Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6

In humans, congenital spinal defects occur with an incidence of 0.5-1 per 1000 live births. One of the most severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade, the genetic basis of several forms of autosomal recessive SCD cases has been solved with the identification of four causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been reported, but to date no genetic etiology has been described for these. Here, we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. We show that this mutation has a deleterious effect on the transcriptional activation activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the patterning of the vertebral precursor tissues, somites; thus, mutation of TBX6 is likely to be causative of SCD in this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases even in small families with few affected individuals.

Supramolecular control of the magnetic anisotropy in two-dimensional high-spin Fe arrays at a metal interface

Magnetic atoms at surfaces are a rich model system for solid-state magnetic bits exhibiting either classical(1,2) or quantum(3,4) behaviour. Individual atoms, however, are difficult to arrange in regular patterns(1-5). Moreover, their magnetic properties are dominated by interaction with the substrate, which, as in the case of Kondo systems, often leads to a decrease or quench of their local magnetic moment(6,7). Here, we show that the supramolecular assembly of Fe and 1,4-benzenedicarboxylic acid molecules on a Cu surface results in ordered arrays of high-spin mononuclear Fe centres on a 1.5nm square grid. Lateral coordination with the molecular ligands yields unsaturated yet stable coordination bonds, which enable chemical modification of the electronic and magnetic properties of the Fe atoms independently from the substrate. The easy magnetization direction of the Fe centres can be switched by oxygen adsorption, thus opening a way to control the magnetic anisotropy in supramolecular layers akin to that used in metallic thin films.

The Learning Component of Dynamic Allocation Indices

For a multiarmed bandit problem with exponential discounting the optimal allocation rule is defined by a dynamic allocation index defined for each arm on its space. The index for an arm is equal to the expected immediate reward from the arm, with an upward adjustment reflecting any uncertainty about the prospects of obtaining rewards from the arm, and the possibilities of resolving those uncertainties by selecting that arm. Thus the learning component of the index is defined to be the difference between the index and the expected immediate reward. For two arms with the same expected immediate reward the learning component should be larger for the arm for which the reward rate is more uncertain. This is shown to be true for arms based on independent samples from a fixed distribution with an unknown parameter in the cases of Bernoulli and normal distributions, and similar results are obtained in other cases.

Kulttuurisia kohtaamisia : Suomalaiset kuvataiteilijat ja Rooma 1800-luvulla

Dozens of Finnish artists, practically all the professional sculptors and painters, travelled to and stayed in Rome during the 19th century. The study at hand concentrates for the first time on the Finnish artists in Rome in corpore, and analyses their way of life based on a broad variety of previously unknown and unexplored sources from a number of archives in both Scandinavia and Rome. The extensive corpus of source material is scrutinized with microhistorical precision from the point of view of cultural history. The new information thus achieved adds to the previous knowledge of Rome s often overlooked importance as a source of inspiration in Scandinavian culture in general and significantly clarifies our understanding of the development of Finnish artistic life and cultural identity in the 19th century. The study proves that in Finland, like in all of Europe, the stay in Rome was considered to be a necessary part of becoming a true artist. Already the journey was an integral part of the encounter with Rome, corresponding with the civilized ideal of the period. The stay in Rome provided a northern artist with overwhelming opportunities that were incomparable to the unestablished and modest forms of artistic life Finland could offer. Without domestic artistic institutions or traditions, the professional status of Finnish painters and sculptors took shape abroad, firstly through the encounter with Rome and the different networks the Finnish artists belonged to during and after their stay in the eternal city. The Finnish artists were an integral part of the international artistic community in the cultural capital of Europe, which gave a totally new impetus to their work and contributed to their cosmopolitan identification. For these early masters of Finnish art, the Scandinavian communality and universal artistic identity seemed to be more significant than their nationality. In all, the scrutiny of Finnish artists in their wide social, ideological and international framework gives an interesting aspect to the cultural ambiance of the 19th century, in both Rome and Finland. The study highlights many long-forgotten artists who were influential in shaping Finnish art, culture and identity in their time.

