Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

Shared common variants in prostate cancer and blood lipids

Background Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors. Methods We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n = 50 000) and CVD risk factors (n = 200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR. Results We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR < 0.01). For T2D, we detected one locus adjacent to HNF1B. Conclusions We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.

Modeling the role of competition and cooperation in the evolution of katydid acoustic synchrony

The precise timing of individual signals in response to those of signaling neighbors is seen in many animal species. Synchrony is the most striking of the resultant timing patterns. One of the best examples of acoustic synchrony is in katydid choruses where males produce chirps with a high degree of temporal overlap. Cooperative hypotheses that speculate on the evolutionary origins of acousti synchrony include the preservation of the species-specific call pattern, reduced predation risks, and increased call intensity. An alternative suggestion is that synchrony evolved as an epiphenomenon of competition between males in response to a female preference for chirps that lead other chirps. Previous models investigating the evolutionary origins of synchrony focused only on intrasexual competitive interactions. We investigated both competitive and cooperative hypotheses for the evolution of synchrony in the katydid Mecopoda ``Chirper'' using physiologically and ecologically realistic simulation models incorporating the natural variation in call features, ecology, female preferences, and spacing patterns, specifically aggregation. We found that although a female preference for leading chirps enables synchronous males to have some selective advantage, it is the female preference for the increased intensity of aggregations of synchronous males that enables synchrony to evolve as an evolutionarily stable strategy.

Space in Musical Semiosis : An Abductive Theory of the Musical Composition Process

Space in musical semiosis is a study of musical meaning, spatiality and composition. Earlier studies on musical composition have not adequately treated the problems of musical signification. Here, composition is considered an epitomic process of musical signification. Hence the core problems of composition theory are core problems of musical semiotics. The study employs a framework of naturalist pragmatism, based on C. S. Peirce’s philosophy. It operates on concepts such as subject, experience, mind and inquiry, and incorporates relevant ideas of Aristotle, Peirce and John Dewey into a synthetic view of esthetic, practic, and semiotic for the benefit of grasping musical signification process as a case of semiosis in general. Based on expert accounts, music is depicted as real, communicative, representational, useful, embodied and non-arbitrary. These describe how music and the musical composition process are mental processes. Peirce’s theories are combined with current morphological theories of cognition into a view of mind, in which space is central. This requires an analysis of space, and the acceptance of a relativist understanding of spatiality. This approach to signification suggests that mental processes are spatially embodied, by virtue of hard facts of the world, literal representations of objects, as well as primary and complex metaphors each sharing identities of spatial structures. Consequently, music and the musical composition process are spatially embodied. Composing music appears as a process of constructing metaphors—as a praxis of shaping and reshaping features of sound, representable from simple quality dimensions to complex domains. In principle, any conceptual space, metaphorical or literal, may set off and steer elaboration, depending on the practical bearings on the habits of feeling, thinking and action, induced in musical communication. In this sense, it is evident that music helps us to reorganize our habits of feeling, thinking, and action. These habits, in turn, constitute our existence. The combination of Peirce and morphological approaches to cognition serves well for understanding musical and general signification. It appears both possible and worthwhile to address a variety of issues central to musicological inquiry in the framework of naturalist pragmatism. The study may also contribute to the development of Peircean semiotics.

Encounters with the Virtual : The Experience of Art In Gilles Deleuze's Philosophy

