Identification of novel pathway partners of p68 and p72 RNA helicases through Oncomine meta-analysis

<p>Abstract</p> <p>Background</p> <p>The Oncomine™ database is an online collection of microarrays from various sources, usually cancer-related, and contains many "multi-arrays" (collections of analyzed microarrays, in a single study). As there are often many hundreds of tumour samples/microarrays within a single multi-array results from coexpressed genes can be analyzed, and are fully searchable. This gives a potentially significant list of coexpressed genes, which is important to define pathways in which the gene of interest is involved. However, to increase the likelihood of revealing truly significant coexpressed genes we have analyzed their frequency of occurrence over multiple studies (meta-analysis), greatly increasing the significance of results compared to those of a single study.</p> <p>Results</p> <p>We have used the DEAD-box proteins p68(Ddx5) and p72(Ddx17) as models for this coexpression frequency analysis as there are defined functions for these proteins in splicing and transcription (known functions which we could use as a basis for quality control). Furthermore, as these proteins are highly similar, interact together, and may be to some degree functionally redundant, we then analyzed the overlap between coexpressed genes of p68 and p72. This final analysis gave us a highly significant list of coexpressed genes, clustering mainly in splicing and transcription (recapitulating their published roles), but also revealing new pathways such as cytoskeleton remodelling and protein folding. We have further tested a predicted pathway partner, RNA helicase A(Dhx9) in a reciprocal meta-analysis that identified p68 and p72 as being coexpressed, and further show a direct interaction of Dhx9 with p68 and p72, attesting to the predictive nature of this technique.</p> <p>Conclusion</p> <p>In summary we have extended the capabilities of Oncomine™ by analyzing the frequency of coexpressed genes over multiple studies, and furthermore assessing the overlap with a known pathway partner (in this case p68 with p72). We have shown our predictions corroborate previously published studies on p68 and p72, and that novel predictions can be easily tested. These techniques are widely applicable and should increase the quality of data from future meta-analysis studies.</p

Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway

<p>Abstract</p> <p>Background</p> <p>The transcription factor GATA3 has recently been shown to be necessary for mammary gland morphogenesis and luminal cell differentiation. There is also an increasing body of data linking GATA3 to the estrogen receptor α (ERα) pathway. Among these it was shown that GATA3 associates with the promoter of the ERα gene and ERα can reciprocally associate with the GATA3 gene. GATA3 has also been directly implicated in a differentiated phenotype in mouse models of mammary tumourigenesis. The purpose of our study was to compare coexpressed genes, by meta-analysis, of GATA3 and relate these to a similar analysis for ERα to determine the depth of overlap.</p> <p>Results</p> <p>We have used a newly described method of meta-analysis of multiple cancer studies within the Oncomine database, focusing here predominantly upon breast cancer studies. We demonstrate that ERα and GATA3 reciprocally have the highest overlap with one another. Furthermore, we show that when both coexpression meta-analysis lists for ERα and GATA3 are compared there is a significant overlap between both and, like ERα, GATA3 coexpresses with ERα pathway partners such as pS2 (<it>TFF1</it>), <it>TFF3</it>, <it>FOXA1</it>, <it>BCL2</it>, <it>ERBB4</it>, <it>XBP1</it>, <it>NRIP1</it>, <it>IL6ST</it>, keratin 18(<it>KRT18</it>) and cyclin D1 (<it>CCND1</it>). Moreover, as these data are derived from human tumour samples this adds credence to previous cell-culture or murine based studies.</p> <p>Conclusion</p> <p>GATA3 is hypothesized to be integral to the ERα pathway given the following: (1) The large overlap of coexpressed genes as seen by meta-analysis, between GATA3 and ERα, (2) The highest coexpressing gene for GATA3 was ERα and <it>vice-versa</it>, (3) GATA3, like ERα, coexpresses with many well-known ERα pathway partners such as pS2.</p

