Olivier Messiaenin väriharmoniat

Tutkielmassani käsittelen ranskalaisen säveltäjän Olivier Messiaenin (1908-1992) synestesiaan liittyvää harmonista ajattelua. Messiaen oli ääni-väri -synesteetikko, toisin sanoen hän näki kuulemansa musiikin väreinä. Tältä pohjalta hän kehitti monimutkaisten sointujen ja asteikkojen järjestelmän, jonka puitteissa hän pystyi ikään kuin maalaamaan musiikillaan haluamansa värit. Esittelen aluksi tämänhetkistä synestesiatutkimusta lähinnä kolmen vallitsevassa asemassa olevan päälinjan pohjalta. Näitä edustavat yhdysvaltalainen Richard Cytowic, britti Simon Baron-Cohen ja saksalainen Hinderk Emrich. Käyn läpi heidän määritelmänsä synestesiasta ja näkemyksiään synesteettisistä säveltäjistä. Messiaen on jossain määrin tuonut esiin musiikkinsa värejä lähes uransa alusta lähtien, mutta huomiot ovat yleensä olleet melko ylimalkaisia ja epäjärjestelmällisiä. Tuon esiin näitä eri lähteistä löytyneitä Messiaenin näkemyksiä ja kokemuksia tarkasteltuna Messiaenin henkilökohtaisen sävellysfilosofian pohjalta sekä tiettyihin Messiaenin sävellyksiin ja niiden harmonisiin rakenteisiin liittyen. Messiaenin kuoleman jälkeen vuosina 1994-2002 julkaistun seitsenosaisen teossarjan Traité de rythme, de couleur, et d'ornitologie viimeisessä osassa Messiaen esittää järjestelmällisesti kaikkien erikoissointujensa ja moodiensa värityksen. Tarkastelen Messiaenin käyttämiä harmonioita jakamalla ne yleisiin ja erikoissointuihin sekä moodeihin. Määritellessäni näitä harmonioita käytän metodina sävelluokkajoukkojen teoriaa, jonka avulla kaikki sävelyhdistelmät voidaan määritellä yksiselitteisesti. Esittelen joukkoteoriaa ja siihen liittyviä käsitteitä siinä määrin kuin se liittyy tutkielmaani, enkä siis yritäkään tuoda esiin analyysimetodia koko laajuudessaan. Olen rekonstruoinut visuaalisesti Messiaenin käyttämät noin 150 harmonista väriä, ja tutkielmani liitteenä olevalla CD-romilla esitän ne soivassa ja näkyvässä muodossa. Tällä CD-romilla on myös analyysiMessiaenin urkuteoksen Méditations sur le mystère de la Sainte Trinité 5. osan alusta, jossa tutkin käytännön tasolla värien ilmenemistä Messiaenin musiikissa. Tutkielmani keskeinen osa onkin tämä CD-rom, ja siitä ilmennee myös tutkielmani lähtökohta ja tavoite: luoda työkalu Messiaenin musiikin värisisältöjen hahmottamiseen.

