.

Kinetic modeling of mechanisms of industrially important organic reactions in gas and liquid phase

This dissertation is based on 5 articles which deal with reaction mechanisms of the following selected industrially important organic reactions: 1. dehydrocyclization of n-butylbenzene to produce naphthalene 2. dehydrocyclization of 1-(p-tolyl)-2-methylbutane (MB) to produce 2,6-dimethylnaphthalene 3. esterification of neopentyl glycol (NPG) with different carboxylic acids to produce monoesters 4. skeletal isomerization of 1-pentene to produce 2-methyl-1-butene and 2-methyl-2-butene The results of initial- and integral-rate experiments of n-butylbenzene dehydrocyclization over selfmade chromia/alumina catalyst were applied when investigating reaction 2. Reaction 2 was performed using commercial chromia/alumina of different acidity, platina on silica and vanadium/calcium/alumina as catalysts. On all catalysts used for the dehydrocyclization, major reactions were fragmentation of MB and 1-(p-tolyl)-2-methylbutenes (MBes), dehydrogenation of MB, double bond transfer, hydrogenation and 1,6-cyclization of MBes. Minor reactions were 1,5-cyclization of MBes and methyl group fragmentation of 1,6- cyclization products. Esterification reactions of NPG were performed using three different carboxylic acids: propionic, isobutyric and 2-ethylhexanoic acid. Commercial heterogeneous gellular (Dowex 50WX2), macroreticular (Amberlyst 15) type resins and homogeneous para-toluene sulfonic acid were used as catalysts. At first NPG reacted with carboxylic acids to form corresponding monoester and water. Then monoester esterified with carboxylic acid to form corresponding diester. In disproportionation reaction two monoester molecules formed NPG and corresponding diester. All these three reactions can attain equilibrium. Concerning esterification, water was removed from the reactor in order to prevent backward reaction. Skeletal isomerization experiments of 1-pentene were performed over HZSM-22 catalyst. Isomerization reactions of three different kind were detected: double bond, cis-trans and skeletal isomerization. Minor side reaction were dimerization and fragmentation. Monomolecular and bimolecular reaction mechanisms for skeletal isomerization explained experimental results almost equally well. Pseudohomogeneous kinetic parameters of reactions 1 and 2 were estimated by usual least squares fitting. Concerning reactions 3 and 4 kinetic parameters were estimated by the leastsquares method, but also the possible cross-correlation and identifiability of parameters were determined using Markov chain Monte Carlo (MCMC) method. Finally using MCMC method, the estimation of model parameters and predictions were performed according to the Bayesian paradigm. According to the fitting results suggested reaction mechanisms explained experimental results rather well. When the possible cross-correlation and identifiability of parameters (Reactions 3 and 4) were determined using MCMC method, the parameters identified well, and no pathological cross-correlation could be seen between any parameter pair.

External knowledge transfer mechanisms in service business acquisition

In knowledge-intensive economy an effective knowledge transfer is a part of the firm’s strategy to achieve a competitive advantage in the market. Knowledge transfer related to a variety of mechanisms depends on the nature of knowledge and context. The topic is, however, very little empirical studied and there is a research gap in scientific literature. This study examined and analyzed external knowledge transfer mechanisms in service business and especially in the context of acquisitions. The aim was to find out what kind of mechanisms was used when the buyer began to transfer data e.g. their own agendas and practices to the purchased units. Another major research goal was to identify the critical factors which contributed to knowledge transfer through different mechanisms. The study was conducted as a multiple-case study in a consultative service business company, in its four business units acquired by acquisition, in various parts of the country. The empirical part of the study was carried out as focus group interviews in each unit, and the data were analyzed using qualitative methods. The main findings of this study were firstly the nine different knowledge transfer mechanisms in service business acquisition: acquisition management team as an initiator, unit manager as a translator, formal training, self-directed learning, rooming-in, IT systems implementation, customer relationship management, codified database and ecommunication. The used mechanisms brought up several aspects as giving the face to changing, security of receiving right knowledge and correctly interpreted we-ness atmosphere, and orientation to use more consultative touch with customers. The study pointed out seven critical factors contributed to different mechanisms: absorption, motivation, organizational learning, social interaction, trust, interpretation and time resource. The two last mentioned were new findings compared to previous studies. Each of the mechanisms and the related critical factors contributed in different ways to the activity in different units after the acquisition. The role of knowledge management strategy was the most significant managerial contribution of the study. Phenomenon is not recognized enough although it is strongly linked in knowledge based companies. The recognition would help to develop a better understanding of the business through acquisitions, especially in situations such as where two different knowledge strategies combines in new common company.