My thesis concerns the notion of existence as an encounter, as developed in the philosophy of Gilles Deleuze (1925 1995). What this denotes is a critical stance towards a major current in Western philosophical tradition which Deleuze nominates as representational thinking. Such thinking strives to provide a stable ground for identities by appealing to transcendent structures behind the apparent reality and explaining the manifest diversity of the given by such notions as essence, idea, God, or totality of the world. In contrast to this, Deleuze states that abstractions such as these do not explain anything, but rather that they need to be explained. Yet, Deleuze does not appeal merely to the given. He sees that one must posit a genetic element that accounts for experience, and this element must not be naïvely traced from the empirical. Deleuze nominates his philosophy as transcendental empiricism and he seeks to bring together the approaches of both empiricism and transcendental philosophy. In chapter one I look into the motivations of Deleuze s transcendental empiricism and analyse it as an encounter between Deleuze s readings of David Hume and Immanuel Kant. This encounter regards, first of all, the question of subjectivity and results in a conception of identity as non-essential process. A pre-given concept of identity does not explain the nature of things, but the concept itself must be explained. From this point of view, the process of individualisation must become the central concern. In chapter two I discuss Deleuze s concept of the affect as the basis of identity and his affiliation with the theories of Gilbert Simondon and Jakob von Uexküll. From this basis develops a morphogenetic theory of individuation-as-process. In analysing such a process of individuation, the modal category of the virtual becomes of great value, being an open, indeterminate charge of potentiality. As the virtual concerns becoming or the continuous process of actualisation, then time, rather than space, will be the privileged field of consideration. Chapter three is devoted to the discussion of the temporal aspect of the virtual and difference-without-identity. The essentially temporal process of subjectification results in a conception of the subject as composition: an assemblage of heterogeneous elements. Therefore art and aesthetic experience is valued by Deleuze because they disclose the construct-like nature of subjectivity in the sensations they produce. Through the domain of the aesthetic the subject is immersed in the network of affectivity that is the material diversity of the world. Chapter four addresses a phenomenon displaying this diversified indentity: the simulacrum an identity that is not grounded in an essence. Developed on the basis of the simulacrum, a theory of identity as assemblage emerges in chapter five. As the problematic of simulacra concerns perhaps foremost the artistic presentation, I shall look into the identity of a work of art as assemblage. To take an example of a concrete artistic practice and to remain within the problematic of the simulacrum, I shall finally address the question of reproduction particularly in the case recorded music and its identity regarding the work of art. In conclusion, I propose that by overturning its initial representational schema, phonographic music addresses its own medium and turns it into an inscription of difference, exposing the listener to an encounter with the virtual.

Theoretical description of time-resolved pump/probe photoemission in TaS2: a single-band DFT+DMFT(NRG) study within the quasiequilibrium approximation

In this work, we theoretically examine recent pump/probe photoemission experiments on the strongly correlated charge-density-wave insulator TaS2.We describe the general nonequilibrium many-body formulation of time-resolved photoemission in the sudden approximation, and then solve the problem using dynamical mean-field theory with the numerical renormalization group and a bare density of states calculated from density functional theory including the charge-density-wave distortion of the ion cores and spin-orbit coupling. We find a number of interesting results: (i) the bare band structure actually has more dispersion in the perpendicular direction than in the two-dimensional planes; (ii) the DMFT approach can produce upper and lower Hubbard bands that resemble those in the experiment, but the upper bands will overlap in energy with other higher energy bands; (iii) the effect of the finite width of the probe pulse is minimal on the shape of the photoemission spectra; and (iv) the quasiequilibrium approximation does not fully describe the behavior in this system.

Seasonal effects of foliar application of phosphonate on phosphonate translocation, in vitro pollen viability and pollen germination in `Hass' avocado (Persea americana Mill.)

Phosphonate fungicides are used widely in the control of diseases caused by Phytophthora cinnamomi Rands. For the most part phosphonate is seen as a safe to use on crops with phytotoxicity rare. However, recent research has shown that phosphonate has detrimental effects on the floral biology of some indigenous Australian plants. Since phosphonate fungicides are regularly used for the control of Phytophthora root rot in avocados, research was carried out to study the translocation of phosphonate fungicide in 'Hass' trees and any effects on their floral biology. Field-grown trees were sprayed with 0, 0.06 or 0.12 M mono-dipotassium phosphonate (pH 7.2) at summer flush maturity, floral bud break or anthesis. Following treatment, phosphonic acid concentrations were determined in leaves, roots, inflorescence rachi and flowers and in vitro pollen germination and pollen tube growth studied. Phosphonic acid concentration in the roots and floral parts was related to their sink strength at the respective times of application with concentration in roots highest (36.9.mg g±1) after treatment at summer flush maturity and in flowers (234.7 mg g±1) after treatment during early anthesis. Phosphonate at >0.03 M was found to be significantly phytotoxic to in vitro pollen germination and pollen tube growth. However, this rate gave a concentration far in excess of that measured in plant tissues following standard commercial applications of mono-dipotassium phosphonate fungicide. There was a small effect on pollen germination and pollen tube growth when 0.06 and 0.12 M mono-dipotassium phosphonate was applied during early anthesis. However, under favourable pollination and fruit set conditions it is not expected to have commercial impact on tree yield. However, there may be detrimental commercial implications from phosphonate sprays at early anthesis if unfavourable climatic conditions for pollination and fruit set subsequently occur. A commercial implication from this study is that phosphonic acid root concentrations can be elevated and maintained with strategic foliar applications of phosphonate fungicide timed to coincide with peaks in root sink strength. These occur at the end of the spring and summer flushes when shoot growth is relatively quiescent. Additional foliar applications may be advantageous in under high disease-pressure situations but where possible should be timed to minimize overlap with other significant growth events in the tree such as rapid inflorescence, and fruit development and major vegetative flushing.