Approaching Sacred Pregnancy : The Cult of the Visitation and Narrative Altarpieces in Late Fifteenth-Century Florence

The study focuses on the Visitation as a narrative subject of altarpieces in late fifteenth-century Florence. Although the Visitation was a well-known story in both verbal and visual representations since the early medieval period, it became a popular subject of altarpieces only towards the end of the fifteenth century. In this study, the first part provides an overview of the complex religious and historical background to an emerging cult of the Visitation. Devotional practices focusing on the Visitation belong in a context of late medieval Marian devotion and in 1389 a new feast of the Visitation was introduced into the liturgical calendar of the Catholic Church. Because of the ongoing schism within the Catholic Church, the feast was not unanimously accepted across Western Europe until the later part of the fifteenth century. Contrary to a widely disseminated view, the feast of the Visitation cannot be associated with Franciscan spirituality, but was rather a clearly defined Dominican project that primarily emphasised the importance of peace and unity within the Christian Church. Simultaneously with the gradual acceptance of the new feast, visual representations of the Visitation began to appear at the centre of altarpieces. The Visitation exemplifies an increasing preference for narrative subjects within the genre of the altarpiece. The second part of the study presents an analysis of the concept of the narrative altarpiece and highlights the complexities involved in combining a narrative content with the traditional devotional function of the altarpiece. In detailed case studies some prominent art works produced in Florence between 1490 and 1503 are discussed within a framework of contextual analysis, narrative theory and iconography. Altarpieces by Domenico Ghirlandaio, Piero di Cosimo and Mariotto Albertinelli represent visual manifestations of a cult of the Visitation with roots in late medieval devotional practices. At the same time, the altarpieces highlight the multiple functions of altarpieces in a culture where art works responded to a variety of social and religious needs. Building on earlier studies, each case study presents new insights and evidence not considered in previous art historical research.

Climate information needs of Gascoyne-Murchison pastoralists: a representative study of the Western Australian grazing industry

The Gascoyne-Murchison region of Western Australia experiences an arid to semi-arid climate with a highly variable temporal and spatial rainfall distribution. The region has around 39.2 million hectares available for pastoral lease and supports predominantly catle and sheep grazing leases. In recent years a number of climate forecasting systems have been available offering rainfall probabilities with different lead times and a forecast period; however, the extent to which these systems are capable of fulfilling the requirements of the local pastoralists is still ambiguous. Issues can range from ensuring forecasts are issued with sufficient lead time to enable key planning or decisions to be revoked or altered, to ensuring forecast language is simple and clear, to negate possible misunderstandings in interpretation. A climate research project sought to provide an objective method to determine which available forecasting systems had the greatest forecasting skill at times of the year relevant to local property management. To aid this climate research project, the study reported here was undertaken with an overall objective of exploring local pastoralists' climate information needs. We also explored how well they understand common climate forecast terms such as 'mean', median' and 'probability', and how they interpret and apply forecast information to decisions. A stratified, proportional random sampling was used for the purpose of deriving the representative sample based on rainfall-enterprise combinations. In order to provide more time for decision-making than existing operational forecasts that are issued with zero lead time, pastoralists requested that forecasts be issued for May-July and January-March with lead times counting down from 4 to 0 months. We found forecasts of between 20 and 50 mm break-of-season or follow-up rainfall were likely to influence decisions. Eighty percent of pastoralists demonstrated in a test question that they had a poor technical understanding of how to interpret the standard wording of a probabilistic median rainfall forecast. this is worthy of further research to investigate whether inappropriate management decisions are being made because the forecasts are being misunderstood. We found more than half the respondents regularly access and use weather and climate forecasts or outlook information from a range of sources and almost three-quarters considered climate information or tools useful, with preferred methods for accessing this information by email, faxback service, internet and the Department of Agriculture Western Australia's Pastoral Memo. Despite differences in enterprise types and rainfall seasonality across the region we found seasonal climate forecasting needs were relatively consistent. It became clear that providing basic training and working with pastoralists to help them understand regional climatic drivers, climate terminology and jargon, and the best ways to apply the forecasts to enhance decision-making are important to improve their use of information. Consideration could also be given to engaging a range of producers to write the climate forecasts themselves in the language they use and understand, in consultation with the scientists who prepare the forecasts.

Drag på parnassen. Två sextiotalsstudier. : Del I: Medelklass med mänskligt ansikte. Medelklassradikalism i fyra romaner av Christer Kihlman, Jarl Sjöblom, Marianne Alopaeus och Ulla-Lena Lundberg. Del II: Modernistdebatten. Sak, person och fält i en finlandssvensk litteraturdebatt år 1965.

