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.
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