Event Identification as a Decision Process with Non-linear Representation of Text

We propose scale-free Identifier Network(sfIN), a novel model for event identification in documents. In general, sfIN first encodes a document into multi-scale memory stacks, then extracts special events via conducting multi-scale actions, which can be considered as a special type of sequence labelling. The design of large scale actions makes it more efficient processing a long document. The whole model is trained with both supervised learning and reinforcement learning.Comment: 8 pages, 8 figure

Additional file 9: of Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain

RNA-seq of N2a WT undifferentiated versus WT differentiated N2a. (XLSX 5557 kb

Light induces Rh1 accumulation in ppr mutant PRs.

<p>(A) Western blots of proteins regulating phototransduction. Protein was extracted from heads of flies containing control or <i>ppr</i>^<i>A</i> mutant eyes. (B–C) TEM of a single PR from 2–3-d-old, dark-reared control or <i>ppr</i>^<i>A</i> eye clones. (D–G) Whole mount Rh1 (red) immunostaining in control (D, F) and <i>ppr</i>^<i>A</i> mutant PR (E, G). Rhabdomeres are marked by Phalloidin/Actin (green). Flies used in this experiment were 3–4 d old and raised in the dark (D, E) or exposed to ~30 h of light (F, G). (H–K) Arr2::GFP (green or grey) levels in rhabdomeres of <i>ppr</i>^<i>A</i> mosaic retina. RFP (red) marks wild-type PRs (-/+) and yellow dotted lines encircle <i>ppr</i>^<i>A</i> mutant PRs (-/-, lacking RFP). Rhabdomeres are costained with Phalloidin/Actin (blue). Flies were raised in constant dark and dissected and fixed under dim red light. Prior to fixation, flies were kept in dark (H) or blue light (I) for 1.5 min, allowing Arr2::GFP to translocate to rhabdomeres. Alternatively, flies were kept in blue light for 30 min and then shifted to orange light for 60 min to assess release of Arr2::GFP from rhabdomeres (J). (K) Quantification of the difference in green fluorescence intensity between mosaic ommatidia of <i>ppr</i> and wild-type rhabdomeres. Error bars represent ± SEM; statistical significance was determined using a two-tailed Student’s <i>t</i> test (<i>p</i>-values: * <0.05, ***<0.001).</p

Light-induced ATP synthesis is reduced in <i>ppr</i> mutant eyes.

<p>(A) Relative mtRNA levels, normalized to precursor RNA transcribed from the heavy strand (+) of the mitochondrial genome, in control and <i>ppr</i>^<i>A</i> third instar larvae. (B) Relative mtDNA content, normalized to nuclear DNA, in control and <i>ppr</i>^<i>A</i> third instar larvae. (C) Relative mtRNA levels, normalized to nuclear RNA RP49. (D) Activities of mitochondrial electron transport chain (ETC) protein complexes (CI, CII, CIII, CIV) and Citrate synthase (CS) from third instar larval extracts. Genotypes shown are control, <i>ppr</i>^<i>A</i> and <i>ppr</i>^<i>A</i>; genomic rescue (CH322-75O21). ETC complex activity was normalized to CS, and data are expressed as percentage of the activity detected in controls. (E) O_<b>2</b> consumption assayed by polarography. O_<b>2</b> consumption was measured from isolated third instar larvae-derived mitochondria in the presence of CI-specific substrates. State III is the ADP-stimulated O_<b>2</b> consumption rate; State IV represents the ADP-limited O_<b>2</b> consumption rate; RCR is the Respiratory Control Ratio (state III rate / state IV rate). (F–G) Relative ATP levels from control and <i>ppr</i>^<i>A</i> third instar larval extracts (F) and adult eyes (exposed to 1 h light, 1,800 Lux) (G). (H) Relative change in ATP levels in adult heads upon 1 h exposure to light (1,800 Lux). In A–H, error bars represent mean ± standard deviation (SD); statistical significance was determined using a two-tailed Student’s <i>t</i> test (<i>p</i>-values: *** < 0.001, ** < 0.01, * <0.05).</p

<i>ppr</i> is required to maintain PR depolarization upon repetitive stimulation.

<p>(A) ERG traces during repetitive light stimuli (1 sec light and 1.5 sec dark) recorded from eye clones of control, <i>ppr</i>^<i>A</i> and <i>ppr</i>^<i>E</i> (left). Quantification of the change in ERG amplitude, relative to the amplitude of the response to the initial light stimulus, is shown on the right. Error bars represent ± SEM. (B) Recovery time of ERG amplitude (light response) in control, <i>ppr</i>^<i>A</i><i>and ppr</i>^<i>E</i> eye clones. Following 30 sec of light exposure (~1,700 Lux), ERG amplitudes were measured after 5, 30, 60, 90 or 120 sec of recovery in dark. ERG traces after 5 sec and 2 min are shown (middle), and quantification of the relative ERG amplitude is shown on the right. Error bars represent ± SEM; NS (two-tailed Student’s <i>t</i> test not significant). (C) Schematic presentation of the phototransduction cascade and the mechanism of Rh1 recycling and endocytosis. When exposed to blue light, Rh1 is converted to meta-Rh1 (MRh1). Through a G-protein cascade, MRh1 activates the TRP and TRPL channels, leading to a Ca²⁺ influx and PR depolarization. MRh1 is quickly phosphorylated by GPRK1 and bound by Arrestin2 (Arr2), leading to the inactivation of MRh1 [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002197#pbio.1002197.ref030" target="_blank">30</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002197#pbio.1002197.ref031" target="_blank">31</a>]. Subsequently, MRh1 is converted to Rh1 by orange light. Rh1 is recycled through a Ca²⁺-dependent pathway leading to Arr2 released from Rh1 [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002197#pbio.1002197.ref032" target="_blank">32</a>–<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002197#pbio.1002197.ref034" target="_blank">34</a>]. A fraction of Rh1 forms a stable complex with Arr2 when exposed to light. This complex is endocytosed and degraded by the endolysosomal system (Reviewed in [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002197#pbio.1002197.ref015" target="_blank">15</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002197#pbio.1002197.ref017" target="_blank">17</a>]).</p

PR degeneration is not induced by oxidative stress in <i>ppr</i> mutants.

