The present research tested whether and how regulatory focus as a motivational variable influences the ways in which people appraise, process, and react to events in romantic relationships. Regulatory focus theory distinguishes between (1) a prevention focus, which emphasizes the fulfillment of security needs, duties and obligations, and is associated with heightened sensitivity to aversive outcomes, and (2) a promotion focus, which emphasizes the fulfillment of nurturance needs, accomplishments and aspirations, and is associated with heightened sensitivity to rewarding outcomes. Based on regulatory focus theory, it was assumed that promotion and prevention focused people would appraise, react to, and process interpersonal events involving a romantic partner in different ways. In addition, it was expected that the distinct ways of experiencing such events are reflected in differences in relationship quality. Three studies using college student samples were conducted to test these notions. Evidence was found that individual differences in chronic prevention focus affect the ways in which people react to aversive events in relationships. No support was obtained for regulatory focus theory??s predictions regarding prevention focus processes in association with rewarding outcomes, and predictions related to the promotion focus system were also not supported. As expected, chronic promotion focus was related to higher relationship quality, and chronic prevention focus was associated with lower relationship quality. Implications and suggestions for future research are discussed.

No description available.

Globalement, un tiers de la population mondiale est infectée par Mycobacterium tuberculosis, l'agent infectieux de la tuberculose (TB). Fort heureusement, seuls 5 à 10 % des individus infectés développent un jour une TB active. Les individus non malades restent cependant infectés à vie, on parle d'infection latente. Chaque année, 8-10 millions nouveaux cas de tuberculose active sont recensés et M. tuberculosis est responsable de 1,5 à 2 millions de décès. Depuis plus d'une décennie, M. tuberculosis s'est étroitement associé à l'infection par le virus de l'immunodéficience humaine. Cette alliance néfaste représente une importante menace pour les pays en voie de développement, car ces 2 pathogènes déciment les forces vives de ces populations. Il faut malheureusement rajouter à ce triste tableau une fréquence grandissante de souches multi-résistantes, voire extensivement multi-résistantes. Face à ces souches, les avancées thérapeutiques du siècle dernier sont pratiquement réduites à néant. Considérant ces données, il est désormais crucial d'améliorer nos outils de dépistage de l'infection latente, de diagnostic de la maladie active, de prévention (vaccins) et de traitement. Pour atteindre ces objectifs, une des pistes est la caractérisation détaillée des réponses immunitaires. En comparant les réponses immunitaires des sujets infectés de manière latente à celles liées à la maladie active, nous pourrons peut-être comprendre certains mécanismes de protection. L'étude des réponses immunitaires induites par la « Heparin-Binding-Hemagglutinin » (HBHA) s'est faite dans cet objectif. La HBHA est une adhésine exprimée par le complexe M. tuberculosis. Elle est impliquée dans la dissémination extrapulmonaire du bacille et constitue donc un facteur de virulence. Par ailleurs, une vaccination de souris par seulement 3 doses de 5 µg de HBHA suffit à protéger de l'infection avec une efficacité comparable à celle du vaccin BCG. Chez l'homme, les sujets sains mais infectés développent d'importantes sécrétions d'interféron-gamma (IFN-γ) en réponse à cet antigène, alors que la majorité des patients tuberculeux ne le font pas. Cette différence est importante pour comprendre une des raisons d'échappement de M. tuberculosis au contrôle immunitaire. La HBHA est une protéine méthylée et la méthylation s’avère essentielle pour ses propriétés immunoprotectrices. Nos travaux présentés ici se sont axés sur deux éléments de la réponse immunitaire à la HBHA chez l'homme : d'une part, l'exploitation de la réponse périphérique d'IFN-γ à la HBHA comme outil de dépistage de l'infection latente et, d'autre part, l'étude des raisons de la faible sécrétion d'IFN-γ spécifique de la HBHA lors de la maladie active. L'évaluation de la sécrétion périphérique d'IFN-γ en réponse à la HBHA a permis de démontrer