HST ACS images of the young SN remnant Cas A are used to explore the expansion and spatial distribution of its highest velocity debris. Proper motions of over 1800 outlying ejecta knots are reported. The distribution of transverse expansion velocities for these knots shows a striking bipolar asymmetry with the highest velocity knots confined to nearly opposing northeast and southwest `jets'. The jets appear kinematically and chemically distinct with respect to the remnant's highest velocity debris seen in other directions. Significant gaps in the spatial distribution of outlying ejecta lie in directions which are approximately perpendicular to the jets. Extrapolations of 9 month proper motions for all outer ejecta knots and a subsample of 72 bright and compact knots suggest explosion dates (assuming no knot deceleration) of 1662 +/- 27 and 1672 +/- 18, respectively. We find some evidence for non-uniform deceleration in different directions with knots located along the northwestern limb among the least decelerated ejecta suggesting a convergence date of 1681 +/-19. The remnant's central X-ray point source lies some $7''$ to the southeast of the estimated expansion center (PA = 169 deg) indicating a projected motion of ~350 km/s toward the middle of the broad southern outer ejecta knot gap.Comment: 13 pages, 5 figures, ApJ, in pres

Summary Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nrf2/Nfe2l2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine EGFR signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

MicroRNAs (miRNAs) and transcription factors (TFs) are primary metazoan gene regulators. Whereas much attention has focused on finding the targets of both miRNAs and TFs, the transcriptional networks that regulate miRNA expression remain largely unexplored. Here, we present the first genome-scale Caenorhabditis elegans miRNA regulatory network that contains experimentally mapped transcriptional TF → miRNA interactions, as well as computationally predicted post-transcriptional miRNA → TF interactions. We find that this integrated miRNA network contains 23 miRNA ↔ TF composite feedback loops in which a TF that controls a miRNA is itself regulated by that same miRNA. By rigorous network randomizations, we show that such loops occur more frequently than expected by chance and, hence, constitute a genuine network motif. Interestingly, miRNAs and TFs in such loops are heavily regulated and regulate many targets. This "high flux capacity" suggests that loops provide a mechanism of high information flow for the coordinate and adaptable control of miRNA and TF target regulons.[Keywords: MicroRNA; transcription factor; regulatory network; network motif; feedback; C. elegans] Supplemental material is available at http://www.genesdev.org.

MIWI catalytic activity is required for spermatogenesis, indicating that piRNA-guided cleavage is critical for germ cell development. To identify meiotic piRNA targets, we augmented the mouse piRNA repertoire by introducing a human meiotic piRNA cluster. This triggered a spermatogenesis defect by inappropriately targeting the piRNA machinery to mouse mRNAs essential for germ cell development. Analysis of such de novo targets revealed a signature for pachytene piRNA target recognition. This enabled identification of both transposable elements and meiotically expressed protein-coding genes as targets of native piRNAs. Cleavage of genic targets began at the pachytene stage and resulted in progressive repression through meiosis, driven at least in part via the ping-pong cycle. Our data support the idea that meiotic piRNA populations must be strongly selected to enable successful spermatogenesis, both driving the response away from essential genes and directing the pathway toward mRNA targets that are regulated by small RNAs in meiotic cells.

Target prediction for animal microRNAs has been hindered by the small number of verified targets available for evaluating the accuracy of predicted microRNA:target interactions. Recently, a dataset of 3404 microRNA-associated mRNA transcripts was identified by immuno-precipitation (IP) of the RNA-induced silencing complex (RISC) components, AIN-1 and AIN-2. Analysis of this dataset reveals enrichment for defining characteristics of functional microRNA target interactions, including structural accessibility of target sequences, the total free energy of microRNA:target hybridization, and the topology of base-pairing to the 5’ seed region of the microRNA. These enriched characteristics form the basis for a quantitative microRNA target prediction method, mirWIP (microRNA targets by Weighting IP dataset parameters), that optimizes sensitivity to verified microRNA:target interactions and specificity to the AIN-IP dataset. The mirWIP method can capture all of the known conserved microRNA:mRNA target relationships in C. elegans at a lower false positive rate than the current standard methods.

