Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Idyll eller verklighet? : Albert Edelfelt och Gunnar Berndtson i det moderna genombrottets ambivalens

Idyll or Reality? Albert Edelfelt, Gunnar Berndtson and the ambivalent breakthrough of modernity Albert Edelfelt (1854-1905) and Gunnar Berndtson (1854-1895) have much in common. In this dissertation, I study their paintings of local peasants and fishermen and of the gentry’s summer in the county of Uusimaa in southern Finland, in the context of Nordic history of ideas. The breakthrough of modernity, with its attention on debating social problems, provides a novel angle into the oeuvres of the two artists. My focus is on the paintings which emerge in the collision of the public discussion of social matters and the values of the artists’ manorial milieu. The artists’ relation to the public discussion is scrutinized through two of the main topics: the question of the common people and democracy, and the question of equality between men and women. My dissertation is a contextual study which is based on the analysis of the artworks of Edelfelt and Berndtson, on their letters, and on the study of drama and fiction of their time. The notion “liberté, egalité, fraternité” is linked to the breakthrough of modernity. Both artists were aware of the ideal of equality. They used the means and the themes of contemporary art in their presentations, but their pictures contain the ideal of an earlier epoch: the hardworking, but still complacent common people. This conception of the common people is also reflected in the poems of J. L. Runeberg. Women of the late 19th century challenged woman’s primary role as wife and mother. In Edelfelt’s and Berndtson’s depictions of the gentry enjoying summer, women and children have the main role. Notwithstanding the debate of the breakthrough of modernity they depicted women almost without exception as good mothers. Their paintings often depict lazy days in the sunshine, which were, in reality, rare moments for the mistress of the house. Edelfelt’s and Berndtson’s subjects from the Uusimaa countryside coincide with the topics of the breakthrough of modernity, but both the pictures of the common people and the depictions of the gentry enjoying summer, are a retouched picture of reality, often an idyll, in which the public discussion of social matters is evident only materially or not at all.

Matkalla suomalaiseksi ja hoiva-alan ammattilaiseksi? : Venäläis- ja virolaistaustaisten naisten ja suomalaisuuden kohtaamiset kuulumista rakentamassa

The research examines the process by which a sense of belonging to Finnish society is constructed among women of Russian and Estonian background who are multiply marginalised in Finnish society. It does so by analysing the encounters between their nationality and 'being Finnis'. Attention is focused on the question of what kind of "journey" they take after moving to Finland, how a sense of belonging is constructed especially along the paths followed in education and at work, and what kind of agency is available to them. The thesis is connected with post-colonial research and also draws from studies on citizenship and nationality as well as the social structures of interaction, when analysing careers. As the educational system forms the most central context of the research, the work is also focused on educational sociology. The research methodology includes life history and a narrative approach. The raw data is from thematic interviews concerning the life experiences of women of immigrant backgrounds. They were studying in Finland to be practical nurses or to complete Bachelor of Social Service degree. According to the study, the women had been encountered as alien, strange, and carrying a shade of "otherness". The experience of inclusion in Finnish communities and society turned out to be conditional, an inclusion based on the notion of a citizen worker, which is defined by national needs. The person from abroad is placed in the position of someone who fills gaps in the services of the welfare state. The choice of education in the care sector and the overall necessity of obtaining Finnish education turned out to be socially directed. Gendered structures of education and working life were found to act as a frame in which the decisions of the immigrant women were made. Although national education policy emphasis as an orientation to global labour markets, the immigrant student is placed above all in the position of an object to be made suitable for the Finnish labour market. Citizenship, a goal of education, requires consent to being "socialised" into Finnish society as well as learning to be Finnish. One s only option to negotiate appearing suitable as a member is to construct oneself into someone who adopts Finnish and Western cultural values, values which favour individuality. However, Finnish education is a resource to Finnishness. Finnish education enables a sense of being Finnish, and empowers the job applicant for example, and in addition to providing cultural, human and social capital strengthen inclusion as well. The study confirms the view that the encounter of an immigrant is still characterised by its colonial nature. It shows that encounters with Finns and Finnish society place the person of immigrant background, even one receiving a Finnish education, in the position of "the other". The journey as an immigrant continues. The immigrant has access only to certain predefined subject positions, which limits agency. When categorised as an immigrant, one becomes a per-son who is different and "other", while the sense of belonging as a member of Finnish society without conditions appears to be somewhat unreachable. Yet, new arrivals are capable of acting change. An immigrant woman can challenge the positions offered to her and present herself as strong. Her life story has often included struggle, and she has the fortitude strength to change her circumstances. Key words: life story, post-colonial encounter, nationality, citizenship, the career of immi-grant, position, agency

Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels

Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P<1.09 × 10−9) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N=1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research.

Pain among employees : risk factors and consequences

The overall objective of this study was to gain epidemiological knowledge about pain among employee populations. More specifically, the aims were to assess the prevalence of pain, to identify socio-economic risk groups and work-related psychosocial risk factors, and to assess the consequences in terms of health-related functioning and sickness absence. The study was carried out among the municipal employees of the City of Helsinki. Data comprised questionnaire survey conducted in years 2000-2002 and register data on sickness absence. Altogether 8960 40-60 year old employees participated to the survey (response rate 67%). Pain is common among ageing employees. Approximately 29 per cent of employees reported chronic pain and 15 per cent acute pain, and about seven per cent reported moderately or severely limiting disabling chronic pain. Pain was more common among those with lower level of education or in a low occupational class. -- Psychosocial work environment was associated with pain reports. Job strain, bullying at workplace, and problems in combining work and home duties were associated with pain among women. Among men combining work and home duties was not associated with pain, whereas organizational injustice showed associations. Pain affects functional capacity and predicts sickness absence. Those with pain reported lower level of both mental and physical functioning than those with no pain, physical functioning being more strongly affected than mental. Bodily location of pain or whether pain was acute or chronic had only minor impact on the variation in functioning, whereas the simple count of painful locations was associated with widest variation. Pain accounted for eight per cent of short term (1-3 day) sickness absence spells among men and 13 per cent among women. Of absence spells lasting between four and 14 days pain accounted for 23 per cent among women and 25 per cent among men, corresponding figures for over 14 day absence spells being 37 and 30 per cent. The association between pain and sickness absence was relatively independent of physical and psychosocial work factors, especially among women. The results of this study provide a picture of the epidemiology of pain among employees. Pain is a significant problem that seriously affects work ability. Information on risk groups can be utilized to make prevention measures more effective among those at high risk, and to decrease pain rates and thereby narrow the differences between socio-economic groups. Furthermore, the work-related psychosocial risk factors identified in this study are potentially modifiable, and it should be possible to target interventions on decreasing pain rates among employees.

Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata

Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scores > 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05 x 10(-8)) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention.

Adult-type hypolactasia: Genotype-phenotype correlation

Adult-type hypolactasia (primary lactose malabsorption, lactase non-persistence) is the most common enzyme deficiency worldwide, and manifests with symptoms of lactose intolerance such as abdominal pain, gas formation and diarrhea. In humans with adult-type hypolactasia, lactase activity is high at birth, but declines during childhood to about one-tenth of the activity at birth. In 2002, a one base polymorphism C/T-13910, located 14 kilobases from the starting codon of the lactase-phlorizin hydrolase (LPH) gene was observed to be associated with the persistence of lactase activity. The T-13910 allele (C/T-13910 and T/T-13910 genotypes) associates with persistence of lactase activity throughout life, whereas the C/C-13910 genotype associates with adult-type hypolactasia. In this thesis work, the timing and mechanism of decline of lactase enzyme activity during development was studied using the C/T-13910 polymorphism as a molecular marker. We observed an excellent correlation between low lactase activity and the C/C-13910 genotype in all subjects > 12 years of age, irrespective their ethnicity. In children of African origin, the lactase activity declined somewhat earlier than among Finnish children. Furthermore, we observed an increasing imbalance in the relative lactase mRNA expression from the C-13910 and T-13910 alleles in Finnish children beginning from five years of age. The genetic test for adult-type hypolactasia showed a sensitivity of 93% and a specificity of 100% in the Finnish children and adolescents > 12 years of age. The relation of milk consumption and the milk-related abdominal complaints to the C/T-13910 genotypes associated with lactase persistence/non-persistence was studied by a questionnaire-based approach in > 2100 Finns. Both Finnish children and adults with the C/C-13910 genotype consumed significantly less dairy products compared to those with the C/T-13910 and T/T-13910 genotypes. Flatulence was the only of the abdominal symptoms of lactose intolerance that subjects with the C/C-13910 genotype reported significantly more often than those with the C/T-13910 and T/T-13910 genotypes. A minor proportion (<10%) of subjects with the C/C-13910 genotype, nevertheless, reported drinking milk without any symptoms afterwards. There was no association between cow's milk allergy starting as a newborn and adult-type hypolactasia. In an association study an increased risk of colorectal cancer was observed among those with molecular diagnosis of adult-type hypolactasia. It warrants further studies to clarify whether the increased risk observed in the Finnish population is associated with lactose or decreased intake of dairy products in these subjects.