rétrospectivement que celle-ci permet de détecter plus de 90 % des sujets réagissant positivement à l'injection intradermique de tuberculine. De manière intéressante, l'utilisation d'un test commercial, le QuantiFERON TB Gold IT (QFT-IT) n'a permis de détecter que la moitié des sujets infectés sains. De notre point de vue, le QFT-IT ne peut être recommandé seul pour le dépistage systématique de l'infection latente par M. tuberculosis. De manière parallèle, un test de stimulation basé uniquement sur la sécrétion d’IFN-γ suite à une stimulation à l'ESAT-6, composant du QFT-IT, n'a pas permis d'augmenter la sensibilité, ni d'ajouter une plus-value au test basé sur la HBHA. A l'instar de l'intradermoréaction à la tuberculine, le dépistage de la maladie active reste décevant que ce soit par l'utilisation de la HBHA ou de l'ESAT-6. La TB active est caractérisée par une basse sécrétion périphérique d'IFN-γ en réponse à la stimulation par la HBHA. Cette faible sécrétion est cependant réversible, puisque un traitement efficace permet d'atteindre des taux d'IFN-γ significativement plus élevés. Ceci nous démontre qu'il s'agit d'une suppression associée à la phase active de l'infection. Nous avons d'abord évalué l'importance de la modulation de la sécrétion d'IFN-γ en réponse à la HBHA par 2 cytokines immunomodulatrices, l'interleukine-10 (IL-10) et le Transforming-Growth-Factor-Beta (TGF-ß). De manière intéressante, alors que ces 2 cytokines sont associées à l'infection par M. tuberculosis, la HBHA n'est inductrice ni d'IL-10, ni de TGF-ß. Les lymphocytes T régulateurs (Treg) expriment 2 marqueurs d'intérêt : le CD25, composant du récepteur à l'IL-2, et Foxp3, un gène régulateur majeur des cellules Treg. Ces cellules sont décrites comme suppressives de réponses immunitaires déclenchées par des antigènes du Soi et du non-Soi. Nous avons montré que la proportion de lymphocytes Treg périphériques est augmentée en cas de TB active. Par ailleurs, nous avons également démontré que ces cellules suppriment la sécrétion d'IFN-γ et la prolifération induite par la HBHA après stimulation des cellules mononucléées sanguines périphériques de patients tuberculeux in vitro. Cependant, la réponse anti-HBHA des patients tuberculeux, qui est démasquée par la déplétion des lymphocytes Treg, n'est pas dirigée contre des épitopes protecteurs. En effet, la méthylation n'influence pas leur sécrétion d'IFN-γ. De ce point de vue, les lymphocytes Treg sont impliqués dans la maladie tuberculeuse et influencent négativement les réponses dirigées contre un antigène protecteur. Cependant, il semble que la TB active soit également associée à une ignorance d'épitopes protecteurs. Enfin, nous avons également démontré qu'il était possible d'induire des lymphocytes Treg au départ de cellules sanguines périphériques de sujets infectés sains. En effet, la stimulation in vitro des cellules sanguines périphériques en présence de BCG et de TGF-ß est un moyen rapide pour induire l'apparition de lymphocytes Treg fonctionnels in vitro. Ceci nous interroge quant aux rôles des lymphocytes Treg dans la pathogenèse de la maladie. En effet, un excès de TGF-ß circulant est observé dans certaines conditions cliniques à haut-risque de TB post-primaire. De ce point de vue, les lymphocytes Treg pourraient être des acteurs déterminant dans la perte du contrôle à long terme de l'infection et, par là, pourraient être des cibles thérapeutiques d'intérêts lors de l'infection par M. tuberculosis. /Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It is estimated approximately one third of the World’s population is infected with M. tuberculosis. Fortunately, only 5 to 10 % of the infected individuals will develop the disease throughout their life. However, the other healthy infected individuals remain infected for life: this is the latent TB infection (LTBI). Every year, 8 to 10 million new cases of TB are recorded globally, and about 2 to 3 million of people die from the disease. During the last several decades the co-infection of M. tuberculosis and the human immunodeficiency virus have worsened the picture. This dreadful association currently affects mostly the poorest people of the World. Unfortunately, bad news never stands alone. We now witness increasing emergence of multi-drug-resistant and even of extensively-multi-drug-resistant M. tuberculosis strains. Against these strains current therapeutics are virtually useless. The