Increased interleukin-10 production by ASC-deficient CD4(+) T cells impairs bystander T-cell proliferation.

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important component of the inflammasome, functioning as an adaptor protein that facilitates the recruitment and activation of procaspases that in turn promote the maturation of interleukin-1β (IL-1β) and IL-18. Despite initial focus on the inflammatory properties of ASC there is emerging evidence that highlights the importance of ASC in facilitating adaptive immune responses. However, the cellular and molecular basis for the involvement of ASC in adaptive immunity remains largely unexplored. We have previously demonstrated that activated ASC-deficient T cells have dampened proliferative responses. We have therefore explored the underlying cellular mechanism(s) by which ASC regulates T-cell proliferation. We show that under activating conditions (anti-CD3/CD28 stimulation) in bulk T-cell cultures the presence of ASC(-/-)  CD4(+) T cells is sufficient to suppress the proliferative responses of neighbouring T cells. Furthermore, ASC(-/-)  CD4(+) T cells upon activation exhibit a suppressive cytokine profile, with elevated production of IL-10 and reduced secretion of T helper type 1 cytokines, interferon-γ and IL-2. This increase in IL-10 secretion within the activated ASC(-/-)  CD4(+) T-cell compartment was not associated with a proportional increase in conventional Foxp3(+) regulatory T (Treg) cells. Interestingly, when equal numbers of fluorescence-activated cell sorted ASC(+/+) and ASC(-/-) Treg cells (CD4(+)  CD44(intermediate/high)  CD25(+) ) were activated in vitro, the ASC(-/-) fraction produced significantly more IL-10 than their wild-type counterparts, suggesting that ASC(-/-) Treg cells have greater suppressive capacity. Collectively, these results imply that the ASC may influence the development and functioning of Treg cells.

Modeling and Simulation ofReal-Time System as a Tool to Improve Capacity Management - Case Fenix

Tämän tutkimustyön kohteena on TietoEnator Oy:n kehittämän Fenix-tietojärjestelmän kapasiteettitarpeen ennustaminen. Työn tavoitteena on tutustua Fenix-järjestelmän eri osa-alueisiin, löytää tapa eritellä ja mallintaa eri osa-alueiden vaikutus järjestelmän kuormitukseen ja selvittää alustavasti mitkä parametrit vaikuttavat kyseisten osa-alueiden luomaan kuormitukseen. Osa tätä työtä on tutkia eri vaihtoehtoja simuloinnille ja selvittää eri vaihtoehtojen soveltuvuus monimutkaisten järjestelmien mallintamiseen. Kerätyn tiedon pohjaltaluodaan järjestelmäntietovaraston kuormitusta kuvaava simulaatiomalli. Hyödyntämällä mallista saatua tietoa ja tuotantojärjestelmästä mitattua tietoa mallia kehitetään vastaamaan yhä lähemmin todellisen järjestelmän toimintaa. Mallista tarkastellaan esimerkiksi simuloitua järjestelmäkuormaa ja jonojen käyttäytymistä. Tuotantojärjestelmästä mitataan eri kuormalähteiden käytösmuutoksia esimerkiksi käyttäjämäärän ja kellonajan suhteessa. Tämän työn tulosten on tarkoitus toimia pohjana myöhemmin tehtävälle jatkotutkimukselle, jossa osa-alueiden parametrisointia tarkennetaan lisää, mallin kykyä kuvata todellista järjestelmää tehostetaanja mallin laajuutta kasvatetaan.

Screening of papaya accessions resistant to Papaya lethal yellowing virus and capacity of Tetranychus urticae to transmit the virus

The objective of this work was to produce a polyclonal antiserum against the coat protein (CP) of Papaya lethal yellowing virus (PLYV) and to determine its specificity and sensibility in the diagnosis of the virus, as well as to evaluate the genetic resistance to PLYV in papaya (Carica papaya) accessions and to investigate the capacity of the two-spotted spider mite Tetranychus urticae to acquire and transmit PLYV to the plants. Sixty-five papaya accessions were evaluated. For each accession, ten plants were mechanically inoculated using PLYV-infected plant extracts, and three plants were mock inoculated with phosphate buffer alone and used as negative controls. Ninety days after inoculation, newly-emerging systemic leaves were collected from the inoculated plants, and viral infection was diagnosed by indirect Elisa, using polyclonal antiserum sensible to the in vitro-expressed PLYV CP. Viral transmission by T. urticae was evaluated in greenhouse. The experiments were repeated twice. Polyclonal antiserum recognized the recombinant PLYV CP specifically and discriminated PLYV infection from infections caused by other plant viruses. Out of the 65 papaya accessions evaluated, 15 were considered resistant, 18 moderately resistant, and 32 susceptible. The two-spotted spider mite T. urticae was capable of acquiring PLYV, but not of transmitting it to papaya.

