An Evolutionary Framework for Association Testing in Resequencing Studies

Sequencing technologies are becoming cheap enough to apply to large numbers of study participants and promise to provide new insights into human phenotypes by bringing to light rare and previously unknown genetic variants. We develop a new framework for the analysis of sequence data that incorporates all of the major features of previously proposed approaches, including those focused on allele counts and allele burden, but is both more general and more powerful. We harness population genetic theory to provide prior information on effect sizes and to create a pooling strategy for information from rare variants. Our method, EMMPAT (Evolutionary Mixed Model for Pooled Association Testing), generates a single test per gene (substantially reducing multiple testing concerns), facilitates graphical summaries, and improves the interpretation of results by allowing calculation of attributable variance. Simulations show that, relative to previously used approaches, our method increases the power to detect genes that affect phenotype when natural selection has kept alleles with large effect sizes rare. We demonstrate our approach on a population-based re-sequencing study of association between serum triglycerides and variation in ANGPTL4.</p

Polar motion and UT1: Comparison of VLBI, lunar laser, satellite laser, satellite Doppler, and conventional astrometric determinations

Very long baseline interferometry observations made with a 3900 km baseline interferometer (Haystack Observatory in Massachusetts to Owens Valley Observation in California) were used to estimate changes in the X-component of the position of the Earth's pole and in UT1. These estimates are compared with corresponding ones from lunar laser ranging, satellite laser ranging, satellite Doppler, and stellar observations

The Lithium Content of the Galactic Halo Stars

Thanks to the accurate determination of the baryon density of the universe by the recent cosmic microwave background experiments, updated predictions of the standard model of Big Bang nucleosynthesis now yield the initial abundance of the primordial light elements with an unprecedented precision. In the case of $^7$Li, the CMB+SBBN value is significantly higher than the generally reported abundances for Pop II stars along the so-called Spite plateau. In view of the crucial importance of this disagreement which has cosmological, galactic and stellar implications, we decided to tackle the most critical issues of the problem by revisiting a large sample of literature Li data in halo stars that we assembled following some strict selection criteria on the quality of the original analyses. [Abridged]Comment: 34 pages. Accepted for publication in A&A. Includes additional references and minor correction

A framework for automated anomaly detection in high frequency water-quality data from in situ sensors

River water-quality monitoring is increasingly conducted using automated in situ sensors, enabling timelier identification of unexpected values. However, anomalies caused by technical issues confound these data, while the volume and velocity of data prevent manual detection. We present a framework for automated anomaly detection in high-frequency water-quality data from in situ sensors, using turbidity, conductivity and river level data. After identifying end-user needs and defining anomalies, we ranked their importance and selected suitable detection methods. High priority anomalies included sudden isolated spikes and level shifts, most of which were classified correctly by regression-based methods such as autoregressive integrated moving average models. However, using other water-quality variables as covariates reduced performance due to complex relationships among variables. Classification of drift and periods of anomalously low or high variability improved when we applied replaced anomalous measurements with forecasts, but this inflated false positive rates. Feature-based methods also performed well on high priority anomalies, but were also less proficient at detecting lower priority anomalies, resulting in high false negative rates. Unlike regression-based methods, all feature-based methods produced low false positive rates, but did not and require training or optimization. Rule-based methods successfully detected impossible values and missing observations. Thus, we recommend using a combination of methods to improve anomaly detection performance, whilst minimizing false detection rates. Furthermore, our framework emphasizes the importance of communication between end-users and analysts for optimal outcomes with respect to both detection performance and end-user needs. Our framework is applicable to other types of high frequency time-series data and anomaly detection applications

