High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.

Chromosome 17q11-q21 is a region of the genome likely to harbor susceptibility to autism (MIM(209850)) based on earlier evidence of linkage to the disorder. This linkage is specific to multiplex pedigrees containing only male probands (MO) within the Autism Genetic Resource Exchange (AGRE). Earlier, Stone et al.(1) completed a high-density single nucleotide polymorphism association study of 13.7 Mb within this interval, but common variant association was not sufficient to account for the linkage signal. Here, we extend this single nucleotide polymorphism-based association study to complete the coverage of the two-LOD support interval around the chromosome 17q linkage peak by testing the majority of common alleles in 284 MO trios. Markers within an interval containing the gene, CACNA1G, were found to be associated with Autism Spectrum Disorder at a locally significant level (P=1.9 × 10(-5)). While establishing CACNA1G as a novel candidate gene for autism, these alleles do not contribute a sufficient genetic effect to explain the observed linkage, indicating that there is substantial genetic heterogeneity despite the clear linkage signal. The region thus likely harbors a combination of multiple common and rare alleles contributing to the genetic risk. These data, along with earlier studies of chromosomes 5 and 7q3, suggest few if any major common risk alleles account for Autism Spectrum Disorder risk under major linkage peaks in the AGRE sample. This provides important evidence for strategies to identify Autism Spectrum Disorder genes, suggesting that they should focus on identifying rare variants and common variants of small effect

Uniqueness and Non-uniqueness in the Einstein Constraints

The conformal thin sandwich (CTS) equations are a set of four of the Einstein equations, which generalize the Laplace-Poisson equation of Newton's theory. We examine numerically solutions of the CTS equations describing perturbed Minkowski space, and find only one solution. However, we find {\em two} distinct solutions, one even containing a black hole, when the lapse is determined by a fifth elliptic equation through specification of the mean curvature. While the relationship of the two systems and their solutions is a fundamental property of general relativity, this fairly simple example of an elliptic system with non-unique solutions is also of broader interest.Comment: 4 pages, 4 figures; abstract and introduction rewritte

The Einstein constraints: uniqueness and non-uniqueness in the conformal thin sandwich approach

We study the appearance of multiple solutions to certain decompositions of Einstein's constraint equations. Pfeiffer and York recently reported the existence of two branches of solutions for identical background data in the extended conformal thin-sandwich decomposition. We show that the Hamiltonian constraint alone, when expressed in a certain way, admits two branches of solutions with properties very similar to those found by Pfeiffer and York. We construct these two branches analytically for a constant-density star in spherical symmetry, but argue that this behavior is more general. In the case of the Hamiltonian constraint this non-uniqueness is well known to be related to the sign of one particular term, and we argue that the extended conformal thin-sandwich equations contain a similar term that causes the breakdown of uniqueness.Comment: 9 pages, 1 figur

3+1 Approach to the Long Wavelength Iteration Scheme

Large-scale inhomogeneities and anisotropies are modeled using the Long Wavelength Iteration Scheme. In this scheme solutions are obtained as expansions in spatial gradients, which are taken to be small. It is shown that the choice of foliation for spacetime can make the iteration scheme more effective in two respects: (i) the shift vector can be chosen so as to dilute the effect of anisotropy on the late-time value of the extrinsic curvature of the spacelike hypersurfaces of the foliation; and (ii) pure gauge solutions present in a similar calculation using the synchronous gauge vanish when the spacelike hypersurfaces have extrinsic curvature with constant trace. We furthermore verify the main conclusion of the synchronous gauge calculation which is large-scale inhomogeneity decays if the matter--considered to be that of a perfect-fluid with a barotropic equation of state--violates the strong-energy condition. Finally, we obtain the solution for the lapse function and discuss its late-time behaviour. It is found that the lapse function is well-behaved when the matter violates the strong energy condition.Comment: 21 pages, TeX file, already publishe

Initial data for fluid bodies in general relativity

We show that there exist asymptotically flat almost-smooth initial data for Einstein-perfect fluid's equation that represent an isolated liquid-type body. By liquid-type body we mean that the fluid energy density has compact support and takes a strictly positive constant value at its boundary. By almost-smooth we mean that all initial data fields are smooth everywhere on the initial hypersurface except at the body boundary, where tangential derivatives of any order are continuous at that boundary. PACS: 04.20.Ex, 04.40.Nr, 02.30.JrComment: 38 pages, LaTeX 2e, no figures. Accepted for publication in Phys. Rev.

The diagonalization method in quantum recursion theory

As quantum parallelism allows the effective co-representation of classical mutually exclusive states, the diagonalization method of classical recursion theory has to be modified. Quantum diagonalization involves unitary operators whose eigenvalues are different from one.Comment: 15 pages, completely rewritte

Atmosphere Assessment for MARS Science Laboratory Entry, Descent and Landing Operations

On August 6, 2012, the Mars Science Laboratory rover, Curiosity, successfully landed on the surface of Mars. The Entry, Descent and Landing (EDL) sequence was designed using atmospheric conditions estimated from mesoscale numerical models. The models, developed by two independent organizations (Oregon State University and the Southwest Research Institute), were validated against observations at Mars from three prior years. In the weeks and days before entry, the MSL "Council of Atmospheres" (CoA), a group of atmospheric scientists and modelers, instrument experts and EDL simulation engineers, evaluated the latest Mars data from orbiting assets including the Mars Reconnaissance Orbiter's Mars Color Imager (MARCI) and Mars Climate Sounder (MCS), as well as Mars Odyssey's Thermal Emission Imaging System (THEMIS). The observations were compared to the mesoscale models developed for EDL performance simulation to determine if a spacecraft parameter update was necessary prior to entry. This paper summarizes the daily atmosphere observations and comparison to the performance simulation atmosphere models. Options to modify the atmosphere model in the simulation to compensate for atmosphere effects are also presented. Finally, a summary of the CoA decisions and recommendations to the MSL project in the days leading up to EDL is provided

Phase transitions in biological membranes

Native membranes of biological cells display melting transitions of their lipids at a temperature of 10-20 degrees below body temperature. Such transitions can be observed in various bacterial cells, in nerves, in cancer cells, but also in lung surfactant. It seems as if the presence of transitions slightly below physiological temperature is a generic property of most cells. They are important because they influence many physical properties of the membranes. At the transition temperature, membranes display a larger permeability that is accompanied by ion-channel-like phenomena even in the complete absence of proteins. Membranes are softer, which implies that phenomena such as endocytosis and exocytosis are facilitated. Mechanical signal propagation phenomena related to nerve pulses are strongly enhanced. The position of transitions can be affected by changes in temperature, pressure, pH and salt concentration or by the presence of anesthetics. Thus, even at physiological temperature, these transitions are of relevance. There position and thereby the physical properties of the membrane can be controlled by changes in the intensive thermodynamic variables. Here, we review some of the experimental findings and the thermodynamics that describes the control of the membrane function.Comment: 23 pages, 15 figure

Modulation of emotional appraisal by false physiological feedback during fMRI

BACKGROUND James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined. METHODOLOGY/PRINCIPAL FINDINGS We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level. CONCLUSIONS/SIGNIFICANCE Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order "cognitive" representations of bodily arousal state

Modulation of emotional appraisal by false physiological feedback during fMRI

BACKGROUND James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined. METHODOLOGY/PRINCIPAL FINDINGS We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level. CONCLUSIONS/SIGNIFICANCE Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order "cognitive" representations of bodily arousal state