Absorptive capacity and the effect of social integration mechanisms in knowledge utilization

Tiedosta on tullut määräävä tekijä yrityksensuorituskyvylle. Yritykset hankkivat aktiivisesti uutta tietoa ulkoisesta ympäristöstään ja tallentavat sitä tietokantoihinsa. Uusi tieto on innovaatioiden ja uusien ideoiden peruselementti. Uudet ideat pitää myös kaupallistaa, jotta niiden avulla voidaan hankkia kilpailuetua. Absorptiivisen kapasiteetin malli yhdistää tiedon prosessointiin liittyvät kyvykkyydet, jotka vaikuttavat yrityksen kykyyn hyödyntää tietoa tehokkaasti. Ennen kuin tietoa voidaan käyttää uusien tuotteiden ja palveluiden luomiseen, täytyy sitä jakaa yrityksessä ja muuttaa se yrityksen toimintaa palvelevaksi. Aiemmissa tutkimuksissa innovaatiot ovat vahvasti liitetty yrityksen kykyyn uudistua. Tämä pro gradu -tutkielma tutkii sosiaalisten integraatiomekanismien vaikutusta potentiaalisen absorptiivisen kapasiteetin muuttamiseen toteutuneeksi absorptiiviseksi kapasiteetiksi. Yksilöiden ja osastojen välisen yhteistyön sekä luottamuksen vaikutus tiedon sisäistämiseen tutkittiin. Tutkielma pohjautuu monikansallisessa yrityksessä keväällä 2006 suoritettuun uudistumiskyky-tutkimukseen. Tutkielma keskittyy yrityksen kykyyn uudistua uuden tiedon ja innovaatioiden avulla. Tutkielma on kvantitatiivinen tapaustutkimus. Tutkielmassa tehtyjen havaintojen mukaan sosiaaliset integraatiomekanismit ovat tärkeitä uuden tiedon hyödyntämisessä. Tiedon eksplisiittyyden havaitaan vaikuttavan tiedon muuttamiseen yritykselle hyödylliseksi resurssiksi.

Adaptive changes in a radial maze task: Efficient selection of baited arms with reduced foraging in senescent hooded rats

Qualitative differences in strategy selection during foraging in a partially baited maze were assessed in young and old rats. The baited and non-baited arms were at a fixed position in space and marked by a specific olfactory cue. The senescent rats did more re-entries during the first four-trial block but were more rapid than the young rats in selecting the reinforced arms during the first visits. Dissociation between the olfactory spatial cue reference by rotating the maze revealed that only few old subjects relied on olfactory cues to select the baited arms and the remainder relied mainly on the visuo-spatial cues.

Diving capacity and foraging behaviour of the water shrew (Neomys fodiens)

With regard to semi-aquatic mammals, Schröpfer & Stubbe (1992) distinguished three riparian guilds: the herbivores with the water vole and the beaver; the megacarnivores with the mink and the otter; and the macrocarnivores with water shrews and desmans. Among water shrews, the evolution of aquatic foraging behaviour occurred several times: Nectogale and Chimarrogale in Asia, several species of the genus Sorex in America, and Neomys in Eurasia (Churchfield, 1990). The fairly common European water shrew N. fodiens is the best known. However, the reports on the degree of adaptation to the water habitat are conflicting. Therefore some important findings from the literature are reviewed in this introduction, whereas new data are presented in the following sections. The swimming locomotion of water shrews was analysed by Ruthardt & Schröpfer (1985) and Köhler (1991), and the related morphological adaptation were reviewed by Hutterer (1985) and Churchfield (this volume pp. 49-51). They obviously present a compromise between the requirements for activity on land and in the water. Thermoregulation is a major problem for semi-aquatic mammals, because heat conductance in water is 25-fold greater than in air (Calder, 1969). According to this author, the body temperature of immersed American Sorex palustris dropped by a rate of 2.8 °C per min. However, this may be an experimental artefact, because Neomys fodiens can maintain its body temperature at 37 °C during an immersion of 6 min (Vogel, 1990).

