The function of NR3B and NR4A orphan nuclear receptors in osteoblasts

Nuclear receptors (NRs) comprise a large family of proteins that mediate the effects of small lipophilic molecules such as steroid hormones. In addition, there are a group of NRs which lack identified natural ligands and are referred as orphan NRs. In this thesis, the function of two such orphan NR families, the NR3B (ERR��, ERR�� and ERR��) and the NR4A family (NGFI-B, Nurr1 and Nor1), was studied. NR3B and NR4A receptors regulate many biological processes such as energy metabolism and carcinogenesis. In addition, NR3B and NR4A receptors are expressed in bone. Therefore, the signaling and function of NR3B and NR4A orphan nuclear receptors was studied specifically in osteoblasts. NR4A receptors were found to be regulated by NR3B receptors and the Wnt/��-catenin signaling pathway as ERR��, ERR�� and ��-catenin repressed the transcriptional activity of NR4A receptors in U2-OS cells. NGFI-B was found to repress the transcriptional activity of ERR�� in HeLa cells. The phytoestrogen equol was identified as a new agonist for ERR�� and ERR�� in PC-3, U2-OS, and SaOS-2 cells. Equol increased the transcriptional activity of ERR�� by increasing ERR�� co-activator binding and by inducing a conformational change in the ligand binding pocket of ERR��. The growth inhibitory effect of equol on PC-3 prostate cancer cells was decreased by blocking ERR�� expression by siRNA. Therefore, ERR�� could mediate some of the beneficial health effects of equol. The Wnt/��-catenin signaling pathway is important for the differentiation and function of osteoblasts. NR3B and NR4A receptors were found to repress the transcriptional activity mediated by ��-catenin in U2-OS cells. The mesenchymal stem cells (MSCs) isolated from ERR�� knockout (KO) mice showed diminished proliferation and osteoblastic differentiation compared to the wild-type cells. The overexpression of ERR�� in osteoblastic MC3T3-E1 cell line increased their mineralization. Bone sialoprotein (BSP) was shown to be a direct target gene for ERR�� and ERR�� as the BSP promoter was activated by ERR�� or ERR�� and PGC-1�� in HeLa cells. The adipogenic differentiation of ERR�� KO MSCs was also decreased and they expressed less adipogenic marker genes. In conclusion, the studies described in this thesis demonstrated that the transcriptional activity of NR3B and NR4A receptors can be regulated by other orphan NRs and signaling pathways in osteoblasts. NR3B receptors can also be regulated by ligands and a new agonist, equol, was identified for ERR�� and ERR��. New roles for NR3B and NR4A were also identified as they were shown to converge with the Wnt signaling pathway in osteoblasts, ERR�� was shown to mediate the growth inhibitory effect of equol in prostate cancer cells, and ERR�� was shown to regulate positively MSC proliferation, osteoblastic differentiation and adipogenesis.

Juverh��lsoproblem orsakade av Streptococcus agalactiae p�� stora mj��lkg��rdar med mj��lkningsrobot

Streptococcus agalactiae ���juverinflammation var tidigare ett stort problem i m��nga l��nder, inklusive Finland. I och med f��rb��ttrad mj��lkningshygien och antibiotikabehandlingar har bakterien s�� gott som eradikerats fr��n mj��lkbes��ttningarna. Nu verkar bakterien i viss m��n ha kommit tillbaka till v��ra stora mj��lkg��rdar. Avhandlingens experimentella del utf��rdes p�� en mj��lkg��rd, med ca 180 mj��lkande och tre mj��lkningsrobotar, som haft problem med Str. agalactiae. Man hoppades utreda hur stort problemet p�� g��rden var samt m��jliga smittov��gar. Man unders��kte ocks�� m��jligheten att anv��nda mj��lkningsrobotens automatiska provtagningsutrustning f��r provtagning av bakteriella prov. PCRmetoden j��mf��rdes med konventionell odling vid diagnostik av juverinflammationer orsakade av Str. agalactiae. P�� g��rden gick man igenom anteckningar samt h��lso- och seminkort f��r att f�� en bild ��ver situationen. Man gjorde en uppf��ljning av mj��lkningen f��r tolv kor vid den ena mj��lkningsroboten. Man tog 47 stycken kospecifika mj��lkprov samt ett prov fr��n mj��lktanken. Mj��lkprov i tre serier b��de mj��lkade f��r hand och direkt fr��n mj��lkuppsamlaren p�� mj��lkningsroboten togs. Man tog sammanlagt 23 renlighetsprov fr��n mj��lkningsroboten, tre fr��n den automatiska provtagningsutrustningen samt tv�� fr��n djursk��tarnas h��nder. Fr��n den automatiska provtagningsutrustningen togs ��ven ett genomsk��ljningsprov. Av mj��lkprov som tidigare tagits p�� g��rden hade man hittat Str. agalactiae i ca 17%. I denna studie hittades Str. agalactiae i tre kospecifika mj��lkprov, vilket motsvarar en prevalens p�� ca 2%. Vid uppf��ljningen av mj��lkningarna uppt��cktes inget alarmerande, men spenarnas h��lsa samt tommj��lkningar ��r n��got som b��r f��ljas upp. Av renlighetsproven hittades Str. agalactiae i ett prov taget fr��n borsth��llaren. Svaren fr��n mj��lkproven tagna i serier tyder p�� att den automatiska provtagningsutrustningen inte g��r att anv��nda till bakteriella prov, eftersom mj��lken fr��n en Str. agalactiae ���infekterad ko verkar p��verka resultatet ocks�� hos f��ljande kor. Resultatet ��r v��ntat, eftersom mj��lkprov alltid skall tas aseptiskt och det g��r inte med den automatiska provtagningsutrustningen s�� som den i dagsl��get ��r utvecklad. Fr��n sju av nio mj��lkprov, d��r man hittat Str. agalactiae med PCR-metoden, hittades bakterien ocks�� med konventionell odling. Fr��n tankmj��lksprovet kunde man inte hitta Str. agalactiae med konventionell odling. PCR-metoden verkar enligt den h��r studien vara mer k��nslig att uppt��cka Str. agalactiae j��mf��rt med konventionell odling.

