School of Physics - Research Publications

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    INTERFEROME: the database of interferon regulated genes.
    Samarajiwa, SA ; Forster, S ; Auchettl, K ; Hertzog, PJ (Oxford University Press (OUP), 2009-01)
    INTERFEROME is an open access database of types I, II and III Interferon regulated genes (http://www.interferome.org) collected from analysing expression data sets of cells treated with IFNs. This database of interferon regulated genes integrates information from high-throughput experiments with annotation, ontology, orthologue sequences from 37 species, tissue expression patterns and gene regulatory information to enable a detailed investigation of the molecular mechanisms underlying IFN biology. INTERFEROME fulfils a need in infection, immunity, development and cancer research by providing computational tools to assist in identifying interferon signatures in gene lists generated by high-throughput expression technologies, and their potential molecular and biological consequences.
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    Statistical analysis of an RNA titration series evaluates microarray precision and sensitivity on a whole-array basis
    Holloway, AJ ; Oshlack, A ; Diyagama, DS ; Bowtell, DDL ; Smyth, GK (BMC, 2006-11-22)
    BACKGROUND: Concerns are often raised about the accuracy of microarray technologies and the degree of cross-platform agreement, but there are yet no methods which can unambiguously evaluate precision and sensitivity for these technologies on a whole-array basis. RESULTS: A methodology is described for evaluating the precision and sensitivity of whole-genome gene expression technologies such as microarrays. The method consists of an easy-to-construct titration series of RNA samples and an associated statistical analysis using non-linear regression. The method evaluates the precision and responsiveness of each microarray platform on a whole-array basis, i.e., using all the probes, without the need to match probes across platforms. An experiment is conducted to assess and compare four widely used microarray platforms. All four platforms are shown to have satisfactory precision but the commercial platforms are superior for resolving differential expression for genes at lower expression levels. The effective precision of the two-color platforms is improved by allowing for probe-specific dye-effects in the statistical model. The methodology is used to compare three data extraction algorithms for the Affymetrix platforms, demonstrating poor performance for the commonly used proprietary algorithm relative to the other algorithms. For probes which can be matched across platforms, the cross-platform variability is decomposed into within-platform and between-platform components, showing that platform disagreement is almost entirely systematic rather than due to measurement variability. CONCLUSION: The results demonstrate good precision and sensitivity for all the platforms, but highlight the need for improved probe annotation. They quantify the extent to which cross-platform measures can be expected to be less accurate than within-platform comparisons for predicting disease progression or outcome.
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    Normalization of boutique two-color microarrays with a high proportion of differentially expressed probes
    Oshlack, A ; Emslie, D ; Corcoran, LM ; Smyth, GK (BMC, 2007)
    Normalization is critical for removing systematic variation from microarray data. For two-color microarray platforms, intensity-dependent lowess normalization is commonly used to correct relative gene expression values for biases. Here we outline a normalization method for use when the assumptions of lowess normalization fail. Specifically, this can occur when specialized boutique arrays are constructed that contain a subset of genes selected to test particular biological functions.
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    Gene Regulation in Primates Evolves under Tissue-Specific Selection Pressures
    Blekhman, R ; Oshlack, A ; Chabot, AE ; Smyth, GK ; Gilad, Y ; McVean, G (PUBLIC LIBRARY SCIENCE, 2008-11)
    Regulatory changes have long been hypothesized to play an important role in primate evolution. To identify adaptive regulatory changes in humans, we performed a genome-wide survey for genes in which regulation has likely evolved under natural selection. To do so, we used a multi-species microarray to measure gene expression levels in livers, kidneys, and hearts from six humans, chimpanzees, and rhesus macaques. This comparative gene expression data allowed us to identify a large number of genes, as well as specific pathways, whose inter-species expression profiles are consistent with the action of stabilizing or directional selection on gene regulation. Among the latter set, we found an enrichment of genes involved in metabolic pathways, consistent with the hypothesis that shifts in diet underlie many regulatory adaptations in humans. In addition, we found evidence for tissue-specific selection pressures, as well as lower rates of protein evolution for genes in which regulation evolves under natural selection. These observations are consistent with the notion that adaptive circumscribed changes in gene regulation have fewer deleterious pleiotropic effects compared with changes at the protein sequence level.