Immunology of viral disease, how to curb persistent infection

1. 1. Summaries 1.1. Preamble and extended abstract The present thesis dissertation addresses the question of antiviral immunity from the particular standpoint of the adaptive T cell-mediated immune response. The experimental work is presented in the form of three published articles (two experimental articles and one review article, see sections 4.1, 4.2 and 4.3 on pages 73, 81 and 91, respectively), describing advances both in our understanding of viral control by CD8 T lymphocytes, and in vaccine development against the Human Immunodeficiency Virus Type 1 (HIV-1). Because the articles focus on rather specialized areas of antiviral immunity, the article sections are preceded by a general introduction (section 3) on the immune system in general, and on four viruses that were addressed in the experimental work, namely HIV-1, Cytomegalovirus (CMV), Epstein Barr Virus (EBV) and Influenzavirus (Flu). This introduction section is aimed at providing a glimpse on viral molecular biology and immunity, to help the hypothetical non-expert reader proceeding into the experimental part. For this reason, each section is presented as individual entity and can be consulted separately. The four viruses described are of peculiar relevance to immunity because they induce an array of opposite host responses. Flu causes a self limiting disease after which the virus is eradicated. CMV and EBV cause pauci-symptomatic or asymptomatic diseases after which the viruses establish lifelong latency in the host cells, but are kept in check by immunity. Eventually, HIV-1 establishes both latency - by inserting its genome into the host cell chromosome - and proceeds in destroying the immune system in a poorly controlled fashion. Hence, understanding the fundamental differences between these kinds of viral host interactions might help develop new strategies to curb progressive diseases caused by viruses such as HIV-1. Publication #1: The first article (section 4.1, page 73) represents the main frame of my laboratory work. It analyses the ability of CD8 T lymphocytes recovered from viral-infected patients to secrete interferon γ (IFN-γ) alone or in conjunction with interleukin 2 (IL-2) when exposed in vitro to their cognate viral antigens. CD8 T cells are instrumental in controlling viral infection. They can identify infected cells by detecting viral antigens presented at the surface of the infected cells, and eliminate both the cell and its infecting virus by triggering apoptosis and/or lysis of the infected cell. Recognition of these antigens triggers the cognate CD8 cells to produce cytokines, including IFN-γ and IL-2, which in turn attract and activate other pro-inflammatory cells. IFN-γ triggers both intrinsic antiviral activity of the infected cells and distant activation of pro-inflammatory cells, which are important for the eradication of infection. IL-2 is essential for clonal expansion of the antigen (Ag)-specific CD8 T cell. Hence the existence of Ag-specific CD8 cells secreting both IFN-γand IL-2 should be beneficial for controlling infection. In this first work we determined the percentage of IFN-y/IL-2 double positive and single IFN-γsecreting CD8 T cells against antigens HIV-1, CMV, EBV and Flu in three groups of subjects: (i) HIV-1 infected patients progressing to disease (progressors), (ii) HIV-1-infected subjects not progressing to disease (long-term non progressors or LTNP), and (iii) HIV negative blood donors. The results disclosed a specific IFN-y/IL-2 double positive CD8 response in all subjects able to control infection. In other words, IFN-y/IL-2 double positive CD8 cells were present in virus-specific CD8 T cells against Flu, CMV and EBV as well against HIV-1 in LTNP. In contrast, progressors only had single IFN-γsecreting CD8 T cells. Hence, the ability to develop an IFN-y/IL-2 double positive response might be critical to control infection, independently of the nature of the virus. Additional experiments helped identify the developmental stage of the missing cells (using different markers such as CD45RA and CCR7) and showed a correlation between the absence of IL-2 secreting CD8 T cells and a failure in the proliferation capacity of virus-specific CD8 T cells. Addition of exogenous IL-2 could restore clonal expansion of HIV-1 specific CD8 T cells, at least in vitro. It could further been shown, that IL-2 secreting CD8 T cells are sufficient to support proliferation even in absence of CD4 help. However, the reason for the missing IFN-y/IL-2 double positive CD8 T cell response in HIV-1 progessors has yet to be determined. Publication #2: The second article (section 4.2, page 81) explores new strategies to trigger CD8 T cell immunity against specific HIV-1 proteins believed to be processed and exposed as "infection signal" at the surface of infected cells. Such signals consist of peptide fragments (8- 13 amino acids) originating from viral proteins and presented to CD8 T cells in the frame of particular cell surface molecules of the major histocompatibility complex class I* (MHC I). To mimic "natural" viral infection, the HIV-1 polyprotein Gagpolnef was inserted and expressed in either of two attenuated viruses i.e. vaccinia virus (MVA) or poxvirus (NYVAC). Mice were infected with these recombinant viruses and specific CD8 T cell response to Gagpolnef peptides was sought. Mice could indeed mount a CD8 T cell response against the HIV-1 antigens, indicating that the system worked, at least in this animal model. To further test whether peptides from Gagpolnef could also be presented in the frame of the human MHC class I proteins, a second round of experiments was performed in "humanized" transgenic mice expressing