development of new tools for prevention (vaccines), diagnostics and treatment is crucial. In order to fulfill these objectives, detailed studies on the immune responses is one of the main tracks to explore. Indeed, the comparison of immune responses in LTBI subjects with those in TB patients may provide some clues to understand immune mechanisms of protection. Studies of the immune responses that are specific to Heparin-Binding-Hemagglutinin (HBHA) may be one of these clues. HBHA is an adhesin, which is expressed by the micro-organisms of the M. tuberculosis complex. It largely contributes to the extrapulmonary dissemination of the tubercle bacilli. Hence, HBHA may be qualified as an important virulence factor. Furthermore, vaccination of mice with three doses of only 5 µg HBHA each affords the same level of protection as vaccination with BCG. In humans, peripheral blood mononuclear cells (PBMC) from LTBI subjects secrete significant levels of IFN-γ in response to HBHA, whereas PBMC from TB patients do not. This discrepancy may be a cornerstone in the understanding of some of the mechanisms underlying the immune escape mediated by M. tuberculosis. HBHA is a methylated protein, and the methylation is crucial for its immuno-protective properties. This work focused on 2 major issues of the HBHA-specific immune response in humans: the use of the peripheral IFN-γ secretion in response to HBHA as a diagnostic tool for LTBI and the analysis of the underlying mechanisms to the low IFN-γ secretion during active TB. In our study, the measurement of HBHA-specific IFN-γ secretion resulted in the detection of more than 90 % of the tuberculin-skin-test (TST) positive LTBI. Strikingly, the QuantiFERON TB Gold IT (QFT-IT), a commercial test, failed to identify those LTBI subjects in more than 50 % of the cases. Therefore, we cannot recommend the use of QFT-IT alone instead of the TST for the detection of LTBI. Similarly, a test relying on the detection of IFN-γ secretion upon ESAT-6 stimulation, one of the antigens used in the QFT-IT, was not sufficiently sensitive for the LTBI detection, nor did it improve the sensitivity or the specificity of the HBHA-based test. In contrast to the diagnosis of LTBI, the tests based on HBHA- or ESAT-6-induced IFN-γ secretions displayed poor sensitivity for the diagnosis of active TB. During active TB, the HBHA-specific IFN-γ secretion in the periphery is low. However, this weak secretion is reversible upon effective treatment, as the IFN-γ response to HBHA is increased after completion of chemotherapy. This is strongly suggestive of an immune suppression during active disease. Therefore, we have first evaluated the role of two immunomodulatory cytokines, interleukin-10 (IL-10) and Transforming-Growth-Factor-Beta (TGF-ß), in the suppression of the HBHA-specific IFN-γ secretion. We found that neutralization of neither IL-10 nor TGF-ß with specific antibodies induced HBHA-specific IFN-γ secretion by PBMC of TB patients in vitro. In contrast, depletion of regulatory T cells (Treg) that express 2 major markers, CD25, a constituent of the IL-2 receptor, and Foxp3, a master regulatory gene, resulted in increased HBHA-specific IFN-γ secretion by the PBMC of TB patients. These cells are known to be involved in the suppression of immune responses to both Self and non-Self antigens. We further show that the size of the peripheral Treg cell population increases during active disease. In addition to suppressing the HBHA-specific IFN-γ secretion these cells suppress T cell proliferation in response to HBHA in vitro. However, even after depletion of the Treg cells, the uncovered HBHA-specific immune responses are not directed to the methylated epitopes during TB disease. Finally, we show that Treg cells can be induced (or expanded) from the PBMC of LTBI subjects. Stimulation of those PBMC with BCG in the presence of TGF-ß resulted in a quick appearance of functional Treg cells in vitro. This observation strongly suggests a role of Treg cells in the pathogenesis of TB, in particular in the progression of latency to reactivation. Interestingly, excessive concentration of TGF-ß, associated with various clinical conditions, is high risk factor for post-primary TB. Thus, Treg cells may result in the loss of immune control against latent M. tuberculosis infection. Therefore, Treg cells may represent potential therapeutic targets during M. tuberculosis infection.

