Probing MST1 Kinase Sequence and Structure for Rational Drug Discovery (Targeting diabetes by blocking protein-protein interactions)

Apoptotic beta cell death is an underlying cause majorly for type I and to a lesser extent for type II diabetes. Recently, MST1 kinase was identified as a key apoptotic agent in diabetic condition. In this study, I have examined MST1 and closely related kinases namely, MST2, MST3 and MST4, aiming to tackle diabetes by exploring ways to selectively block MST1 kinase activity. The first investigation was directed towards evaluating possibilities of selectively blocking the ATP binding site of MST1 kinase that is essential for the activity of the enzymes. Structure and sequence analyses of this site however revealed a near absolute conservation between the MSTs and very few changes with other kinases. The observed residue variations also displayed similar physicochemical properties making it hard for selective inhibition of the enzyme. Second, possibilities for allosteric inhibition of the enzyme were evaluated. Analysis of the recognized allosteric site also posed the same problem as the MSTs shared almost all of the same residues. The third analysis was made on the SARAH domain, which is required for the dimerization and activation of MST1 and MST2 kinases. MST3 and MST4 lack this domain, hence selectivity against these two kinases can be achieved. Other proteins with SARAH domains such as the RASSF proteins were also examined. Their interaction with the MST1 SARAH domain were evaluated to mimic their binding pattern and design a peptide inhibitor that interferes with MST1 SARAH dimerization. In molecular simulations the RASSF5 SARAH domain was shown to strongly interact with the MST1 SARAH domain and possibly preventing MST1 SARAH dimerization. Based on this, the peptidic inhibitor was suggested to be based on the sequence of RASSF5 SARAH domain. Since the MST2 kinase also interacts with RASSF5 SARAH domain, absolute selectivity might not be achieved.

Expectations of elderly people on the nurse-client relationship and interaction in home care : "When I see the nurse's smiling face it feels likes sunshine on a rainy and gloomy day"

The purpose of the thesis was to explore expectations of elderly people on the nurse-client relationship and interaction in home care. The aim is to improve the quality of care to better meet the needs of the clients. A qualitative approach was adopted. Semi-structured theme interviews were used for data collection. The interviews were conducted during spring 2006. Six elderly clients of a private home care company in Southern Finland acted as informants. Content analysis was used as the method of data analysis. The findings suggest that clients expect nurses to provide professional care with loving-kindness. Trust and mutual, active interaction were expected from the nurse-client relationship. Clients considered it important that the nurse recognizes each client's individual needs. The nurse was expected to perform duties efficiently, but in a calm and unrushed manner. A mechanic performance of tasks was considered negative. Humanity was viewed as a crucial element in the nurse-client relationship. Clients expressed their need to be seen as human beings. Seeing beyond the illness was considered important. A smiling nurse was described to be able to alleviate pain and anxiety. Clients hoped to have a close relationship with the nurse. The development of a close relationship was considered to be more likely if the nurse is familiar and genuine. Clients wish the nurses to have a more attending presence. Clients suggested that the work areas of the nurses could be limited so that they would have more time to transfer from one place to another. Clients felt that they would benefit from this as well. The nurses were expected to be more considerate. Clients wished for more information regarding changes that affect their care. They wished to be informed about changes in schedules and plans. Clients hoped for continuity from the nurse-client relationship. Considering the expectations of clients promotes client satisfaction. Home care providers have an opportunity to reflect their own care behaviour on the findings. To better meet the needs of the clients, nurses could apply the concept of loving-kindness in their work, and strive for a more attending presence.

Worldly Saints : Social Interaction of Dominican Penitent Women in Italy, 1200-1500

Doctoral dissertation, University of Turku

Copresence video conference mediated interaction

Abstract

Interaction of prechilling, temperature, osmotic stress, and light in Picea abies seed germination

Summary

Sensitivity of temperate grassland species to elevated atmospheric CO2 and the interaction with temperature and water stress

Selostus: Kohonneen hiilidioksidipitoisuuden, lämpötilan ja kuivuuden vaikutus nurmikasveihin