human MHC molecules. The transgenic mice were also able to load Gagpolnef peptides on their human MHC molecule, and these cells could be detected and destroyed by Ag-specific CD8 T cells isolated from HIV-1-infected patients. Therefore, expressing Gagpolnef on attenuated recombinant viruses might represent a valid strategy for anti-HIV-1 immunization in human. Publication #3: This is a review paper (section 4.3, page 91) describing the immune response to CMV and newly developed methods to detect this cellular immune response. Some of it focuses on the detection of T cells by using in vitro manufactured tetramers. These consist of four MHC class I molecules linked together and loaded with the appropriate antigenic peptide. The tetramer can be labeled with a fluorochrome and analyzed with a fluorescence-activated cell sorter. Taken together, the work presented indicates that (i) an appropriate CD8 T cell response consisting of IFN-y/IL-2 double positive effectors, can potentially control viral infection, including HIV-1 infection, (ii) such a response might be triggered by recombinant viral vaccines, and (iii) CD8 T cell response can be monitored by a variety of techniques, including recently-developed MHC class I tetramers. 1. 2. Préambule et résumé élargi Le présent travail de thèse s'intéresse à l'immunité antivirale du point de vue particulier de la réponse adaptative des cellules T. Le travail expérimental est présenté sous la forme de trois articles publiés (2 articles expérimentaux et 1 article de revue, voir sections 4.1, 4.2 et 4.3, pages 58, 66 et 77, respectivement), décrivant des progrès dans la compréhension du contrôle de l'infection virale par les lymphocytes T CD8, ainsi que dans le développement de nouveaux vaccins contre le Virus d'Immunodéficience de Humaine de type 1 (VIH-1). En raison du caractère spécialisé de l'immunité antivirale de type cellulaire, les articles sont précédés par une introduction générale (section 3), dont le but est de pourvoir le lecteur non avisé avec des bases nécessaire à une meilleure appréhension du travail expérimental. Cette introduction présente les grandes lignes du système immunitaire, et décrit de façon générale les 4 virus utilisés dans le travail expérimental: à savoir le virus VIH-1, le Cytomégalovirus (CMV), le virus Epstein Barr (EBV) et le virus Influenza A (Flu). Toutes les sections sont présentées de façon individuelle et peuvent être consultées séparément. La description des 4 virus a une pertinence particulière quant à leur interaction avec le système immun. En effet, ils induisent une panoplie de réponses immunitaires s'étendant aux extrêmes de la réaction de l'hôte. Influenza A est à l'origine d'une maladie cytopathique aiguë, au décours de laquelle le virus est éradiqué par l'hôte. CMV et EBV sont classiquement à l'origine d'infections pauci-symptomatiques, voire asymptomatiques, après lesquelles les virus persistent de façon latente dans la cellule hôte. Cependant, ils restent sous le contrôle du système immun, qui peut prévenir une éventuelle réactivation. Enfin, VIH-1 s'établit à la fois en infection latente - par l'insertion de son génome dans le chromosome des cellules hôtes - et en infection productive et cytopathique, échappant au contrôle immunitaire et détruisant ses cellules cibles. La compréhension des différences fondamentales entre ces différents types d'interactions virus-hôte devraient faciliter le développement de nouvelles stratégies antivirales. Article 1: Le premier article (section 4.1 Page 58) représente l'objet principal de mon travail de laboratoire. Il analyse la capacité des lymphocytes T CD8 spécifiques de différent virus à sécréter de l'interféron gamma (IFN-y) et/ou de l'interleukine 2 (IL-2) après stimulation par leur antigène spécifique. Les cellules T CD8 jouent un rôle crucial dans le contrôle des infections virales. Elles identifient les cellules infectées en détectant des antigènes viraux présentés à la surface de ces mêmes cellules, et éliminent à la fois les cellules infectées et les virus qu'elles contiennent en induisant l'apoptose et/ou la lyse des cellules cibles. Parallèlement, l'identification de l'antigène par la cellule T CD8 la stimule à sécréter des cytokines. L'IFN-γen est un exemple. L'IFN-γ stimule les cellules infectées à développer une activé antivirale intrinsèque. De plus, il attire sur place d'autres cellules de l'inflammation, et active leur fonction d'éradication des pathogènes. L'IL-2 est un autre exemple. L'IL-2 est essentielle à l'expansion clonale des cellules T CD8 spécifiques à un virus donné. Elle est donc essentielle à augmenter le pool de lymphocytes antiviraux. En conséquence, la double capacité de sécréter de l'IFN-γ et de IL-2 pourrait être un avantage pour le contrôle antiviral par les cellules T CD8. Dans ce travail nous avons comparé les proportions de lymphocytes T CD8 doubles positifs (IFN-γ/IL-2) et simples positifs (IFN-γ) chez trois groupes de sujets: (i) des patients infectés par VIH-1 qui ne contrôlent pas l'infection (progresseurs), (ii) des patients infectés par VIH-1, mais contrôlant l'infection malgré l'absence de traitement ("long term non progressors" [LTNP]) et (iii) des donneurs de sang négatifs pour l'infection à VIH-1. Les résultats ont montré que les individus capables de contrôler une infection possédaient des cellules T CD8 doubles positifs (IFN-γ/IL-2), alors que les patients ne contrôlant pas l'infection procédaient prioritairement des CD8 simples positifs (IFN-γ). Spécifiquement, les lymphocytes T spécifiques pour Flu, CMV, EBV, et VII-1-1 chez les LTNP étaient tous IFN-γ/IL-2 doubles positifs. Au contraire, les lymphocytes T CD8 spécifique à VIH-1 étaient IFN-γ simples positifs chez les progresseurs. La