Adenoviral Gene Therapy for Advanced Head and Neck Cancer

Advanced stage head and neck cancers (HNC) with distant metastasis, as well as prostate cancers (PC), are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment is the use of oncolytic adenoviruses, especially in combination therapy with conventional cancer therapies. The safety of the approach has been tested in many clinical trials. However, antitumor efficacy needs to be improved in order to establish oncolytic viruses as a viable treatment alternative. To be able to test in vivo the effects on anti-tumor efficiency of a multimodal combination therapy of oncolytic adenoviruses with the standard therapeutic combination of radiotherapy, chemotherapy and Cetuximab monoclonal antibody (mAb), a xenograft HNC tumor model was developed. This model mimics the typical clinical situation as it is initially sensitive to cetuximab, but resistance develops eventually. Surprisingly, but in agreement with recent findings for chemotherapy and radiotherapy, a higher proportion of cells positive for HNC cancer stem cell markers were found in the tumors refractory to cetuximab. In vitro as well as in vivo results found in this study support the multimodal combination therapy of oncolytic adenoviruses with chemotherapy, radiotherapy and monoclonal antibody therapy to achieve increased anti-tumor efficiency and even complete tumor eradication with lower treatment doses required. In this study, it was found that capsid modified oncolytic viruses have increased gene transfer to cancer cells as well as an increased antitumor effect. In order to elucidate the mechanism of how oncolytic viruses promote radiosensitization of tumor cells in vivo, replicative deficient viruses expressing several promising radiosensitizing viral proteins were tested. The results of this study indicated that oncolytic adenoviruses promote radiosensitization by delaying the repair of DNA double strand breaks in tumor cells. Based on the promising data of the first study, two tumor double-targeted oncolytic adenoviruses armed with the fusion suicide gene FCU1 or with a fully human mAb specific for human Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) were produced. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. Anti-CTLA4 mAb promotes direct killing of tumor cells via apoptosis and most importantly immune system activation against the tumors. These armed oncolytic viruses present increased anti-tumor efficacy both in vitro and in vivo. Furthermore, by taking advantage of the unique tumor targeted gene transfer of oncolytic adenoviruses, functional high tumor titers but low systemic concentrations of the armed proteins were generated. In addition, supernatants of tumor cells infected with Ad5/3-24aCTLA4, which contain anti-CTLA4 mAb, were able to effectively immunomodulate peripheral blood mononuclear cells (PBMC) of cancer patients with advanced tumors. -- In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of advanced and metastatic HNC and PC.

The Routledge Companion to Social Media and Politics

Social media are now widely used for political protests, campaigns, and communication in developed and developing nations, but available research has not yet paid sufficient attention to experiences beyond the US and UK. This collection tackles this imbalance head-on, compiling cutting-edge research across six continents to provide a comprehensive, global, up-to-date review of recent political uses of social media. Drawing together empirical analyses of the use of social media by political movements and in national and regional elections and referenda, The Routledge Companion to Social Media and Politics presents studies ranging from Anonymous and the Arab Spring to the Greek Aganaktismenoi, and from South Korean presidential elections to the Scottish independence referendum. The book is framed by a selection of keystone theoretical contributions, evaluating and updating existing frameworks for the social media age. "Comprehensive and definitive, this is an outstanding book that provides a panoramic view of politics in an era of social media. From the Mediterranean to East Asia to Oceania, from Scandinavia to sub-Sahara Africa to Latin America, the volume as a whole is truly global, yet with nuanced regional and national analyses in each chapter. Theoretically informed, the research presented here breaks new empirical grounds using latest digital methods. The result is a milestone for our collective understanding of new media technology and comparative politics in the twenty-first century." ―Jack Linchuan Qiu, The Chinese University of Hong Kong "This book brings together top scholars from across disciplines and across the globe to examine social media use in a variety of political systems and for distinct purposes. It is required reading for anyone interested in understanding the many ways that digital communication technologies now are used in political life." ―Jennifer Stromer-Galley, Syracuse University

