Capacity of an I-beam made of S960 QC based on Eurocode 3

The capacity of beams is a very important factor in the study of durability of structures and structural members. The capacity of a high-strength steel I-beam made of S960 QC was investigated in this study. The investigation included assessment of the service limits and ultimate limits of the steel beam. The thesis was done according to European standards for steel structures, Eurocode 3. An analytical method was used to determine the throat thickness, deformation, elastic and plastic moment capacities as well as the fatigue life of the beam. The results of the analytical method were compared with those obtained by Finite Element Analysis (FEA). Elastic moment capacity obtained by the analytical method was 172 kNm. FEA and the analytical method predicted the maximum lateral-torsional buckling (LTB) capacity in the range of 90-93 kNm and the probability of failure as a result of LTB is estimated to be 50%. The lateral buckling capacity meant that the I-beam can carry a safe load of 300 kN instead of the initial load of 600 kN. The beam is liable to fail shortly after exceeding the elastic moment capacity. Based on results in of the different approaches, it was noted that FEA predicted higher deformation values on the load-deformation curve than the analytical results. However, both FEA and the analytical methods predicted identical results for nominal stress range and moment capacities. Fatigue life was estimated to be in the range of 53000-64000 cycles for bending stress range using crack propagation equation and strength-life approach. As Eurocode 3 is limited to steel grades up to S690, results for S960 must be verified with experimental data and appropriate design rules.

Sphingosine-1-phosphate-evoked invasion of follicular thyroid cancer cells : evidence for the involvement of HIF-Iα, MMP2 and MMP9

Sphingolipids are widely expressed molecules, which traditionally were considered to have majorly structural properties. Nowadays, however, they are implicated in a wide range of different biological processes. The bioactive lipid sphingosine 1-phosphate (S1P) has emerged during the past decade as one of the most studied molecules due to its proliferative and pro-migratory abilities both during normal physiology and in the pathology of a subset of different diseases. Migration and invasion of cancer cells require changes in cell behavior and modulation of the tissue microenvironment. Tumor aggressiveness is markedly enhanced by hypoxia, in which hypoxia inducible transcription factors 1-2α (HIF-1-2α) are activated to promote metabolism, proliferation and migration. Invasion requires degradation of the extracellular matrix (ECM) achieved by several degrading and remodeling enzymes. Matrix metalloproteinases (MMPs) are broadly expressed and well accepted as proteolytic enzymes with essential roles both in normal physiology and in pathology. Previously, S1P was shown to strongly evoke migration of follicular ML-1 thyroid cancer cells. The objective of this study was to further investigate and understand the mechanisms behind this regulation. In the first project it was demonstrated that S1P enhances the expression and activity of HIF-1α. S1P enhanced the expression of HIF-1α by increasing its synthesis and stability. The S1P-increased HIF-1α was mediated via S1P3, Gi/0, PI3K, PKCβI, ERK1/2, mTOR and translation factors p70S6K and eIF4E. Finally, it was shown that HIF-1α mediated S1P-induced migration. The ECM is constituted of a complex and coordinated assembly of many types of proteins. In order to be able to invade, cells need to break down the ECM, therefore several key players in this event were investigated in the second project. S1P increased the secretion and activity of MMP2 and MMP9 via S1P-receptor 1 and 3 and that these MMPs participated in the S1P-facilitated invasion of ML-1 cells. In this interplay, calpains and Rac1 were involved, both of which are crucial players in migration and invasion. The prognosis for some types of thyroid cancer is relatively good. However, there are forms of thyroid cancers, for which there are no treatments or the current available treatments are inefficient. Thus, new medical interventions are urgently needed. In the third project the significance of the S1P-receptor modulating drug FTY720, which is currently used for the treatment of multiple sclerosis (MS), was studied. The effect of FTY720 was tested on several thyroid cancer cell lines, and it inhibited the proliferation and invasion of all cancer cell lines tested. In ML-1 cells, FTY720 attenuated invasion by blocking signaling intermediates important for migration and invasion of the cells. Moreover, FTY720 inhibited the proliferation of ML-1 cells by increasing the expression of p21 and p27, hence, inducing cell arrest in G1 phase of the cell cycle. Thus, it can be suggested that FTY720 could be used in the treatment of thyroid cancer.