Formal and informal mechanisms for knowledge protection and sharing

The most important knowledge in firms is mostly tacit and embedded in individuals within the organization. This background knowledge that firms possess is used for creation of new knowledge and innovations. As firms today greatly concentrate on their core competencies, they need external knowledge from various collaboration partners. Thus, collaborative relationship governance, as well as control (use of appropriability mechanisms) over background (the input from each firm in innovative activities) and foreground knowledge (the output of collaboration activities) is needed in order to successfully create and capture value from innovative activities without losing core knowledge and competitiveness. Even though research has concentrated on knowledge protection and knowledge sharing, studies that combine both of these views and examine the effects of sharing and protection on value creation and capture have been rather limited. Studies have mainly focused on the protection of the output of innovation while forgetting the protection of the input of innovation. On the other hand, as the research concentrating on the output of innovation tends to favor formal mechanisms, informal mechanisms have remained more unknown to researchers as well as managers. This research aims to combine the perspectives of knowledge sharing and knowledge protection and their relationship with value creation and value capture. The sharing and protection are viewed from two points of view: the use of appropriability mechanisms, as well as governance of the collaborative relationship. The study consists of two parts. The first part introduces the research topic and discusses the overall results. The second part comprises six complementary research publications. Both qualitative and quantitative research methods are used in the study. In terms of results, the findings enhance understanding of the combined use of formal and informal mechanisms for knowledge protection and sharing. Informal mechanisms appear to be emphasized in the protection of background knowledge, and thus are prerequisites for innovation, whereas formal mechanisms are relied on more for protecting the results of innovative activities. However, the simultaneous use of the formal and informal mechanisms that are relevant to the particular industry and innovation context is recommendedthroughout the collaborative innovation process. Further, the study adds to the current knowledge on HRM as an appropriability mechanism: on the firm level its uses include assessing and hedging against employee-related risks such as knowledge leaking and knowledge leaving. A further contribution is to the research on HRM protection and its interrelations with other appropriability mechanisms, its constituents, and its potential use in the area of knowledge protection.

Role and regulatory mechanisms of heat shock factor 2

Protein homeostasis is essential for cells to prosper and survive. Various forms of stress, such as elevated temperatures, oxidative stress, heavy metals or bacterial infections cause protein damage, which might lead to improper folding and formation of toxic protein aggregates. Protein aggregation is associated with serious pathological conditions such as Alzheimer’s and Huntington’s disease. The heat shock response is a defense mechanism that protects the cell against protein-damaging stress. Its ancient origin and high conservation among eukaryotes suggest that the response is crucial for survival. The main regulator of the heat shock response is the transcription factor heat shock factor 1 (HSF1), which induces transcription of genes encoding protective molecular chaperones. In vertebrates, a family of four HSFs exists (HSF1-4), with versatile functions not only in coping with acute stress, but also in development, longevity and cancer. Thus, knowledge of the HSFs will aid in our understanding on how cells survive suboptimal circumstances, but will also provide insights into normal physiological processes as well as diseaseassociated conditions. In this study, the function and regulation of HSF2 have been investigated. Earlier gene inactivation experiments in mice have revealed roles for HSF2 in development, particularly in corticogenesis and spermatogenesis. Here, we demonstrate that HSF2 holds a role also in the heat shock response and influences stress-induced expression of heat shock proteins. Intriguingly, DNA-binding activity of HSF2 upon stress was dependent on the presence of intact HSF1, suggesting functional interplay between HSF1 and HSF2. The underlying mechanism for this phenomenon could be configuration of heterotrimers between the two factors, a possibility that was experimentally verified. By changing the levels of HSF2, the expression of HSF1-HSF2 heterotrimer target genes was altered, implementing HSF2 as a modulator of HSF-mediated transcription. The results further indicate that HSF2 activity is dependent on its concentration, which led us to ask the question of how accurate HSF2 levels are achieved. Using mouse spermatogenesis as a model system, HSF2 was found to be under direct control of miR-18, a miRNA belonging to the miR-17~92 cluster/Oncomir-1 and whose physiological function had remained unclear. Investigations on spermatogenesis are severely hampered by the lack of cell systems that would mimic the complex differentiation processes that constitute male germ cell development. Therefore, to verify that HSF2 is regulated by miR-18 in spermatogenesis, a novel method named T-GIST (Transfection of Germ cells in Intact Seminiferous Tubules) was developed. Employing this method, the functional consequences of miR-18-mediated regulation in vivo were demonstrated; inhibition of miR- 18 led to increased expression of HSF2 and altered the expression of HSF2 target genes Ssty2 and Speer4a. Consequently, the results link miR-18 to HSF2-mediated processes such as germ cell maturation and quality control and provide miR-18 with a physiological role in gene expression during spermatogenesis.Taken together, this study presents compelling evidence that HSF2 is a transcriptional regulator in the heat shock response and establishes the concept of physical interplay between HSF2 and HSF1 and functional consequences thereof. This is also the first study describing miRNA-mediated regulation of an HSF.

