990 resultados para POSSIBLE INVOLVEMENT


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The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in modulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4 (HNF-4 ) as a novel regulator of human apoAV gene. Inhibition of HNF-4 expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4 directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4 consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor- coactivator-1 was capable of stimulating the HNF-4 -dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4 . Intriguingly, EMSAs and mice with a liver-specific disruption of the HNF-4 gene revealed a species-distinct regulation of apoAV by HNF-4 , which resembles that of a subset of HNF-4 target genes. Taken together, our data provide new insights into the binding properties and the modulation of HNF-4 and underscore the role of HNF-4 in regulating triglyceride metabolism.

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Tutkielma tarkastelee vapaa alue konseptia osana yritysten kansainvälistä toimitusketjua. Tarkoituksena on löytää keinoja, millä tavoin vapaa alueen houkuttelevuutta voidaan lisätä yritysten näkökulmasta ja millaista liiketoimintaa yritysten on vapaa alueella mahdollista harjoittaa. Tutkielmassa etsitään tekijöitä, jotka vaikuttavat vapaa alueen menestykseen ja jotka voisivat olla sovellettavissa Kaakkois-Suomen ja Venäjän raja-alueelle ottaen huomioon vallitsevat olosuhteet ja lainsäädäntö rajoittavina tekijöinä. Menestystekijöitä ja liiketoimintamalleja haetaan tutkimalla ja analysoimalla lyhyesti muutamia olemassa olevia ja toimivia vapaa alueita. EU tullilain harmonisointi ja kansainvälisen kaupan vapautuminen vähentää vapaa alueen perinteistä merkitystä tullivapaana alueena. Sen sijaan vapaa alueet toimivat yhä enenevissä määrin logistisina keskuksina kansainvälisessä kaupassa ja tarjoavat palveluita, joiden avulla yritykset voivat parantaa logistista kilpailukykyään. Verkostoituminen, satelliitti-ratkaisut ja yhteistoiminta ovat keinoja, millä Kaakkois-Suomen alueen eri logistiikkapalvelujen tarjoajat voivat parantaa suorituskykyään ja joustavuutta kansainvälisessä toimitusketjussa.

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Immunoglobulin G4 related disease (IgG4-RD) has been recognized since early 2000s as an entity comprising a set of inflammatory diseases with common histopathological features. The disease may affect almost all organs and tissues, and often occurs in a subacute fashion in males over 50 years as a mass or diffuse enlargement of affected organs. The histopathological appearance is characterized by a lymphoplasmacytic infiltration with predominantly IgG4-positive plasma cells and progressive fibrosis. Its clinical and radiological features can make the distinction with a malignancy difficult. The disease responds well to systemic glucocorticoids however with a high rate of recurrence after treatment discontinuation.

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Työn päätavoitteena oli tutkia, miten toimintoperusteisia kustannuslaskentaprojekteja (ABC) voidaan ohjata tehokkaammin tulevaisuudessa, ja löytää toimintojohtamisen (ABM) tuki liiketoiminnan strategiselle johtamiselle verkottuvassa yritysmaailmassa. Lisäksi tavoitteena oli määritellä ABC-projektien johtamismallien viitekehys ja vertailla toteutettuja ABC-hankkeita.Toimintolaskentaa ja prosessijohtamista selvitettiin kirjallisuuden ja asiantuntijoiden haastatteluiden avulla. Tutkimuksen empiirisen osan ABC-hankkeiden tiedot pohjautuvat projekteissa tiiviisti mukana olleiden henkilöiden haastatteluihin. Kolmen eri yhtiön hankkeet kuvattiin, ja niiden analysoinnin pohjalta esitettiin mahdollisia jatkotoimenpiteitä liiketoiminnan johtamisen näkökulmasta. Lopuksi työssä pohdittiin myös liiketoiminnan ohjaamisen tulevaisuutta ja jatkotutkimustarpeita.Eri ABC-projektien vertailun pohjalta havaittiin mahdollisia hankekohtaisia kehitysalueita, kuten tietojärjestelmien yhtenäisyys, joustavuus, strateginen oppiminen tulevaisuudessa ja resurssien kohdentaminen. Lisäksi toteutettuja hankkeita arvioitiin liiketoiminnan ohjausta tukevan vuorovaikutteisen resurssisuunnittelun pohjalta. Työssä luotiin ABC-projektien johtamismallien kautta viitekehyksiä mahdollisille jatkohankkeille korostamalla prosessimaisuutta ja ulkoista verkottumista.Lopuksi esitetään, että ennen ABC-hankkeen aloitusta on yrityksen nykyinen tila ja tietojärjestelmät analysoitava. Projektia ei saa toteuttaa vain yhden hyväksi koetun tavan mukaisesti, vaan onnistunut ABC-projektin läpivienti vaatii monien erilaisten toteutus- ja ajattelumallien yhdistämistä. ABC-sovellusten on tuettava sekä operatiivista toimintaa että strategista liiketoiminnan johtamista. Tehokas verkottuminen mahdollistaa lopulta ulkoisten prosessien hallinnan yhdessä organisaation sidosryhmien kanssa.