Suomalainen sotilasidentiteetti yhteiskunnan muutoksessa toisen maailmansodan j��lkeen

Toisen maailmansodan p����ttyminen vuonna 1945 ja sit�� seurannut Suomen poliittinen uudelleenasemointi asettivat my��s suomalaisen identiteettipolitiikan uudelleenarvioitavaksi. Erityisesti puolustusvoimissa ja ylip����t����n suomalaisen sotilaan identiteetin kohdalla muutos oli suuri, sill�� toista maailmansotaa edelt��nyt kansalaissotilaan luominen oli perustunut pitk��lti Neuvostoliiton ja Ven��j��n uhkaan. Sotaa muita kuin it��ist�� naapuria vastaan ei pidetty uskottavana. Tilanteen muututtua pohjaa maanpuolustustahdolle, is��nmaalle ja ylip����t����n sotilaalliselle varautumiselle oli haettava muista l��hteist��. Tutkielma k��sittelee suomalaisen sotilasidentiteetin tilaa 1960-luvun alussa (1960-1965). Asiaa tarkastellaan puolustusvoimien ja sen piiriss�� toimineiden henkil��iden n��k��vinkkelist��. Tarkoituksena on selvitt����, miten he n��kiv��t tilanteen, sen kehityksen ja mit�� toimenpiteit�� kenties tarvittiin identiteetin ohjaamiseksi oikeaan suuntaan. Alkuper��isl��htein�� ty��ss�� on k��ytetty p����asiassa puolustusvoimain vaikutuspiiriss�� julkaistuja sanoma- ja aikakauslehti�� tutkimusjaksolta. Aikaisempaa historiantutkimusta aiheesta ko. tutkimusjaksolta on julkaistu v��h��n. Tutkimus peilaa vahvasti Juha M��lkin v��it��stutkimukseen (2008), jossa tutkittiin suomalaisen kansalaissotilaan luomisty��t�� 1920- ja 1930-luvuilla. M��lkin tutkimus toimii ty��ss�� monin paikoin vertailukohtana sotaa edelt��neeseen tilanteeseen. Toisena t��rke��n�� metodologisena l��ht��kohtana tutkielmalle on Vilho Harlen ja Sami Moision (2000) k��sitys suomalaisesta identiteettiprojektista ja suomalaisen identiteetin rakentamisesta ���toiseutta��� vastaan. Tutkielma selvitt���� suomalaisen sotilasidentiteetin rakentumista kolmella tasolla. Ensimm��isell�� tasolla selvitet����n, millaisena suomalainen sotilas n��htiin luonteensa valossa ja millaisia piirteit�� yhdistettiin h��nen persoonaansa yleisell�� tasolla. Samalla selvitet����n, miten n��m�� piirteet vaikuttivat sotilaalliseen kurinpitoon ja johtamiseen. Toinen taso kartoittaa, miten poliittisen johdon valitsema puolueettomuuspolitiikka vaikutti identiteetin perustaan, siihen miten is��nmaallisuus haluttiin m����ritell�� sek�� niihin k��yt��nn��n toimiin, joita valittu linja vaati. Kolmas taso keskittyy asevelvollisi��ss�� olleeseen nuorisoon ja siihen, miten heid��t n��htiin muun muassa 1960-luvun nuorisoradikalismin ja rauhanaatteiden valossa. Tutkielman loppup����telm�� on, ett�� suomalainen oli kansallisten ominaispiirteidens�� puolesta pitk��lti hyv��ksytty ���aikuinen��� kansalainen. My��s sotilaille kielteiset piirteet, kuten vaikkapa ���purnaaminen��� oli otettu osaksi suomalaisen sotilaan kuvaa. Samalla puolustusvoimain piiriss�� oltiin kuitenkin huolestuneita kansalaisten sitoutumisesta is��nmaahan ja maanpuolustukseen henkisell�� tasolla. Esimerkiksi nuorison radikaalit aatteet n��htiin uhkana oikeanlaiselle identiteetille. Edellytyksen�� hyv��ksytt��v��lle sotilasidentiteetille n��htiin poliittisen johdon valitseman puolueettomuusasenteen laaja ja ehdoton hyv��ksyminen. T��lt�� osin kaikkien suomalaisten olisi ajateltava samalla tavoin.