<p>Several lines of cellular and physiological evidence have suggested the presence of a novel class of systemically mobile plant molecules that are recognized by antibodies generated against vertebrate atrial natriuretic peptides (ANPs). Functional characterization of these immunoanalogues, referred to as immunoreactive plant natriuretic peptides (irPNPs) or plant natriuretic peptides (PNPs), has shown that they play important roles in a number of cellular processes crucial for plant growth and maintenance of cellular homeostasis. Although the various biological roles of PNPs in plants are known, their exact mode of action remains elusive. To elucidate the mechanisms of action for these immunoanalogues, we have prepared a biologically active recombinant PNP from Arabidopsis thaliana (AtPNP-A) and the biological activity was demonstrated by showing its ability to induce water uptake into Arabidopsis thaliana protoplasts. In addition, the molecule was shown to downregulate photosynthesis while at the same time up-regulating respiration, transpiration as well as net water uptake and retention capacities in the sage Plectranthus ecklonii. Further analysis of the recombinant AtPNP-A indicated that the peptide can induce systemic response signalling though the phloem. A recombinant Arabidopsis wall associated kinase-like protein (AtWAKL10) that has a domain organization resembling that of vertebrate natriuretic peptide (NP) receptors was also partially characterized as a possible receptor for the recombinant AtPNP-A. Vertebrate NP receptors contain an extracellular ligand-binding domain and an intracellular guanylate cyclase (GC)/kinase domain and signal through the activity of their GC domain that is capable of generating intracellular cGMP from GTP. The structural resemblance of AtWAKL10 to vertebrate NP receptors could suggest a functional homology with receptor molecules and it is conceivable that such a receptor may recognize PNPs as ligands. The characterization of the recombinant AtWAKL10 showed that the molecule functions as both a GC and a kinase in vitro. This strengthened the suggestion that AtWAKL10 could be a possible AtPNP-A receptor especially considering the fact that AtPNP-A applications to plant cells also<br /> trigger cGMP transients. Furthermore, a bioinformatic analysis of the functions of AtPNP-A and AtWAKL10 has inferred both molecules in plant pathogen responses and defense mechanisms, thus indirectly functionally linking the two proteins.</p>

The European market is constantly changing and business across national borders is be-coming a daily feature. Companies no longer settle for trading within their own national borders and perhaps cannot even afford to restrict themselves to such a small area if they wish to expand. The new view of EC Company Law given by the European Court of Justice makes it possible for companies to move to another Member State and still be recognised as a legitimate company. This view is based on the incorporation theory, i.e. the theory that a company shall be governed by the law of the state in which it is incorporated. However, with this change come new threats to the market. Scholars fear that the European market will take the same approach as that of the US, where the state of Delaware has been able to attract more than half of the larger enterprises on the market in the regulatory competition between the states. In addition to that, the European market has been intro-duced to new supranational companies, i.e. companies that are above national law and answer to EC law, and these companies could have a large impact on the changes of the market. The SE Company and the proposed European Private Company may come to prevent a European Delaware. In this paper it is argued that a regulatory competition is going to occur within the Union in the near future – if it has not already – based on changes made by some Member States in order to attract more companies to incorporate under their jurisdiction. It will not fully resemble the situation in the US since the two market fields differ from one another. It is also argued that a European Delaware may come to exist, but that the mere existence of a regulatory competition does not have to result in such a state. A Delaware effect may be prevented by the European Private Company, if this form comes to exist. It is the thesis of this paper that the market in addition to the EPC, in order to actually be able to prevent the somewhat unwished competition, must meet three vital requirements. First of all, the EPC must differ from the statute of the SE Company, meaning it must be separated from national law since it otherwise would be an element of competition in itself. Second, the market – and then mostly through new Company Law Directives – must keep the freedom restricted. If the Directives allowed companies unrestricted freedom of establishment that would mean a possibility to move cross-border without the need for a EPC, which in turn would not be able to prevent a European Delaware. Third, there cannot be a working reincorporation within the Union, meaning Member States cannot be allowed to benefit from tax revenues that derive from such a move, since that would be yet another element to the regulatory competition. / Den europeiska marknaden undergår konstant förändringar och handeln över de nationella gränserna har blivit ett dagligt inslag. Företag nöjer sig ej längre med att endast bedriva verksamhet inom det egna landets gränser och om de önskar att expandera är det måhända inte möjligt att begränsa sig till ett sådant litet område. Europadomstolens nya syn på europeisk bolagsrätt gör det nu möjligt för företag att flytta från en medlemsstat till en annan och fortfarande räknas som ett legalt företag. Denna syn är baserad på den s.k. inkorporeringsteorin, d.v.s. teorin att ett företag skall regleras av lagen i den stat i vilken företaget har inkorporerats. Men med denna förändring kommer nya hot på marknaden. Akademiker befarar att den europeiska marknaden kommer ta an samma ton som