“That you too were the I”: Forms of polyphonic communication in John Ashbery’s poetry

Tarkastelen tutkimuksessani amerikkalaisen John Ashberyn (1927–) runoudessa lmenevää moniäänisyyttä. Runoutta pidetään yleensä yksiäänisenä puheena, kun taas omaanin ajatellaan erityisesti Mihail Bahtinin vaikutuksesta olevan luonnostaan oniääninen kirjallisuudenlaji. Ashberyn postmoderni runous haastaa tämän äsityksen. Ashbery tunnetaan vakiintuneita runouskäsityksiä vastaan kirjoittavana avantgarde-runoilijana. Pääasiallisina tutkimuskohteinani ovat Ashberyn pitkä runoelma nimeltä ”Litany” (1979) sekä lyhyiden runojen valikoima <i>Your Name Herei> (2000). Vertailukohtana tarkastelen Ashberyn yhdessä James Schuylerin kanssa kirjoittamaa romaania <i>A Nest of Ninniesi> (1969). Teoreettisena pohjana on käytetty Ashberyä käsittelevän muun tutkimuksen lisäksi muun muassa jälkistrukturalistisiin teorioihin liittyviä ajatuksia pronominien vaikutuksesta siihen miten lukija muodostaa käsityksen subjektiivisesta läsnäolosta runossa. Ashbery käyttää persoonapronomineja ilman selkeitä viittaussuhteita. Viittaussuhteiden hämärtymisen ja fragmentaarisuuden vuoksi Ashberyn runoja pidetään usein vaikeina, eikä niistä ole helppo löytää yhtä selkeää aihetta. Hajanaisuus on kuitenkin motivoitua, koska juuri se mahdollistaa moniäänisyyden ja avoimen tekstin, joka voi sisältää monia merkityksiä. Kun runossa ei ole yhden puhujan hallitsevaa ääntä, lukijan rooli merkitysten muodostajana nousee keskeiseksi. ”Litany” on selkeästi metatekstuaalinen runo, jossa fiktiivinen taso sekoittuu runouden, taiteen ja kritiikin mahdollisuuksien pohdintaan. Runo hahmottelee uudenlaista, moniäänistä teorian ja runouden rajoja purkavaa kommunikaation muotoa. Toisen persoonan pronominien voidaan runossa usein ajatella puhuttelevan lukijaa. <i>Your Name Herei> -kokoelmassa puolestaan toisen persoonan pronominipositiot määrittyvät usein tietyiksi henkilöhahmoiksi runojen maailmassa, ja pronominipositioiden kautta runoissa rakentuu moniäänisiä dialogeja määrittymättömien henkilöhahmojen välille. Näin lukijan huomio suunnataan ensisijaisesti kommunikaation ja arkipäivän kielenkäytön kliseiden sävyihin ja asiayhteyksiin pikemminkin kuin yksittäisten lausumien sisältöön. <i>A Nest of Ninnies i>-romaani toimii näennäisestä dialogisuudestaan huolimatta ennen kaikkea yksiäänisesti, sillä romaanin yksiulotteisten henkilöhahmojen esittämiä ajatuksia hallitsee parodioimaan pyrkivä kertojanääni. Ashberyn runojen ja romaanin tarkasteleminen osoittaa, että käsitys runoudesta väistämättä yksiäänisenä ja romaanista moniäänisenä ei ole kaikilta osin ongelmaton. Moniääninen, monimerkityksinen runo voi tarjota toiselle itsenäisen aseman.

The Structure and Function of αI Domains in Collagen Receptor and Leukocyte Integrins

Integrins are heterodimeric, signaling transmembrane adhesion receptors that connect the intracellular actin microfilaments to the extracellular matrix composed of collagens and other matrix molecules. Bidirectional signaling is mediated via drastic conformational changes in integrins. These changes also occur in the integrin αI domains, which are responsible for ligand binding by collagen receptor and leukocyte specific integrins. Like intact integrins, soluble αI domains exist in the closed, low affinity form and in the open, high affinity form, and so it is possible to use isolated αI domains to study the factors and mechanisms involved in integrin activation/deactivation. Integrins are found in all mammalian tissues and cells, where they play crucial roles in growth, migration, defense mechanisms and apoptosis. Integrins are involved in many human diseases, such as inflammatory, cardiovascular and metastatic diseases, and so plenty of effort has been invested into developing integrin specific drugs. Humans have 24 different integrins, four of which are collagen receptor (α1β1, α2β1, α10β1, α11β1) and five leukocyte specific integrins (αLβ2, αMβ2, αXβ2, αDβ2, αEβ7). These two integrin groups are quite unselective having both primary and secondary ligands. This work presents the first systematic studies performed on these integrin groups to find out how integrin activation affects ligand binding and selectivity. These kinds of studies are important not only for understanding the partially overlapping functions of integrins, but also for drug development. In general, our results indicated that selectivity in ligand recognition is greatly reduced upon integrin activation. Interestingly, in some cases the ligand binding properties of integrins have been shown to be cell type specific. The reason for this is not known, but our observations suggest that cell types with a higher integrin activation state have lower ligand selectivity, and vice versa. Furthermore, we solved the three-dimensional structure for the activated form of the collagen receptor α1I domain. This structure revealed a novel intermediate conformation not previously seen with any other integrin αI domain. This is the first 3D structure for an activated collagen receptor αI domain without ligand. Based on the differences between the open and closed conformation of the αI domain we set structural criteria for a search for effective collagen receptor drugs. By docking a large number of molecules into the closed conformation of the α2I domain we discovered two polyketides, which best fulfilled the set structural criteria, and by cell adhesion studies we showed them to be specific inhibitors of the collagen receptor integrins.