Dissecting Complex Traits Using the Drosophila Synthetic Population Resource

For most complex traits we have a poor understanding of the positions, phenotypic effects, and population frequencies of the underlying genetic variants contributing to their variation. Recently, several groups have developed multi-parent advanced intercross mapping panels in different model organisms in an attempt to improve our ability to characterize causative genetic variants. These panels are powerful and are particularly well suited to the dissection of phenotypic variation generated by rare alleles and loci segregating multiple functional alleles. We describe studies using one such panel, the Drosophila Synthetic Population Resource, and the implications for our understanding of the genetic basis of complex traits. In particular, we note that many loci of large effect appear to be multiallelic. If multiallelism is a general rule, analytical approaches designed to identify multiallelic variants should be a priority for both genome wide association studies and multi-parental panels

Effect of the velopharynx on intraluminal pressures in reconstructed pharynges derived from individuals with and without sleep apnea

The most collapsible part of the upper airway in the majority of individuals is the velopharynx which is the segment positioned behind the soft palate. As such it is an important morphological region for consideration in elucidating the pathogenesis of obstructive sleep apnea (OSA). This study compared steady flow properties during inspiration in the pharynges of nine male subjects with OSA and nine body-mass index (BMI)- and age-matched control male subjects without OSA. The k–ωωSST turbulence model was used to simulate the flow field in subject-specific pharyngeal geometric models reconstructed from anatomical optical coherence tomography (aOCT) data. While analysis of the geometry of reconstructed pharynges revealed narrowing at velopharyngeal level in subjects with OSA, it was not possible to clearly distinguish them from subjects without OSA on the basis of pharyngeal size and shape alone. By contrast, flow simulations demonstrated that pressure fields within the narrowed airway segments were sensitive to small differences in geometry and could lead to significantly different intraluminal pressure characteristics between subjects. The ratio between velopharyngeal and total pharyngeal pressure drops emerged as a relevant flow-based criterion by which subjects with OSA could be differentiated from those without

The Genetic Architecture of Methotrexate Toxicity Is Similar in Drosophila melanogaster and Humans

The severity of the toxic side effects of chemotherapy varies among patients, and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three quantitative trait loci (QTL) affecting MTX toxicity; two colocalize with the fly orthologs of human genes believed to mediate MTX toxicity and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single-marker association scans of candidate gene exons fail to implicate amino acid variants as the causative single-nucleotide polymorphisms, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single single-nucleotide polymorphism located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors

Rodenticidal Effects of Zinc Phosphide and Strychnine of Nontarget Species

When three rodenticide treatments—zinc phosphide (prebaited) and strychnine (both with and without prebait)were evaluated, zinc phosphide was the most effective in reducing active burrows of prairie dogs; but, it also resulted in a reduction in deer mouse densities. One month after treatment, counts of fecal pellets of eastern cottontails were greater on areas treated with strychnine without prebait than on sites treated with zinc phosphide. Eight months after treatment, no differences could be detected among rodenticides for either leporid. Horned lark densities were reduced 61% on sites treated with strychnine only

WIYN Open Cluster Study. XXXIX. Abundances in NGC 6253 from HYDRA Spectroscopy of the Li 6708 A Region

High-dispersion spectra of 89 potential members of the old, super-metal-rich open cluster, NGC 6253, have been obtained with the HYDRA multi-object spectrograph. Based upon radial-velocity measurements alone, 47 stars at the turnoff of the cluster color-magnitude diagram (CMD) and 18 giants are identified as potential members. Five turnoff stars exhibit evidence of binarity while proper-motion data eliminates two of the dwarfs as members. The mean cluster radial velocity from probable single-star members is -29.4 +/- 1.3 km/sec (sd). A discussion of the current estimates for the cluster reddening, derived independently of potential issues with the BV cluster photometry, lead to an adopted reddening of E(B-V) = 0.22 +/- 0.04. From equivalent width analyses of 38 probable single-star members near the CMD turnoff, the weighted average abundances are found to be [Fe/H] = +0.43 +/- 0.01, [Ni/H] = +0.53 +/- 0.02 and [Si/H] = +0.43 (+0.03,-0.04), where the errors refer to the standard errors of the weighted mean. Weak evidence is found for a possible decline in metallicity with increasing luminosity among stars at the turnoff. We discuss the possibility that our turnoff stars have been affected by microscopic diffusion. For 15 probable single-star members among the giants, spectrum synthesis leads to abundances of +0.46 (+0.02,-0.03) for [Fe/H]. While less than half the age of NGC 6791, NGC 6253 is at least as metal-rich and, within the uncertainties, exhibits the same general abundance pattern as that typified by super-metal-rich dwarfs of the galactic bulge.Comment: 5 Tables, 9 figures, 45 page

Comparison of two- and three-dimensional echocardiography with cineventriculography for measurement of left ventricular volume in patients