Esteettinen kokemus kulttuurisiltana : Soile Yli-M��yryn taide kiinalaisen, japanilaisen ja suomalaisen yleis��n kokemana

AESTHETIC EXPERIENCE AS A BRIDGE ACROSS CULTURES Soile Yli-M��yry s art as experienced by Chinese, Japanese and Finnish audiences This study focuses on surveying and analysing experiences of Soile Yli-M��yry s art in eleven different countries. Questionnaires were translated into nine different languages. In addition, interviews were conducted on the experiences of Chinese, Japanese and Finnish art audiences concerning a painting called Sun Wind . The study was mainly inspired by John Dewey s ideas of art as an interactive communication where the artist, the piece and those who experience it make up an interactive process. In this process experience is a meeting point with both individual and communal characteristics. The data was collected in conjunction with exhibitions in 1997���2005. The survey was carried out in eleven countries (Finland, United States, Brazil, China, Taiwan, Japan, India, Israel, Argentina, Germany and Switzerland). The survey data was made up of 2,563 returned questionnaires. The interviews in China, Japan and Finland were about the same painting Sun Wind , which was transported from Finland to Japan (Tokyo) and China. A total of 89 people were interviewed in Shanghai Art Museum, 30 people in Port-Ginza Gallery, Tokyo and 45 people in Soile Yli-M��yry s Gallery in Finland. Three hypotheses that were turned into research questions directed the study: 1. Are there differences/ similarities between culturally different communities in the meanings attributed to experiences, e.g. according to emotional dimensions, or do experiences focus more on reflecting on one s own life or meanings attributed to the world around us? What kinds of experiential dimensions are there in different countries? Do similar, analogous experiences that transcend cultural barriers emerge in culturally different countries such as China, Japan and Finland? 2. Does the data display different types of experiencing subjects which are typical to a subject s own country or are they experiences that can be compared to those generated by an ideal landscape , where the art touches the subconscious and collective selfhood, being thus transnational and timeless? Closer analysis focuses on audience experiences in China, Japan and Finland (interviews, textual survey data). 3. Are the experiences and interpretations of experts similar/different to those of larger audiences? The survey data has been analysed with the help of cross-tabulation. After content analysis of the interviews and textual survey data, different ways of experiencing subjects were sketched by country (China, Japan, Finland). The types were both similar and dissimilar. The most important types were social/ecological (China), therapeutic/reserved (Japan) and narrative/projecting (Finland). There were differences in how experiences were emphasised: the Chinese public approached their experiences from the viewpoint of pragmatism and utility, where they could obtain new ideas for their own work or experiencing the exhibition gave courage to approach their own lives from a new perspective. In turn, the Japanese public experienced the art from a therapeutic angle and from a very reserved perspective, which Dylan Evans (2001, 13���17) has described as typical to Japanese culture. The experiences of the Finnish audience were strongly therapeutic and narrative. The people projected their emotions onto the piece and in a concrete manner forged them into a story. The partly similar results of this study in China, Japan and Finland demonstrate that the art displayed in the exhibitions contain images of the beginning or elements connected to the beginning of life, which touch the subconscious in the way an ideal landscape would. Experiencing the meaningfulness of one s own life through art is a common thread and a bridge across cultures that unites the experiences of the audiences of this study, be they Taoists, Confucians, Buddhists or Maoists in China, Shinto followers, Zen Buddhists in Japan or Evangelist-Lutherans in Finland. Keywords: experience, reception, bridge across cultures, types of experiencing subjects, experiential process, ideal landscape, elementality

Genetic and epigenetic mechanisms of tumor predisposition in hereditary non-polyposis colorectal carcinoma and sporadic cancers