The objective of my dissertation Pull (or Draught, or Moves) at the Parnassus , is to provide a deeper understanding of Nordic Middle Class radicalism of the 1960 s as featured in Finland-Swedish literature. My approach is cultural materialist in a broad sense; social class is regarded a crucial aspect of the contents and contexts of the novels and literary discussions explored. In the first volume, Middle Class With A Human Face , novels by Christer Kihlman, Jarl Sjöblom, Marianne Alopaeus, and Ulla-Lena Lundberg, respectively, are read from the points of view of place, emotion, and power. The term "cryptotope" is used to designate the hidden places found to play an important role in all of these four narratives. Also, the "chronotope of the provincial small town", described by Mikhail Bakhtin in 1938, is exemplified in Kihlman s satirical novel, as is the chronotope of of war (Algeria, Vietnam) in those of Alopaeus and Lundberg s. All the four novels signal changes in the way general "scripts of emotions", e.g. jealousy, are handled and described. The power relations in the novels are also read, with reference to Michel Foucault. As the protagonists in two of them work as journalists, a critical discussion about media and Bourgeois hegemony is found; the term "repressive legitimation" is created to grasp these patterns of manipulation. The Modernist Debate , part II of the study, concerns a literary discussion between mainly Finland-Swedish authors and critics. Essayist Johannes Salminen (40) provided much of the fuel for the debate in 1963, questioning the relevance to contemporary life of the Finland-Swedish modernist tradition of the 1910 s and 1920 s. In 1965, a group of younger authors and critics, including poet Claes Andersson (28), followed up this critique in a debate taking place mainly in the newspaper Vasabladet. Poets Rabbe Enckell (62), Bo Carpelan (39) and others defended a timeless poetry. This debate is contextualized and the changing literary field is analyzed using concepts provided by sociologist Pierre Bourdieu. In the thesis, the historical moment of Middle Class radicalism with a human face is regarded a temporary luxury that new social groups could afford themselves, as long as they were knocking over the statues and symbols of the Old Bourgeoisie. This is not to say that all components of the Sixties strategy have lost their power. Some of them have survived and even grown, others remain latent in the gene bank of utopias, waiting for new moments of change.

Local dispersion and damage of Corymbia citriodora subsp. variegata (Myrtaceae) regrowth by eriophyid mites (Acari: Eriophyoidea).

Eriophyid mites (Acari: Eriophyoidea: Eriophyidae: Rhombacus sp. and Acalox ptychocarpi Keifer) are recently-emerged pests of commercial eucalypt plantations in subtropical Australia. They cause severe blistering, necrosis and leaf loss to Corymbia citriodora subsp. variegata (F. Muell.) K.D. Hill & L.A.S. Johnson, one of the region's most important hardwood plantation species. In this study we examine the progression, incidence and severity of these damage symptoms. We also measure within-branch colonisation by mites to identify dispersive stages, and estimate the relative abundance of the two co-occurring species. Rhombacus sp., an undescribed species, was numerically dominant, accounting for over 90% of all adult mites. Adults were the dispersive stage, moving mostly within branches, but 12% of recruitment onto new leaves occurred on previously uninfested branches. Damage incidence and severity were correlated, while older leaves had more damage than younger leaves. "Patch-type" damage was less frequent but was associated with higher mite numbers and damage scores than "spot-type" damage, while leaf discoloration symptoms related mostly to leaf age.

Determining and quantifying components of an aquaculture soundscape.

Recirculating aquaculture systems have a unique anthropogenic-based soundscape which is characterized by the type of equipment utilized, the structural configuration of walls, tanks, equipment, the substrate the tanks are situated on and even the activities of the personnel operating the facility. The soundscape of recirculation facilities is inadequately understood and remains poorly characterized, although it is generally accepted that the dominant sounds found in such facilities are within the hearing range of fish. The objective of this study was to evaluate the soundscape in a recirculating aquaculture facility from an intra-tank perspective and determine how the soundscape is shaped by a range of characteristics within the facility. Sounds were recorded across an operating aquaculture facility including different tank designs. The sounds recorded fell within previously measured pressure level ranges for recirculating systems, with the highest maximum sound pressure level (SPL) recorded at 124 dB re 1 mu Pa-2/Hz (with an FFT bin width of 46.9 Hz, centered at 187.5 Hz). The soundscape within the tanks was stratified and positively correlated with depth, the highest sound pressure occurring at the base of the tanks. Each recording of the soundscape was dominated by a frequency component of 187.5 Hz (corresponding centre of the 4th 46.9 Hz FFT analysis bin) that produced the highest observed SPL Analysis of sound recordings revealed that this peak SPL was associated with the acoustic signature of the pump. The soundscape was also evaluated for impacts of tank hood position, time of day, transient sounds and airstone particle size types, all of which were found to appreciably influence sound levels and structure within the tank environment. This study further discusses the distinctiveness of the soundscape, how it is shaped by the various operating components and considers the aquaculture soundscape in relation to natural soundscapes found within aquatic tropical environments.