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Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.

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Tämä diplomityö on tehty Andritz Oy:lle Washers & Filters tuoteryhmään. Työ on osa 3D-suunnittelujärjestelmän käyttöönottoprojektia. Tavoitteena on arvioida uuden laitesuunnittelujärjestelmän vaikutuksia yrityksen tietojärjestelmiin ja toimintatapoihin sekä etsiä potentiaalisia tulevaisuuden kehityskohteita. Suunnittelutietoa hyödyntäviä sidosryhmien edustajia haastattelemalla selvitettiin järjestelmille ja ohjelmistoille asetettavia vaatimuksia. Ohjelmistoihin tutustumalla saatiin käsitys niiden nykytilasta ja kehityssuunnista. 3D-geometrian hyödyntämiseen perustuvilla järjestelmillä voidaan poistaa päällekäistä työtä sekä lyhentää läpimenoaikoja suunnittelussa ja valmistuksessa sijoittamalla työvaiheita rinnakkain. Suurimmat 3D-suunnittelun edut saavutetaan tuotekehitysvaiheessa, tuotemuutoksia tehtäessä sekä valmistusprosesseja suunniteltaessa. Ongelmallisimmat osa-alueet tietojärjestelmien kehittämisessä ovat ensi-sijaisesti tiedonsiirto ohjelmistojen välillä, työntekijöiden muutosvastarinta sekä laadukkaiden järjestelmien korkea hinta. Laajojen tietojärjestelmä-projektien läpivienti on hyvin haastavaa ja onnistuminen vaatii kaikkien sidosryhmien mukana olemista ja tarkkaa projektin koordinointia.

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This paper proposes to reflect from a semiotic perspective on the transformation that brands have undergone since the rise of the Internet. After a brief theoretical introduction to digital communication and the semiotics of brands, the case of the Google brand is analyzed by applying concepts of generative and interpretive semiotics. The paper holds that the iconic and linguistic enunciations are secondary with respect to interaction. In digital media interaction — the interactive experience that the Internet user lives — is a fundamental component of the hypermedia cocktail and occupies a central position in the brand building process. The article concludes with some of the questions and special characteristics raised by so-called eBranding.