Mammographic mass-screening and future breast cancer burden in Finland

A population-based early detection program for breast cancer has been in progress in Finland since 1987. According to regulations during the study period 1987-2001, free of charge mammography screening was offered every second year to women aged 50-59 years. Recently, the screening service was decided to be extended to age group 50-69. However, the scope of the program is still frequently discussed in public and information about potential impacts of mass-screening practice changes on future breast cancer burden is required. The aim of this doctoral thesis is to present methodologies for taking into account the mass-screening invitation information in breast cancer burden predictions, and to present alternative breast cancer incidence and mortality predictions up to 2012 based on scenarios of the future screening policy. The focus of this work is not on assessing the absolute efficacy but the effectiveness of mass-screening, and, by utilizing the data on invitations, on showing the estimated impacts of changes in an existing screening program on the short-term predictions. The breast cancer mortality predictions are calculated using a model that combines incidence, cause-specific and other cause survival on individual level. The screening invitation data are incorporated into modeling of breast cancer incidence and survival by dividing the program into separate components (first and subsequent rounds and years within them, breaks, and post screening period) and defining a variable that gives the component of the screening program. The incidence is modeled using a Poisson regression approach and the breast cancer survival by applying a parametric mixture cure model, where the patient population is allowed to be a combination of cured and uncured patients. The patients risk to die from other causes than breast cancer is allowed to differ from that of a corresponding general population group and to depend on age and follow-up time. As a result, the effects of separate components of the screening program on incidence, proportion of cured and the survival of the uncured are quantified. According to the predictions, the impacts of policy changes, like extending the program from age group 50-59 to 50-69, are clearly visible on incidence while the effects on mortality in age group 40-74 are minor. Extending the screening service would increase the incidence of localized breast cancers but decrease the rates of non-localized breast cancer. There were no major differences between mortality predictions yielded by alternative future scenarios of the screening policy: Any policy change would have at the most a 3.0% reduction on overall breast cancer mortality compared to continuing the current practice in the near future.

Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents

We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives 6(a–k) and their precursors 5(a–k) as potential chemotherapeutic agents. In each case, the structures of the compounds were determined by FTIR, 1H NMR and mass spectroscopy. Among the synthesized molecules, methyl 1-(4-methoxyphenethyl)-2-(4-fluoro-3-nitrophenyl)-1H-benzimidazole-5-carboxylate (5a) induced maximum cell death in leukemic cells with an IC50 value of 3 μM. Using FACS analysis we show that the compound 5a induces S/G2 cell cycle arrest, which was further supported by the observed down regulation of CDK2, Cyclin B1 and PCNA. The observed downregulation of proapoptotic proteins, upregulation of antiapoptotic proteins, cleavage of PARP and elevated levels of DNA strand breaks indicated the activation of apoptosis by 5a. These results suggest that 5a could be a potent anti-leukemic agent.