Halun häilyvät rajat : Magnus Enckellin maalausten maskuliinisuuksien ja feminiinisyyksien representaatioista ja itsen luomisesta

My PhD-thesis The uneasy borders of desire Magnus Enckell's representations of masculinities and femininities and the question how to create the self concentrates on the works of Finnish fin-de-siècle artist Magnus Enckell (1870-1925). My thesis deals with representations of masculinities, femininities, sexualities and different identity-positions. My research is about questions concerning representational ways of melancholy, androgyny, narcissism, themes of Golden Age and Double in Enckell s ouvre. These themes are analyzed by contextualizing them with different, but intersecting, discourses of varied scientific, artistic and occult ideas in the fin-de-siècle. The main point is analyze how the subject is constructed in both Foucauldian and Freudian sense and what one has to know about oneself. My approaches are based on ideas expressed in different discourses as queer-theory, Michel Foucault s genealogical epistemology and knowledge-power theory, psychoanalysis, art history and visual culture studies. My starting point lays is Foucault s idea expressed in his The History of Sexuality that the constitution of homosexual or as well as heterosexual subject inaugurates possibilities for transgressive activities e.g. by giving own voice to the sexualized subject. My main thesis is to suggest that Enckell s works in their multiple and ambiguous ways construct a phantasmatic position for viewer who may identify oneself to different desires, may construct or deconstruct a sexual identity for oneself or try to define the truth about oneself. Enckell s works should be considered as a contradictory processes which both seduce person to construct an identity and as well as lure person to pursue for the deconstruction of specific and permanent identity by celebrating the ambiguousness and discontinuity in one s identity. I m suggesting that the gazing subject feels pleasure in finding one s identity but the one must face the exposure of the melancholic structure which forms the basis of sexual desire. The subject may try to resolve one s melancholy by creating a phantasy about the original and unisexual being where desires, sexualities, phantasies and identities haven t been diverged. This can be fantasized in terms of art which forms a double for the melancholic subject who is in this limited and imaginary way able to forget for a while one s existential solitude.

On the Cubicity of Interval Graphs

A k-cube (or ``a unit cube in k dimensions'') is defined as the Cartesian product R-1 x . . . x R-k where R-i (for 1 <= i <= k) is an interval of the form [a(i), a(i) + 1] on the real line. The k-cube representation of a graph G is a mapping of the vertices of G to k-cubes such that the k-cubes corresponding to two vertices in G have a non-empty intersection if and only if the vertices are adjacent. The cubicity of a graph G, denoted as cub(G), is defined as the minimum dimension k such that G has a k-cube representation. An interval graph is a graph that can be represented as the intersection of intervals on the real line - i. e., the vertices of an interval graph can be mapped to intervals on the real line such that two vertices are adjacent if and only if their corresponding intervals overlap. We show that for any interval graph G with maximum degree Delta, cub(G) <= inverted right perpendicular log(2) Delta inverted left perpendicular + 4. This upper bound is shown to be tight up to an additive constant of 4 by demonstrating interval graphs for which cubicity is equal to inverted right perpendicular log(2) Delta inverted left perpendicular.