The Interaction of the Calcium Sensitiser Levosimendan with Cardiac Troponin C

Cardiac failure is one of the leading causes of mortality in developed countries. As life expectancies of the populations of these countries grow, the number of patients suffering from cardiac insufficiency also increase. Effective treatments including the use of calcium sensitisers are being sought. They cause a positive inodilatory effect on cardio-myocytes without deleterious effects (arrhythmias) resulting from increases in intracellular calcium concentration. Levosimendan is a novel calcium sensitiser that hasbeen proved to be a welltolerated and effective treatment for patients with severe decompensated heart failure. Cardiac troponin C (cTnC) is its target protein. However, there have been controversies about the interactions between levosimendan and cTnC. Some of these controversies have been addressed in this dissertation. Furthermore, studies on the calcium sensitising mechanism based on the interactions between levosimendan and cTnC as followed by nuclear magnetic resonance(NMR) are presented and discussed. Levosimendan was found to interact with bothdomains of the calcium-saturated cTnC in the absence of cardiac troponin I (cTnI). In the presence of cTnI, the C-domain binding site was blocked and levosimendan interacted only with the regulatory domain of cTnC. This interaction may have caused the observed calcium sensitising effect by priming the N-domain for cTnI binding thereby extending the lifetime of that complex. It is suggested that this is achieved by shifting the equilibrium between open and closed conformations.

Investigation of interaction between native and impurity defects in ZnSe

Zinc selenide is a prospective material for optoelectronics. The fabrication of ZnSe­based light-emitting diodes is hindered by complexity of p-type doping of the component materials. The interaction between native and impurity defects, the tendency of doping impurity to form associative centres with native defects and the tendency to self-compensation are the main factors impeding effective control of the value and type of conductivity. The thesis is devoted to the study of the processes of interaction between native and impurity defects in zinc selenide. It is established that the Au impurity has the most prominent amphoteric properties in ZnSe among Cu, Ag and Au impurities, as it forms a great number of both Au; donors and Auz„ acceptors. Electrical measurements show that Ag and Au ions introduced into vacant sites of the Zn sublattice form simple single-charged Agz„+ and Auzn+ states with d1° electron configuration, while Cu ions can form both single-charged Cuz„ (d1) and double-charged Cuzr`+ (d`o) centres. Amphoteric properties of Ag and Au transition metals stimulated by time are found for the first time from both electrical and luminescent measurements. A model that explains the changes in electrical and luminescent parameters by displacement of Ag ions into interstitial sites due to lattice deformation forces is proposed. Formation of an Ag;-donor impurity band in ZnSe samples doped with Ag and stored at room temperature is also studied. Thus, the properties of the doped samples are modified due to large lattice relaxation during aging. This fact should be taken into account in optoelectronic applications of doped ZnSe and related compounds.