Development of regulatory T cells in the human thymus

The role of the immune system is to protect an organism against pathogens while maintaining tolerance against self. T cells are an essential component of the immune system and they develop in the thymus. The AIRE (autoimmune regulator) gene product plays an important role in T cell development, as it promotes expression of peripheral tissue antigens in the thymus. Developing T cells, thymocytes, which recognize self-antigens with high affinity are deleted. However, this deletion process is not perfect and not all autoreactive T cells are destroyed. When the distinction between self and non-self fails, tolerance breaks and the immune system attacks the host s own tissues. This results in autoimmunity. Regulatory T cells contribute to the maintenance of self-tolerance. They can actively suppress the function of autoreactive cells. Several populations of cells with regulatory properties have been described, but the best characterized population is the natural regulatory T cells (Treg cells), which develop in the thymus and express the transcription factor FOXP3. The thymic development of Treg cells in humans is the subject of this thesis. Thymocytes at different developmental stages were analyzed using flow cytometry. The CD4-CD8- double-negative (DN) thymocytes are the earliest T cell precursors in the T cell lineage. My results show that the Treg cell marker FOXP3 is up-regulated already in a subset of these DN thymocytes. FOXP3+ cells were also found among the more mature CD4+CD8+ double-positive (DP) cells and among the CD4+ and CD8+ single-positive (SP) thymocytes. The different developmental stages of the FOXP3+ thymocytes were isolated and their gene expression examined by quantitative PCR. T cell receptor (TCR) repertoire analysis was used to compare these different thymocyte populations. My data show that in humans commitment to the Treg cell lineage is an early event and suggest that the development of Treg cells follows a linear developmental pathway, FOXP3+ DN precursors evolving through the DP stage to become mature CD4+ Treg cells. Most T cells have only one kind of TCR on their cell surface, but a small fraction of cells expresses two different TCRs. My results show that the expression of two different TCRs is enriched among Treg cells. Furthermore, both receptors were capable of transmitting signals when bound by a ligand. By extrapolating flow cytometric data, it was estimated that the majority of peripheral blood Treg cells are indeed dual-specific. The high frequency of dual-specific cells among human Treg cells suggests that dual-specificity has a role in directing these cells to the Treg cell lineage. It is known that both genetic predisposition and environmental factors influence the development of autoimmunity. It is also known that the dysfunction or absence of Treg cells leads to the development of autoimmune manifestations. APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) is a rare monogenic autoimmune disease, caused by mutations in the AIRE gene. In the absence of AIRE gene product, deletion of self-specific T cells is presumably disturbed and autoreactive T cells escape to the periphery. I examined whether Treg cells are also affected in APECED. I found that the frequency of FOXP3+ Treg cells and the level of FOXP3 expression were significantly lower in APECED patients than in controls. Additionally, when studied in cell cultures, the suppressive capacity of the patients' Treg cells was impaired. Additionally, repertoire analysis showed that the TCR repertoire of Treg cells was altered. These results suggest that AIRE contributes to the development of Treg cells in humans and the selection of Treg cells is impaired in APECED patients. In conclusion, my thesis elucidates the developmental pathway of Treg cells in humans. The differentiation of Tregs begins early during thymic development and both the cells dual-specificity and AIRE probably affect the final commitment of Treg cells.

Genomic and functional profiling of gastric cancer

Helicobacter pylori infection is a risk factor for gastric cancer, which is a major health issue worldwide. Gastric cancer has a poor prognosis due to the unnoticeable progression of the disease and surgery is the only available treatment in gastric cancer. Therefore, gastric cancer patients would greatly benefit from identifying biomarker genes that would improve diagnostic and prognostic prediction and provide targets for molecular therapies. DNA copy number amplifications are the hallmarks of cancers in various anatomical locations. Mechanisms of amplification predict that DNA double-strand breaks occur at the margins of the amplified region. The first objective of this thesis was to identify the genes that were differentially expressed in H. pylori infection as well as the transcription factors and signal transduction pathways that were associated with the gene expression changes. The second objective was to identify putative biomarker genes in gastric cancer with correlated expression and copy number, and the last objective was to characterize cancers based on DNA copy number amplifications. DNA microarrays, an in vitro model and real-time polymerase chain reaction were used to measure gene expression changes in H. pylori infected AGS cells. In order to identify the transcription factors and signal transduction pathways that were activated after H. pylori infection, gene expression profiling data from the H. pylori experiments and a bioinformatics approach accompanied by experimental validation were used. Genome-wide expression and copy number microarray analysis of clinical gastric cancer samples and immunohistochemistry on tissue microarray were used to identify putative gastric cancer genes. Data mining and machine learning techniques were applied to study amplifications in a cross-section of cancers. FOS and various stress response genes were regulated by H. pylori infection. H. pylori regulated genes were enriched in the chromosomal regions that are frequently changed in gastric cancer, suggesting that molecular pathways of gastric cancer and premalignant H. pylori infection that induces gastritis are interconnected. 16 transcription factors were identified as being associated with H. pylori infection induced changes in gene expression. NF-κB transcription factor and p50 and p65 subunits were verified using elecrophoretic mobility shift assays. ERBB2 and other genes located in 17q12- q21 were found to be up-regulated in association with copy number amplification in gastric cancer. Cancers with similar cell type and origin clustered together based on the genomic localization of the amplifications. Cancer genes and large genes were co-localized with amplified regions and fragile sites, telomeres, centromeres and light chromosome bands were enriched at the amplification boundaries. H. pylori activated transcription factors and signal transduction pathways function in cellular mechanisms that might be capable of promoting carcinogenesis of the stomach. Intestinal and diffuse type gastric cancers showed distinct molecular genetic profiles. Integration of gene expression and copy number microarray data allowed the identification of genes that might be involved in gastric carcinogenesis and have clinical relevance. Gene amplifications were demonstrated to be non-random genomic instabilities. Cell lineage, properties of precursor stem cells, tissue microenvironment and genomic map localization of specific oncogenes define the site specificity of DNA amplifications, whereas labile genomic features define the structures of amplicons. These conclusions suggest that the definition of genomic changes in cancer is based on the interplay between the cancer cell and the tumor microenvironment.