Modeling of electrolyte sorption – from phase equilibria to dynamic separation systems

In this thesis, general approach is devised to model electrolyte sorption from aqueous solutions on solid materials. Electrolyte sorption is often considered as unwanted phenomenon in ion exchange and its potential as an independent separation method has not been fully explored. The solid sorbents studied here are porous and non-porous organic or inorganic materials with or without specific functional groups attached on the solid matrix. Accordingly, the sorption mechanisms include physical adsorption, chemisorption on the functional groups and partition restricted by electrostatic or steric factors. The model is tested in four Cases Studies dealing with chelating adsorption of transition metal mixtures, physical adsorption of metal and metalloid complexes from chloride solutions, size exclusion of electrolytes in nano-porous materials and electrolyte exclusion of electrolyte/non-electrolyte mixtures. The model parameters are estimated using experimental data from equilibrium and batch kinetic measurements, and they are used to simulate actual single-column fixed-bed separations. Phase equilibrium between the solution and solid phases is described using thermodynamic Gibbs-Donnan model and various adsorption models depending on the properties of the sorbent. The 3-dimensional thermodynamic approach is used for volume sorption in gel-type ion exchangers and in nano-porous adsorbents, and satisfactory correlation is obtained provided that both mixing and exclusion effects are adequately taken into account. 2-Dimensional surface adsorption models are successfully applied to physical adsorption of complex species and to chelating adsorption of transition metal salts. In the latter case, comparison is also made with complex formation models. Results of the mass transport studies show that uptake rates even in a competitive high-affinity system can be described by constant diffusion coefficients, when the adsorbent structure and the phase equilibrium conditions are adequately included in the model. Furthermore, a simplified solution based on the linear driving force approximation and the shrinking-core model is developed for very non-linear adsorption systems. In each Case Study, the actual separation is carried out batch-wise in fixed-beds and the experimental data are simulated/correlated using the parameters derived from equilibrium and kinetic data. Good agreement between the calculated and experimental break-through curves is usually obtained indicating that the proposed approach is useful in systems, which at first sight are very different. For example, the important improvement in copper separation from concentrated zinc sulfate solution at elevated temperatures can be correctly predicted by the model. In some cases, however, re-adjustment of model parameters is needed due to e.g. high solution viscosity.

The Peace and Security Council of the African Union : its relationship with the United Nations, African Union and sub-regional mechanisms