The Timing of Nine Globular Cluster Pulsars

We have used the Robert C. Byrd Green Bank Telescope to time nine previously known pulsars without published timing solutions in the globular clusters M62, NGC 6544, and NGC 6624. We have full timing solutions that measure the spin, astrometric, and (where applicable) binary parameters for six of these pulsars. The remaining three pulsars (reported here for the first time) were not detected enough to establish solutions. We also report our timing solutions for five pulsars with previously published solutions, and find good agreement with past authors, except for PSR J1701-3006B in M62. Gas in this system is probably responsible for the discrepancy in orbital parameters, and we have been able to measure a change in the orbital period over the course of our observations. Among the pulsars with new solutions we find several binary pulsars with very low mass companions (members of the so-called "black widow" class) and we are able to place constraints on the mass-to-light ratio in two clusters. We confirm that one of the pulsars in NGC 6624 is indeed a member of the rare class of non-recycled pulsars found in globular clusters. We also have measured the orbital precession and Shapiro delay for a relativistic binary in NGC 6544. If we assume that the orbital precession can be described entirely by general relativity, which is likely, we are able to measure the total system mass (2.57190(73) M_sun) and companion mass (1.2064(20) M_sun), from which we derive the orbital inclination [sin(i) = 0.9956(14)] and the pulsar mass (1.3655(21) M_sun), the most precise such measurement ever obtained for a millisecond pulsar. The companion is the most massive known around a fully recycled pulsar.Comment: Published in ApJ; 33 pages, 5 figures, 7 table

The N- or C-terminal domains of DSH-2 can activate the C. elegans Wnt/β-catenin asymmetry pathway

AbstractDishevelleds are modular proteins that lie at the crossroads of divergent Wnt signaling pathways. The DIX domain of dishevelleds modulates a β-catenin destruction complex, and thereby mediates cell fate decisions through differential activation of Tcf transcription factors. The DEP domain of dishevelleds mediates planar polarity of cells within a sheet through regulation of actin modulators. In Caenorhabditis elegans asymmetric cell fate decisions are regulated by asymmetric localization of signaling components in a pathway termed the Wnt/β-catenin asymmetry pathway. Which domain(s) of Disheveled regulate this pathway is unknown. We show that C. elegans embryos from dsh-2(or302) mutant mothers fail to successfully undergo morphogenesis, but transgenes containing either the DIX or the DEP domain of DSH-2 are sufficient to rescue the mutant phenotype. Embryos lacking zygotic function of SYS-1/β-catenin, WRM-1/β-catenin, or POP-1/Tcf show defects similar to dsh-2 mutants, including a loss of asymmetry in some cell fate decisions. Removal of two dishevelleds (dsh-2 and mig-5) leads to a global loss of POP-1 asymmetry, which can be rescued by addition of transgenes containing either the DIX or DEP domain of DSH-2. These results indicate that either the DIX or DEP domain of DSH-2 is capable of activating the Wnt/β-catenin asymmetry pathway and regulating anterior–posterior fate decisions required for proper morphogenesis

Robustness of sex-differences in functional connectivity over time in middle-aged marmosets

Nonhuman primates (NHPs) are an essential research model for gaining a comprehensive understanding of the neural mechanisms of neurocognitive aging in our own species. In the present study, we used resting state functional connectivity (rsFC) to investigate the relationship between prefrontal cortical and striatal neural interactions, and cognitive flexibility, in unanaesthetized common marmosets (Callithrix jacchus) at two time points during late middle age (8 months apart, similar to a span of 5-6 years in humans). Based on our previous findings, we also determine the reproducibility of connectivity measures over the course of 8 months, particularly previously observed sex differences in rsFC. Male marmosets exhibited remarkably similar patterns of stronger functional connectivity relative to females and greater cognitive flexibility between the two imaging time points. Network analysis revealed that the consistent sex differences in connectivity and related cognitive associations were characterized by greater node strength and/or degree values in several prefrontal, premotor and temporal regions, as well as stronger intra PFC connectivity, in males compared to females. The current study supports the existence of robust sex differences in prefrontal and striatal resting state networks that may contribute to differences in cognitive function and offers insight on the neural systems that may be compromised in cognitive aging and age-related conditions such as mild cognitive impairment and Alzheimer\u27s disease