den amerikanska där staten Delaware har lyckats locka till sig merparten av de stora företagen på marknaden i den statliga konkurrensen. I tillägg till det nyss sagda har det introducerats nya överstatliga företag på den europeiska marknaden, d.v.s. företag som står över nationella bestämmelser och istället endast regleras av EG lagstiftning, och dessa företag kan komma att ha en stor inverkan på de förändringar som händer på marknaden. Europabolaget och det proponerade Privata Europabolaget kan därigenom komma att hindra ett Europeiskt Delaware. Det är i denna uppsats hävdat att en regelverkskonkurrens mellan medlemsstaterna kom-mer att ske på marknaden – om det inte redan har – baserat på de förändringar som vissa medlemsstater redan gjort i respektive lagstiftning för att på så sätt locka till sig fler företag. Situationen kommer inte att till fullo likna den amerikanska eftersom de två marknaderna skiljer sig från varandra. Det är också argumenterat att ett europeiskt Delaware kan uppenbara sig, men att detta inte kommer ske enbart för att det finns en regelverkskonkurrens inom EU. En Delaware-effekt kan komma att hindras av det Privata Europabolaget, om denna form i framtiden accepteras. Teorin enligt denna uppsats är att i det fall ett europeiskt Delaware skall hindras måste den europeiska marknaden uppfylla tre viktiga krav. Först och främst måste det Privata Europabolagets statut skilja sig från Europabolagets, d.v.s. det måste vara separerat från nationella bestämmelser eftersom det i annat fall skulle vara ytterligare en beståndsdel av regelverkskonkurrensen. För det andra måste marknaden – främst genom de nya bolagsdirektiven – hålla friheten på marknaden under kontroll. Om direktiven tillåter företagen att utan hinder utnyttja etableringsfriheten skulle det innebära en möjlighet att röra sig över de nationella gränserna utan ett överstatligt bolag och det i sin tur skulle innebära att det Privata Europabolaget inte skulle kunna hindra ett europeiskt Delaware. För det tredje finns det inget utrymme för en fungerande återinkorporering inom Unionen, d.v.s. att medlemsstaterna inte kan tillåtas dra fördel av de skatteinkomster som kan uppkomma genom en sådan flytt eftersom det skulle gynna regleverkskonkurrensen.

Regular exercise is challenging and lapses in activity may lead to non-adherence. Adherence may be particularly challenging for symptomatic individuals with disease-related symptoms that may impede exercise. The combined use of cognitive-behavioural strategies including problem-solving has been strongly encouraged for promoting exercise adherence. However, evidence supporting the link between the use of the independent strategy of problem-solving and exercise adherence is limited. The overall purpose of this dissertation was to examine problem-solving relative to exercise-lapse related problems. Using two theoretical frameworks that offer insight into problem-solving (Model of Social Problem-Solving and Social Cognitive Theory), three studies were conducted to examine proposed relationships in various asymptomatic and symptomatic exercising samples. In Study 1A, relationships between self-regulatory efficacy (SRE) for exercise and problem-solving approach (task-diagnostic and self-diagnostic) were explored in a sample of exercising university students (n = 79). Results indicated that SRE beliefs were significantly and (1) positively related to task-diagnostic problem-solving approach and (2) negatively related to self-diagnostic problem-solving approach. In Study 1B, relationships between problem-solving effectiveness and exercise-related social cognitions were examined in the same sample. Findings demonstrated that problem-solving effectiveness was positively associated with social cognitive correlates of exercise adherence linked to adaptation. Relationships demonstrated in Study 1 provide preliminary support for previously unexamined problem-solving research questions relative to exercise. In Study 2, relationships between problem-solving effectiveness and exercise-related social cognitions (self-efficacy and persistence) were examined in a sample of exercising cardiac rehabilitation initiates (n = 52). These relationships were considered relative to two distinct components of the problem-solving process (seeking solutions to problems and carrying out solutions), which have not previously been examined relative to exercise lapses. Findings indicated significant relationships between problem-solving effectiveness and (a) self-efficacy for problem-solving (seeking solutions to problems), (b) persistence with problem-solving, (c) self-efficacy for solution implementation (carrying out solutions) and (d) persistence with solution implementation. In Study 3, problem-solving was examined among exercising cancer survivors (n = 35) with cancer-related fatigue, a problematic exercise barrier. Partial support was demonstrated for differences between more and less effective problem-solvers on fatigue-related variables. An under-examined area in problem-solving research was also examined in this study; the relationship between problem-solving and positive psychological functioning. Findings indicated significant differences for positive psychological functioning between individuals with higher and lower positive problem orientation. Taken together, the three studies represent an initial attempt to advance exercise and problem-solving literature by illustrating important theoretical relationships in three samples of exercisers, and addressing important gaps in the exercise and problem-solving literature. In regard to the latter point, the research was the first to examine (a) variables that may link problem-solving to exercise adherence, (b) two distinct components of the problem-solving process relative to an exercise lapse situation, and (c) potential links between problem-solving and selected positive psychological outcomes. Future research directions relative to problem-solving and exercise are suggested as possible next steps to advance this preliminary research.