Crude oil and agricultural futures: An analysis of correlation dynamics

Correlations between oil and agricultural commodities have varied over previous decades, impacted by renewable fuels policy and turbulent economic conditions. We estimate smooth transition conditional correlation models for 12 agricultural commodities and WTI crude oil. While a structural change in correlations occurred concurrently with the introduction of biofuel policy, oil and food price levels are also key influences. High correlation between biofuel feedstocks and oil is more likely to occur when food and oil price levels are high. Correlation with oil returns is strong for biofuel feedstocks, unlike with other agricultural futures, suggesting limited contagion from energy to food markets.

Characterization of Mycobacterium leprae RecA intein, a LAGLIDADG homing endonuclease, reveals a unique mode of DNA-binding, helical distortion and cleavage, compared to a canonical LAGLIDADG homing endonuclease

Mycobacterium leprae, which has undergone reductive evolution leaving behind a minimal set of essential genes, has retained intervening sequences in four of its genes implicating a vital role for them in the survival of the leprosy bacillus. A single in-frame intervening sequence has been found embedded within its recA gene. Comparison of M. leprae recA intervening sequence with the known intervening sequences indicated that it has the consensus amino acid sequence necessary for being a LAGLIDADG-type homing endonuclease. In light of massive gene decay and function loss in the leprosy bacillus, we sought to investigate whether its recA intervening sequence encodes a catalytically active homing endonuclease. Here we show that the purified M. leprae RecA intein (PI-MleI) binds to cognate DNA and displays endonuclease activity in the presence of alternative divalent cations, Mg2+ or Mn2+. A combination of approaches including four complementary footprinting assays such as DNase I, Cu/phenanthroline, methylation protection and KMnO4, enhancement of 2-aminopurine fluorescence and mapping of the cleavage site revealed that PI-MleI binds to cognate DNA flanking its insertion site, induces helical distortion at the cleavage site and generates two staggered double-strand breaks. Taken together, these results implicate that PI-MleI possess a modular structure with separate domains for DNA target recognition and cleavage, each with distinct sequence preferences. From a biological standpoint, it is tempting to speculate that our findings have implications for understanding the evolution of LAGLIDADG family of homing endonucleases

Sugarcane productivity response to different fallow and soybean residue management practices in the Bundaberg district

