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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
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
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