Avhandlingen undersöker den Afrikanska Unionens freds- och säkerhetsråd och dess roll i framhävandet och upprätthållandet av fred, säkerhet och stabilitet i Afrika. Detta freds- och säkerhetsråd etablerades formellt 2004 och opererar under den Afrikanska Unionen (AU) som å sin sida upprättades 2002. Den Afrikanska Unionens freds- och säkerhetsråds roll i framhävandet av fred, säkerhet och stabilitet gör rådet till en hörnsten inom ramen för konfliktförebyggande och -hantering, samt konfliktlösning på den afrikanska kontinenten. Den Afrikanska Unionens freds- och säkerhetsråd spelar också en högst viktig roll i implementeringen av ansvaret att beskydda civilbefolkningen i konfliktsituationer. För uppfyllandet av sitt mandat att framhäva och upprätthålla fred, säkerhet och stabilitet i Afrika krävs det att freds- och säkerhetsrådet samarbetar med andra institutioner och mekanismer som handhar internationella och regionala freds- och säkerhetsärenden. Avhandlingen analyserar tre dimensioner av denna typ av relationer som freds- och säkerhetsrådet bör etablera med dessa organ och mekanismer för att kunna utföra sitt mandat effektivt. Först analyseras relationen mellan Afrikanska Unionens freds- och säkerhetsråd och Förenta Nationernas säkerhetsråd som också beskrivs i artikel 17 (1) i protokollet som förde till etablerandet av AU:s freds- och säkerhetsråd. Analysen understryker FN:s säkerhetsråd som det organ som bär det primära ansvaret i förhållande till fred och säkerhet, medan AU:s freds- och säkerhetsråd fungerar som en kompletterande komponent i sin roll som ett regionalt organ. Avhandlingen fortsätter med att analysera förhållandet mellan AU:s freds- och säkerhetsråd och andra organ inom AU, samt andra relevanta institutioner som framgår av artikel 10, 18 (1), 19 och 20 i protokollet för rådets etablerande. Avhandlingen diskuterar i detalj hur samarbetet mellan AU:s freds- och säkerhetsråd och dessa institutioner och organ kunde förstärkas till fördel för effektivt framhävande och upprätthållande av fred och säkerhet i Afrika. Slutligen analyserar avhandlingen samarbetet mellan AU:s freds- och säkerhetsråd och sub-regionala mekanismer etablerade under regionala ekonomiska gemenskaper som beskrivs i artikel 16 i protokollet för etablerandet av rådet. Avhandlingen diskuterar i detalj rollen för de sub-regionala mekanismerna i den afrikanska freds- och säkerhetsarkitekturen. Avhandlingen diskuterar vidare förhållandet mellan de sub-regionala mekanismerna och den afrikanska stand-by styrkan ASF och förutsättningarna för detta arrangemang att bemöta afrikanska konflikter. Avhandlingen fokuserar också på en harmoniserings- och samarbetsprocess i förhållande till de sub-regionala mekanismerna, de regionala ekonomiska gemenskaperna och den Afrikanska Unionens freds- och säkerhetsråd. Kort sagt beskriver avhandlingen hur förhållandet mellan AU:s freds- och säkerhetsråd och de ovan nämnda organ och mekanismer har en faktisk och potentiell möjlighet att effektivt bidra till fred, säkerhet och stabilitet i Afrika. Avhandlingen identifierar utmaningarna kring att göra detta till ett fungerande förhållande samtidigt som den genererar både generella och specifika rekommendationer om hur dessa utmaningar bäst kan bemötas. Några av dessa utmaningar utgörs av följande aspekter: konflikten mellan AU:s och FN:s reglemang i bemötandet av freds- och säkerhetsutmaningar; de olika metoderna i FN och AU vid implementeringen av principen av universell jurisdiktion; konflikten mellan de olika mandaten som AU:s freds- och säkerhetsråd och FN:s säkerhetsråd har i förhållande till implementeringen av principen om intervention; och konflikten mellan lagarna och metoderna i förhållande till AU:s freds- och säkerhetsråd och de regionala mekanismerna. En av de huvudsakliga rekommendationerna i avhandlingen i bemötandet av de ovan nämnda utmaningarna är att harmonisera de olika systemen för att försäkra att det föreligger ett samordnat bemötande av konflikter i Afrika. Efter att ha identifierat luckorna i AU:s freds- och säkerhetsprotokoll med speciell fokus på förhållandet mellan rådet och de relevanta organen och mekanismerna rekommenderar avhandlingen ett antal tillägg och modifieringar till instrumentet ifråga för att effektivera, stärka och upprätthålla detta förhållande. Avhandlingen föreslår att dessa tillägg och modifieringar skulle företas under 2014 då detta år markerar 10 år efter att AU:s freds- och säkerhetsråd etablerades. Idén bakom detta företagandet ligger i att 10 år torde vara en tillfredställande tidsperiod för att mäta hur freds- och säkerhetsrådet har fungerat och hur dess förhållande med de relevanta institutionerna och mekanismerna kunde förbättras. Avhandlingen representerar den bredaste och nyaste studien inom ramen för artikel 16, 17, 18, 19 och 20 i protokollet för AU:s freds- och säkerhetsråd och introducerar ett innovativt bemötande av utmaningar till fred, säkerhet och stabilitet på den afrikanska kontinenten. Avhandlingen bidrar till teorin och praxisen i AU:s freds- och säkerhetsråd vilket kan vara av intresse för både forskare och praktiker i folkrätt såväl som i internationella freds- och säkerhetsstudier, speciellt i Afrika.

Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting

Breast cancer that has metastasized to bone is currently an incurable disease, causing significant morbidity and mortality. The aim of this thesis work was to elucidate molecular mechanisms of bone metastasis and thereby gain insights into novel therapeutic approaches. First, we found that L‐serine biosynthesis genes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1) and phosphoserine phosphatase (PSPH), were up‐regulated in highly bone metastatic MDA‐MB‐231(SA) cells as compared with the parental breast cancer cell line. Knockdown of serine biosynthesis inhibited proliferation of MDA‐MB‐231(SA) cells, and L‐serine was essential for the formation of bone resorbing osteoclasts. Clinical data demonstrated that high expression of PHGDH and PSAT1 was associated with decreased relapse‐free and overall survival and with features typical of poor outcome in breast cancer. Second, RNA interference screening pointed out heparan sulfate 6‐O‐sulfotransferase 2 (HS6ST2) as a critical gene for transforming growth factor β (TGF‐β)‐induced interleukin 11 (IL‐11) production in MDA‐MB‐231(SA) cells. Exogenous heparan sulfate glycosaminoglycans heparin and K5‐NSOS also inhibited TGF‐β‐induced IL‐11 production in MDA‐MB‐231(SA) cells. Furthermore, K5‐NSOS decreased osteolytic lesion area and tumor burden in bone in mice. Third, we discovered that the microRNAs miR‐204, ‐211 and ‐379 inhibited IL‐11 expression in MDA‐MB‐231(SA) cells through direct targeting of the IL‐11 mRNA. MiR‐379 also inhibited Smad‐mediated signaling. Gene expression profiling of miR‐204 and ‐379 transfected cells indicated that these microRNAs down‐regulate several bone metastasis‐relevant genes, including prostaglandin‐endoperoxide synthase 2 (PTGS2). Taken together, this study identified three potential treatment strategies for bone metastatic breast cancer: inhibition of serine biosynthesis, heparan sulfate glycosaminoglycans and restoration of miR‐204/‐211/‐379.

Organizational mechanisms and conditions of individuals for knowledge sharing in post-acquisition integration

The challenges of knowledge sharing after cross-border acquisitions are widely recognised. The study took a new view to the subject by applying a two-level framework provided by the knowledge governance approach. The purpose of the study was to investigate the effects of organizational mechanisms on the conditions of individuals for knowledge sharing in post-acquisition integration context. Qualitative research methods were used in this case study. Individual interviews were performed within an international firm after a recent cross-border acquisition. The results showed that integrators, the rotation of the personnel from the acquiring firm and visits and meetings enhance the conditions at the individual level for knowledge sharing after the acquisition. Respectively, strategic change, matrix structure and foreign HRM practices challenge the conditions at the individual level for knowledge sharing in the early post-acquisition integration phase. The findings are supported by the prior research on knowledge management in acquisitions. In particular, the study enlightens how organizational level actions influence the conditions of individuals for knowledge sharing. The study suggests that organizations should adjust organizational mechanisms to support the conditions of individuals, in order to promote knowledge sharing in the early phase of the integration.

Integration in project business : mechanisms for integrating customers and the project network during the life-cycle of industrial projects

This thesis focuses on integration in project business, i.e. how projectbased companies organize their product and process structures when they deliver industrial solutions to their customers. The customers that invest in these solutions run their businesses in different geographical, political and economical environments, which should be acknowledged by the supplier when providing solutions comprising of larger and more complex scopes than previously supplied to these customers. This means that the suppliers are increasing their supply range by taking over some of the activities in the value chain that have traditionally been handled by the customer. In order to be able to provide the functioning solutions, including more engineering hours, technical equipment and a wider project network, a change is needed in the mindset in order to be able to carry out and take the required responsibility that these new approaches bring. For the supplier it is important to be able to integrate technical products, systems and services, but the supplier also needs to have the capabilities to integrate the cross-functional organizations and departments in the project network, the knowledge and information between and within these organizations and departments, along with inputs from the customer into the product and process structures during the lifecycle of the project under development. Hence, the main objective of this thesis is to explore the challenges of integration that industrial projects meet, and based on that, to suggest a concept of how to manage integration in project business by making use of integration mechanisms. Integration is considered the essential process for accomplishing an industrial project, whereas the accomplishment of the industrial project is considered to be the result of the integration. The thesis consists of an extended summary and four papers, that are based on three studies in which integration mechanisms for value creation in industrial project networks and the management of integration in project business have been explored. The research is based on an inductive approach where in particular the design, commissioning and operations functions of industrial projects have been studied, addressing entire project life-cycles. The studies have been conducted in the shipbuilding and power generation industries where the scopes of supply consist of stand-alone equipment, equipment and engineering, and turnkey solutions. These industrial solutions include demanding efforts in engineering and organization. Addressing the calls for more studies on the evolving value chains of integrated solutions, mechanisms for inter- and intra-organizational integration and subsequent value creation in project networks have been explored. The research results in thirteen integration mechanisms and a typology for integration is proposed. Managing integration consists of integrating the project network (the supplier and the sub-suppliers) and the customer (the customer’s business purpose, operations environment and the end-user) into the project by making use of integration mechanisms. The findings bring new insight into research on industrial project business by proposing integration of technology and engineering related elements with elements related to customer oriented business performance in contemporary project environments. Thirteen mechanisms for combining products and the processes needed to deliver projects are described and categorized according to the impact that they have on the management of knowledge and information. These mechanisms directly relate to the performance of the supplier, and consequently to the functioning of the solution that the project provides. This thesis offers ways to promote integration of knowledge and information during the lifecycle of industrial projects, enhancing the development towards innovative solutions in project business.