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The main objective of this dissertation is to create new knowledge on an administrative innovation, its adoption, diffusion and finally its effectiveness. In this dissertation the administrative innovation is approached through a widely utilized management philosophy, namely the total quality management (TQM) strategy. TQM operationalizes a self-assessment procedure, which is based on continual improvement principles and measuring the improvements. This dissertation also captures the theme of change management as it analyzes the adoption and diffusion of the administrative innovation. It identifies innovation characteristics as well as organisational and individual factors explaining the adoption and implementation. As a special feature, this study also explores the effectiveness of the innovation based on objective data. For studying the administrative innovation (TQM model), a multinational Case Company provides a versatile ground for a deep, longitudinal analysis. The Case Company started the adoption systematically in the mid 1980s in some of its units. As part of their strategic planning today, the procedure is in use throughout the entire global company. The empirical story begins from the innovation adoption decision that was made in the Case Company over 22 years ago. In order to be able to capture the right atmosphere and backgrounds leading to the adoption decision, key informants from that time were interviewed, since the main target was to clarify the dynamics of how an administrative innovation develops. In addition, archival material was collected and studied, available memos and data relating to the innovation, innovation adoption and later to the implementation contained altogether 20500 pages of documents. A survey was furthermore conducted at the end of 2006 focusing on questions related to the innovation, organization and leadership characteristics and the response rate totalled up to 54%. For measuring the effectiveness of the innovation implementation, the needed longitudinal objective performance data was collected. This data included the profit unit level experience of TQM, the development of the self assessment scores per profit unit and performance data per profit unit measured with profitability, productivity and customer satisfaction. The data covered the years 1995-2006. As a result, the prerequisites for the successful adoption of an administrative innovation were defined, such as the top management involvement, support of the change agents and effective tools for implementation and measurement. The factors with the greatest effect on the depth of the implementation were the timing of the adoption and formalization. The results also indicated that the TQM model does have an effect on the company performance measured with profitability, productivity and customer satisfaction. Consequently this thesis contributes to the present literature (i) by taking into its scope an administrative innovation and focusing on the whole innovation implementation process, from the adoption, through diffusion until its consequences, (ii) because the studied factors with an effect on the innovation adoption and diffusion are multifaceted and grouped into individual, organizational and environmental factors, and a strong emphasis is put on the role of the individual change agents and (iii) by measuring the depth and consistency of the administrative innovation. This deep analysis was possible due to the availability of longitudinal data with triangulation possibilities.

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AIMS/HYPOTHESIS: Exposure of pancreatic beta cells to cytokines released by islet-infiltrating immune cells induces alterations in gene expression, leading to impaired insulin secretion and apoptosis in the initial phases of type 1 diabetes. Long non-coding RNAs (lncRNAs) are a new class of transcripts participating in the development of many diseases. As little is known about their role in insulin-secreting cells, this study aimed to evaluate their contribution to beta cell dysfunction. METHODS: The expression of lncRNAs was determined by microarray in the MIN6 beta cell line exposed to proinflammatory cytokines. The changes induced by cytokines were further assessed by real-time PCR in islets of control and NOD mice. The involvement of selected lncRNAs modified by cytokines was assessed after their overexpression in MIN6 cells and primary islet cells. RESULTS: MIN6 cells were found to express a large number of lncRNAs, many of which were modified by cytokine treatment. The changes in the level of selected lncRNAs were confirmed in mouse islets and an increase in these lncRNAs was also seen in prediabetic NOD mice. Overexpression of these lncRNAs in MIN6 and mouse islet cells, either alone or in combination with cytokines, favoured beta cell apoptosis without affecting insulin production or secretion. Furthermore, overexpression of lncRNA-1 promoted nuclear translocation of nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB). CONCLUSIONS/INTERPRETATION: Our study shows that lncRNAs are modulated during the development of type 1 diabetes in NOD mice, and that their overexpression sensitises beta cells to apoptosis, probably contributing to their failure during the initial phases of the disease.