capacité de développer une réponse IFN-γ/IL-2 pourraient être primordiale pour le contrôle de l'infection, indépendamment de la nature du virus. En effet, il a été montré que l'absence de sécrétion d'IL2 par les lymphocytes T CD8 corrélait avec leur incapacité de proliférer. Dans nos mains, cette prolifération a pu être restaurée in vitro par l'adjonction exogène d'IL-2. Toutefois, la faisabilité de ce type de complémentation in vivo n'est pas claire. Des expériences additionnelles ont permis de préciser de stade de développement des lymphocytes doubles positifs et simples positifs par le biais des marqueurs CD45RA et CCR7. Il reste maintenant à comprendre pourquoi certains lymphocytes T CD8 spécifiques sont incapables à sécréter de l'IL-2. Article 2: Le deuxième article explore des nouvelles stratégies pour induire une immunité T CD8 spécifique aux protéines du VIH-1, qui sont édités et exposés à la surface des cellules infectées. Ces signaux consistent en fragments de peptide de 8-13 acide aminés provenant de protéines virales, et exposées à la surface des cellules infectées dans le cadre des molécules spécialisées d'histocompatibilité de classe I (en anglais "major histocompatibility class I" ou MHC I). Pour mimer une infection virale, la polyprotéine Gagpolnef du VIH-1 a été insérée et exprimée dans deux vecteurs viraux atténués, soit MVA (provenant de vaccinia virus) ou NYVAC (provenant d'un poxvirus). Ensuite des souris ont été infectées avec ces virus recombinants et la réponse T CD8 aux peptides issus de Gagpolnef a été étudiée. Les souris ont été capables de développer une réponse de type CD8 T contre ces antigènes du VIH-1. Pour tester si ces antigènes pouvaient aussi être présentés par dans le cadre de molécules MHC humaines, des expériences supplémentaires ont été faites avec des souris exprimant un MHC humain. Les résultats de ces manipulations ont montré que des cellules T CD8 spécifique aux protéines du VIH pouvaient être détectées. Ce travail ouvre de nouvelles options quant à l'utilisation des virus recombinants exprimant Gagpolnef comme stratégie vaccinale contre le virus VIH-I chez l'homme. Article 3: Ces revues décrivent la réponse immunitaire à CMV ainsi que des nouvelles méthodes pouvant servir à sa détection. Une partie du manuscrit décrit la détection de cellule T à l'aide de tétramères. Il s'agit de protéines chimériques composées de 4 quatre molécules MHC liées entre elles. Elles sont ensuite "chargées" avec le peptide antigénique approprié, et utilisée pour détecter les cellules T CD8 spécifiques à ce montage. Elles sont aussi marquées par un fluorochrome, qui permet une analyse avec un cytomètre de flux, et l'isolement ultime des CD8 d'intérêt. En résumé, le travail présenté dans cette thèse indique que (i) une réponse T CD8 appropriée - définie par la présence des cellules effectrices doublement positives pour l'IFN-γ et l'IL-2 - semble indispensable pour le contrôle des infections virales, y compris par le VIH-1, (ii) une telle réponse peut être induite par des vaccin viral recombinant, et (iii) la réponse T CD8 peut être analysée et suivie grâce à plusieurs techniques, incluant celle des tétramères de MHC class I. 1.3. Résumé pour un large public Le système immunitaire humain est composé de différents éléments (cellules, tissus et organes) qui participent aux défenses de l'organisme contre les pathogènes (bactéries, virus). Parmi ces cellules, les lymphocytes T CD8, également appelés cellules tueuses, jouent un rôle important dans la réponse immunitaire et le contrôle des infections virales. Les cellules T CD8 reconnaissent de manière spécifique des fragments de protéines virales qui sont exposés à la surface des cellules infectées par le virus. Suite à cette reconnaissance, les cellules T CD8 sont capables de détruire et d'éliminer ces cellules infectées, ainsi que les virus qu'elles contiennent. Dans le contexte d'une infection par le virus de l'immunodéficience humaine (VIH), le virus responsable du SIDA, il a pu être montré que la présence des cellules T CD8 est primordiale. En effet, en l'absence de ces cellules, les individus infectés par le VIH progressent plus rapidement vers le SIDA. Au cours de la vie, l'Homme est exposé à plusieurs virus. Mais à l'opposé du VIH, certains d'entre eux ne causent pas des maladies graves : par exemple le virus de la grippe (Influenza), le cytomégalovirus ou encore le virus d'Epstein-Barr. Certains de ces virus peuvent être contrôlés et éliminés de l'organisme (p. ex. le virus de la grippe), alors que d'autres ne sont que contrôlés par notre système immunitaire et restent présents en petite quantité dans le corps sans avoir d'effet sur notre santé. Le sujet de mon travail de thèse porte sur la compréhension du mécanisme de contrôle des infections virales par le système immunitaire : pourquoi certains virus peuvent être contrôlés ou même éliminés de l'organisme alors que d'autres, et notamment le VIH, ne le sont pas. Ce travail a permis de démontrer que les cellules T CD8 spécifiques du VIH ne sécrètent pas les mêmes substances, nécessaires au développement d'une réponse antivirale efficace, que les cellules T CD8 spécifiques des virus contrôlés (le virus de la grippe, le cytomégalovirus et le virus d'Epstein-Barr). Parallèlement nous avons également observé que les lymphocytes T CD8 spécifiques du VIH ne possèdent pas la capacité de se diviser. Ils sont ainsi incapables d'être présents en quantité suffisante pour assurer un combat efficace contre le virus du SIDA. La (les) différence(s) entre les cellules T CD8 spécifiques aux virus contrôlés (grippe, cytomégalovirus et Epstein-Barr) et au VIH pourront peut-être nous amener à comprendre comment restaurer une immunité efficace contre ce dernier.