Liquid transportation and distribution during (re)wetting : impact on coated papers in printing

In many industrial applications, such as the printing and coatings industry, wetting of porous materials by liquids includes not only imbibition and permeation into the bulk but also surface spreading and evaporation. By understanding these phenomena, valuable information can be obtained for improved process control, runnability and printability, in which liquid penetration and subsequent drying play important quality and economic roles. Knowledge of the position of the wetting front and the distribution/degree of pore filling within the structure is crucial in describing the transport phenomena involved. Although exemplifying paper as a porous medium in this work, the generalisation to dynamic liquid transfer onto a surface, including permeation and imbibition into porous media, is of importance to many industrial and naturally occurring environmental processes. This thesis explains the phenomena in the field of heatset web offset printing but the content and the analyses are applicable in many other printing methods and also other technologies where water/moisture monitoring is crucial in order to have a stable process and achieve high quality end products. The use of near-infrared technology to study the water and moisture response of porous pigmented structures is presented. The use of sensitive surface chemical and structural analysis, as well as the internal structure investigation of a porous structure, to inspect liquid wetting and distribution, complements the information obtained by spectroscopic techniques. Strong emphasis has been put on the scale of measurement, to filter irrelevant information and to understand the relationship between interactions involved. The near-infrared spectroscopic technique, presented here, samples directly the changes in signal absorbance and its variation in the process at multiple locations in a print production line. The in-line non-contact measurements are facilitated by using several diffuse reflectance probes, giving the absolute water/moisture content from a defined position in the dynamic process in real-time. The nearinfrared measurement data illustrate the changes in moisture content as the paper is passing through the printing nips and dryer, respectively, and the analysis of the mechanisms involved highlight the roles of the contacting surfaces and the relative liquid carrier properties of both non-image and printed image areas. The thesis includes laboratory studies on wetting of porous media in the form of coated paper and compressed pigment tablets by mono-, dual-, and multi-component liquids, and paper water/moisture content analysis in both offline and online conditions, thus also enabling direct sampling of temporal water/moisture profiles from multiple locations. One main focus in this thesis was to establish a measurement system which is able to monitor rapid changes in moisture content of paper. The study suggests that near-infrared diffuse reflectance spectroscopy can be used as a moisture sensitive system and to provide accurate online qualitative indicators, but, also, when accurately calibrated, can provide quantification of water/moisture levels, its distribution and dynamic liquid transfer. Due to the high sensitivity, samples can be measured with excellent reproducibility and good signal to noise ratio. Another focus of this thesis was on the evolution of the moisture content, i.e. changes in moisture content referred to (re)wetting, and liquid distribution during printing of coated paper. The study confirmed different wetting phases together with the factors affecting each phase both for a single droplet and a liquid film applied on a porous substrate. For a single droplet, initial capillary driven imbibition is followed by equilibrium pore filling and liquid retreat by evaporation. In the case of a liquid film applied on paper, the controlling factors defining the transportation were concluded to be the applied liquid volume in relation to surface roughness, capillarity and permeability of the coating giving the liquid uptake capacity. The printing trials confirmed moisture gradients in the printed sheet depending on process parameters such as speed, fountain solution dosage and drying conditions as well as the printed layout itself. Uneven moisture distribution in the printed sheet was identified to be one of the sources for waving appearance and the magnitude of waving was influenced by the drying conditions.