Concordant molecular and phenotypic data delineate new taxonomy and conservation priorities for the endangered mountain yellow-legged frog

The mountain yellow-legged frog Rana muscosa sensu lato, once abundant in the Sierra Nevada of California and Nevada, and the disjunct Transverse Ranges of southern California, has declined precipitously throughout its range, even though most of its habitat is protected. The species is now extinct in Nevada and reduced to tiny remnants in southern California, where as a distinct population segment, it is classified as Endangered. Introduced predators (trout), air pollution and an infectious disease (chytridiomycosis) threaten remaining populations. A Bayesian analysis of 1901 base pairs of mitochondrial DNA confirms the presence of two deeply divergent clades that come into near contact in the Sierra Nevada. Morphological studies of museum specimens and analysis of acoustic data show that the two major mtDNA clades are readily differentiated phenotypically. Accordingly, we recognize two species, Rana sierrae, in the northern and central Sierra Nevada, and R. muscosa, in the southern Sierra Nevada and southern California. Existing data indicate no range overlap. These results have important implications for the conservation of these two species as they illuminate a profound mismatch between the current delineation of the distinct population segments (southern California vs. Sierra Nevada) and actual species boundaries. For example, our study finds that remnant populations of R. muscosa exist in both the southern Sierra Nevada and the mountains of southern California, which may broaden options for management. In addition, despite the fact that only the southern California populations are listed as Endangered, surveys conducted since 1995 at 225 historic (1899-1994) localities from museum collections show that 93.3% (n=146) of R. sierrae populations and 95.2% (n=79) of R. muscosa populations are extinct. Evidence presented here underscores the need for revision of protected population status to include both species throughout their ranges.

Representations and properties of para-Bose oscillator operators. I. Energy position and momentum eigenstates

Para-Bose commutation relations are related to the SL(2,R) Lie algebra. The irreducible representation [script D]alpha of the para-Bose system is obtained as the direct sum Dbeta[direct-sum]Dbeta+1/2 of the representations of the SL(2,R) Lie algebra. The position and momentum eigenstates are then obtained in this representation [script D]alpha, using the matrix mechanical method. The orthogonality, completeness, and the overlap of these eigenstates are derived. The momentum eigenstates are also derived using the wave mechanical method by specifying the domain of the definition of the momentum operator in addition to giving it a formal differential expression. By a careful consideration in this manner we find that the two apparently different solutions obtained by Ohnuki and Kamefuchi in this context are actually unitarily equivalent. Journal of Mathematical Physics is copyrighted by The American Institute of Physics.

Satellites in the X-ray photoelectron spectra of transition-metal and rare-earth compounds

An attempt has been made at synthesis and in resolving some of the uncertainties related to the assignments of charge-transfer satellites in the X-ray photoelectron spectra of transition-metal and rare-earth compounds. New satellites are reported in the ligand core-hole spectra as well as in the metal core-level spectra of oxides of second- and third-row transition metals including rare earths. Satellites in the ligand levels and the metal levels tend to be mutually exclusive, a behaviour that can be understood on the basis of metal-ligand overlap. Systematics in the intensities and energy separations of satellites in the first-row transition-metal compounds have been examined in order to gain an insight into the nature of these satellites. A simple model involving the sudden approximation has been employed to explain the observed systematics in intensities of satellites appearing next to metal and ligand core levels on the basis of metal-ligand overlap.

