Manuale Aboense

Halberstadtiae : Laurentius Stuchs 1522

Role and Function of c-Jun Protein Complex in Cancer Cell Behavior

Transcription factors play a crucial role in the regulation of cell behavior by modulating gene expression profiles. Previous studies have described a dual role for the AP-1 family transcription factor c-Jun in the regulation of cellular fate. In various cell types weak and transient activations of c-Jun N-terminal kinase (JNK) and c-Jun appear to contribute to proliferation and survival, whereas strong and prolonged activation of JNK and c-Jun result in apoptosis. These opposite roles played by c-Jun are cell type specific and the molecular mechanisms defining these antonymous c-Jun-mediated responses remain incompletely understood. c-Jun activity in transformed cells is regulated by signalling cascades downstream of oncoproteins such as Ras and Raf. In addition, the pro-proliferative role and the survival promoting function for c-Jun has been described in various cancer models. Furthermore, c-Jun was described to be overexpressed in different cancer types. However, the molecular mechanisms by which c-Jun exerts these oncogenic functions are not all clearly established. Therefore it is of primary interest to further identify molecular mechanisms and functions for c-Jun in cancer. Regulation of gene expression is tightly dependent on accurate protein-protein interactions. Therefore, co-factors for c-Jun may define the functions for c-Jun in cancer. Identification of protein-protein interactions promoting cancer may provide novel possibilities for cancer treatment. In this study, we show that DNA topoisomerase I (TopoI) is a transcriptional co-factor for c-Jun. Moreover, c-Jun and TopoI together promote expression of epidermal growth factor receptor (EGFR) in cancer cells. We also show that the clinically used TopoI inhibitor topotecan reduces EGFR expression. Importantly, the effect of TopoI on EGFR transcription was shown to depend on c-Jun as Jun-/- cells or cells treated with JNK inhibitor SP600125 are resistant to topotecan treatment both in regulation of EGFR expression and cell proliferation. Moreover, c-Jun regulates the nucleolar localization and the function of the ribonucleic acid (RNA) helicase DDX21, a previously identified member of c-Jun protein complex. In addition, c-Jun stimulates rRNA processing by supporting DDX21 rRNA binding. Finally, this study characterizes a DDX21 dependent expression of cyclin dependent kinase (Cdk) 6, a correlation of DDX21 expression with prostate cancer progression and a substrate binding dependency of DDX21 nucleolar localization in prostate cancer cells. Taken together, the results of this study validate the c-Jun-TopoI interaction and precise the c-Jun-DDX21 interaction. Moreover, these results show the importance for protein-protein interaction in the regulation of their cellular functions in cancer cell behavior. Finally, the results presented here disclose new exciting therapeutic opportunities for cancer treatment.

Molecular Markers of Oral Lichen Planus

Oral lichen planus (OLP) is a chronic inflammatory mucosal disease and is detected in between 0.5% - 2.2% of the population. WHO has defined OLP as a potentially precancerous disorder, representing a generalized state associated with a significantly increased risk of cancer. However, only 0.5 – 2.9% of OLP lesions will progress to cancer. Currently, there are no prognostic markers to identify the lesions at increased risk for malignant transformation. The main aim of these studies was to identify cellular and molecular markers in order to understand the pathogenesis of atrophic OLP and its progression towards malignancy. Selected markers for cell proliferation, adhesion, apoptosis, and lymphocytic infiltration were assessed by immunohistochemistry in addition to static cytometry analyses for DNA content. DNA quantification of epithelial cells in 82 biopsy samples derived from atrophic lichen planus showed altered DNA content in 41% of the samples. DNA content was associated with proliferation activity, topoisomerase IIalpha, desmocollin-1 and infection with human papillomavirus. CD27+ and CD38+ lymphocytes were detected in inflammatory cell infiltrate, indicating an abnormal homing of B cells from blood circulation to tissue. Physiologic cell death, apoptosis, is frequently seen in OLP, but its pathways are unknown. Here it was shown that caspases 2 and 12 were up-regulated in OLP, indicating that intracellular apoptosis, rather than an external causal factor, is triggering apoptosis. However, this thesis could not identify any singular prognostic marker of malignancy in OLP. Thus, every OLP patient should receive regular follow-up care to identify cancer risk patients at an early stage.

On the Application of Beam on Elastic Foundation Theory to the Analysis of Stiffened Plate Strips

