Kirjallisuutta

Pääosa virallisen vastaväittäjän Markku Helinin Helsingin yliopiston oikeustieteelliselle tiedekunnalle antamasta 25.9.1998 päivätystä lausunnosta

Systems analysis of MVA-C induced immune response reveals its significance as a vaccine candidate against HIV/AIDS of clade C.

Based on the partial efficacy of the HIV/AIDS Thai trial (RV144) with a canarypox vector prime and protein boost, attenuated poxvirus recombinants expressing HIV-1 antigens are increasingly sought as vaccine candidates against HIV/AIDS. Here we describe using systems analysis the biological and immunological characteristics of the attenuated vaccinia virus Ankara strain expressing the HIV-1 antigens Env/Gag-Pol-Nef of HIV-1 of clade C (referred as MVA-C). MVA-C infection of human monocyte derived dendritic cells (moDCs) induced the expression of HIV-1 antigens at high levels from 2 to 8 hpi and triggered moDCs maturation as revealed by enhanced expression of HLA-DR, CD86, CD40, HLA-A2, and CD80 molecules. Infection ex vivo of purified mDC and pDC with MVA-C induced the expression of immunoregulatory pathways associated with antiviral responses, antigen presentation, T cell and B cell responses. Similarly, human whole blood or primary macrophages infected with MVA-C express high levels of proinflammatory cytokines and chemokines involved with T cell activation. The vector MVA-C has the ability to cross-present antigens to HIV-specific CD8 T cells in vitro and to increase CD8 T cell proliferation in a dose-dependent manner. The immunogenic profiling in mice after DNA-C prime/MVA-C boost combination revealed activation of HIV-1-specific CD4 and CD8 T cell memory responses that are polyfunctional and with effector memory phenotype. Env-specific IgG binding antibodies were also produced in animals receiving DNA-C prime/MVA-C boost. Our systems analysis of profiling immune response to MVA-C infection highlights the potential benefit of MVA-C as vaccine candidate against HIV/AIDS for clade C, the prevalent subtype virus in the most affected areas of the world.

A new classification of the Turkish terranes and sutures and its implication for the paleotectonic history of the region

The Turkish part of the Tethyan realm is represented by a series of terranes juxtaposed through Alpine convergent movements and separated by complex suture zones. Different terranes can be defined and characterized by their dominant geological background. The Pontides domain represents a segment of the former active margin of Eurasia, where back-arc basins opened in the Triassic and separated the Sakarya terrane from neighbouring regions. Sakarya was re-accreted to Laurasia through the Balkanic mid-Cretaceous orogenic event that also affected the Rhodope and Strandja zones. The whole region from the Balkans to the Caucasus was then affected by a reversal of subduction and creation of a Late Cretaceous arc before collision with the Anatolian domain in the Eocene. If the Anatolian terrane underwent an evolution similar to Sakarya during the Late Paleozoic and Early Triassic times, both terranes had a diverging history during and after the Eo-Cimmerian collision. North of Sakarya, the Küre back-arc was closed during the Jurassic, whereas north of the Anatolian domain, the back-arc type oceans did not close before the Late Cretaceous. During the Cretaceous, both domains were affected by ophiolite obduction, but in very different ways: north directed diachronous Middle to Late Cretaceous mélange obduction on the Jurassic Sakarya passive margin; Senonian synchronous southward obduction on the Triassic passive margin of Anatolia. From this, it appears that the Izmir-Ankara suture, currently separating both terranes, is composite, and that the passive margin of Sakarya is not the conjugate margin of Anatolia. To the south, the Cimmerian Taurus domain together with the Beydağları domain (part of the larger Greater Apulian terrane), were detached from north Gondwana in the Permian during the opening of the Neotethys (East-Mediterranean basin). The drifting Cimmerian blocks entered into a soft collision with the Anatolian and related terranes in the Eo-Cimmerian orogenic phase (Late Triassic), thus suturing the Paleotethys. At that time, the Taurus plate developed foreland-type basins, filled with flysch-molasse deposits that locally overstepped the lower plate Taurus terrane and were deposited in the opening Neotethys to the south. These olistostromal deposits are characterized by pelagic Carboniferous and Permian material from the Paleotethys suture zone found in the Mersin mélange. The latter, as well as the Antalya and Mamonia domains are represented by a series of exotic units now found south of the main Taurus range. Part of the Mersin exotic material was clearly derived from the former north Anatolian passive margin (Huğlu-type series) and re-displaced during the Paleogene. This led us to propose a plate tectonic model where the Anatolian ophiolitic front is linked up with the Samail/Baër-Bassit obduction front found along the Arabian margin. The obduction front was indented by the Anatolian promontory whose eastern end was partially subducted. Continued slab roll-back of the Neotethys allowed Anatolian exotics to continue their course southwestward until their emplacement along the Taurus southern margin (Mersin) and up to the Beydağları promontory (Antaya-Mamonia) in the latest Cretaceous-Paleocene. The supra-subduction ocean opening at the back of the obduction front (Troodos-type Ocean) was finally closed by Eocene north-south shortening between Africa and Eurasia. This brought close to each other Cretaceous ophiolites derived from the north of Anatolia and those obducted on the Arabian promontory. The latter were sealed by a Maastrichtian platform, and locally never affected by Alpine tectonism, whereas those located on the eastern Anatolian plate are strongly deformed and metamorphosed, and affected by Eocene arc magmatism. These observations help to reconstruct the larger frame of the central Tethyan realm geodynamic evolution.