Genotyping for genetic association studies: Methods and applications

In this thesis, two separate single nucleotide polymorphism (SNP) genotyping techniques were set up at the Finnish Genome Center, pooled genotyping was evaluated as a screening method for large-scale association studies, and finally, the former approaches were used to identify genetic factors predisposing to two distinct complex diseases by utilizing large epidemiological cohorts and also taking environmental factors into account. The first genotyping platform was based on traditional but improved restriction-fragment-length-polymorphism (RFLP) utilizing 384-microtiter well plates, multiplexing, small reaction volumes (5 µl), and automated genotype calling. We participated in the development of the second genotyping method, based on single nucleotide primer extension (SNuPeTM by Amersham Biosciences), by carrying out the alpha- and beta tests for the chemistry and the allele-calling software. Both techniques proved to be accurate, reliable, and suitable for projects with thousands of samples and tens of markers. Pooled genotyping (genotyping of pooled instead of individual DNA samples) was evaluated with Sequenom s MassArray MALDI-TOF, in addition to SNuPeTM and PCR-RFLP techniques. We used MassArray mainly as a point of comparison, because it is known to be well suited for pooled genotyping. All three methods were shown to be accurate, the standard deviations between measurements being 0.017 for the MassArray, 0.022 for the PCR-RFLP, and 0.026 for the SNuPeTM. The largest source of error in the process of pooled genotyping was shown to be the volumetric error, i.e., the preparation of pools. We also demonstrated that it would have been possible to narrow down the genetic locus underlying congenital chloride diarrhea (CLD), an autosomal recessive disorder, by using the pooling technique instead of genotyping individual samples. Although the approach seems to be well suited for traditional case-control studies, it is difficult to apply if any kind of stratification based on environmental factors is needed. Therefore we chose to continue with individual genotyping in the following association studies. Samples in the two separate large epidemiological cohorts were genotyped with the PCR-RFLP and SNuPeTM techniques. The first of these association studies concerned various pregnancy complications among 100,000 consecutive pregnancies in Finland, of which we genotyped 2292 patients and controls, in addition to a population sample of 644 blood donors, with 7 polymorphisms in the potentially thrombotic genes. In this thesis, the analysis of a sub-study of pregnancy-related venous thromboses was included. We showed that the impact of factor V Leiden polymorphism on pregnancy-related venous thrombosis, but not the other tested polymorphisms, was fairly large (odds ratio 11.6; 95% CI 3.6-33.6), and increased multiplicatively when combined with other risk factors such as obesity or advanced age. Owing to our study design, we were also able to estimate the risks at the population level. The second epidemiological cohort was the Helsinki Birth Cohort of men and women who were born during 1924-1933 in Helsinki. The aim was to identify genetic factors that might modify the well known link between small birth size and adult metabolic diseases, such as type 2 diabetes and impaired glucose tolerance. Among ~500 individuals with detailed birth measurements and current metabolic profile, we found that an insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene was associated with the duration of gestation, and weight and length at birth. Interestingly, the ACE insertion allele was also associated with higher indices of insulin secretion (p=0.0004) in adult life, but only among individuals who were born small (those among the lowest third of birth weight). Likewise, low birth weight was associated with higher indices of insulin secretion (p=0.003), but only among carriers of the ACE insertion allele. The association with birth measurements was also found with a common haplotype of the glucocorticoid receptor (GR) gene. Furthermore, the association between short length at birth and adult impaired glucose tolerance was confined to carriers of this haplotype (p=0.007). These associations exemplify the interaction between environmental factors and genotype, which, possibly due to altered gene expression, predisposes to complex metabolic diseases. Indeed, we showed that the common GR gene haplotype associated with reduced mRNA expression in thymus of three individuals (p=0.0002).

Integrative functional genomics analysis of sustained polyploidy phenotypes in breast cancer cells identifies an oncogenic profile for GINS2

Aneuploidy is among the most obvious differences between normal and cancer cells. However, mechanisms contributing to development and maintenance of aneuploid cell growth are diverse and incompletely understood. Functional genomics analyses have shown that aneuploidy in cancer cells is correlated with diffuse gene expression signatures and that aneuploidy can arise by a variety of mechanisms, including cytokinesis failures, DNA endoreplication and possibly through polyploid intermediate states. Here, we used a novel cell spot microarray technique to identify genes with a loss-of-function effect inducing polyploidy and/or allowing maintenance of polyploid cell growth of breast cancer cells. Integrative genomics profiling of candidate genes highlighted GINS2 as a potential oncogene frequently overexpressed in clinical breast cancers as well as in several other cancer types. Multivariate analysis indicated GINS2 to be an independent prognostic factor for breast cancer outcome (p = 0.001). Suppression of GINS2 expression effectively inhibited breast cancer cell growth and induced polyploidy. In addition, protein level detection of nuclear GINS2 accurately distinguished actively proliferating cancer cells suggesting potential use as an operational biomarker.

How to deal with sparse macroseismic data

This study discusses the scope of historical earthquake analysis in low-seismicity regions. Examples of non-damaging earthquake reports are given from the Eastern Baltic (Fennoscandian) Shield in north-eastern Europe from the 16th to the 19th centuries. The information available for past earthquakes in the region is typically sparse and cannot be increased through a careful search of the archives. This study applies recommended rigorous methodologies of historical seismology developed using ample data to the sparse reports from the Eastern Baltic Shield. Attention is paid to the context of reporting, the identity and role of the authors, the circumstances of the reporting, and the opportunity to verify the available information by collating the sources. We evaluate the reliability of oral earthquake recollections and develop criteria for cases when a historical earthquake is attested to by a single source. We propose parametric earthquake scenarios as a way to deal with sparse macroseismic reports and as an improvement to existing databases.