On the innovation capacity of technologyrelated knowledge-intensive business services. A case study of the technology and engineering consulting (TEC) sector in Singapore

Even though the research on innovation in services has expanded remarkably especially during the past two decades, there is still a need to increase understanding on the special characteristics of service innovation. In addition to studying innovation in service companies and industries, research has also recently focused more on services in innovation, as especially the significance of so-called knowledge intensive business services (KIBS) for the competitive edge of their clients, othercompanies, regions and even nations has been proved in several previous studies. This study focuses on studying technology-based KIBS firms, and technology andengineering consulting (TEC) sector in particular. These firms have multiple roles in innovation systems, and thus, there is also a need for in-depth studies that increase knowledge about the types and dimensions of service innovations as well as underlying mechanisms and procedures which make the innovations successful. The main aim of this study is to generate new knowledge in the fragmented research field of service innovation management by recognizing the different typesof innovations in TEC services and some of the enablers of and barriers to innovation capacity in the field, especially from the knowledge management perspective. The study also aims to shed light on some of the existing routines and new constructions needed for enhancing service innovation and knowledge processing activities in KIBS companies of the TEC sector. The main samples of data in this research include literature reviews and public data sources, and a qualitative research approach with exploratory case studies conducted with the help of the interviews at technology consulting companies in Singapore in 2006. These complement the qualitative interview data gathered previously in Finland during a larger research project in the years 2004-2005. The data is also supplemented by a survey conducted in Singapore. The respondents for the survey by Tan (2007) were technology consulting companies who operate in the Singapore region. The purpose ofthe quantitative part of the study was to validate and further examine specificaspects such as the influence of knowledge management activities on innovativeness and different types of service innovations, in which the technology consultancies are involved. Singapore is known as a South-east Asian knowledge hub and is thus a significant research area where several multinational knowledge-intensive service firms operate. Typically, the service innovations identified in the studied TEC firms were formed by several dimensions of innovations. In addition to technological aspects, innovations were, for instance, related to new client interfaces and service delivery processes. The main enablers of and barriers to innovation seem to be partly similar in Singaporean firms as compared to the earlier study of Finnish TEC firms. Empirical studies also brought forth the significance of various sources of knowledge and knowledge processing activities as themain driving forces of service innovation in technology-related KIBS firms. A framework was also developed to study the effect of knowledge processing capabilities as well as some moderators on the innovativeness of TEC firms. Especially efficient knowledge acquisition and environmental dynamism seem to influence the innovativeness of TEC firms positively. The results of the study also contributeto the present service innovation literature by focusing more on 'innovation within KIBs' rather than 'innovation through KIBS', which has been the typical viewpoint stressed in the previous literature. Additionally, the study provides several possibilities for further research.