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The endodermis is a highly conserved cell layer present in the root of all vascular plants, except Lycophytes. This tissue layer establishes a protective diffusion barrier surrounding the vasculature and is expected to prevent passive, uncontrolled flow of nutrients through the root. This barrier property is achieved by the production of Casparian strips (CS), a localized cell wall impregnation of lignin in the anticlinal walls of each endodermal cell, forming a belt-like structure sealing the extracellular space. The CS act as a selective barrier between the external cell layers and the vascular cylinder and are thought to be important in many aspects of root function. For instance, selective nutrient uptake and sequestration from the soil, resistance to different abiotic and biotic stresses are expected to involve functional CS. Although discovered 150 years ago, nothing was known about the genes involved in CS establishment until recently. The use of the model plant Arabidopsis thaliana together with both reverse and forward genetic approaches led to the discovery of an increasing number of genes involved in different steps of CS formation during the last few years. One of these genes encodes SCHENGEN3 (SGN3), a leucine-rich repeat receptor-like kinase (LRR-RLK). SGN3 was discovered first by reverse genetic due to its endodermis-enriched expression, and the corresponding mutant displays strong endodermal permeability of the apoplastic tracer Propidium Iodide (PI) indicative of defective CS. One aim of this thesis is to study the role of SGN3 at the molecular level in order to understand its involvement in establishing an impermeable CS. The endodermal permeability of sgn3 is shown to be the result of incorrect localization of key proteins involved in CS establishment (the "Casparian strip domain proteins", CASPs), leading to non-functional CS interrupted by discontinuities. CASPs localize in the plasma membrane domain subjacent to the CS, named the Casparian Strip membrane Domain (CSD). The CSD discontinuities in sgn3 together with SGN3 localization in close proximity to the CASPs lead to the assumption that SGN3 is involved in the formation of a continuous CSD. In addition, SGN3 might have a second role, acting as a kinase reporting CSD integrity leading to lignin and suberin production in CSD/CS defective plants. Up to now, sgn3 is the strongest and most specific CS mutant available, displaying tracer penetration along the whole length of the seedling root. For this reason, this mutant is well suited in order to characterize the physiological behaviour of CS affected plants. Due to the lack of such mutants in the past, it was not possible to test the presumed functions of CS by using plants lacking this structure. We decided to use sgn3 for this purpose. Surprisingly, sgn3 overall growth is only slightly affected. Nevertheless, processes expected to rely on functional CS, such as water transport through the root, nutrient homeostasis, salt tolerance and resistance to an excess of some nutrients are altered in this mutant. On the other hand, homeostasis for most elements and drought tolerance are not affected in sgn3. It is surprising to observe that homeostatic defects are specific, with a decrease in potassium and an increase in magnesium levels. It indicates a backup system, set up by the plant in order to counteract free diffusion of nutrients into the stele. For instance, potassium shortage in sgn3 upregulates the transcription of potassium influx transport proteins and genes known to be induced by potassium starvation. Moreover, sgn3 mutant is hypersensitive to low potassium conditions. Hopefully, these results about SGN3 will help our understanding of CS establishment at the molecular level. In addition, physiological experiments using sgn3 should give us a framework for future experiments and help us to understand the different roles of CS and their involvement during nutrient radial transport through the root. -- L'endoderme est un tissu présent dans les racines de toutes les plantes vasculaires à l'exception des Lycophytes. Ce tissu établit une barrière protectrice entourant les tissus vasculaires dans le but d'éviter la diffusion passive et incontrôlée des nutriments au travers de la racine. Cette propriété de barrière provient de la production des cadres de Caspary, une imprégnation localisée de lignine des parties anticlinales de la paroi de chaque cellule d'endoderme. Cela donne naissance à un anneau/cadre qui rend étanche l'espace extracellulaire. Les cadres de Caspary agissent comme une barrière sélective entre les couches externes de la racine et le cylindre central et sont supposés être importants dans beaucoup d'aspects du fonctionnement de la racine. Par exemple, l'absorption sélective de nutriments et leur séquestration à partir du sol ainsi que la résistance contre différents stress abiotiques et biotiques sont supposés impliquer des cadres de Caspary fonctionnels. Bien que découverts il y a 150 ans, rien n'était connu concernant les gènes impliqués dans Ja formation des cadres de Caspary jusqu'à récemment. Durant ces dernière années, l'utilisation de la plante modèle Arabidopsis thaliana ainsi que des approches de génétique inverse et classique ont permis la découverte d'un nombre croissant de gènes