Multiple locus linkage analysis of genomewide expression in yeast.

With the ability to measure thousands of related phenotypes from a single biological sample, it is now feasible to genetically dissect systems-level biological phenomena. The genetics of transcriptional regulation and protein abundance are likely to be complex, meaning that genetic variation at multiple loci will influence these phenotypes. Several recent studies have investigated the role of genetic variation in transcription by applying traditional linkage analysis methods to genomewide expression data, where each gene expression level was treated as a quantitative trait and analyzed separately from one another. Here, we develop a new, computationally efficient method for simultaneously mapping multiple gene expression quantitative trait loci that directly uses all of the available data. Information shared across gene expression traits is captured in a way that makes minimal assumptions about the statistical properties of the data. The method produces easy-to-interpret measures of statistical significance for both individual loci and the overall joint significance of multiple loci selected for a given expression trait. We apply the new method to a cross between two strains of the budding yeast Saccharomyces cerevisiae, and estimate that at least 37% of all gene expression traits show two simultaneous linkages, where we have allowed for epistatic interactions. Pairs of jointly linking quantitative trait loci are identified with high confidence for 170 gene expression traits, where it is expected that both loci are true positives for at least 153 traits. In addition, we are able to show that epistatic interactions contribute to gene expression variation for at least 14% of all traits. We compare the proposed approach to an exhaustive two-dimensional scan over all pairs of loci. Surprisingly, we demonstrate that an exhaustive two-dimensional scan is less powerful than the sequential search used here. In addition, we show that a two-dimensional scan does not truly allow one to test for simultaneous linkage, and the statistical significance measured from this existing method cannot be interpreted among many traits

Tau-aggregation inhibitor therapy for Alzheimer's disease

Article Accepted Date: 9 December 2013 Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

Rationale for tau aggregation inhibitor therapy in Alzheimer's disease and other tauopathies

Preprin

Observations of far-infrared fine structure lines: o III88.35 micrometer and oI 63.2 micrometer

Observations of the O III 88.35 micrometer line and the O I63.2 micrometer were made with a far infrared spectrometer. The sources M17, NGC 7538, and W51 were mapped in the O III line with 1 arc minute resolution and the emission is found to be quite widespread. In all cases the peak of the emission coincides with the maximum radio continuum. The far infrared continuum was mapped simultaneously and in M17, NGC 7538, and W51 the continuum peak is found to be distinct from the center of ionization. The O III line was also detected in W3, W49, and in a number of positions in the Orion nebula. Upper limits were obtained on NGS 7027, NGC 6572, DR21, G29.9-0.0 and M82. The 63.2 micrometer O I line was detected in M17, M42, and marginally in DR21. A partial map of M42 in this line shows that most of the emission observed arises from the Trapezium and from the bright optical bar to the southeast

Spectral variation in the X-ray pulsar GX 1+4 during a low-flux episode

The X-ray pulsar GX 1+4 was observed with the RXTE satellite for a total of 51ks between 1996 July 19 - 21. During this period the flux decreased smoothly from an initial mean level of ~ 6 X 10^36 erg/s to a minimum of ~ 4 X 10^35 erg/s (2-60 keV, assuming a source distance of 10 kpc) before partially recovering towards the initial level at the end of the observation. BATSE pulse timing measurements indicate that a torque reversal took place approximately 10 d after this observation. Both the mean pulse profile and the photon spectrum varied significantly. The observed variation in the source may provide important clues as to the mechanism of torque reversals. The single best-fitting spectral model was based on a component originating from thermal photons with kT ~ 1 keV Comptonised by a plasma of temperature kT \~ 7 keV. Both the flux modulation with phase during the brightest interval and the evolution of the mean spectra over the course of the observation are consistent with variations in this model component; with, in addition, a doubling of the column density nH contributing to the mean spectral change. A strong flare of duration 50 s was observed during the interval of minimum flux, with the peak flux ~ 20 times the mean level. Although beaming effects are likely to mask the true variation in Mdot thought to give rise to the flare, the timing of a modest increase in flux prior to the flare is consistent with dual episodes of accretion resulting from successive orbits of a locally dense patch of matter in the accretion disc.Comment: 8 pages, 3 figures, submitted to MNRA