Examination of Genetic Components Affecting Human Obesity-Related Quantitative Traits

Obesity increases the risk for several conditions, including type 2 diabetes mellitus, cardiovascular disease, hypertension, osteoarthirits and certain types of cancer. Twin- and family studies have shown that there is a major genetic component in the determination of body mass. In recent years several technological and scientific advance have been made in obesity research. For instance, novel replicated loci have been revealed by a number of genome wide association studies. This thesis aimed to investigate the association of genetic factors and obesity-related quantitative traits. The first study investigated the role of the lactase gene in anthropometric traits. We genetically defined lactose persistence by genotyping 31 720 individuals of European descent. We found that lactase persistence was significantly correlated with weight and body mass index but not with height. In the second study we performed the largest whole genome linkage scan for body mass index to date. The sample consisted of 4401 twin families and 10 535 individuals from six European countries. We found supporting evidence for two loci (3q29 and 7q36). We observed that the heritability estimate increased substantially when additional family members were removed from the analyses, which suggests reduced environmental variance in the twin sample. In the third study we assessed metabonomic, transcriptomic and genomic variation in a Finnish population cohort of 518 individuals. We formed gene expression networks to portray pathways and showed that a set of highly correlated genes of an inflammatory pathway associated with 80 serum metabolites (of 134 quantified measures). Strong association was found, for example, with several lipoprotein subclasses. We inferred causality by using genetic variation as anchors. The expression of the network genes was found to be dependent on the circulatory metabolite concentrations.

Meta-analysis of genome-wide association for migraine in six population-based European cohorts

Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10,980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value<10(-5). The best result was obtained for SNP rs9908234, which had a P-value of 8.00 x 10(-8). This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate.

Oncolytic Adenoviruses for Gynecologic Cancer

Gene therapy is a promising novel approach for treating cancers resistant to or escaping currently available modalities. Treatment approaches are based on taking advantage of molecular differences between normal and tumor cells. Various strategies are currently in clinical development with adenoviruses as the most popular vehicle. Recent developments include improving targeting strategies for gene delivery to tumor cells with tumor specific promoters or infectivity enhancement. A rapidly developing field is as well replication competent agents, which allow improved tumor penetration and local amplification of the anti-tumor effect. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment options and therefore synergistic effects are possible. This study focused on development of adenoviral vectors suitable for treatment of various gynecologic cancer types, describing the development of the field from non-replicating adenoviral vectors to multiple-modified conditional replicating viruses. Transcriptional targeting of gynecologic cancer cells by the use of the promoter of vascular endothelial growth factor receptor type 1 (flt-1) was evaluated. Flt-1 is not expressed in the liver and thus an ideal promoter for transcriptional targeting of adenoviruses. Our studies implied that the flt-1 promoter is active in teratocarcinomas.and therefore a good candidate for development of oncolytic adenoviruses for treatment of this often problematic disease with then poor outcome. A tropism modified conditionally replicating adenovirus (CRAd), Ad5-Δ24RGD, was studied in gynecologic cancers. Ad5-Δ24RGD is an adenovirus selectively replication competent in cells defective in the p16/Rb pathway, including many or most tumor cells. The fiber of Ad5-Δ24RGD contains an integrin binding arginine-glycine-aspartic acid motif (RGD-4C), allowing coxackie-adenovirus receptor independent infection of cancer cells. This approach is attractive because expression levels of CAR are highly variable and often low on primary gynecological cancer cells. Oncolysis could be shown for a wide variety of ovarian and cervical cancer cell lines as well as primary ovarian cancer cell spheroids, a novel system developed for in vitro analysis of CRAds on primary tumor substrates. Biodistribution was evaluated and preclinical safety data was obtained by demonstrating lack of replication in human peripheral blood mononuclear cells. The efficicacy of Ad5-Δ24RGD was shown in different orthotopic murine models including a highly aggressive intraperitoneal model of disseminated ovarian cancer cells, where Ad5-Δ24RGD resulted in complete eradication of intraperitoneal disease in half of the mice. To further improve the selectivity and specificity of CRAds, triple-targeted oncolytic adenoviruses were cloned, featuring the cyclo-oxygenase-2 (cox-2) promoter, E1A transcomplementation and serotype chimerism. Those viruses were evaluated on ovarian cancer cells for specificity and oncolytic potency with regard to two different cox2 versions and three different variants of E1A (wild type, delta24 and delta2delta24). Ad5/3cox2Ld24 emerged as the best combination due to enhanced selectivity without potency lost in vitro or in an aggressive intraperitoneal orthotopic ovarian tumor model. In summary, the preclinical therapeutic efficacy of the CRAds tested in this study, taken together with promising biodistribution and safety data, suggest that these CRAds are interesting candidates for translation into clinical trials for gynecologic cancer.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Modeling population growth and site specific control of the invasive Lantana camara L. (Verbenaceae) under differing fire regimes