AbstractObjectives. We compared two- and three-dimensional echocardiopaphy with cineventriculography for measurement of left ventricular volume in patients.Background. Three-dimensional echocardiography has been shown to be highly accurate and superior to two-dimensional echocardiography in measuring left ventricular volume in vitro. However, there has been little comparison of the two methods in patients.Methods. Two- and three-dimensional echocardiography were performed in 35 patients (mean age 48 years) 1 to 3 h before left ventricular cineventriculography. Three-dimensional echocardiography used an acoustic spatial locator to register image position. Volume was computed using a polyhedral surface reconstruction algorithm based on multiple nonparallel, unevenly spaced short-axis cross sections. Two-dimensional echocardiography used the apical biplane summation of disks method. Single-plane cineventriculographic volumes were calculated using the summation of disks algorithm. The methods were compared by linear regression and a limits of agreement analysis. For the latter, systematic error was assessed by the mean of the deferences (cineventriculography minus echocardiography), and the limits of agreement were defined as ±2 SD from the mean difference.Results. Three-dimensional echocardiographic volumes demonstrated excellent correlation (end-diastole r = 0.97; end-systole r = 0.98) with cineventriculography. Standard errors of the estimate were approximately half those of two-dimensional echocardiography (end-diastole ±11.0 ml vs. ±21.5 ml; end-systole ±10.2 ml vs. ±17.0 ml). By limits of agreement analysis the end-diastolic mean diferences for two- and three-dimensional echocardiography were 21.1 and 12.9 ml, respectively. The limits of agreement (±2 SD) were ±54.0 and ±24.8 ml, respectively. For end-systole, comparable improvement was obtained by three-dimensional echocardiography. Results for ejection fraction by the two methods were similar.Conclusions. Three-dimensional echocardiography correlates highly with cineventriculography for estimation of ventricular volumes in patients and has approximately half the variability of two-dimensional echocardiography for these measurements. On the basis of this study, three-dimensional echocardiography is the preferred echocardiographic technique for measurement of ventricular volume. Three-dimensional echocardiography is equivalent to two-dimensional echocardiography for measuring ejection fraction

The Extreme Behavior of the Radio-loud Narrow-line Seyfert 1 Galaxy J0849+5108

Simultaneous radio, optical (both photometry and polarimetry), X-ray, and γ-ray observations of the radio-loud narrow-line Seyfert 1 (RL-NLSy1) galaxy J0849+5108 are presented. A massive three-magnitude optical flare across five nights in 2013 April is detected, along with associated flux increases in the γ-ray, infrared, and radio regimes; no comparable event was detected in the X-rays, though this may be due to poor coverage. A spectral energy distribution (SED) for the object using quasi-simultaneous data centered on the optical flare is compared to the previously published SEDs for the object by D'Ammando et al. The flare event coincided with a high degree of optical polarization. High amplitude optical microvariability is clearly detected, and is found to be of comparable amplitude when the object is observed in both faint and bright states. The object is also seen to undergo rapid shifts in polarization in both degree and electric vector position angle within a single night. J0849+5108 appears to show even more extreme variability than that previously reported for the similar object J0948+0022. These observations appear to support the growing claim that some RL-NLSy1 galaxies constitute a sub-class of blazar-like active galactic nuclei

A Pilot Study Of Group Mindfulness‐Based Cognitive Therapy (Mbct) For Combat Veterans With Posttraumatic Stress Disorder (Ptsd)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98769/1/da22104.pd

NGC2180: a disrupting open cluster

The spatial dependence of luminosity and mass functions of evolved open clusters is discussed in this work using J and H 2MASS photometry. The target objects are the overlooked open cluster NGC2180 and the intermediate-age open cluster NGC3680. We conclude that, although in an advanced dynamical state (mass segregated), NGC3680 does not present strong signs of dissolution. On the other hand, NGC2180 presents flat, eroded LFs throughout its structure, indicating that in addition to mass segregation, Galactic tidal stripping has been effective in depleting this cluster of stars. Accordingly, NGC2180 may be the missing link between evolved open clusters and remnants. We study both clusters in the context of dynamical states estimated from diagnostic-diagrams involving photometric and structural parameters. Both clusters are dynamically evolved systems. In particular, NGC2180 is closer to open cluster remnants than NGC3680.Comment: 9 pages, 8 figure

Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response

Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a “death conformation” of the MutS homologous proteins that is distinguishable from their “repair conformation.” This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death. We investigated the parameters for a small reserpine-like molecule that are required to interact with MSH2/MSH6 to induce MSH2/MSH6-dependent cytotoxic response. A multidisciplinary approach involving structural modeling, chemical synthesis, and cell biology analyzed reserpine analogs and modifications. We demonstrate that the parameters controlling the induction of MSH2/MSH6-dependent cytotoxicity for reserpine-analogous molecules reside in the specific requirements for methoxy groups, the size of the molecule, and the orientation of molecules within the protein-binding pocket. Reserpine analog rescinnamine showed improved MSH2-dependent cytotoxicity. These results have important implications for the identification of compounds that require functional MMR proteins to exhibit their full cytotoxicity, which will avoid resistance in MMR-deficient cells