Intragenic recombination between pseudogenes as a source of new disease specificity at a simple resistance locus

BACKGROUND: Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity. NEW METHOD: In the present study we use a source-based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction. RESULTS: A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving coil. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach. COMPARISON WITH EXISTING METHOD(S): Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings. CONCLUSIONS: It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects

Overcoming the Metaphysics of Consciousness: Being/Artaud

Some recent theories of the mind have invoked the theatre as a metaphor to explain consciousness. This paper suggests that there is something irreducible to consciousness and that theatre can be an invaluable tool for exploring such subject matter. Rather than explain the mind through theory, performance practices can use immediate experience to investigate consciousness. Of course, Antonin Artaud’s ‘Theatre of Cruelty’ articulates the hope of apprehending consciousness through immediate experience, overcoming ‘literature’ and the alienating ossification of language. For Artaud, the ‘self’ has always been stolen at birth yet he suggests it can be returned through the theatre. The Theatre of Cruelty is an overcoming of the metaphysical obstructions of ‘being’. Martin Heidegger’s Being and Time also seeks to reveal the concept of 'Being' by destroying the historical misunderstanding of the term. Heidegger' claims that 'Dasein' (Being-there), the human subject, is maintained by a radical continuity with the world in which it exists. Because human subjects are 'absorbed' in the world of practical activity, projects and tasks, they tend to misrecognise themselves as a ‘thing’. But consciousness is not a ‘thing’ like other entities in the world. Such misrecognition is the fundamental error in what Heidegger calls metaphysics. My contention is that the Theatre of Cruelty is Artaud’s attempt at articulating a practical investigation of consciousness, resisting the metaphysical structures of language and logic and calling for the priority of ‘experience’. Cruelty is a return of the pre-theoretical, unspeakable words needed to explore the Being of consciousness. Such is an attempt to overcome the metaphysics of consciousness onstage.The conference was sponsored by A.D.S.A., the Department of Performance Studies, the School of Letters, Arts and Media, and the Faculty of Arts of the University of Sydney

Unique reproduction system of invasive ants avoids genetic bottlenecks

INTRODUCTION: Advanced glycation endproducts (AGEs) may be involved in the development of atherosclerosis, beyond diabetes and renal disease. Skin autofluorescence (AF) is a non-invasive marker for AGEs. We examined whether skin AF is increased in (subclinical) atherosclerosis and associated with the degree of atherosclerosis independent of diabetes and renal function. METHODS: A cross-sectional study of 223 patients referred for primary (n = 163) or secondary (n = 60) prevention between 2006 and 2012 was performed. Skin AF was measured using the AGE-Reader. Ultrasonography was used to assess plaques in carotid and femoral arteries and computed tomography for the calculation of the coronary artery calcium score (CACS; in primary prevention only). Primary prevention patients were divided into a group with subclinical atherosclerosis defined as >1 plaque or CACS>100 (n = 67; age 53 year [interquartile range 48-56]; 49% male) and without (controls; 96; 43 [38-51]; 55%). Secondary prevention were patients with peripheral arterial disease (60; 64 [58-70]; 73%). RESULTS: Skin AF was higher in subclinical and clinical atherosclerosis compared with controls (skin AF 2.11 [interquartile range 1.83-2.46] and 2.71 [2.15-3.27] vs. 1.87 [1.68-2.12] respectively; P = 0.005 and <0.001). In a multivariate analysis, the association of skin AF with the atherosclerosis categories was independent of age, sex, diabetes, presence of the metabolic syndrome, Framingham Risk Score, and renal function. Skin AF correlated with most cardiovascular risk factors, Framingham risk score, and IMT and CACS. CONCLUSIONS: Skin AF is increased in documented subclinical and clinical atherosclerosis, independent of known risk factors such as diabetes and renal disease. These data suggest that AGEs may be associated with the burden of atherosclerosis and warrant a prospective study to investigate its clinical usability as a risk assessment tool for primary prevention

Is synthetic hexaploid wheat a useful germplasm source for increasing grain size and yield in bread wheat breeding?

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Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Patching cardiac and head motion artefacts in diffusion-weighted images.