Artificially Intelligent and Adaptive Methods for Prediction and Analysis of Superheater Fireside Corrosion in Fluidized Bed Boilers

Superheater corrosion causes vast annual losses for the power companies. With a reliable corrosion prediction method, the plants can be designed accordingly, and knowledge of fuel selection and determination of process conditions may be utilized to minimize superheater corrosion. Growing interest to use recycled fuels creates additional demands for the prediction of corrosion potential. Models depending on corrosion theories will fail, if relations between the inputs and the output are poorly known. A prediction model based on fuzzy logic and an artificial neural network is able to improve its performance as the amount of data increases. The corrosion rate of a superheater material can most reliably be detected with a test done in a test combustor or in a commercial boiler. The steel samples can be located in a special, temperature-controlled probe, and exposed to the corrosive environment for a desired time. These tests give information about the average corrosion potential in that environment. Samples may also be cut from superheaters during shutdowns. The analysis ofsamples taken from probes or superheaters after exposure to corrosive environment is a demanding task: if the corrosive contaminants can be reliably analyzed, the corrosion chemistry can be determined, and an estimate of the material lifetime can be given. In cases where the reason for corrosion is not clear, the determination of the corrosion chemistry and the lifetime estimation is more demanding. In order to provide a laboratory tool for the analysis and prediction, a newapproach was chosen. During this study, the following tools were generated: · Amodel for the prediction of superheater fireside corrosion, based on fuzzy logic and an artificial neural network, build upon a corrosion database developed offuel and bed material analyses, and measured corrosion data. The developed model predicts superheater corrosion with high accuracy at the early stages of a project. · An adaptive corrosion analysis tool based on image analysis, constructedas an expert system. This system utilizes implementation of user-defined algorithms, which allows the development of an artificially intelligent system for thetask. According to the results of the analyses, several new rules were developed for the determination of the degree and type of corrosion. By combining these two tools, a user-friendly expert system for the prediction and analyses of superheater fireside corrosion was developed. This tool may also be used for the minimization of corrosion risks by the design of fluidized bed boilers.

Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

Background: Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements. Results: We first present a new method for globally optimizing nonlinear models of metabolic pathways that are based on the Generalized Mass Action (GMA) representation. The optimization task is posed as a nonconvex nonlinear programming (NLP) problem that is solved by an outer- approximation algorithm. This method relies on solving iteratively reduced NLP slave subproblems and mixed-integer linear programming (MILP) master problems that provide valid upper and lower bounds, respectively, on the global solution to the original NLP. The capabilities of this method are illustrated through its application to the anaerobic fermentation pathway in Saccharomyces cerevisiae. We next introduce a method to identify the feasibility parametric regions that allow a system to meet a set of physiological constraints that can be represented in mathematical terms through algebraic equations. This technique is based on applying the outer-approximation based algorithm iteratively over a reduced search space in order to identify regions that contain feasible solutions to the problem and discard others in which no feasible solution exists. As an example, we characterize the feasible enzyme activity changes that are compatible with an appropriate adaptive response of yeast Saccharomyces cerevisiae to heat shock Conclusion: Our results show the utility of the suggested approach for investigating the evolution of adaptive responses to environmental changes. The proposed method can be used in other important applications such as the evaluation of parameter changes that are compatible with health and disease states.