Occupational burnout and health

Occupational burnout and heath Occupational burnout is assumed to be a negative consequence of chronic work stress. In this study, it was explored in the framework of occupational health psychology, which focusses on psychologically mediated processes between work and health. The objectives were to examine the overlap between burnout and ill health in relation to mental disorders, musculoskeletal disorders, and cardiovascular diseases, which are the three commonest disease groups causing work disability in Finland; to study whether burnout can be distinguished from ill health by its relation to work characteristics and work disability; and to determine the socio-demographic correlates of burnout at the population level. A nationally representative sample of the Finnish working population aged 30 to 64 years (n = 3151-3424) from the multidisciplinary epidemiological Health 2000 Study was used. Burnout was measured with the Maslach Burnout Inventory - General Survey. The diagnoses of common mental disorders were based on the standardized mental health interview (the Composite International Diagnostic Interview), and physical illnesses were determined in a comprehensive clinical health examination by a research physician. Medically certified sickness absences exceeding 9 work days during a 2-year period were extracted from a register of The Social Insurance Institution of Finland. Work stress was operationalized according to the job strain model. Gender, age, education, occupational status, and marital status were recorded as socio-demographic factors. Occupational burnout was related to an increased prevalence of depressive and anxiety disorders and alcohol dependence among the men and women. Burnout was also related to musculoskeletal disorders among the women and cardiovascular diseases among the men independently of socio-demographic factors, physical strenuousness of work, health behaviour, and depressive symptoms. The odds of having at least one long, medically-certified sickness absence were higher for employees with burnout than for their colleagues without burnout. For severe burnout, this association was independent of co-occurring common mental disorders and physical illnesses for both genders, as was also the case for mild burnout among the women. In a subgroup of the men with absences, severe burnout was related to a greater number of absence days than among the women with absences. High job strain was associated with a higher occurrence of burnout and depressive disorders than low job strain was. Of these, the association between job strain and burnout was stronger, and it persisted after control for socio-demographic factors, health behaviour, physical illnesses, and various indicators of mental health. In contrast, job strain was not related to depressive disorders after burnout was accounted for. Among the working population over 30 years of age, burnout was positively associated with age. There was also a tendency towards higher levels of burnout among the women with low educational attainment and occupational status and among the unmarried men. In conclusion, a considerable overlap was found between burnout, mental disorders, and physical illnesses. Still, burnout did not seem to be totally redundant with respect to ill health. Burnout may be more strongly related to stressful work characteristics than depressive disorders are. In addition, burnout seems to be an independent risk factor for work disability, and it could possibly be used as a marker of health-impairing work stress. However, burnout may represent a different kind of risk factor for men and women, and this possibility needs to be taken into account in the promotion of occupational health.

Self-Assembly of Bile Steroid Analogues: Molecules, Fibers, and Networks

Structural and rheological features of a series of molecular hydrogels formed by synthetic bile salt analogues have been scrutinized. Among seven gelators, two are neutral compounds, while the others are cationic systems among which one is a tripodal steroid derivative. Despite the fact that the chemical structures are closely related, the variety of physical characteristics is extremely large in the structures of the connected fibers (either plain cylinders or ribbons), in the dynamical modes for stress relaxation of the associated SAFINs, in the scaling laws of the shear elasticity (typical of either cellular solids or fractal floc-like assemblies), in the micron-scale texture and the distribution of ordered domains (spherulites, crystallites) embedded in a random mesh, in the type of nodal zones (either crystalline-like, fiber entanglements, or bundles), in the evolution of the distribution and morphology of fibers and nodes, and in the sensitivity to added salt. SANS appears to be a suitable technique to infer all geometrical parameters defining the fibers, their interaction modes, and the volume fraction of nodes in a SAFIN. The tripodal system is particularly singular in the series and exhibits viscosity overshoots at the startup of shear flows, an “umbrella-like” molecular packing mode involving three molecules per cross section of fiber, and scattering correlation peaks revealing the ordering and overlap of 1d self-assembled polyelectrolyte species.

Landscape painting

The images in this exhibition were based on questioning relationships between the histories of painting and photography, which helped to establish the indexical references that became both photography’s most powerful attribute and most subtle illusion. Debates over the objectivity or subjectivity of the photograph and the uneasy relationship between painting and photography, as played out in the history of art, have been brought into sharp relief with the contemporary proliferation of digital images. The digital realm of photography gives rise to a general and relative skepticism of verity, but it can be argued that to artist/photographers, this representational malleability is precisely what their purpose becomes. In researching current issues of the indexical in photographic practice, landscape provides a potent vehicle for exploring issues of representation and illusion, the nexus of painting and photography, and the digital realm. One of contemporary photography’s most resonant themes is a return to pictorial subjects and methods, including a renewed interest in floribunda, still life and landscape. The resulting deconstruction and reconstruction of landscape ‘painting’ in this body of work- the monochrome, linear abstraction, painterly representationalsism and pictorialist detail is presented as a perceptual, aesthetic and digital act. The exhibition incorporates landscape painting’s simplicity and complexity, photography’s significance of representation and minimalist aesthetics in an over-mediated world.