GRAIN LEGUME ROTATIONS underpin the sustainability of the Australian sugarcane farming system, offering a number of soil health and environmental benefits. Recent studies have highlighted the potential for these breaks to exacerbate nitrous oxide (N2O) emissions. An experiment was implemented in 2012 to evaluate the impact of two fallow management options (bare fallow and soybean break crop) and different soybean residue management practices on N2O emissions and sugarcane productivity. The bare fallow plots were conventionally tilled, whereas the soybean treatments were either tilled, not tilled, residue sprayed with nitrification inhibitor (DMPP) prior to tillage or had a triticale ‘catch crop’ sown between the soybean and sugarcane crops. The fallow plots received either no nitrogen (N0) or fully fertilised (N145) whereas the soybean treatments received 25 kg N/ha at planting only. The Fallow N145 treatment yielded 8% more cane than the soybean tilled treatment. However there was no statistical difference in sugar productivity. Cane yield was correlated with stalk number that was correlated to soil mineral nitrogen status in January. There was only 30% more N/ha in the above-ground biomass between the Fallow N145 and the Fallow N0 treatment; highlighting poor fertiliser nitrogen use efficiency. Supplying adequate nitrogen to meet productivity requirements without causing environmental harm remains a challenge for the Australian sugar industry. The soybean direct drill treatment significantly reduced N2O emissions and produced similar yields and profitability to the soybean tilled treatment (outlined in a companion paper by Wang et.al. in these proceedings). Furthermore, this study has highlighted that the soybean direct drill technique provides an opportunity to enable grain legume cropping in the sugarcane farming system to capture all of the soil health/environmental benefits without exacerbating N2O emissions from Australian sugarcane soils.

Can technology provide a glimmer of hope for economic growth in the midst of chaos? A case of Zimbabwe

In this paper we examine the effect of technology on economic growth in Zimbabwe over the period 1975–2014 whilst accounting for structural breaks. We use the extended Cobb–Douglas type Solow (Q J Econ 70(1):65–94, 1956) framework and the ARDL bounds procedure to examine cointegration and short run and long run effects. Using unit root tests, we note that structural changes in Zimbabwe are generally marked by the period 1982 onwards. We find that mobile technology has a positive short-run (0.09 %) and long-run (0.08 %) impact on the output per capita. The structural changes post-1982 periods show positive impact in the short-run (0.06) and the long-run (0.09), whereas the coefficient of trend in the short-run (−0.03) and the long-run (−0.04) is negative. The Granger non-causality test shows a unidirectional causality from capital stock (investment) per capita to output per capita and a bi-directional causality between mobile cellular technology and output per capita. The plausible reasons for estimated magnitude effects and the direction of causality are explained for policy deliberation.

Pappi ja Raamattu : Suomen evankelis-luterilaisen kirkon pappien suhde Raamattuun