A Direct Measurement of the IGM Opacity to HI Ionizing Photons

We present a new method to directly measure the opacity from HI Lyman limit (LL) absorption k_LL along quasar sightlines by the intergalactic medium (IGM). The approach analyzes the average (``stacked'') spectrum of an ensemble of quasars at a common redshift to infer the mean free path (MFP) to ionizing radiation. We apply this technique to 1800 quasars at z=3.50-4.34 drawn from the Sloan Digital Sky Survey (SDSS), giving the most precise measurements on k_LL at any redshift. From z=3.6 to 4.3, the opacity increases steadily as expected and is well parameterized by MFP = (48.4 +/- 2.1) - (38.0 +/- 5.3)*(z-3.6) h^-1 Mpc (proper distance). The relatively high MFP values indicate that the incidence of systems which dominate k_LL evolves less strongly at z>3 than that of the Lya forest. We infer a mean free path three times higher than some previous estimates, a result which has important implications for the photo-ionization rate derived from the emissivity of star forming galaxies and quasars. Finally, our analysis reveals a previously unreported, systematic bias in the SDSS quasar sample related to the survey's color targeting criteria. This bias potentially affects all z~3 IGM studies using the SDSS database.Comment: 7 pages, 4 figures; Accepted to ApJ

The ribosomal protein RACK1 is required for microRNA function in both C. elegans and humans

Despite the importance of microRNAs (miRNAs) in gene regulation, it is unclear how the miRNA-Argonaute complex-or miRNA-induced silencing complex (miRISC)-can regulate the translation of their targets in such diverse ways. We demonstrate here a direct interaction between the miRISC and the ribosome by showing that a constituent of the eukaryotic 40S subunit, receptor for activated C-kinase (RACK1), is important for miRNA-mediated gene regulation in animals. In vivo studies demonstrate that RACK1 interacts with components of the miRISC in nematodes and mammals. In both systems, the alteration of RACK1 expression alters miRNA function and impairs the association of the miRNA complex with the translating ribosomes. Our data indicate that RACK1 can contribute to the recruitment of miRISC to the site of translation, and support a post-initiation mode of miRNA-mediated gene repression. © 2011 European Molecular Biology Organization

On The Nature of Variations in the Measured Star Formation Efficiency of Molecular Clouds

Measurements of the star formation efficiency (SFE) of giant molecular clouds (GMCs) in the Milky Way generally show a large scatter, which could be intrinsic or observational. We use magnetohydrodynamic simulations of GMCs (including feedback) to forward-model the relationship between the true GMC SFE and observational proxies. We show that individual GMCs trace broad ranges of observed SFE throughout collapse, star formation, and disruption. Low measured SFEs (<<1%) are "real" but correspond to early stages, the true "per-freefall" SFE where most stars actually form can be much larger. Very high (>>10%) values are often artificially enhanced by rapid gas dispersal. Simulations including stellar feedback reproduce observed GMC-scale SFEs, but simulations without feedback produce 20x larger SFEs. Radiative feedback dominates among mechanisms simulated. An anticorrelation of SFE with cloud mass is shown to be an observational artifact. We also explore individual dense "clumps" within GMCs and show that (with feedback) their bulk properties agree well with observations. Predicted SFEs within the dense clumps are ~2x larger than observed, possibly indicating physics other than feedback from massive (main sequence) stars is needed to regulate their collapse.Comment: Fixed typo in the arXiv abstrac

Measuring the Sources of the Intergalactic Ionizing Flux

We use a wide-field (0.9 square degree) X-ray sample with optical and GALEX ultraviolet observations to measure the contribution of Active Galactic Nuclei (AGNs) to the ionizing flux as a function of redshift. Our analysis shows that the AGN contribution to the metagalactic ionizing background peaks around z=2. The measured values of the ionizing background from the AGNs are lower than previous estimates and confirm that ionization from AGNs is insufficient to maintain the observed ionization of the intergalactic medium (IGM) at z>3. We show that only sources with broad lines in their optical spectra have detectable ionizing flux and that the ionizing flux seen in an AGN is not correlated with its X-ray color. We also use the GALEX observations of the GOODS-N region to place a 2-sigma upper limit of 0.008 on the average ionization fraction fnu(700 A)/fnu(1500 A) for 626 UV selected galaxies in the redshift range z=0.9-1.4. We then use this limit to estimate an upper bound to the galaxy contribution in the redshift range z=0-5. If the z~1.15 ionization fraction is appropriate for higher redshift galaxies, then contributions from the galaxy population are also too low to account for the IGM ionization at the highest redshifts (z>4).Comment: 15 pages, Accepted by The Astrophysical Journa