<p>My dissertation focuses on employing microeconomic techniques to study markets and questions that are important and complex, and also have potential policy implications. Two of my chapters analyze the health industry with an emphasis on hospitals, patient welfare, and regulation. The remaining chapter focuses on the housing market in Los Angeles and explores real estate flipping.</p><p>The second chapter of my dissertation studies the impact of state level regulations on hospital bed capacity decisions. The regulations are intended to decrease hospital investments without diminishing patient access. I find that the regulation decreases total hospital investment in bed capacity as expected. When running simulations to estimate how hospitals would behave differently were the regulatory policy changed, I find that total patient utility is negatively affected by the presence of the regulation as many patients get turned away from their preferred hospital due to overcrowding. This analysis has important policy implications as it suggests that the regulation has been ineffective in ensuring that patient welfare was unharmed by the restrictions.</p><p>The third chapter is based on joint research with Patrick Bayer and James W. Roberts and studies the housing market in the Los Angeles metropolitan area from 1988 to 2009. Using novel data, I identify which housing transactions involve flippers who aim not to live in the house, but rather to quickly resell it for financial gain. I find that flipper behavior varies based on how frequently I observe the individual engage in such behavior. Experienced flippers, who are observed to flip many houses in the data, target homes being sold at below market value and earn their returns from buying them at a discount. Their effect on long term prices in the neighborhood is negligable. Inexperienced flippers who are less active, seek to earn their profits by timing the market and are more active when house prices were rapidly appreciating from 1999 to 2005. Their activity increases housing prices in the neighborhood in the short term, but decreases them in the long term. Such results are consistent with the claim that real estate flipping contributed to the housing bubble.</p><p>The fourth chapter of my dissertation again focuses on the hospital industry and looks at the question of how patient composition changes as a hospital becomes busier and has to turn patients away. I develop a theoretical model which predicts that hospitals are more likely to turn away less profitable patients. As a result, when a hospital becomes more full and therefore is more likely to have to turn patients away, its composition of patients will change and become more profitable on the whole. I test this theory by empirically analyzing the effect of hospital congestion on the composition of hospital patients using hospital discharge data. The findings are consistent with my theoretical model as when hospitals become more crowded, the fraction of uninsured patients and mental health patients (who are typically not profitable to a hospital) decreases. This result suggests that hospitals are more likely to turn away unprofitable patients while continuing to admit more profitable patients.</p> / Dissertation

Numerous studies have demonstrated that tumour cells have the ability to alter immune function to create an immune suppressed environment. This allows tumour cells to escape immune surveillance and consequently the tumour can progress. Dendritic and T cells have critical roles in immune activation and tolerance and are thus major targets of tumour-mediated immune suppression. Understanding the mechanism(s) by which tumour cells modulate the immune system will facilitate the development of immune system-based therapies for cancer treatments. In this study we sought to determine the nature of, and cellular and molecular mechanisms underlying, changes in immune status during tumour progression using mouse models of prostate cancer. Detailed analysis of the immunological status in a mouse prostate dysplasia model (12T-7slow) revealed that immune suppression accompanied tumour progression. We found that T cells isolated from tumour-bearing hosts were hypo-responsive to antigen stimulation. Furthermore, we demonstrated that CD4+CD25+ regulatory T cells were responsible, at least in part, for this alteration. Anti-CD25 antibody treatment reduced, but did not prevent, tumour growth in either a transplanted prostate tumour model or a spontaneously developing prostate tumour model. In addition, an altered dendritic cell phenotype and an elevated frequency of CD4+CD25+ regulatory T cells were observed within the tumour mass. Similar alterations were observed in the prostate-specific Pten knockout mice which develop advanced prostate adenocarcinoma. Interestingly, evidence of immune activation, such as an increased frequency of activated T cells, was detected in the tumour microenvironment in both mouse prostate tumour models. To identify factors that may play critical roles in the altered immune cell phenotype observed in the tumour microenvironment, a global gene expression profiling analysis was carried out to evaluate the changes in immune-related gene expression patterns. This analysis provided additional evidence for the co-existence of immune suppression and immune activation. Moreover, subsequent analyses suggested that one differentially expressed transcript, interferon regulatory factor 7, and its target genes might be involved in modulating immune cells and/or tumour progression. Taken together, these studies have important implications for designing specific and effective anti-tumour immune therapy strategies that involve manipulation of tumour cells, dendritic cells and regulatory T cells.