Individuals with inherited deficiency in DNA mismatch repair(MMR) (Lynch syndrome) LS are predisposed to different cancers in a non-random fashion. Endometrial cancer (EC) is the most common extracolonic malignancy in LS. LS represents the best characterized form of hereditary nonpolyposis colorectal carcinoma (HNPCC). Other forms of familial non-polyposis colon cancer exist, including familial colorectal cancer type X (FCCX). This syndrome resembles LS, but MMR gene defects are excluded and the predisposition genes are unknown so far. To address why different organs are differently susceptible to cancer development, we examined molecular similarities and differences in selected cancers whose frequency varies in LS individuals. Tumors that are common (colorectal, endometrial, gastric) and less common (brain, urological) in LS were characterized for MMR protein expression, microsatellite instability (MSI), and by altered DNA methylation. We also studied samples of histologically normal endometrium, endometrial hyperplasia,and cancer for molecular alterations to identify potential markers that could predict malignant transformation in LS and sporadic cases. Our results suggest that brain and kidney tumors follow a different pathway for cancer development than the most common LS related cancers.Our results suggest also that MMR defects are detectable in endometrial tissues from a proportion of LS mutation carriers prior to endometrial cancer development. Traditionally (complex) atypical hyperplasia has been considered critical for progression to malignancy. Our results suggest that complex hyperplasia without atypia is equally important as a precursor lesion of malignancy. Tumor profiles from Egypt were compared with colorectal tumors from Finland to evaluate if there are differences specific to the ethnic origin (East vs.West). Results showed for the first time a distinct genetic and epigenetic signature in the Egyptian CRC marked by high methylation of microsatellite stable tumors associated with advanced stage, and low frequency of Wnt signaling activation, suggesting a novel pathway. DNA samples from FCCX families were studied with genome wide linkage analysis using microsatellite markers. Selected genes from the linked areas were tested for possible mutations that could explain predisposition to a large number of colon adenomas and carcinomas seen in these families. Based on the results from the linkage analysis, a number of areas with tentative linkage were identified in family 20. We narrowed down these areas by additional microsatellite markers to found a mutation in the BMPR1A gene. Sequencing of an additional 17 FCCX families resulted in a BMPR1A mutation frequency of 2/18 families (11%). Clarification of the mechanisms of the differential tumor susceptibility in LS increases the understanding of gene and organ specific targets of MMR deficiency. While it is generally accepted that widespread MMR deficiency and consequent microsatellite instability (MSI) drives tumorigenesis in LS, the timing of molecular alterations is controversial. In particular, it is important to know that alterations may occur several years before cancer formation, at stages that are still histologically regarded as normal. Identification of molecular markers that could predict the risk of malignant transformation may be used to improve surveillance and cancer prevention in genetically predisposed individuals. Significant fractions of families with colorectal and/or endometrial cancer presently lack molecular definition altogether. Our findings expand the phenotypic spectrum of BMPR1A mutations and, for the first time, link FCCX families to the germline mutation of a specific gene. In particular, our observations encourage screening of additional families with FCCX for BMPR1A mutation, which is necessary in obtaining a reliable estimate of the share of BMPR1A-associated cases among all FCCX families worldwide. Clinically, the identification of predisposing mutations enables targeted cancer prevention in proven mutation carriers and thereby reduces cancer morbidity and mortality in the respective families.

��idin hoiva, jaettu vanhemmuus ��� ja vapaus valita. Perhevapaiden uudistamisen argumentointi 1970-luvulta 2000-luvulle

Tutkimuksessa tarkastellaan perhevapaista Suomessa k��yty�� poliittista keskustelua ja sen pitk��n aikav��lin muutosta. Tutkimuksessa syvennyt����n 1970-luvun uudistusaaltoon, jolloin is��t otettiin mukaan j��rjestelm����n, sek�� 2000-lukuun, jolloin isi�� on eri keinoin kannustettu vapaiden k��ytt����n. T��ss�� yhteydess�� selvitet����n itse uudistusprosesseja, mutta keskei-nen tutkimuskohde ovat p����t��ksentekoon osallistuneiden toimijoiden perhevapaita koske-vien n��kemysten argumentointitavat. Tutkimuksen aineisto koostuu mm. valtiop��iv��asia-kirjoista, ty��ryhm��muistioista, hallitusten ja puolueiden ohjelmista ja ty��markkinaj��rjest��jen kannanotoista. Aineistoa l��hestyt����n kehysanalyysin sek�� argumentaatioteorian menetel-mien avulla. N��ill�� kiinnitet����n huomio niihin tekniikoihin, joilla poliittisessa argumentoin-nissa on pyritty saamaan esitetyille toimenpiteille mahdollisimman laaja kannatus. 1970-luvulla keskustelu vanhempainlomista oli hyvin polarisoitunutta. Isien hoivaajaroolin kas-vattaminen oli osa vasemmiston diskurssia, joka pyrki tasa-arvoon niin kodeissa kuin ty��-markkinoillakin. Konservatiivien ��idinhoivan diskurssi sit�� vastoin piti ��iti�� luonnostaan pa-rempana hoitajana lapselle ja vaati pitk��n ��itiysloman jatkeeksi kotihoidon tukea, jota va-semmisto puolestaan vastusti. 2000-luvun p����teemoja ovat olleet vanhemmuuden kus-tannusten tasaisempi jakaminen sek�� isien kannustaminen vapaiden k��ytt����n. Isien kan-nustamiseksi on esitetty erilaisia malleja is��kiinti��ist��: perusteina ovat olleet muun muassa is�����lapsi-suhde, tasa-arvo sek�� Pohjoismaiden positiiviset kokemukset kiinti��ist��. Ty��nan-tajat ja konservatiivit ovat kuitenkin pit��neet kiinti��it�� vanhempien valinnanvapauden rajoit-tamisena, vaikka ne muuten ovatkin argumentoineet tasaarvon ja isien kannustamisen puolesta. Is��kiinti��iden kannattajat taas eiv��t en���� 2000-luvulla ole kyseenalaistaneet ko-tihoidon tukea, joka on pident��nyt naisten katkoja ty��el��m��st�� ja jolla on suuri merkitys lasten hoidon ep��tasaiselle jakautumiselle.