The Pastor and the Bible: Finnish Evangelical Lutheran Pastors Relationship with the Bible Since 1970s there has been extensive discussion in Finland about questions relating to the interpretation of the Bible. The themes of this discussion have focused on the trustworthiness and authority of the Bible, and the discussion has attracted participation not only from representatives of the Evangelical Lutheran Church of Finland but also from representatives of the academic community. The discussion has resulted in extensive publication on the relation of postmodern theology to the Bible. Despite this debate and the texts that have been produced, there is little empirical data on how Evangelical Lutheran pastors with theological education view the Bible. In the present study, 22 pastors of the Evangelical Lutheran Church of Finland were interviewed about how they defined their relationship with the Bible. The interview material was analyzed by means of data-based content analysis. The analysis showed, first, that the pastors viewed the Bible as a mirror of the spiritual growth that they had experienced in the past. Second, the Bible was viewed as a source in the interpretation of matters of faith. The third theme concerned the pastors key experiences in their relationship with the authority of the Bible. The time periods that were significant in defining pastors spiritual growth and past perspective on the Bible included childhood, youth, the period of theological education, and the time spent as a pastor. In childhood, the Bible was part of the spiritual atmosphere of the home, and parents and grandparents made a crucial contribution to the child s emerging view of the Bible. In childhood, the Bible was essentially the Old Testament and its exciting stories. In youth, reading the Bible became more personal, and the teachings of Jesus began to take on a more central role. In youth, most of the interviewees had strong experiences of faith and began to view the Bible as an absolute and divine source of dogma. The period of theological studies meant a change in their relationship with the Bible and particularly, revelation of the human aspects of the Bible. These changes were associated with a deepening of belief in the Bible and also a painful crisis in questions related to the trustworthiness of the Bible. For many of the interviewees, their relationship with the Bible changed also when they started their work as pastors. When faced with a call to work as a pastor, the interviewees created a synthesis of the secure faith that they had experienced in their childhood and the more critical views with which they had become acquainted during their theological education. Pastorhood meant the beginning of public teaching of the Bible. The interviewees felt that, in this new role, they discovered again - but now in a deeper sense - the trustworthiness in the bible that they had experienced during their childhood. Based on the interviewees experiences during the periods mentioned above, five different interpretations were formed regarding how the interviewed pastors viewed their past relationship with the Bible. These interpretations were detachment from literal interpretation of the Bible (1), changes in their relationship with the Bible arising from experiences of faith (2), a slow process during which their relationship with the Bible became more human (3), overcoming hardships (4), and no change in their relationship with the Bible (5). In interpretations 1-3, the past was described as a linear development and journey towards a more coherent relationship with the Bible. Interpretations 4-5, in turn, reflected a desire to detach oneself from the perspectives of linear development and change and, instead, emphasize the immutable and process-like nature of one s relationship with the Bible. Concerning the Bible as a source in matters of faith, a conspicuous aspect of the interviews was that all pastors wanted to disconnect themselves from a fundamentalistic view of the Bible, regarding this as an intellectually dishonest relationship with the Bible. On the other hand, none of the interviewees supported a totally relativist view of the Bible. Instead, all interviewees regarded the Bible as a vital source for both them and the Evangelical Lutheran Church. Between the two poles of extremely fundamental and extremely relativistic views, four different categories of viewing the Bible emerged from the interviews: absolute truth (a), a book about the message of salvation (b), a book about holiness and generous love (c), and a source of inspiration (d). The views in categories (a) and (b) emphasized the divine nature of the Bible. According to the pastors who expressed these views, the Bible contains a clear and trustworthy message of God. The views in categories (c) and (d), in turn, emphasized the human aspects of the Bible. The pastors who expressed these views regarded the Bible as a collection of books that was born in a specific historical and cultural context and includes material characteristic to this time. Due to the time-bound nature of the Bible, each generation has to update its view of the Bible. The views in categories (c) and (d) arose from human reality. Comparisons of the views in the different categories indicated that despite their obvious differences, they also shared some common features. The views in categories (a) and (d) shared the common feature of absoluteness, which was seen in category (a) as an emphasis on dogmatism and in category (d) as an emphasis on rationalism. The views in categories (b) and (c), in turn, shared the common feature of a flexible and dynamic relationship with the Bible. The key experiences that appeared to characterize pastors relationship with the authority of the Bible were a joy that arises from self-evidence, awakening to confusion, fear of openness, falling back upon paradoxes, and new confidence. These experiences reveal the circular nature of the process that was common to all interviewees interpretation of their relationship with the Bible. That is, the interviewees experiences of their relationship with the Bible seem to go through a circular process that is activated again and again in new life events. It is like a journey from self-evidence towards critical questions and again back to new confidence. The interview material showed, hence, that relationship with the Bible are characterized by a process that involves experiences of trust, questioning and new trust. The present study brings out the multifaceted reality of pastors relationship with the Bible. The study breaks down contradictions between conservative and liberal views of the Bible by showing how representatives of these opposing poles share commonalities in their attitudes. The study points to a close association between an individual s life history and his or her relationship with the Bible, and lays the groundwork for future studies to investigate the relation between personality and view of the Bible.