Pulse Profiles, Accretion Column Dips and a Flare in GX 1+4 During a Faint State

The Rossi X-ray Timing Explorer (RXTE) spacecraft observed the X-ray pulsar GX 1+4 for a period of 34 hours on July 19/20 1996. The source faded from an intensity of ~20 mCrab to a minimum of <~0.7 mCrab and then partially recovered towards the end of the observation. This extended minimum lasted ~40,000 seconds. Phase folded light curves at a barycentric rotation period of 124.36568 +/- 0.00020 seconds show that near the center of the extended minimum the source stopped pulsing in the traditional sense but retained a weak dip feature at the rotation period. Away from the extended minimum the dips are progressively narrower at higher energies and may be interpreted as obscurations or eclipses of the hot spot by the accretion column. The pulse profile changed from leading-edge bright before the extended minimum to trailing-edge bright after it. Data from the Burst and Transient Source Experiment (BATSE) show that a torque reversal occurred <10 days after our observation. Our data indicate that the observed rotation departs from a constant period with a Pdot/P value of ~-1.5% per year at a 4.5 sigma significance. We infer that we may have serendipitously obtained data, with high sensitivity and temporal resolution about the time of an accretion disk spin reversal. We also observed a rapid flare which had some precursor activity, close to the center of the extended minimum.Comment: 19 pages, 6 figures, accepted for publication in Astrophysical Journal (tentatively scheduled for vol. 529 #1, 20 Jan 2000

Saddle-point van Hove singularity and the phase diagram of high-Tc cuprates

We examine the generic phase behavior of high-Tc cuprate superconductors in terms a universal van Hove singularity in the strongly overdoped region. Using a rigid ARPES-derived dispersion we solve the BCS gap equation and show that the pairing interaction or pairing energy cutoff must be a rapidly declining function of doping. This result is prejudicial to a phonon-based pairing interaction and more consistent with a magnetic or magnetically enhanced interaction.Comment: 5 pages, 2 figures, submitted to Physical Review

Detection of interstellar NH sub 3 in the far-warm and dense gas in Orion-KL

The detection of the (J,K) = a(4,3) yields s(3,3) rotation inversion transition of ammonia at 124.6 microns toward the center of the Orion-KL region is reported. The line is in emission and has a FWHM or = to 30 km s 0.15. The far IR ammonia line emission probably comes mainly from the 'hot core', a compact region of warm, very dense gas previously identified by the radio inversion lines of NH3. The a(4,3) yields s(3,3) line is very optically thick, and since it is seen in emission, radiative excitation of the (4,3) NH3 level by far IR emission from dust within the source can be ruled out. Radiative excitation via the 10 microns of vibrational transitions of NH3 also seems unlikely. Hence, the (4,3) level is probably collisionally excited and the gas in the hot core region is warmer than the dust. Since the far IR line emission is highly trapped, densities of approximately 10 to the 7th power cu cm are high enough to explain the observations. Shock heating by the mass outflow from IRc2 may account for the high gas temperatures in the hot core region

Far-infrared rotational emission by carbon monoxide

Accurate theoretical collisional excitation rates are used to determine the emissivities of CO rotational lines 10 to the 4th power/cu cm n(H2), 100 K T 2000 K, and J 50. An approximate analytic expression for the emissitivities which is valid over most of this region is obtained. Population inversions in the lower rotational levels occur for densities n(H2) approximately 10 (to the 3rd to 5th power)/cu cm and temperatures T approximately 50 K. Interstellar shocks observed edge on are a potential source of millimeter wave CO maser emission. The CO rotational cooling function suggested by Hollenbach and McKee (1979) is verified, and accurate numerical values given. Application of these results to other linear molecules should be straightforward