It is at the population level that an invasion either fails or succeeds. Lantana camara L. (Verbenaceae) is a weed of great significance in Queensland Australia and globally but its whole life-history ecology is poorly known. Here we used 3 years of field data across four land use types (farm, hoop pine plantation and two open eucalyptus forests, including one with a triennial fire regime) to parameterise the weed’s vital rates and develop size-structured matrix models. Lantana camara in its re-colonization phase, as observed in the recently cleared hoop pine plantation, was projected to increase more rapidly (annual growth rate, λ = 3.80) than at the other three sites (λ 1.88–2.71). Elasticity analyses indicated that growth contributed more (64.6 %) to λ than fecundity (18.5 %) or survival (15.5 %), while across size groups, the contribution was of the order: juvenile (19–27 %) ≥ seed (17–28 %) ≥ seedling (16–25 %) > small adult (4–26 %) ≥ medium adult (7–20 %) > large adult (0–20 %). From a control perspective it is difficult to determine a single weak point in the life cycle of lantana that might be exploited to reduce growth below a sustaining rate. The triennial fire regime applied did not alter the population elasticity structure nor resulted in local control of the weed. However, simulations showed that, except for the farm population, periodic burning could work within 4–10 years for control of the weed, but fire frequency should increase to at least once every 2 years. For the farm, site-specific control may be achieved by 15 years if the biennial fire frequency is tempered with increased burning intensity.

Suunnittelunäkemys metsäorganisaatioissa ja sen vaikutus tietojärjestelmälle asetettaviin vaatimuksiin

Department of Forest Resource Management in the University of Helsinki has in years 2004?2007 carried out so-called SIMO -project to develop a new generation planning system for forest management. Project parties are organisations doing most of Finnish forest planning in government, industry and private owned forests. Aim of this study was to find out the needs and requirements for new forest planning system and to clarify how parties see targets and processes in today's forest planning. Representatives responsible for forest planning in each organisation were interviewed one by one. According to study the stand-based system for managing and treating forests continues in the future. Because of variable data acquisition methods with different accuracy and sources, and development of single tree interpretation, more and more forest data is collected without field work. The benefits of using more specific forest data also calls for use of information units smaller than tree stand. In Finland the traditional way to arrange forest planning computation is divided in two elements. After updating the forest data to present situation every stand unit's growth is simulated with different alternative treatment schedule. After simulation, optimisation selects for every stand one treatment schedule so that the management program satisfies the owner's goals in the best possible way. This arrangement will be maintained in the future system. The parties' requirements to add multi-criteria problem solving, group decision support methods as well as heuristic and spatial optimisation into system make the programming work more challenging. Generally the new system is expected to be adjustable and transparent. Strict documentation and free source code helps to bring these expectations into effect. Variable growing models and treatment schedules with different source information, accuracy, methods and the speed of processing are supposed to work easily in system. Also possibilities to calibrate models regionally and to set local parameters changing in time are required. In future the forest planning system will be integrated in comprehensive data management systems together with geographic, economic and work supervision information. This requires a modular method of implementing the system and the use of a simple data transmission interface between modules and together with other systems. No major differences in parties' view of the systems requirements were noticed in this study. Rather the interviews completed the full picture from slightly different angles. In organisation the forest management is considered quite inflexible and it only draws the strategic lines. It does not yet have a role in operative activity, although the need and benefits of team level forest planning are admitted. Demands and opportunities of variable forest data, new planning goals and development of information technology are known. Party organisations want to keep on track with development. One example is the engagement in extensive SIMO-project which connects the whole field of forest planning in Finland.