Common variants in the trichohyalin gene are associated with straight hair in Europeans

Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining approximately 6% of variance (p=1.5x10(-31)). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations.

Memoirs 1920-1960

Education as artist in "Odenwaldschule" and Oberammergau; return to Berlin and studies in the "Kunstgewerbeschule"; emigration to Paris in 1933; artist circle including Max Ernst; flight to Switzerland in 1942; busts of Pablo Casals and Emil Ludwig; emigration to New York; bust of Bruno Walter.

Die letzten Lebensjahre meines Vaters Prof. Ernst Neisser 1939-1942

Description of Prof. Neisser's last years in form of a letter written by his daughter to a relative in the USA; concentrates mainly on suicide of Ernst Neisser and his cousin in 1942 to escape deportation.

Stand and Deliver

'Stand and Deliver' is an installation integrating three elements; a large-scale fabric work, a series of pencil and ink drawings on watercolour paper, and a lecture performance recorded as a digital video. 'Stand and Deliver' offers a feminist perspective on the archival impulse and utilizes the strategy of Revision to open up new critical directions for feminism’s own histories and archives. It is part of a broader practice strategy to re-perform a subjective feminist archive. 'Stand and Deliver' was developed and presented as a solo exhibition for First Draft Gallery, Sydney in 2014. 'Stand and Deliver II' was revised for the exhibition 'Quaternary', curated by Courtney Pedersen, held at the QUT Art Museum, Brisbane in 2015. 'Quaternary' was included as part of the 'Women of the World' (WOW) Festival, Brisbane 2015, at QUT Gardens Point Precinct.

Elihu Stone collection undated, 1913-1962.

Collection contains materials pertaining to the life and work of Stone.

If dung beetles (Scarabaeidae: Scarabaeinae) arose in association with dinosaurs, did they also suffer a mass co-extinction at the K-Pg boundary?

The evolutionary success of beetles and numerous other terrestrial insects is generally attributed to co-radiation with flowering plants but most studies have focused on herbivorous or pollinating insects. Non-herbivores represent a significant proportion of beetle diversity yet potential factors that influence their diversification have been largely unexamined. In the present study, we examine the factors driving diversification within the Scarabaeidae, a speciose beetle family with a range of both herbivorous and non-herbivorous ecologies. In particular, it has been long debated whether the key event in the evolution of dung beetles (Scarabaeidae: Scarabaeinae) was an adaptation to feeding on dinosaur or mammalian dung. Here we present molecular evidence to show that the origin of dung beetles occurred in the middle of the Cretaceous, likely in association with dinosaur dung, but more surprisingly the timing is consistent with the rise of the angiosperms. We hypothesize that the switch in dinosaur diet to incorporate more nutritious and less fibrous angiosperm foliage provided a palatable dung source that ultimately created a new niche for diversification. Given the well-accepted mass extinction of non-avian dinosaurs at the Cretaceous-Paleogene boundary, we examine a potential co-extinction of dung beetles due to the loss of an important evolutionary resource, i.e., dinosaur dung. The biogeography of dung beetles is also examined to explore the previously proposed "out of Africa" hypothesis. Given the inferred age of Scarabaeinae as originating in the Lower Cretaceous, the major radiation of dung feeders prior to the Cenomanian, and the early divergence of both African and Gondwanan lineages, we hypothesise that that faunal exchange between Africa and Gondwanaland occurred during the earliest evolution of the Scarabaeinae. Therefore we propose that both Gondwanan vicariance and dispersal of African lineages is responsible for present day distribution of scarabaeine dung beetles and provide examples.