Molecular profiling of indoor microbial communities in moisture damaged and non-damaged buildings

Epidemiological studies have shown an elevation in the incidence of asthma, allergic symptoms and respiratory infections among people living or working in buildings with moisture and mould problems. Microbial growth is suspected to have a key role, since the severity of microbial contamination and symptoms show a positive correlation, while the removal of contaminated materials relieves the symptoms. However, the cause-and-effect relationship has not been well established and knowledge of the causative agents is incomplete. The present consensus of indoor microbes relies on culture-based methods. Microbial cultivation and identification is known to provide qualitatively and quantitatively biased results, which is suspected to be one of the reasons behind the often inconsistent findings between objectively measured microbiological attributes and health. In the present study the indoor microbial communities were assessed using culture-independent, DNA based methods. Fungal and bacterial diversity was determined by amplifying and sequencing the nucITS- and16S-gene regions, correspondingly. In addition, the cell equivalent numbers of 69 mould species or groups were determined by quantitative PCR (qPCR). The results from molecular analyses were compared with results obtained using traditional plate cultivation for fungi. Using DNA-based tools, the indoor microbial diversity was found to be consistently higher and taxonomically wider than viable diversity. The dominant sequence types of fungi, and also of bacteria were mainly affiliated with well-known microbial species. However, in each building they were accompanied by various rare, uncultivable and unknown species. In both moisture-damaged and undamaged buildings the dominant fungal sequence phylotypes were affiliated with the classes Dothideomycetes (mould-like filamentous ascomycetes); Agaricomycetes (mushroom- and polypore-like filamentous basidiomycetes); Urediniomycetes (rust-like basidiomycetes); Tremellomycetes and the family Malasseziales (both yeast-like basidiomycetes). The most probable source for the majority of fungal types was the outdoor environment. In contrast, the dominant bacterial phylotypes in both damaged and undamaged buildings were affiliated with human-associated members within the phyla Actinobacteria and Firmicutes. Indications of elevated fungal diversity within potentially moisture-damage-associated fungal groups were recorded in two of the damaged buildings, while one of the buildings was characterized by an abundance of members of the Penicillium chrysogenum and P. commune species complexes. However, due to the small sample number and strong normal variation firm conclusions concerning the effect of moisture damage on the species diversity could not be made. The fungal communities in dust samples showed seasonal variation, which reflected the seasonal fluctuation of outdoor fungi. Seasonal variation of bacterial communities was less clear but to some extent attributable to the outdoor sources as well. The comparison of methods showed that clone library sequencing was a feasible method for describing the total microbial diversity, indicated a moderate quantitative correlation between sequencing and qPCR results and confirmed that culture based methods give both a qualitative and quantitative underestimate of microbial diversity in the indoor environment. However, certain important indoor fungi such as Penicillium spp. were clearly underrepresented in the sequence material, probably due to their physiological and genetic properties. Species specific qPCR was a more efficient and sensitive method for detecting and quantitating individual species than sequencing, but in order to exploit the full advantage of the method in building investigations more information is needed about the microbial species growing on damaged materials. In the present study, a new method was also developed for enhanced screening of the marker gene clone libraries. The suitability of the screening method to different kinds of microbial environments including biowaste compost material and indoor settled dusts was evaluated. The usability was found to be restricted to environments that support the growth and subsequent dominance of a small number microbial species, such as compost material.

"Litrasev viinapulloj ja s��ittem��t��ista kalijjaa" : Diftongin reduktio ja geminaatio er����n pyh��j��rvisist�� nuorista koostuvan ryhm��n puhekieless��

Tutkielmassa tarkastellaan er����n 16- ja 17-vuotiaista syntyper��isist�� pyh��j��rvisist�� nuorista tyt��ist�� ja pojista koostuvan sosiaalisen ryhm��n puhekielt�� diftongin reduktion ja geminaatioilmi��iden kautta. Geminaatioilmi��ist�� tarkastellaan yleisgeminaatiota ja it��murteiden erikoisgeminaatiota mutta p����paino on it��murteiden erikoisgeminaatiossa. Tutkimuspaikkakunta Pyh��j��rvi sijaitsee maantieteellisesti Pohjois-Pohjanmaalla mutta kuuluu lingvistisesti savolaismurteisiin. Tutkielman tavoitteena on selvitt����, kuinka elinvoimaisia tarkasteltavaksi valitut piirteet ovat sek�� kuinka paljon ja miten ne varioivat ryhm��n puhekieless��. Aineistoa analysoidaan p����asiassa kvantitatiivisesti. Kvalitatiivisesti piirteiden k��ytt���� tarkastellaan etenkin vuorovaikutuksen mutta my��s sukupuolen n��k��kulmasta. Tutkittavia kielenoppaita on kuusi: kolme tytt���� ja kolme poikaa. Tyt��t ovat lukio- ja pojat ammattikouluopiskelijoita. Kielenoppaiden muodostama ryhm�� pohjautuu yl��kouluaikaisiin yst��vyyssuhteisiin ja oli jo olemassa ennen aineistonkeruuta. Tutkielman aineistona on 5 tuntia ryhm��n j��senten v��lisi�� keskusteluja: 2,5 tuntia tytt��jen keskist�� keskustelua, 1,5 tuntia poikien keskustelua ja 1 tunti keskustelua, jossa kaikki ryhm��n j��senet olivat l��sn�� koko ryhm��n kesken. Kukin keskustelu on tallennettu sek�� ����ni- ett�� videonauhalle. Nauhoitukset on tehty maalis- ja toukokuussa 2010. Tutkielman kvantitatiivinen analyysi perustuu korvakuulolla tehtyihin mittauksiin ja niihin perustuviin absoluuttisiin frekvensseihin. Sek�� diftongin reduktio ett�� molemmat geminaatioilmi��t ovat ryhm��n puhekieless�� elinvoimaisia piirteit��, joskin diftongin reduktion kohdalla esiintyminen on labiilia. Etenkin yleisgeminaatio on ryhm��n puhekieless��, my��s idiolekteittain katsottuna, taajaan esiintyv�� ja l��hes varioimaton piirre: geminoituminen esiintyy t��ysgeminaattana l��hes aina yleisgeminaation sallivissa konteksteissa. Geminoituminen on vahvempaa ensi- kuin j��lkitavuissa. Sen sijaan sek�� diftongin reduktio ett�� it��murteiden erikoisgeminaatio varioivat ryhm��n puhekieless�� yleiskielisten ja eriasteisten murteellisten varianttien v��lill��. Suurin osa diftongeista, niin i-, u- kuin y-loppuisistakin, esiintyy yleiskielisess�� muodossa ja redusoituessaan reduktion liev��ss�� asteessa. It��murteiden erikoisgeminaation mahdollistavissa konteksteissa yleiskielisi�� variantteja on niin ik����n murrevariantteja enemm��n. Murrevarianttien enemmist�� on t��ysgeminaatallisia. Tutkielmassa selvi���� lis��ksi, ett�� eri diftongien ja konsonanttien v��lill�� on ryhm��n puhekieless�� eroja sek�� piirteiden asteittaisessa ett�� m����r��llisess�� esiintymisess��, samoin kuin eri ����nneymp��rist��iss�� esiintymisess��kin. My��s idiolektien v��lill�� on eroja diftongin reduktion ja it��murteiden erikoisgeminaation esiintymisess��. Aineisto osoittaa, ett�� sek�� diftongin reduktion ett�� it��murteiden erikoisgeminaation esiintymisess�� on selvi�� leksikaalisia rajoitteita kielenoppaiden puheessa. Kun diftongi ai tai ei muodostaa lekseemin yksin (ai dialogipartikkelina ja ei kieltosanana), se on yleiskielinen. Diftongi ��i puolestaan esiintyy poikkeuksellisen vahvana varianttina affektisissa yhteyksiss�� lekseemiss�� ��iti. Affektisuus vaikuttaa liittyv��n my��s konsonanttiyhtymien lj, rp ja rv j��lkikomponenttien geminoitumiseen vahvistavasti lekseemeiss�� kaljaa, turpaan ja hirvee. Tarkasteluun valittujen puhekielen piirteiden esiintymisess�� voi havaita s����nn��nmukaisuutta my��s lauserakennetta ja kielenk��ytt���� laajemmin tarkastelemalla. Referoinnin ja tarinankerronnan yhteydess�� diftongin reduktion ja it��murteiden erikoisgeminaation k��ytt�� yleistyy ja vahvistuu. Vahvistuminen on puhetilanteen ja keskusteluun osallistuvien vuorovaikutusteht��vien motivoimaa. T��ll��in on kyse selv��st�� murteella tyylittelyst��. Itsekorjauksen ja liitepartikkelin -kO avulla muodostettujen kysymysten yhteydess�� piirteet puolestaan esiintyv��t aineistossa yleiskielisin��. Yleisgeminaatioon edell�� mainitut eiv��t n��yt�� vaikuttavan. Sukupuolten v��lill�� on huomattavissa eroja tarkasteltujen kielenpiirteiden esiintymisess�� ja k��yt��ss��. Tutkielma osoittaa, ett�� pojat ovat tarkasteluun valittujen kielenpiirteiden valossa jonkin verran tytt��j�� murteellisempia. Sukupuolten v��lisi�� murteellisuuseroja voidaan selitt���� etenkin opiskelupaikkakunnan, koulutuksen, sosiaalisten kontaktien, kielenk��yt��n tapojen ja vuorovaikutusteht��vien avulla. Tutkimus tarjoaa tietoa nykypuhesuomen variaatiosta kolmen puhekielen piirteen kautta. Ty�� j��tt���� paljon tarkasteltavaa my��s t��m��n tutkielman j��lkeiselle tutkimukselle. Edelleen selvitett��v��ksi j����v��t monet muut kielenpiirteet ryhm��n puhekieless��. Erityisen mielenkiintoinen tutkimuskohde olisi persoonapronominien variaatio (min�� ~ m�� ~ m����). Luonnollinen jatke tutkielmalle olisi my��s ryhm��n reaaliaikainen seuraaminen valittujen kielenpiirteiden osalta.