A Candidate HIV/AIDS Vaccine (MVA-B) that Enhances the Magnitude and Polyfunctionality of Memory HIV-1-Specific T-Cell Responses

Background: The poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (MVA-B) is currently used as a HIV/AIDS vaccine candidate. A general strategy to try to improve the immunogenicity of poxvirus HIV-1 vaccine candidates is the deletion of known or suggested immunomodulatory vaccinia virus (VACV) genes.Methods: We have generated and characterized the innate immune sensing and the immunogenicity profile of a new HIV-1 vaccine candidate, which contains a deletion in a VACV gene.Results: We show that this VACV protein is expressed early during virus infection and localizes to the cytoplasm of infected cells. Deletion of this VACV gene from the MVA-B had no effect on virus growth kinetics; therefore this VACV protein is not essential for virus replication. The innate immune signals elicited by the MVA-B deletion mutant in human macrophages and monocyte-derived dendritic cells were characterized. In a DNA prime/MVA boost immunization protocol in mice, flow cytometry analysis revealed that the MVA-B deletion mutant enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4 + and CD8 + T-cell memory immune responses, with most of the HIV-1 responses mediated by the CD8 + T-cell compartment with an effector phenotype. Significantly, while MVA-B induced preferentially Env- and Gag-specific CD8 + T-cell responses, the MVA-B deletion mutant induced more GPN-specific CD8 + T-cell responses. Furthermore, the MVA-B deletion mutant enhanced the levels of antibodies against Env in comparison with MVA-B.Conclusion: These findings revealed that this new VACV protein can be considered as an immunomodulator and that deleting this gene in MVA-B confers an immunological benefit by inducing innate immune responses and increasing the magnitude and quality of the T-cell memory immune responses to HIV-1 antigens. Our observations are relevant for the improvement of MVA vectors as HIV-1 vaccines.

Kirjallisuutta

Virallisen vastaväittäjän, professori Asko Lehtosen Turun yliopiston oikeustieteelliselle tiedekunnalle antama 26.9.2005 päivätty lausunto

Kirjallisuutta

Kirjoitus perustuu virallisen vastaväittäjän, professori Per Ole Träskmanin Turun yliopiston oikeustieteelliselle tiedekunnalle antamaan 11.11.2004 päivättyyn lausuntoon

Uuden täydennysyhteistyömallin toteuttaminen: vaikutukset toimittajayritykseen

Pärjätäkseen nykypäivän kiristyvässä kilpailussa yritysten on kuuluttava kilpailukykyiseen toimitusketjuun ja toimittava yhteistyössä muiden yritysten kanssa. Yksi tunnetuimmista yhteistyömenetelmistä on täydennysyhteistyö, jossa toimittaja vastaa toimitusten suunnittelusta ilman perinteistä tilaus-toimitus-prosessia. Täydennysyhteistyöstä käytetään eri nimityksiä toimialasta ja toimitusketjun portaasta riippuen, mutta yleisellä tasolla on kyse samoista periaatteista: toimittajalla on vastuu varaston täydentämisestä ja sillä on käytössään täydennyspäätöksiin tarvittavaa tietoa. Työssä tarkastellaan tapausta, jossa toimittaja on ottanut käyttöön uuden täydennysyhteistyöhön liittyvän toimintatavan ja täydennystoimitusten laskentaan käytettävän työkalun. Tavoitteena on selvittää uuden täydennysyhteistyömallin käyttöönoton vaikutukset toimittajan näkökulmasta. Kirjallisuuskatsauksen avulla kartoitetaan täydennystoimitusten suunnitteluun vaikuttavat tekijät. Työssä kuvataan vanha ja uusi täydennysyhteistyömalli ja niitä vertaillaan keskenään. Uuden tyädennysyhteistyömallin vaikutuksia tutkitaan kolmella tasolla: yhteistyön mahdollistajat, suunnittelu ja prosessit sekä suorituskyky. Tutkimuksen perusteella uuden täydennysyhteistyömallin etuja ovat muun muassa tiedon käsittelyn nopeus ja helppous. Puutteeksi koetaan toimitussuunnitelman muuttamisen hankaluus työkalussa. Vaikka lähes kaikkien tutkimusotoksen tuotteiden keskimääräiset varastotasot olivat alentuneet uuden täydennysyhteistyömallin käyttöönoton jälkeen, varastotavoitteiden saavuttaminen ei ollut parantunut. Tuloksiin vaikuttavat useattekijät, joista tärkeimpiä ovat kysynnän vaihtelu ja volyymi sekä varastotavoite. Lisäksi ennustetarkkuus vaikuttaa toimitusten suunnitteluun ja siten varastonsuorituskykyyn.