Stor Anna, Liten Anna och tio andra personporträtt : Om innehållsliga och språkliga mönster i en mediegenres kvinnobeskrivningar

The aim of this licentiate thesis is to analyse how femininity is constructed in twelve portrait interviews of women in the dailies Dagens Nyheter (Stockholm) and Hufvudstadsbladet (Helsinki) in September 1996, and to explore the portrait interview as a media genre. The qualitative analysis has a feminist and constructionist perspective and is connected to critical text analysis. It was carried out on two levels: first, femininity is identified on the linguistic level by choice of words, and second on the level of content (topical motifs/themes). The portrait interview as a genre constitutes a third dimension in the analysis: The aim is not towards the identification of femininity, but rather towards the identification of the portrait interview a relatively unexplored media genre. References (Swedish: omtal) to the principal character (or protagonist) are traced mainly through reference chains which consist of names, pronouns and substantive phrases. The interviewees were referred to by their full names in Dagens Nyheter (with the exception of the oldest and youngest interviewees, both of whom were mainly referred to by their first names), while the style of reference varied more in Hufvudstadsbladet. The position of the principal character was also analysed through her relation in the text to minor characters from her working life and from her private life. These minor characters maintained their subordinate positions in all of the portraits except that of the youngest principal character, in which the subsidiary voices became at least as strong as the voice of the principal character. Three frequently-recurring topical motifs occurred in the portraits: The first involved explanations for the principal character s success divided into three categories, agent, affect and ambition, the second concerned using journeys or trips as symbols for turning points in life, and the third referred to the ambiguity in the contradiction between private (family/other private life) and public (work) life. This ambiguity is connected to the portrait interview as a text type (genre) which features conclusions at the end of portraits, which in turn is characteristic of reportage. However, the analysis showed that the conclusions of the portrait interviews often also included elements of ambiguity. This was evident in the contradictions be14 tween private and public life that arose in the portrait interviews that focused on these two spheres. The portraits that focused on the principal character s public life showed ambiguity on a more general level concerning questions about being a woman and having a profession, and they often ended with a description of some details of her private life. The women in the portraits were all constructed as being successful, in terms of having achieved direct success, reflective success or success in the form of life wisdom. The women of direct success were described as ambitious individuals with no sidetracks on their life paths, while those of reflective success were described as active heroines who had received help from different agents, who could use their affects as enriching ingredients in life, but who in the end had control over their own lives (life stories). The elderly women were constructed as having achieved life wisdom and their portraits were focused upon the past. The portrait interview as a genre is characterised by journalistic freedom (in relation to the more strict news genre), by a now room (Swedish nurum ) where the journalist meets the principal character (usually via spoken dialogue that she or he transforms into written text to be read by a mass-media audience) and by the relatively closed structure of the portrait. The portrait is relatively independent in relation to the news genre and in relation to the context of what has previously been written, what is being written at the time and what will be written in the future the principal character does not need to belong to the newspaper s usual gallery of actors. Furthermore, the principal character is constructed as being independent in relation to the subsidiary characters and other media actors. The conflict is within the principal character herself and within her life story, unlike the news genre in which equal actors are in conflict with each other. The portrait is also independent in relation to the news lifespan; the publishing timetable is not as strict as in the news genre, but is still dependent on the factors initiating the portrait. The enclosures consist of a raw analysis of two of twelve portrait interviews and of copies of all portraits.