The main objective of this thesis is to show that plate strips subjected to transverse line loads can be analysed by using the beam on elastic foundation (BEF) approach. It is shown that the elastic behaviour of both the centre line section of a semi infinite plate supported along two edges, and the free edge of a cantilever plate strip can be accurately predicted by calculations based on the two parameter BEF theory. The transverse bending stiffness of the plate strip forms the foundation. The foundation modulus is shown, mathematically and physically, to be the zero order term of the fourth order differential equation governing the behaviour of BEF, whereas the torsion rigidity of the plate acts like pre tension in the second order term. Direct equivalence is obtained for harmonic line loading by comparing the differential equations of Levy's method (a simply supported plate) with the BEF method. By equating the second and zero order terms of the semi infinite BEF model for each harmonic component, two parameters are obtained for a simply supported plate of width B: the characteristic length, 1/ λ, and the normalized sum, n, being the effect of axial loading and stiffening resulting from the torsion stiffness, nlin. This procedure gives the following result for the first mode when a uniaxial stress field was assumed (ν = 0): 1/λ = √2B/π and nlin = 1. For constant line loading, which is the superimposition of harmonic components, slightly differing foundation parameters are obtained when the maximum deflection and bending moment values of the theoretical plate, with v = 0, and BEF analysis solutions are equated: 1 /λ= 1.47B/π and nlin. = 0.59 for a simply supported plate; and 1/λ = 0.99B/π and nlin = 0.25 for a fixed plate. The BEF parameters of the plate strip with a free edge are determined based solely on finite element analysis (FEA) results: 1/λ = 1.29B/π and nlin. = 0.65, where B is the double width of the cantilever plate strip. The stress biaxial, v > 0, is shown not to affect the values of the BEF parameters significantly the result of the geometric nonlinearity caused by in plane, axial and biaxial loading is studied theoretically by comparing the differential equations of Levy's method with the BEF approach. The BEF model is generalised to take into account the elastic rotation stiffness of the longitudinal edges. Finally, formulae are presented that take into account the effect of Poisson's ratio, and geometric non linearity, on bending behaviour resulting from axial and transverse inplane loading. It is also shown that the BEF parameters of the semi infinite model are valid for linear elastic analysis of a plate strip of finite length. The BEF model was verified by applying it to the analysis of bending stresses caused by misalignments in a laboratory test panel. In summary, it can be concluded that the advantages of the BEF theory are that it is a simple tool, and that it is accurate enough for specific stress analysis of semi infinite and finite plate bending problems.

Vita & merita m. Isaaci B. Rothovii

Arkit: 1 arkintunnukseton lehti, 2B-2C4.

Aliupseerikurssin johtajavalintojen yhteys Reserviupseerikurssin tulenjohtolinjalla menestymiseen

Puolustusvoimissa on käytössä johtajavalintamenettely, jolla valitaan aselajista riippumatta yhtenäisiin perustein aliupseerikurssi 1:ltä Reserviupseerikurssille komennettavat varusmiehet. Valintamenettely ei siis painota aselajikohtaisia vaatimuksia, jotka voivat aselajien välillä vaihdella paljonkin. Valinnat toteutetaan niitä varten laaditulla valintalomakkeella, joka sisältää kymmenen pisteytettävää kohtaa; peruskoe 1, peruskoe 2b, varusmiehen kuntoindeksi, sotilaan perustutkinto, sopivuus sodan ajan johtajaksi henkilökunnan arvioimana sekä varusmies johtajien arvioimana, vertaisarviointi, johtajatehtävärata, oppimis- ja suoriutumismotivaatio ja oma halukkuus johtajakoulutukseen. Tutkimukseen valikoitui näistä kohdista peruskokeet, sopivuus sodan ajan johtajaksi henkilökunnan arvioimana, johtajatehtävärata, oma halukkuus johtajakoulutukseen sekä lisäksi lomakkeen muodostamat kokonaispisteet. Tutkimuksen teoreettinen osuus rakentuu neljästä luvusta. Luku 2 tarkastelee menestymiseen vaikuttavia tekijöitä, joita ovat oppiminen ja oppimiskäsitys, maailmankuva, arvot ja asenne sekä motivaatio. Luvussa 3 esitellään tulenjohtajan tehtävät ja suoritusvaatimukset, luvussa 4 tarkastellaan aliupseerikurssin johtajavalintoja ja luku 5 käsittelee Reserviupseerikurssia. Työ on luonteeltaan kuvaileva ja vertaileva kvantitatiivinen poikittaistutkimus. Tutkimuksella on tarkoitus vastata kahteen samanarvoiseen kysymykseen, ”Millainen on aliupseerikurssin tulenjohtajavalinnoissa menestymisen yhteys reserviupseerikurssin tulenjohtolinjan loppupisteisiin” sekä ”Millainen on aliupseerikurssin tulenjohtajavalinnoissa menestymisen yhteys reserviupseerikurssin tulenjohtolinjan eri oppiaineiden lopullisiin arvosanoihin”. Yhteyksien selvittämiseksi käytettiin tilastollisia menetelmiä. Aineiston analyysiin käytettiin korrelaatiota ja varianssianalyysia, jota tuettiin Scheffen post hoc –testillä. Aineiston tarkastelu ja analyysit suoritettiin SPSS for Windows 11.5 –ohjelmalla. Tutkimuksen empiirinen aineisto koostui Reserviupseerikurssin 229 tulenjohtolinjan suorittaneista (N=91). Tutkimuksessa selvisi, että aliupseerikurssin johtajavalinnoilla oli vaihtelevasti yhteyttä Reserviupseerikurssin tulenjohtolinjalla menestymiseen. Tutkimuksessa löytyi sekä positiivista että negatiivista yhteyttä, mutta yhteys oli heikkoa. Tuloksissa tilastollisesti merkitsevä yhteys valintalomakkeen kohdista Reserviupseerikurssilla menestymiseen oli vain peruskoe 1:llä. Auk 1:n loppupisteillä oli tilastollisesti merkitsevää yhteyttä liikunnan arvosanaan.