Unravelling the physics of multiphase AGN winds through emission line tracers

Observations of emission lines in active galactic nuclei (AGNs) often find fast (∼1000 km s−1) outflows extending to kiloparsec scales, seen in ionized, neutral atomic and molecular gas. In this work we present radiative transfer calculations of emission lines in hydrodynamic simulations of AGN outflows driven by a hot wind bubble, including non-equilibrium chemistry, to explore how these lines trace the physical properties of the multiphase outflow. We find that the hot bubble compresses the line-emitting gas, resulting in higher pressures than in the ambient interstellar medium or that would be produced by the AGN radiation pressure. This implies that observed emission line ratios such as [O IV]25μm / [Ne II]12μm⁠, [Ne V]14μm / [Ne II]12μm⁠, and [N III]57μm / [N II]122μm constrain the presence of the bubble and hence the outflow driving mechanism. However, the line-emitting gas is under-pressurized compared to the hot bubble itself, and much of the line emission arises from gas that is out of pressure, thermal and/or chemical equilibrium. Our results thus suggest that assuming equilibrium conditions, as commonly done in AGN line emission models, is not justified if a hot wind bubble is present. We also find that ≳50 per cent of the mass outflow rate, momentum flux, and kinetic energy flux of the outflow are traced by lines such as [N II]122μm and [Ne III]15μm (produced in the 104K phase) and [C II]158μm (produced in the transition from 104K to 100 K)

Insect herbivory (Choristoneura fumiferana, Tortricidea) underlies tree population structure (Picea glauca, Pinaceae)

Variation in insect herbivory can lead to population structure in plant hosts as indicated by defence traits. In annual herbaceous, defence traits may vary between geographic areas but evidence of such patterns is lacking for long-lived species. This may result from the variety of selection pressures from herbivores, long distance gene flow, genome properties, and lack of research. We investigated the antagonistic interaction between white spruce (Picea glauca) and spruce budworm (SBW, Choristoneura fumiferana) the most devastating forest insect of eastern North America in common garden experiments. White spruces that are able to resist SBW attack were reported to accumulate the acetophenones piceol and pungenol constitutively in their foliage. We show that levels of these acetophenones and transcripts of the gene responsible for their release is highly heritable and that their accumulation is synchronized with the most devastating stage of SBW. Piceol and pungenol concentrations negatively correlate with rate of development in female SBW and follow a non-random geographic variation pattern that is partially explained by historical damage from SBW and temperature. Our results show that accumulation of acetophenones is an efficient resistance mechanism against SBW in white spruce and that insects can affect population structure of a long-lived plant

A Definitive Survey for Lyman Limit Systems at z~3.5 with the Sloan Digital Sky Survey

We perform a semi-automated survey for tau>=2 Lyman Limit systems (LLSs) in quasar spectra from the Sloan Digital Sky Survey, Data Release 7. From a starting sample of 2473 quasars with zem=3.6-4.4, we analyze 469 spectra meeting strict seletion criteria for a total redshift path Dz=93.8 and identify 192 intervening systems at z>3.3. The incidence of tau>=2 LLSs per unit redshift, l(z), is well described by a single-power law at these redshifts: l(z) = C_LLS [(1+z)/(1+z_*)]^gamma, with z_*=3.7, C_LLS = 1.9+/-0.2, and gamma = 5.2+/-1.5 (68% c.l.). These values are systematically lower than previous estimates (especially at z<4) but are consistent with recent measurements of the mean free path to ionizing radiation. Extrapolations of this power-law to z=0 are inconsistent with previous estimations of l(z) at z<1 and suggest a break at z~2, similar to that observed for the Lya forest. Our results also indicate that the systems giving rise to LLS absorption decrease by ~50% in comoving number density and/or physical size from z=4 to 3.3, perhaps due to an enhanced extragalactic ultraviolet background. The observations place an integral constraint on the HI frequency distribution f(N_HI,X) and indicate that the power-law slope beta= dln[f(N,X)]/dln[N] is likely shallower than beta = -1 at N_HI=10^18 cm^-2. Including other constraints on f(N_HI,X) from the literature, we infer that beta is steeper than beta = -1.7 at N_HI~10^15 cm^-2, implying at least two inflections in f(N_HI,X). We also perform a survey for proximate LLSs (PLLSs) and find that l(z)_PLLS is systematically lower ~25% than intervening systems. Finally, we estimate that systematic effects impose an uncertainty of 10-20% in the l(z) measurements; these effects may limit the precision of all future surveys.Comment: 26 pages, 17 figures (most in color). Submitted to Ap