Ohjailusta kilpailuun : Suomen hallitusten kasvu- ja rakennepolitiikka vuosina 1962-1999

The study examines the contents, changes and the causes of changes of the growth and structural policy exercised by Finnish governments in 1962-1999. The policy is evaluated e.g. on the basis of government programmes. It is divided in the study into three phases: the phase of guided economy 1962-77, the transition period 1977-91 and the phase of competitive economy 1991-99. The opening of the economy has been the central factor influencing the contents of the growth and structural policy. When dividing the policy into ten sectors, it was found that the sectors losing weight during the study period are agricultural and forest policies and welfare policy and the sectors increasing weight are labour policy and environmental policy. Though impacts of the changes in the general line of the growth and structural policy could be seen in sector policies, the breaks in sector policies did not necessarily coincide with the breaks in the general line of the policy. In the study, in particular, the impacts of the factors affecting growth and structural policy thinking (political changes, foreign influences and changes in economics) are evaluated. The policy was influenced more by the prevailing ideological climate ("the spirit of time") than by political changes. Until the 1970s foreign influences mainly came from those individual Western European countries, where the role of government planning was important and where the economic development was favourable. Some impacts from socialist countries could be seen at the end of the 1960s and at the beginning of the 1970s. Since the 1980s the role of international organisations became emphasised. Also the impacts of the changes in economics could be seen in the changes in the general line of the growth and structural policy.

Strategic Information Acquisition: Applications to Herding and Auctions

The information that the economic agents have and regard relevant to their decision making is often assumed to be exogenous in economics. It is assumed that the agents either poses or can observe the payoff relevant information without having to exert any effort to acquire it. In this thesis we relax the assumption of ex-ante fixed information structure and study what happens to the equilibrium behavior when the agents must also decide what information to acquire and when to acquire it. This thesis addresses this question in the two essays on herding and two essays on auction theory. In the first two essays, that are joint work with Klaus Kultti, we study herding models where it is costly to acquire information on the actions that the preceding agents have taken. In our model the agents have to decide both the action that they take and additionally the information that they want to acquire by observing their predecessors. We characterize the equilibrium behavior when the decision to observe preceding agents' actions is endogenous and show how the equilibrium outcome may differ from the standard model, where all preceding agents actions are assumed to be observable. In the latter part of this thesis we study two dynamic auctions: the English and the Dutch auction. We consider a situation where bidder(s) are uninformed about their valuations for the object that is put up for sale and they may acquire this information for a small cost at any point during the auction. We study the case of independent private valuations. In the third essay of the thesis we characterize the equilibrium behavior in an English auction when there are informed and uninformed bidders. We show that the informed bidder may jump bid and signal to the uninformed that he has a high valuation, thus deterring the uninformed from acquiring information and staying in the auction. The uninformed optimally acquires information once the price has passed a particular threshold and the informed has not signalled that his valuation is high. In addition, we provide an example of an information structure where the informed bidder initially waits and then makes multiple jumps. In the fourth essay of this thesis we study the Dutch auction. We consider two cases where all bidders are all initially uninformed. In the first case the information acquisition cost is the same across all bidders and in the second also the cost of information acquisition is independently distributed and private information to the bidders. We characterize a mixed strategy equilibrium in the first and a pure strategy equilibrium in the second case. In addition we provide a conjecture of an equilibrium in an asymmetric situation where there is one informed and one uninformed bidder. We compare the revenues that the first price auction and the Dutch auction generate and we find that under some circumstances the Dutch auction outperforms the first price sealed bid auction. The usual first price sealed bid auction and the Dutch auction are strategically equivalent. However, this equivalence breaks down in case information is acquired during the auction.