Reflexive model of research-based theatre – processing innovation at the crossroads of theatre, reflection and practice-based innovation activities

Contemporary organisations have to embrace the notion of doing ‘more with less’. This challenges knowledge production within companies and public organisations, forcing them to reorganise their structures and rethink what knowledge production actually means in the context of innovation and how knowledge is actually produced among various professional groups within the organisation in their everyday actions. Innovations are vital for organisational survival, and ‘ordinary’ employees and customers are central but too-often ignored producers of knowledge for contemporary organisations. Broader levels of participation and reflexive practices are needed. This dissertation discusses the missing links between innovation research conducted in the context of industrial management, arts, and culture; applied drama and theatre practices (specifically post-Boalian approaches); and learning – especially organising reflection – in organisational settings. This dissertation (1) explores and extends the role of research-based theatre to organising reflection and reflexive practices in the context of practice-based innovation, (2) develops a reflexive model of RBT for investigating and developing practice-based organisational process innovations in order to contribute to the development of a tool for innovation management and analysis, and (3) operationalises this model within private- and publicsector organisations. The proposed novel reflexive model of research-based theatre for investigating and developing practice-based organisational process innovations extends existing methods and offers a different way of organising reflection and reflexive practices in the context of general innovation management. The model was developed through five participatory action research processes conducted in four different organisations. The results provide learning steps – a reflection path – for understanding complex organisational life, people, and relations amid renewal and change actions. The proposed model provides a new approach to organising and cultivating reflexivity in practice-based innovation activities via research-based theatre. The results can be utilised as a guideline when processing practice-based innovation within private or public organisations. The model helps innovation managers to construct, together with their employees, temporary communities where they can learn together through reflecting on their own and each others’ experiences and to break down assumptions related to their own perspectives. The results include recommendations for practical development steps applicable in various organisations with regard to (i) application of research-based theatre and (ii) related general innovation management. The dissertation thus contributes to the development of novel learning approaches in knowledge production. Keywords: practice-based innovation, research-based theatre, learning, reflection, mode 2b knowledge production

De certitudine recuperatae salutis

Inv.: Dedicatio: Otto Reinhold Üxkull, Petrus Stierncrantz.

Muscarinic toxins : characterization of adrenoceptor binding and applicability of membrane anchoring via glycosylphosphatidylinositol tail

Adrenoceptors (ARs), G-protein coupled receptors (GPCRs) at the plasma membrane, respond to endogenous catecholamines noradrenaline and adrenaline. These receptors mediate several important physiological functions being especially important in the cardiovascular system and in the regulation of smooth muscle contraction. Impairments in the function of these receptors can thus lead to severe diseases and disorders such as to cardiovascular diseases and benign prostatic hyperplasia. The Eastern green mamba (Dendroaspis angusticeps) venom has been shown to contain toxins that can antagonize the functions of GPCRs. The most well-known are muscarinic toxins (MTs) targeting muscarinic acetylcholine receptors (mAChRs) with high affinity and selectivity. However, some reports have indicated that these toxins might also act on the α1- and α2-ARs which can be divided into various subtypes; the α1-ARs to α1A-, α1B- and α1D-ARs and α2-ARs to α2A-, α2B- and α2C-ARs. In this thesis, the interaction of four common MTs (MT1, MT3, MT7 and MTα) with the adrenoceptors was characterized. It was also evaluated whether these toxins could be anchored to the plasma membrane via glycosylphosphatidylinositol (GPI) tail. Results of this thesis reveal that muscarinic toxins are targeting several α-adrenoceptor subtypes in addition to their previously identified target receptors, mAChRs. MTα was found to interact with high affinity and selectivity with the α2B-AR whereas MT7 confirmed its selectivity for the M1 mAChR. Unlike MTα and MT7, MT1 and MT3 have a broad range of target receptors among the α-ARs. All the MTs characterized were found to behave as non-competitive antagonists of receptor action. The interaction between MTα and the α2B-AR was studied more closely and it was observed that the second extracellular loop of the receptor functions as a structural entity enabling toxin binding. The binding of MTα to the α2B-AR appears to be rather complex and probably involves dimerized receptor. Anchoring MTs to the plasma membrane did not interfere with their pharmacological profile; all the GPI-anchored toxins created retained their ability to block their target receptors. This thesis shows that muscarinic toxins are able to target several subtypes of α-ARs and mAChRs. These toxins offer thus a possibility to create new subtype specific ligands for the α-AR subtypes. Membrane anchored MTs on the other hand could be used to block α-AR and mAChR actions in disease conditions such as in hypertension and in gastrointestinal and urinary bladder disorders in a cell-specific manner and to study the physiological functions of ARs and mAChRs in vivo in model organisms.

SYLI - an external workflow system for DSpace

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

RCAAP: Building and maintaining a national repository network

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

ORCIDs in the Wild: Implementing ORCIDs into Research Support and Repository Systems

Panel at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Bibliographic import from Scopus and WoS

Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014