Contains fulltext : 89846.pdf (publisher's version ) (Closed access)Motion artefacts are an important but often disregarded problem in diffusion-weighted imaging, which can readily lead to corrupt diffusion model estimations. The new processing method proposed in this paper uses robust tensor estimation that is spatially informed to efficiently detect the most frequently occurring artefacts, namely those that result from head and cardiac motion. Simulations demonstrate that the method is more robust and accurate than previous methods. The tensor estimates are more accurate in motion artefact-free conditions, less sensitive to increases in artefact magnitude and more resistant to increasing artefact frequency. Evaluation with real diffusion-weighted (DW) imaging data shows that the method works excellently, even for datasets with a high degree of motion that otherwise need to be discarded. The method is not limited to diffusion tensor imaging but also yields objective artefact reflecting weights that can be used to inform subsequent processing or estimation of higher-order diffusion models

Cross-sensory calibration of spatial hearing

Contains fulltext : 63125.pdf (publisher's version ) (Open Access)This thesis describes experiments designed to investigate cross-sensory spatial coordination. In particular, it deals with sound localization and its relation to the visual system. The main questions and conclusions are: What is the effect of blindness on sound localization? Barn-owl studies have shown that vision is used to spatially calibrate the auditory system. Relatively little is known about this process in humans. We show that visual feedback may be required to optimally extract sound elevation, but not azimuth, in the presence of background noise. Further, the results suggest that vision shifts the origin for arm pointing from the shoulder to the cyclopean eye. What is the effect of compressed vision on sound localization? Shifting prisms have been used to study cross-sensory spatial plasticity. We compressed vision with 0.5x lenses. The results show that azimuth localization, but not elevation, was compressed accordingly within the visual field of the lenses. The changes in localization behavior outside this field are consistent with a model in which azimuth localization is encoded by recruitment rather than by a population code. How is sound location encoded in the IC? The inferior colliculus is the first nucleus in the ascending auditory pathway that may encode 2D sound position. Response properties of auditory IC neurons to sound position, level and eye position are described. Besides ample tuning to sound position and level, the results show that, albeit in a relatively weak 'gain-field' like fashion, a small fraction of the population was modulated by eye position. How are spectro-temporal properties encoded in the IC? We used sounds with spectro-temporal modulations ('ripples') to determine the excitatory and inhibitory response properties of auditory IC neurons (STRFs). The results show that a wide variety of STRFs is found and that these can be used to linearly predict responses to various sound stimuliRU Radboud Universiteit Nijmegen, 04 juni 2003Promotor : Gielen, C.C.A.M. Co-promotor : Opstal, A.J. van138 p

Cruysberg a spatial hearing deficit in early-blind humans.

Contains fulltext : 120571.pdf (publisher's version ) (Open Access

Involvement of monkey inferior colliculus in spatial hearing.

Contains fulltext : 57793.pdf (publisher's version ) (Open Access)The midbrain inferior colliculus (IC) is implicated in coding sound location, but evidence from behaving primates is scarce. Here we report single-unit responses to broadband sounds that were systematically varied within the two-dimensional (2D) frontal hemifield, as well as in sound level, while monkeys fixated a central visual target. Results show that IC neurons are broadly tuned to both sound-source azimuth and level in a way that can be approximated by multiplicative, planar modulation of the firing rate of the cell. In addition, a fraction of neurons also responded to elevation. This tuning, however, was more varied: some neurons were sensitive to a specific elevation; others responded to elevation in a monotonic way. Multiple-linear regression parameters varied from cell to cell, but the only topography encountered was a dorsoventral tonotopy. In a second experiment, we presented sounds from straight ahead while monkeys fixated visual targets at different positions. We found that auditory responses in a fraction of IC cells were weakly, but systematically, modulated by 2D eye position. This modulation was absent in the spontaneous firing rates, again suggesting a multiplicative interaction of acoustic and eye-position inputs. Tuning parameters to sound frequency, location, intensity, and eye position were uncorrelated. On the basis of simulations with a simple neural network model, we suggest that the population of IC cells could encode the head-centered 2D sound location and enable a direct transformation of this signal into the eye-centered topographic motor map of the superior colliculus. Both signals are required to generate rapid eye-head orienting movements toward sounds.12 p