SN 1885 was a probable subluminous Type Ia supernova which occurred in the bulge of the Andromeda galaxy, M31, at a projected location 16 ′′ from the nucleus. Here we present and analyze Hubble Space Telescope images of the SN 1885 remnant seen in absorption against the M31 bulge via the resonance lines of Ca I, Ca II, Fe I, and Fe II. Viewed in Ca II H & K line absorption, the remnant appears as a nearly black circular spot with an outermost angular radius of 0. ′′ 40 ± 0. ′′ 025, implying a maximum linear radius of 1.52 ± 0.15 pc at M31's estimated distance of 785 ± 30 kpc and hence a 120 yr average expansion velocity of 12,400 ± 1400 km s −1 . The strongest Ca II absorption is organized in a broken ring structure with a radius of 0. ′′ 2 (= 6000 km s −1 ) with several apparent absorption 'clumps' of an angular size around that of the image pixel scale of 0. ′′ 05 (= 1500 km s −1 ). Ca I and Fe I absorption structures appear similar except for a small Fe I absorption peak displaced 0. ′′ 1 off-center of the Ca II structure by a projected velocity of about 3000 km s −1 .Analyses of these images using off-center, delayed-detonation models suggest a low 56 Ni production similar to the subluminous SN Ia explosion of SN 1986G. The strongly lopsided images of of Ca I and Fe I can be understood as resulting from an aspherical chemical distribution, with the best agreement found using an off-center model viewed from an inclination of ∼ 60 • . The detection of small scale Ca II clumps is the first direct evidence for some instabilities and the existence of a deflagration phase in SNe Ia or, alternatively, mixing induced by radioactive decay of 56 Ni over time scales of seconds or days. However, the degree of mixing allowed by the observed images is much smaller than current 3D calculations for Rayleigh-Taylor dominated deflagration fronts. Moreover, the images require a central region of no or little Ca but iron group elements indicative for burning under sufficiently high densities for electron capture taking place, i.e., burning prior to a significant pre-expansion of the WD. Using time-dependent ionization calculations, we show that the presence today of neutral ions in this 120 yr old remnant can be understood as ejecta self-shielding from the UV radiation in the M31 bulge.

Hubble Space Telescope images of the core-collapse supernova remnant Cassiopeia A are used to identify highvelocity knots of ejecta located outside the remnant's main emission shell of expanding debris. These ejecta fragments are found near or ahead of the remnant's forward shock front and mostly lie from 120 00 to 300 00 in radial distance from the remnant's center of expansion. Filter flux ratios when correlated with published spectra show that these knots can be divided into three emission classes: ( 1) knots dominated by [N ii] kk6548, 6583 emissions, (2) knots dominated by [O ii] kk7319, 7330 emissions, and (3) knots displaying filter flux ratios suggestive of [S ii], [O ii], and [Ar iii] k7135 emission line strengths similar to the ''fast-moving knots'' ( FMKs) found in the remnant's bright main shell. Of 1825 knots identified, 444 are strong [N ii] emission knots, 192 are strong [O ii] emission knots, and 1189 are FMK-like knots.In terms of location around the remnant, 972, 207, and 646 knots are found in the remnant's northeast jet, southwest jet, and non-jet regions, respectively. Assuming a distance of 3.4 kpc, derived knot transverse velocities based on proper motion measurements spanning a 9 month interval indicate maximum transverse expansion velocities for these three knot classes of 14,500, 13,500, and 11,500 km s À1 , respectively. We present a catalog of these outlying ejecta clumps comprising finding charts, epoch 2004.2 knot positions, proper motions, photometric filter fluxes, and estimated knot emission type, along with cross-references to previous knot identifications and data. This compilation represents a nearly tenfold increase in the number of outlying, high-velocity ejecta knots identified around the Cassiopeia A remnant.

Maize leafbladeless1 (lbl1) encodes a key component in the trans-acting short-interfering RNA (ta-siRNA) biogenesis pathway. Correlated with a great diversity in ta-siRNAs and the targets they regulate, the phenotypes conditioned by mutants perturbing this small RNA pathway vary extensively across species. Mutations in lbl1 result in severe developmental defects, giving rise to plants with radial, abaxialized leaves. To investigate the basis for this phenotype, we compared the small RNA content between wild-type and lbl1 seedling apices. We show that LBL1 affects the accumulation of small RNAs in all major classes, and reveal unexpected crosstalk between ta-siRNA biogenesis and other small RNA pathways regulating transposons. Interestingly, in contrast to data from other plant species, we found no evidence for the existence of phased siRNAs generated via the one-hit model. Our analysis identified nine TAS loci, all belonging to the conserved TAS3 family. Information from RNA deep sequencing and PARE analyses identified the tasiR-ARFs as the major functional ta-siRNAs in the maize vegetative apex where they regulate expression of AUXIN RESPONSE FACTOR3 (ARF3) homologs. Plants expressing a tasiR-ARF insensitive arf3a transgene recapitulate the phenotype of lbl1, providing direct evidence that deregulation of ARF3 transcription factors underlies the developmental defects of maize ta-siRNA biogenesis mutants. The phenotypes of Arabidopsis and Medicago ta-siRNA mutants, while strikingly different, likewise result from misexpression of the tasiR-ARF target ARF3. Our data indicate that diversity in TAS pathways and their targets cannot fully account for the phenotypic differences conditioned by ta-siRNA biogenesis mutants across plant species. Instead, we propose that divergence in the gene networks downstream of the ARF3 transcription factors or the spatiotemporal pattern during leaf development in which these proteins act constitute key factors underlying the distinct contributions of the ta-siRNA pathway to development in maize, Arabidopsis, and possibly other plant species as well.