Importance of COMT in the regulation of prefrontal dopamine

The prefrontal cortex (PFC), located in the anterior region of the frontal lobe, is considered to have several key roles in higher cognitive and executive functions. In general, the PFC can be seen as a coordinator of thought and action allowing subjects to behave in a goal-directed manner. Due to its anatomical connections with a variety of cortical and subcortical structures, several neurotransmitters, including dopamine, are involved in the regulation of PFC activity. In general, the majority of released dopamine is cleared by the dopamine transporter (DAT). In the PFC however, the number of presynaptic DAT is diminished, emphasizing the relative importance of catechol-O-methyltransferase (COMT) in dopamine metabolism. As a result, the role of COMT in the etiology of psychotic disorders is under constant debate. The present study investigated the role of COMT in prefrontal cortical dopamine metabolism by different neurochemical methods in COMT knockout (COMT-KO) mice. Pharmacological tools to inhibit other dopamine clearing mechanisms were also used for a more comprehensive and collective picture. In addition, this study investigated how a lack of the soluble (S-) COMT isoform affects the total COMT activity as well as the pharmacokinetics of orally administered L-dopa using mutant mice expressing only the membrane-bound (MB-) COMT isoform. Also the role of COMT in striatal and accumbal dopamine turnover during ��9-tetrahydrocannabinol (THC) challenge was studied. We found markedly increased basal dopamine concentrations in the PFC, but not the striatum or nucleus accumbens (NAcc), of mice lacking COMT. Pharmacological inhibition of the noradrenaline transporter (NET) and monoamine oxidase (MAO) elevated prefrontal cortical dopamine levels several-fold, whereas inhibition of DAT did not. The lack of COMT doubled the dopamine raising effects of NET and MAO inhibition. No compensatory expression of either DAT or NET was found in the COMT-KO mice. The lack of S-COMT decreased the total COMT activity by 50-70 % and modified dopamine transmission and the pharmacokinetics of exogenous Ldopa in a sex and tissue specific manner. Finally, we found that subsequent tolcapone and THC increased dopamine levels in the NAcc, but not in the striatum. Conclusively, this study presents neurochemical evidence for the important role of COMT in the PFC and shows that COMT is responsible for about half of prefrontal cortical dopamine metabolism. This study also highlights the previously underestimated proportional role of MB-COMT and supports the clinical evidence of a gene x environment interaction between COMT and cannabis.

Sosiaaliturvan ulkopuolella - kokemuksia kansalaisuuden reunalta

Muuttaessaan maasta toiseen ihminen kohtaa useita rajoja. Ylitt��ess����n kohdemaan valtion rajan h��n kulkee l��pi ensimm��isest�� maahanmuuton portista. Toinen raja erottaa tilap��iset asukkaat pysyvist��: t��m��n maahanmuuton toisen portin l��pikulkemisen my��t�� yksil�� p����see osalliseksi sosiaalisista oikeuksista. Maahanmuuton viimeisest�� portista kuljettuaan yksil�� saavuttaa kyseisen valtion kansalaisuuden. (Hammar 1990, 21.) T��ss�� pro gradu -tutkielmassa tarkastelen toisen maahanmuuton portin aukeamista ja sosiaaliturvan piiriin p����sy�� odottavien maahan-muuttajien kokemuksia. K��yt��n tarkastelussa sosiaalisen kansalaisuuden ja marginaalisuuden k��sitteit��. Tutkielmassa selvit��n, miten sosiaali- ja terveyspalveluiden sek�� toimeentuloturvan ulkopuolelle j����minen vaikuttaa maahanmuuttajien arkeen ja miten he kokevat osallisuutensa ja j��senyytens�� yhteiskunnassa. Tutkimus on l��ht��kohdiltaan fenomenologis-hermeneuttinen ja sovellan l��hestymistapana ko-kemuksiin keskittyv��n narratiivista tutkimusta. Tutkimusaineisto on koottu kev����n 2011 aikana ja se koostuu 10 teemahaastattelusta. Haastateltavien maahanmuuton keinot ja syyt vaihtelivat: he olivat saapuneet Suomeen perhesyist��, ty��n vuoksi tai hakeakseen turvaa. Haastateltavat tavoitettiin Helsingin Diakoniaopiston, Pro-tukipisteen, Kansainv��lisen seurakunnan ja tuttava-verkostojen kautta. Aineiston analyysi toteutettiin sis��ll��nanalyysill�� Atlas-ohjelman avulla syksyn 2011 aikana. Toisen maahanmuuton portin aukeamisen odottaminen oli raskaaksi: tuota aikaa leimasi ep��-varmuus, tyhjyys ja yksin��isyys. Sosiaaliturvan ulkopuolella j����minen aiheutti osalle haastatel-tavista taloudellisia vaikeuksia sek�� ongelmia terveydenhuollon palveluiden piiriin p����semisess��. Toisaalta apua hakeneet haastateltavat olivat sit�� lopulta saaneet. Auttamisty��n ammattilaiset ja maistraatti saivat haastateltavien kertomuksissa portinvartijan aseman. Kaikille sosiaaliturvan ulkopuolelle j����minen ei ollut ongelma vaan he kokivat sosiaaliturvan puutetta suuremmaksi ongelmaksi ty��nteko-oikeuden puuttumisen. Kuulumisen ja ulkopuolisuuden kokemus voivat olla l��sn�� samanaikaisesti, ja kuulumisesta neuvotellaan jatkuvasti esimerkiksi sosiaalisessa kanssak��ymisess�� tai palveluita hakiessa. Insti-tutionaaliset k��yt��nn��t ja poisk����nnytt��misen kokemukset tuottavat marginaalisia identiteettej��. Tasavertainen oikeus sosiaaliturvaan vahvistaa kokemusta kuulumisesta ja kodista. Sosiaaliturva ei kuitenkaan yksin m����rit�� kuulumisen ja kodin kokemusta vaan siihen vaikuttavat my��s muut tekij��t. N��ist�� t��rkeimm��t ovat kehon fyysinen sijoittuminen Suomeen, perhe- ja yst��-vyyssuhteet, ty��, asunto ja rasismin kokemukset.