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    A Combination of Genomic Approaches Reveals the Role of FOXO1a in Regulating an Oxidative Stress Response Pathway
    de Candia, P ; Blekhman, R ; Chabot, AE ; Oshlack, A ; Gilad, Y ; Borevitz, JO (PUBLIC LIBRARY SCIENCE, 2008-02-27)
    BACKGROUND: While many of the phenotypic differences between human and chimpanzee may result from changes in gene regulation, only a handful of functionally important regulatory differences are currently known. As a first step towards identifying transcriptional pathways that have been remodeled in the human lineage, we focused on a transcription factor, FOXO1a, which we had previously found to be up-regulated in the human liver compared to that of three other primate species. We concentrated on this gene because of its known role in the regulation of metabolism and in longevity. METHODOLOGY: Using a combination of expression profiling following siRNA knockdown and chromatin immunoprecipitation in a human liver cell line, we identified eight novel direct transcriptional targets of FOXO1a. This set includes the gene for thioredoxin-interacting protein (TXNIP), the expression of which is directly repressed by FOXO1a. The thioredoxin-interacting protein is known to inhibit the reducing activity of thioredoxin (TRX), thereby hindering the cellular response to oxidative stress and affecting life span. CONCLUSIONS: Our results provide an explanation for the repeated observations that differences in the regulation of FOXO transcription factors affect longevity. Moreover, we found that TXNIP is down-regulated in human compared to chimpanzee, consistent with the up-regulation of its direct repressor FOXO1a in humans, and with differences in longevity between the two species.
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    Stringent constraints on cosmological neutrino-antineutrino asymmetries from synchronized flavor transformation
    Abazajian, KN ; Beacom, JF ; Bell, NF (AMER PHYSICAL SOC, 2002-07-01)
    We assess a mechanism which can transform neutrino-antineutrino asymmetries between flavors in the early universe, and confirm that such transformation is unavoidable in the near bi-maximal framework emerging for the neutrino mixing matrix. We show that the process is a standard Mikheyev-Smirnov-Wolfenstein flavor transformation dictated by a synchronization of momentum states. We also show that flavor ``equilibration'' is a special feature of maximal mixing, and carefully examine new constraints placed on neutrino asymmetries. In particular, the big bang nucleosynthesis limit on electron neutrino degeneracy xi_e < 0.04 does not apply directly to all flavors, yet confirmation of the large-mixing-angle solution to the solar neutrino problem will eliminate the possibility of degenerate big bang nucleosynthesis.
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    CONSTRAINTS ON THE HIGH-l POWER SPECTRUM OF MILLIMETER-WAVE ANISOTROPIES FROM APEX-SZ
    Reichardt, CL ; Zahn, O ; Ade, PAR ; Basu, K ; Bender, AN ; Bertoldi, F ; Cho, H-M ; Chon, G ; Dobbs, M ; Ferrusca, D ; Halverson, NW ; Holzapfel, WL ; Horellou, C ; Johansson, D ; Johnson, BR ; Kennedy, J ; Kneissl, R ; Lanting, T ; Lee, AT ; Lueker, M ; Mehl, J ; Menten, KM ; Nord, M ; Pacaud, F ; Richards, PL ; Schaaf, R ; Schwan, D ; Spieler, H ; Weiss, A ; Westbrook, B (IOP PUBLISHING LTD, 2009-08-20)
    We present measurements of the angular power spectrum of millimeter wave anisotropies with the APEX-SZ instrument. APEX-SZ has mapped 0.8 square degrees of sky at a frequency of 150 GHz with an angular resolution of 1'. These new measurements significantly improve the constraints on anisotropy power at 150 GHz over the range of angular multipoles 3000 < l < 10,000, limiting the total astronomical signal in a flat band power to be less than 105 microK^2 at 95% CL. We expect both submillimeter-bright, dusty galaxies and to a lesser extent secondary CMB anisotropies from the Sunyaev-Zel'dovich effect (SZE) to significantly contribute to the observed power. Subtracting the SZE power spectrum expected for sigma_8=0.8 and masking bright sources, the best fit value for the remaining power is C_l = 1.1^{+0.9}_{-0.8} x 10^{-5} micro K^2 (1.7^{+1.4}_{-1.3} Jy^2 sr^{-1}). This agrees well with model predictions for power due to submillimeter-bright, dusty galaxies. Comparing this power to the power detected by BLAST at 600 GHz, we find the frequency dependence of the source fluxes to be S_nu ~ nu^{2.6^{+0.4}_{-0.2}} if both experiments measure the same population of sources. Simultaneously fitting for the amplitude of the SZE power spectrum and a Poisson distributed point source population, we place an upper limit on the matter fluctuation amplitude of sigma_8 < 1.18 at 95% confidence.