impliqués à différentes étapes de la formation de cette structure. Un des ces gènes code pour SCHENGEN3 (SGN3), un récepteur kinase "leucine-rich repeat receptor-like kinase" (LRR-RLK). SGN3 a été découvert en premier par génétique inverse grâce à son expression enrichie dans l'endoderme. Les cadres de Caspary ne sont pas fonctionnels dans le mutant correspondant, ce qui est visible à cause de la perméabilité de l'endoderme au traceur apoplastique Propidium Iodide (PI). Un des objectifs de cette thèse est d'étudier la fonction de SGN3 au niveau moléculaire dans le but de comprendre son rôle dans la formation des cadres de Caspary. J'ai pu démontrer que la perméabilité de l'endoderme du mutant sgn3 est le résultat de la localisation incorrecte de protéines impliquées dans la formation des cadres de Caspary, les "Casparian strip domain proteins" (CASPs). Cela induit des cadres de Caspary non fonctionnels, contenant de nombreuses interruptions. Les CASPs sont localisés à la membrane plasmique dans un domaine sous-jacent les cadres de Caspary appelé Casparian Strip membrane Domain (CSD). Les interruptions du CSD dans le mutant sgn3, ainsi que la localisation de SGN3 à proximité des CASPs nous font penser à un rôle de SGN3 dans l'élaboration d'un CSD ininterrompu. De plus, SGN3 pourrait avoir un second rôle, agissant en tant que kinase reportant l'intégrité du CSD et induisant la production de lignine et de subérine dans des plantes contenant des cadres de Caspary non fonctionnels. Jusqu'à ce jour, sgn3 est le mutant en notre possession le plus fort et le plus spécifique, ayant un endoderme perméable tout le long de la racine. Pour cette raison, ce mutant est adéquat dans le but de caractériser la physiologie de plantes ayant des cadres de Caspary affectés. De manière surprenante, la croissance de sgn3 est seulement peu affectée. Néanmoins, des processus censés nécessiter des cadres de Caspary fonctionnels, comme le transport de l'eau au travers de la racine, l'homéostasie des nutriments, la tolérance au sel et la résistance à l'excès de certains nutriments sont altérés dans ce mutant. Malgré tout, l'homéostasie de la plupart des nutriments ainsi que la résistance au stress hydrique ne sont pas affectés dans sgn3. De manière surprenante, les altérations de l'ionome de sgn3 sont spécifiques, avec une diminution de potassium et un excès de magnésium. Cela implique un système de compensation établi par la plante dans le but d'éviter la diffusion passive des nutriments en direction du cylindre central. Par exemple, le manque de potassium dans sgn3 augmente la transcription de transporteurs permettant l'absorption de cet élément. De plus, des gènes connus pour être induits en cas de carence en potassium sont surexprimés dans sgn3 et la croissance de ce mutant est sévèrement affectée dans un substrat pauvre en potassium. Ces résultats concernant SGN3 vont, espérons-le, aider à la compréhension du processus de formation des cadres de Caspary au niveau moléculaire. De plus, les expériences de physiologie utilisant sgn3 présentées dans cette thèse devraient nous donner une base pour des expériences futures et nous permettre de comprendre mieux le rôle des cadres de Caspary, et plus particulièrement leur implication dans le transport radial des nutriments au travers de la racine. -- Les plantes terrestres sont des organismes puisant l'eau et les nutriments dont elles ont besoin pour leur croissance dans le sol grâce à leurs racines. De par leur immobilité, elles doivent s'adapter à des sols contenant des quantités variables de nutriments et il leur est crucial de sélectionner ce dont elles ont besoin afin de ne pas s'intoxiquer. Cette sélection est faite grâce à un filtre formé d'un tissu racinaire interne appelé endoderme. L'endoderme fabrique une barrière imperméable entourant chaque cellule appelée "cadre de Caspary". Ces cadres de Caspary empêchent le libre passage des nutriments, permettant un contrôle précis de leur passage. De plus, ils sont censés permettre de résister contre différents stress environnementaux comme la sécheresse, la salinité du sol ou l'excès de nutriments. Bien que découverts il y a 150 ans, rien n'était connu concernant les gènes impliqués dans la formation des cadres de Caspary jusqu'à récemment. Durant ces dernière années, l'utilisation de la plante modèle Arabidopsis thaliana a permis la découverte d'un nombre croissant de gènes impliqués à différentes étapes de la formation de cette structure. Un de ces gènes code pour SCHENGEN3 (SGN3), un récepteur kinase "leucine-rich repeat receptor-like kinase" (LRR- RLK). Nous montrons dans cette étude que le gène SGN3 est impliqué dans la formation des cadres de Caspary, et que le mutant correspondant sgn3 a des cadres de Caspary interrompus. Ces interruptions rendent l'endoderme perméable, l'empêchant de bloquer le passage des molécules depuis le sol vers le centre de la racine. En utilisant ce mutant, nous avons pu caractériser la physiologie de plantes ayant des cadres de Caspary affectés. Cela a permis de découvrir que le transport de l'eau au travers de la racine était affecté dans le mutant sgn3. De plus, l'accumulation de certains éléments dans les feuilles de ce mutant est altérée. Nous avons également pu montrer une sensibilité de ce mutant à un excès de sel ou de certains nutriments comme le fer et le manganèse.