K(2)O(2): The most stable oxide of K

We have analyzed the stability of various oxides of K and find that K(2)O(2) is the most stable one. The additional stability is traced to the presence of oxygen dimers in K(2)O(2) which interact to form molecular orbitals. Other oxides such as KO(2) and KO(3) which also have dimers/trimers of oxygens are found to be less stable. This is traced to the shorter O-O bonds that one finds in them which gives rise to a significant coulomb repulsion between the electrons on the oxygen atoms making up the dimer/trimer, making them less stable.

Right-Definite Multiparameter Sturm���Liouville Problems With Eigenparameter-Dependent Boundary Conditions

We study a system of ordinary differential equations linked by parameters and subject to boundary conditions depending on parameters. We assume certain definiteness conditions on the coefficient functions and on the boundary conditions that yield, in the corresponding abstract setting, a right-definite case. We give results on location of the eigenvalues and oscillation of the eigenfunctions.

Malaria Parasite-Synthesized Heme Is Essential in the Mosquito and Liver Stages and Complements Host Heme in the Blood Stages of Infection

Heme metabolism is central to malaria parasite biology. The parasite acquires heme from host hemoglobin in the intraerythrocytic stages and stores it as hemozoin to prevent free heme toxicity. The parasite can also synthesize heme de novo, and all the enzymes in the pathway are characterized. To study the role of the dual heme sources in malaria parasite growth and development, we knocked out the first enzyme, d-aminolevulinate synthase (ALAS), and the last enzyme, ferrochelatase (FC), in the heme-biosynthetic pathway of Plasmodium berghei (Pb). The wild-type and knockout (KO) parasites had similar intraerythrocytic growth patterns in mice. We carried out in vitro radiolabeling of heme in Pb-infected mouse reticulocytes and Plasmodium falciparum-infected human RBCs using 4-(14) C] aminolevulinic acid (ALA). We found that the parasites incorporated both host hemoglobin-heme and parasite-synthesized heme into hemozoin and mitochondrial cytochromes. The similar fates of the two heme sources suggest that they may serve as backup mechanisms to provide heme in the intraerythrocytic stages. Nevertheless, the de novo pathway is absolutely essential for parasite development in the mosquito and liver stages. PbKO parasites formed drastically reduced oocysts and did not form sporozoites in the salivary glands. Oocyst production in PbALASKO parasites recovered when mosquitoes received an ALA supplement. PbALASKO sporozoites could infect mice only when the mice received an ALA supplement. Our results indicate the potential for new therapeutic interventions targeting the heme-biosynthetic pathway in the parasite during the mosquito and liver stages.

Numerical study of the impact of inoculant and grain transport on macrosegregation and microstructure formation during solidification of an Al-22%Cu alloy

We investigate the impact of the nucleation law for nucleation on Al-Ti-B inoculant particles, of the motion of inoculant particles and of the motion of grains on the predicted macrosegregation and microstructure in a grain-refined Al-22 wt.% Cu alloy casting. We conduct the study by numerical simulations of a casting experiment in a side-cooled 76��76��254 mm sand mould. Macrosegregation and microstructure formation are studied with a volume-averaged two-phase model accounting for macroscopic heat and solute transport, melt convection, and transport of inoculant particles and equiaxed grains. On the microscopic scale it accounts for nucleation on inoculant particles with a given size distribution (and corresponding activation undercooling distribution)and for the growth of globular solid grains. The growth kinetics is described by accounting for limited solute diffusion in both liquid and solid phases and for convective effects. We show that the consideration of a size distribution of the inoculants has a strong impact on the microstructure(final grain size) prediction. The transport of inoculants significantly increases the microstructure heterogeneities and the grain motion refines the microstructure and reduces the microstructure heterogeneities.

Efficiency limitations in a low band-gap diketopyrrolopyrrole-based polymer solar cell

We report the performance and photophysics of a low band-gap diketopyrrolopyrrole-based copolymer used in bulk heterojunction devices in combination with PC71BM. We show that the short lifetime of photogenerated excitons in the polymer constitutes an obstacle towards device efficiency by limiting the diffusion range of the exciton to the donor-acceptor heterojunction. We employ ultrafast transient-probe and fluorescence spectroscopy techniques to examine the excited state loss channels inside the devices. We use the high boiling point solvent additive 1,8-diiodooctane (DIO) to study the photoexcited state losses in different blend morphologies. The solvent additive acts as a compatibiliser between the donor and the acceptor material and leads to smaller domain sizes, higher charge formation yields and increased device efficiency.