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    HIGH-RESOLUTION CMB POWER SPECTRUM FROM THE COMPLETE ACBAR DATA SET
    Reichardt, CL ; Ade, PAR ; Bock, JJ ; Bond, JR ; Brevik, JA ; Contaldi, CR ; Daub, MD ; Dempsey, JT ; Goldstein, JH ; Holzapfel, WL ; Kuo, CL ; Lange, AE ; Lueker, M ; Newcomb, M ; Peterson, JB ; Ruhl, J ; Runyan, MC ; Staniszewski, Z (IOP PUBLISHING LTD, 2009-04-01)
    In this paper, we present results from the complete set of cosmic microwave background (CMB) radiation temperature anisotropy observations made with the Arcminute Cosmology Bolometer Array Receiver (ACBAR) operating at 150 GHz. We include new data from the final 2005 observing season, expanding the number of detector-hours by 210% and the sky coverage by 490% over that used for the previous ACBAR release. As a result, the band-power uncertainties have been reduced by more than a factor of two on angular scales encompassing the third to fifth acoustic peaks as well as the damping tail of the CMB power spectrum. The calibration uncertainty has been reduced from 6% to 2.1% in temperature through a direct comparison of the CMB anisotropy measured by ACBAR with that of the dipole-calibrated WMAP5 experiment. The measured power spectrum is consistent with a spatially flat, LambdaCDM cosmological model. We include the effects of weak lensing in the power spectrum model computations and find that this significantly improves the fits of the models to the combined ACBAR+WMAP5 power spectrum. The preferred strength of the lensing is consistent with theoretical expectations. On fine angular scales, there is weak evidence (1.1 sigma) for excess power above the level expected from primary anisotropies. We expect any excess power to be dominated by the combination of emission from dusty protogalaxies and the Sunyaev-Zel'dovich effect (SZE). However, the excess observed by ACBAR is significantly smaller than the excess power at ell > 2000 reported by the CBI experiment operating at 30 GHz. Therefore, while it is unlikely that the CBI excess has a primordial origin; the combined ACBAR and CBI results are consistent with the source of the CBI excess being either the SZE or radio source contamination.
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    Recovering physical parameters from galaxy spectra using MOPED
    Reichardt, C ; Jimenez, R ; Heavens, AF (BLACKWELL SCIENCE LTD, 2001-11-01)
    We derive physical parameters of galaxies from their observed spectrum, using MOPED, the optimized data compression algorithm of Heavens, Jimenez & Lahav 2000. Here we concentrate on parametrising galaxy properties, and apply the method to the NGC galaxies in Kennicutt's spectral atlas. We focus on deriving the star formation history, metallicity and dust content of galaxies. The method is very fast, taking a few seconds of CPU time to estimate 17 parameters, and so specially suited to study of large data sets, such as the Anglo-Australian 2 degree field galaxy survey and the Sloan Digital Sky Survey. Without the power of MOPED, the recovery of star formation histories in these surveys would be impractical. In the Kennicutt atlas, we find that for the spheroidals a small recent burst of star formation is required to provide the best fit to the spectrum. There is clearly a need for theoretical stellar atmospheric models with spectral resolution better than 1\AA if we are to extract all the rich information that large redshift surveys contain in their galaxy spectra.
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    Improved measurements of the CMB power spectrum with ACBAR
    Kuo, CL ; Ade, PAR ; Bock, JJ ; Bond, JR ; Contaldi, CR ; Daub, MD ; Goldstein, JH ; Holzapfel, WL ; Lange, AE ; Lueker, M ; Newcomb, M ; Peterson, JB ; Reichardt, C ; Ruhl, J ; Runyan, MC ; Staniszweski, Z (IOP PUBLISHING LTD, 2007-08-01)
    We report improved measurements of temperature anisotropies in the cosmic microwave background (CMB) radiation made with the Arcminute Cosmology Bolometer Array Receiver (ACBAR). In this paper, we use a new analysis technique and include 30% more data from the 2001 and 2002 observing seasons than the first release to derive a new set of band-power measurements with significantly smaller uncertainties. The planet-based calibration used previously has been replaced by comparing the flux of RCW38 as measured by ACBAR and BOOMERANG to transfer the WMAP-based BOOMERANG calibration to ACBAR. The resulting power spectrum is consistent with the theoretical predictions for a spatially flat, dark energy dominated LCDM cosmology including the effects of gravitational lensing. Despite the exponential damping on small angular scales, the primary CMB fluctuations are detected with a signal-to-noise ratio of greater than 4 up to multipoles of l=2000. This increase in the precision of the fine-scale CMB power spectrum leads to only a modest decrease in the uncertainties on the parameters of the standard cosmological model. At high angular resolution, secondary anisotropies are predicted to be a significant contribution to the measured anisotropy. A joint analysis of the ACBAR results at 150 GHz and the CBI results at 30 GHz in the multipole range 2000 < l < 3000 shows that the power, reported by CBI in excess of the predicted primary anisotropy, has a frequency spectrum consistent with the thermal Sunyaev-Zel'dovich effect and inconsistent with primary CMB. The results reported here are derived from a subset of the total ACBAR data set; the final ACBAR power spectrum at 150 GHz will include 3.7 times more effective integration time and 6.5 times more sky coverage than is used here.