Äitiys kulttuurisina odotuksina

Tutkimuksen kohteena ovat äitiydelle tuotetut kulttuuriset odotukset, joita tarkastellaan kahdella yhteiskunnallisella keskustelufoorumilla. Tutkimuksessa tarkastellaan yhtäältä lastensuojelun perhetyössä toimivien ammattilaisten ja toisaalta median puhetta äitiydestä. Tutkimuksen tavoitteena on tehdä näkyväksi vaihtoehtoisia tapoja konstruoida äitiyttä hyvänä tai riittämättömänä sekä haastaa pohtimaan erilaisten tulkintojen perusteita ja seurauksia lastensuojelutyössä. Kulttuuriset, äitiyttä koskevat odotukset vaikuttavat myös siihen, miten äitiys henkilökohtaisella tasolla koetaan. Äitiyden kulttuurista määrittelyä analysoidaan kahdesta tekstiaineistosta. Yhtenä aineistona ovat Stakesissa vuonna 1999 toteutetun Perhetyöprojektin yhteydessä kerätyt, lastensuojelussa toimivien perhetyöammattilaisten ryhmäkeskustelut. Toisena aineistona on projektin ajankohtana ilmestyneistä suomalaisista naisten- ja perhelehdistä (Kotiliesi, Anna, Kaksplus) kerätyt äitien haastattelut. Tutkimuksessa kysytään 1) Mihin ammattilaisten äitejä koskeva huolipuhe kiinnittyy ja millaisia kulttuurisia äitiyden odotuksia se konstruoi? 2) Millaisia äitiyden odotuksia median äitihaastattelut konstruoivat? 3) Millaisen äitiyden odotushorisontin nämä puhekäytännöt yhdessä tuottavat? Analyysin teoreettis-metodologisina kulmakivinä ovat sosiaalinen konstruktionismi ja feministinen tietokäsitys. Analyysimenetelmänä on laadullinen, aineistojen ehdoilla etenevä, feministisesti ja kriittisesti sävyttynyt lukutapa, joka hyödyntää teemoittelun, diskurssianalyysin ja feministisen metodologian ideoita ja käsitteitä. Analysoitavana olevissa keskusteluissa äitiyttä konstruoidaan lapsen tarpeiden (ammattilaiset) ja naisen tarpeiden (media) näkökulmista. Ammattilaiset puhuvat tilanteista, joissa äitien toiminta rikkoo kulttuurista hyvän äidin kuvaa, vaarantaa lapsen hyvinvointia ja äitiyteen joudutaan puuttumaan ammatillisesti. Ammattilaisten tulkinnat kuvaavat taitavaa lapsen edun näkökulmasta tehtyä arviointia, jonka kiintopisteenä ovat äidit yksilöllisine ominaisuuksineen ja piirteineen. Ammatillisen huolipuheen keskiössä ovat äidin vuorovaikutussuhteet sekä äidin tunteet, käyttäytyminen ja asenteet. Riittävää äitiyttä konstruoi kodin luominen, kiintymyssuhteen rakentaminen ja lapsen ensisijaiseksi asettaminen. Sen sijaan vaikuttaa siltä, ettei äitiyden arviointia juurikaan tehdä suhteessa äidin muihin identiteetteihin tai äitiyden toteuttamisen kontekstiin. Paikoin ammattilaisten tulkinnat heijastavat myös stereotyyppisiä ja idealistisia odotuksia, joita vasten äitiyttä arvioidaan. Tällaiset piirteet voivat kertoa siitä, että äitien avuntarpeet jäävät lastensuojelutyössä kohtaamatta ja ymmärtämättä. Mediapuhe äitiydestä käydään naiseuden ja äitiyden mallien antamisen kontekstissa. Puheen keskiössä ovat mediajulkisuuteen päässeiden naisten äidiksi tuloon ja äitiyden toteuttamiseen liittyvät valinnat ja käyttäytyminen. Mediapuhe on puhetta kulttuuristen ja ammatillisten äitiyden odotusten rikkomisesta, uudelleen tulkinnasta ja niiden muovaamisesta itselle sopiviksi. Mediapuheessa hyvää äitiyttä konstruoi äidin itsenäisyys ja oma aika, sosiaalisen elämän rikkaus, ammatillinen identiteetti ja persoonalliset valinnat. Aineistojen kautta rakentuu moninaisten ja ristiriitaisten, äitejä eri suuntaan vetävien kulttuuristen odotusten kirjo. Odotukset jäsentyvät neljälle ulottuvuudelle: 1) lapselle omistautuva – itseään toteuttava, 2) emotionaalinen side – rationaalinen tehtävä, 3) odotuksia toteuttava – omaehtoinen, 4) itsenäinen - äitiyttä jakava. Äitiyden toteuttaminen kulttuurisesti ”oikein” on näiden odotusten välissä tasapainoilua. Ulottuvuuksien kautta esille tulevat kaksoisviestit voivat heikentää äitien itsetuntoa, tuottaa riittämättömyyden tunteita tai yllyttää suorittamaan äitiyttä. Myös äitiyden ammatillinen tukeminen edellyttää tasapainoilua, jottei äitejä idealisoida tai syyllistetä kulttuurisia odotuksia vasten.

On Commutation and Conjugacy of Rational Languages and the Fixed Point Method

The research on language equations has been active during last decades. Compared to the equations on words the equations on languages are much more difficult to solve. Even very simple equations that are easy to solve for words can be very hard for languages. In this thesis we study two of such equations, namely commutation and conjugacy equations. We study these equations on some limited special cases and compare some of these results to the solutions of corresponding equations on words. For both equations we study the maximal solutions, the centralizer and the conjugator. We present a fixed point method that we can use to search these maximal solutions and analyze the reasons why this method is not successful for all languages. We give also several examples to illustrate the behaviour of this method.