In the past decade, fast advancements have been made in the sequencing, digitalization and collection of the biological data. However the bottleneck remains at the point of analysis and extraction of patterns from the data. We have developed a method that is aimed at widening this bottleneck by automating the knowledge extraction from the biological data. Our approach is aimed at discovering patterns in a set of DNA sequences based on the location of transcription factor binding sites or any other biological markers with the emphasis of discovering relationships. A variety of statistical and computational methods exists to analyze such data. However, they either require an initial hypothesis, which is later tested, or classify the data based on its attributes. Our approach does not require an initial hypothesis and the classification it produces is based on the relationships between attributes. The value of such approach is that is is able to uncover new knowledge about the data by inducing a general theory based on basic known rules. The core of our approach lies in an inductive logic programming engine, which, based on positive and negative examples as well as background knowledge, is able to induce a descriptive, human-readable theory, describing the data. An application provides an end-to-end analysis of DNA sequences. A simple to use Web interface accepts a set of related sequences to be analyzed, set of negative example sequences to contrast the main set (optional), and a set of possible genetic markers as position-specific scoring matrices. A Java-based backend formats the sequences, determines the location of the genetic markers inside them and passes the information to the ILP engine, which induces the theory. The model, assumed in our background knowledge, is a set of basic interactions between biological markers in any DNA sequence. This makes our approach applicable to analyze a wide variety of biological problems, including detection of cis-regulatory modules and analysis of ChIP-Sequencing experiments. We have evaluated our method in the context of such applications on two real world datasets as well as a number of specially designed synthetic datasets. The approach has shown to have merit even in situations when no significant classification could be determined.

Hematopoietic systems in vertebrates have been the focus of intense study. However immunocyte development is well characterized in very few invertebrate groups. The sea urchin is an attractive model for the study of immune cell development. Larval immunocytes, pigment cells and derivatives of the blastocoelar cells, emerge from a small population of precursors specified at blastula stage. Analyses from the genome reveal a complex system of immune receptors and effectors and a near complete set of homologues of vertebrate transcriptional regulators. Characterization of the expression profile and function of sea urchin homologues of key vertebrate hematopoietic transcription factors imply a conserved role in immunocyte development. SpGatac, an orthologue of the vertebrate Gata-1/2/3 transcription factors and SpScl, an orthologue of Scl/Tal-2/Lyl-1 transcription factors are both required for immune cell specification in the embryo. An important cis-regulatory mechanism that restricts SpGatac expression to the blastocoelar cells involves repression by SpGcm in the pigment cells. Characterization of the expression of several additional transcription factors, including SpE2A, an orthologue of vertebrate E2A/HEB/ITF2, SpId, an orthologue of the Class V bHLH factors that modulate E-protein function, and SpLmo2, an orthologue of the cofactor part of the transcriptional complex that includes Scl and Gata family members, suggests the existence of a conserved regulatory complex for hematopoiesis. Two isoforms of the SpE2A gene were identified. The shorter isoform shares genomic organization and sequence conservation with the mouse paralogue of E2A, HEBAlt. Expression of SpE2A and SpE2AAlt is consistent with a function in immunocyte development in the sea urchin embryo. Findings of the counterpart to a key vertebrate regulatory system functioning in the development of immunocytes in the simple sea urchin embryo lay the foundation for comparative immunocyte developmental gene regulatory network analyses. These will in turn lead to a greater understanding of the evolution of immune systems across phyla and will provide simple invertebrate model systems for detailed comparative investigations of regulatory function with direct relevance to vertebrates.