Phylogeography and hybrid swarms: history of brackish water bivalve diversity in North European marginal seas

This study addressed the large-scale molecular zoogeography in two brackish water bivalve molluscs, Macoma balthica and Cerastoderma glaucum, and genetic signatures of the postglacial colonization of Northern Europe by them. The traditional view poses that M. balthica in the Baltic, White and Barents seas (i.e. marginal seas) represent direct postglacial descendants of the adjacent Northeast Atlantic populations, but this has recently been challenged by observations of close genetic affinities between these marginal populations and those of the Northeast Pacific. The primary aim of the thesis was to verify, quantify and characterize the Pacific genetic contribution across North European populations of M. balthica and to resolve the phylogeographic histories of the two bivalve taxa in range-wide studies using information from mitochondrial DNA (mtDNA) and nuclear allozyme polymorphisms. The presence of recent Pacific genetic influence in M. balthica of the Baltic, White and Barents seas, along with an Atlantic element, was confirmed by mtDNA sequence data. On a broader temporal and geographical scale, altogether four independent trans-Arctic invasions of Macoma from the Pacific since the Miocene seem to have been involved in generating the current North Atlantic lineage diversity. The latest trans-Arctic invasion that affected the current Baltic, White and Barents Sea populations probably took place in the early post-glacial. The nuclear genetic compositions of these marginal sea populations are intermediate between those of pure Pacific and Atlantic subspecies. In the marginal sea populations of mixed ancestry (Barents, White and Northern Baltic seas), the Pacific and Atlantic components are now randomly associated in the genomes of individual clams, which indicates both pervasive historical interbreeding between the previously long-isolated lineages (subspecies), and current isolation of these populations from the adjacent pure Atlantic populations. These mixed populations can be characterized as self-supporting hybrid swarms, and they arguably represent the most extensive marine animal hybrid swarms so far documented. Each of the three swarms still has a distinct genetic composition, and the relative Pacific contributions vary from 30 to 90 % in local populations. This diversity highlights the potential of introgressive hybridization to rapidly give rise to new evolutionarily and ecologically significant units in the marine realm. In the south of the Danish straits and in the Southern Baltic Sea, a broad genetic transition zone links the pure North Sea subspecies M. balthica rubra to the inner Baltic hybrid swarm, which has about 60 % of Pacific contribution in its genome. This transition zone has no regular smooth clinal structure, but its populations show strong genotypic disequilibria typical of a hybrid zone maintained by the interplay of selection and gene flow by dispersing pelagic larvae. The structure of the genetic transition is partly in line with features of Baltic water circulation and salinity stratification, with greater penetration of Atlantic genes on the Baltic south coast and in deeper water populations. In all, the scenarios of historical isolation and secondary contact that arise from the phylogeographic studies of both Macoma and Cerastoderma shed light to the more general but enigmatic patterns seen in marine phylogeography, where deep genetic breaks are often seen in species with high dispersal potential.

Tracking brand positioning for an emerging destination: 2003 to 2015

Few published studies have monitored destination brand image over time. This temporal aspect is an important gap in the literature, given consensus around the role perceptions play in consumers’ decision making, and the ensuing emphasis on imagery in destination branding collateral. Whereas most destination image studies have been a snapshot of perceptions at one point in time, this paper presents findings from a survey implemented four times between 2003 and 2015. Brand image is the core construct in modelling destination branding performance, which has emerged as a relatively new field of research in the past decade. Using the consumer-based brand equity (CBBE) hierarchy, the project has benchmarked and monitored destination brand salience, image and resonance for an emerging regional destination, relative to key competitors, in the domestic Australian market; and the survey instrument has been demonstrated to be reliable in the context of short break holidays by car. What is particularly interesting to date is there has been relatively little change in the market positions of the five destinations, in spite of over a decade of marketing communications by the regional tourism organisations and their stakeholders, and more recently the mass of user-generated travel content on social media. The project didn’t analyse the actual marketing communications for each of the DMOs. Therefore an important implication is that irrespective of the level of marketing undertaken the DMOs seem to have had little control over the perceptions held in their largest market during this time period. Therefore it must be recognised any improvement in perceptions will likely take a long period of time, and so branding needs to be underpinned by a philosophy of a long term financial investment as well as commitment to a consistency of message over time; which given the politics of DMO decision making represents a considerable challenge.