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

Interaction paths promote module integration and network-level robustness of spliceosome to cascading effects

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPThe functionality of distinct types of protein networks depends on the patterns of protein-protein interactions. A problem to solve is understanding the fragility of protein networks to predict system malfunctioning due to mutations and other errors. Spec8111CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2017/08406-7, 2017/06994-9We thank Ana Paula Assis, Pâmela C. Santana and Leandro Giacobelli for helpful comments. PRG was supported by CNPq and FAPESP (2017/08406-7). PPC was supported by FAPESP (2017/06994-9). MC was supported by a PMP/BS postdoctoral fellowship (UFPR/UNIVALI 4

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.

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

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

FANCJ/BACH1 Acetylation at Lysine 1249 Regulates the DNA Damage Response

BRCA1 promotes DNA repair through interactions with multiple proteins, including CtIP and FANCJ (also known as BRIP1/BACH1). While CtIP facilitates DNA end resection when de-acetylated, the function of FANCJ in repair processing is less well defined. Here, we report that FANCJ is also acetylated. Preventing FANCJ acetylation at lysine 1249 does not interfere with the ability of cells to survive DNA interstrand crosslinks (ICLs). However, resistance is achieved with reduced reliance on recombination. Mechanistically, FANCJ acetylation facilitates DNA end processing required for repair and checkpoint signaling. This conclusion was based on the finding that FANCJ and its acetylation were required for robust RPA foci formation, RPA phosphorylation, and Rad51 foci formation in response to camptothecin (CPT). Furthermore, both preventing and mimicking FANCJ acetylation at lysine 1249 disrupts FANCJ function in checkpoint maintenance. Thus, we propose that the dynamic regulation of FANCJ acetylation is critical for robust DNA damage response, recombination-based processing, and ultimately checkpoint maintenance

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