Minimization of biosynthetic costs in adaptive gene expression responses of yeast to environmental changes

Yeast successfully adapts to an environmental stress by altering physiology and fine-tuning metabolism. This fine-tuning is achieved through regulation of both gene expression and protein activity, and it is shaped by various physiological requirements. Such requirements impose a sustained evolutionary pressure that ultimately selects a specific gene expression profile, generating a suitable adaptive response to each environmental change. Although some of the requirements are stress specific, it is likely that others are common to various situations. We hypothesize that an evolutionary pressure for minimizing biosynthetic costs might have left signatures in the physicochemical properties of proteins whose gene expression is fine-tuned during adaptive responses. To test this hypothesis we analyze existing yeast transcriptomic data for such responses and investigate how several properties of proteins correlate to changes in gene expression. Our results reveal signatures that are consistent with a selective pressure for economy in protein synthesis during adaptive response of yeast to various types of stress. These signatures differentiate two groups of adaptive responses with respect to how cells manage expenditure in protein biosynthesis. In one group, significant trends towards downregulation of large proteins and upregulation of small ones are observed. In the other group we find no such trends. These results are consistent with resource limitation being important in the evolution of the first group of stress responses.

Can we translate vitamin D immunomodulating effect on innate and adaptive immunity to vaccine response?

Vitamin D (VitD), which is well known for its classic role in the maintenance of bone mineral density, has now become increasingly studied for its extra-skeletal roles. It has an important influence on the body's immune system and modulates both innate and adaptive immunity and regulates the inflammatory cascade. In this review our aim was to describe how VitD might influence immune responsiveness and its potential modulating role in vaccine immunogenicity. In the first instance, we consider the literature that may provide molecular and genetic support to the idea that VitD status may be related to innate and/or adaptive immune response with a particular focus on vaccine immunogenicity and then discuss observational studies and controlled trials of VitD supplementation conducted in humans. Finally, we conclude with some knowledge gaps surrounding VitD and vaccine response, and that it is still premature to recommend "booster" of VitD at vaccination time to enhance vaccine response.

Lipid anchoring of Arabidopsis phototropin 1 to assess the functional significance of receptor internalization: should I stay or should I go?

The phototropin 1 (phot1) blue light receptor mediates a number of adaptive responses, including phototropism, that generally serve to optimize photosynthetic capacity. Phot1 is a plasma membrane-associated protein, but upon irradiation, a fraction is internalized into the cytoplasm. Although this phenomenon has been reported for more than a decade, its biological significance remains elusive. Here, we use a genetic approach to revisit the prevalent hypotheses regarding the functional importance of receptor internalization. Transgenic plants expressing lipidated versions of phot1 that are permanently anchored to the plasma membrane were used to analyse the effect of internalization on receptor turnover, phototropism and other phot1-mediated responses. Myristoylation and farnesylation effectively prevented phot1 internalization. Both modified photoreceptors were found to be fully functional in Arabidopsis, rescuing phototropism and all other phot1-mediated responses tested. Light-mediated phot1 turnover occurred as in the native receptor. Furthermore, our work does not provide any evidence of a role of phot1 internalization in the attenuation of receptor signalling during phototropism. Our results demonstrate that phot1 signalling is initiated at the plasma membrane. They furthermore indicate that release of phot1 into the cytosol is not linked to receptor turnover or desensitization.

Determination of the complexing capacity of synthetic and real wine for Zn using Absence of Gradients and Nerstian Equilibrium Stripping technique

The complexing capacity of synthetic (0.011 M tartrate in 13.5% ethanol) and real wine (Raimat Abadia) in titrations with added total Zn concentrations up to 0.03 M has been determined following the free Zn concentrations with AGNES (absence of gradients and Nernstian equilibrium stripping) technique. A correction to find the preconcentration factor or gain (Y1) really applied at each one of the ionic strengths reached due to Zn additions along the titration has been applied. The standard implementation of AGNES to real wine led to the observation of two anomalous behaviors: (a) an increasingly negative current in the deposition stage (labeled as “HER” effect) and (b) a minimum in the currents of the stripping stage plot (labeled as the “dip” effect). A practical strategy to apply AGNES avoiding the dip effect has been developed to quantify properly free Zn concentrations. The van den Berg–Ružic–Lee linearization method (assuming the existence of just 1:1 complexes) has been adapted to consider the dilution effect and the ionic strength changes. Aggregated stability constants and total ligand concentrations have been calculated from synthetic and wine titration data. The found complexing capacity in the studied wine (cT,L = 0.0179 ± 0.0007 M) indicates the contribution of ligands other than tartrate (which is confirmed to be the main one).