<p>(A–C) Detection of ROS levels by DHE (red) staining in <i>ppr</i> mutant clones in eye imaginal discs. Mutant clones, encircled by dotted lines, are marked by loss of GFP (green). (B, C) Detection of ROS levels by DHE staining (red) in control (B) and <i>ppr</i> mutant (C) eyes from adult flies exposed to 24 h light (1,800 Lux). (D) Aconitase activity, which is negatively correlated to ROS levels because of its sensitivity to oxidation, is measured in mitochondrial extracts from third instar larvae (Native) or upon treatment with a reducing agent (Reactivated) to control for variations in the total amount of enzyme. Error bars represent ± SD. (E) Relative ERG amplitude from retinas of control, <i>ppr</i>^<i>A</i> and <i>ppr</i>^<i>A</i> expressing hSOD1 in R1-R6 using Rh1-Gal4. All flies carried Rh1-GAL4 in this experiment. Flies were raised in constant light for seven days. Error bars represent ± SEM; NS (two-tailed Student’s <i>t</i> test not significant).</p

Systematic Profiling of Poly(A)+ Transcripts Modulated by Core 3’ End Processing and Splicing Factors Reveals Regulatory Rules of Alternative Cleavage and Polyadenylation

<div><p>Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3’ untranslated regions (3’UTRs) and/or coding sequences. How core cleavage/polyadenylation (C/P) factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3’UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A) sites (pAs), CFI-25/68, PABPN1 and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI-25/68 or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly inhibiting C/P events in introns near the 5’ end of gene and U2 suppressing those in introns with features for efficient splicing. Furthermore, PABPN1 inhibits expression of transcripts with pAs near the transcription start site (TSS), a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results support an APA code where an APA event in a given cellular context is regulated by a number of parameters, including relative location to the TSS, splicing context, distance between competing pAs, surrounding cis elements and concentrations of core C/P factors.</p></div

CDS-APA.

<p><b>(A)</b> Schematic of CDS-APA. <b>(B)</b> Normalized number of genes with regulated CDS-APA as examined by GAAP. Red and blue bars represent genes with upregulated CDS-APA isoforms (UP) and downregulated isoforms (DN), respectively. All CDS-APA isoforms were combined and compared to all 3’-most exon isoforms combined by SAAP. Q-value < 0.05 (SAAP) was used to select genes with significant CDS-APA regulation. Error bars are standard deviation based on 20 times of bootstrapping. Samples are sorted by the total number of genes with CDS-APA changes. Data for C2C12 differentiation are shown at the bottom for comparison. Log2(UP/DN) is log2(ratio) of the number of UP genes to the number of DN genes. <b>(C)</b> Normalized expression changes of intronic pA isoforms in several samples. Introns were divided into first (+1), second (+2), last (-1), and second to last (-2), and middle (between +2 and -2 introns) groups. Only genes with ≥4 introns and only pA isoforms with ≥10 PASS reads in two comparing samples combined were analyzed. Expression changes are log2(ratio) of PASS reads in test sample vs. control sample. Values for five intron groups were normalized by mean-centering to reveal bias of intron location. Error bars are standard error of mean. <b>(D)</b> Features of introns containing pAs of upregulated isoforms, including intron size, and 5’ and 3’ splice site (SS) strengths. Numbers are significance score (SS), which was calculated by –log₁₀(<i>P</i>)*S, where <i>P</i> was based on the Wilcoxon rank sum test comparing an intron set of interest with a background set, and S = 1 when the intron set of interest had a larger median value (intron size, 5’SS strength or 3’SS strength) than the background set or -1 otherwise. The background set was derived from introns that contained detectable pA isoform expression in control samples. Introns were divided into five groups based on location, as in (C). The SS data are colored according to the color scheme shown in the graph.</p

Mutations in <i>ppr</i> cause PR degeneration.

<p>(A) ERG traces from eye clones of control (<i>y w</i> FRT 19A), <i>ppr</i>^<i>A</i>, <i>ppr</i>^<i>E</i>, and <i>ppr</i>^<i>A</i>-carrying genomic transgene (CH322-75O21)-containing wild-type <i>ppr</i> (<i>ppr</i>^<i>A</i><i>Rescue</i>). Arrow and arrowhead indicate “on” and “off” transient respectively. Dashed line indicates the amplitude. Top: upon eclosion, flies were raised in dark for 2–3 d, after which ERGs were recorded. Bottom: flies were reared for 5 wk in a 12 h light/12 h dark cycle. (B) Table presenting all identified <i>ppr</i> alleles, their lethal stage, and molecular lesion. Lethality in these alleles is rescued by a genomic copy of <i>ppr</i> or ubiquitous expression of <i>ppr</i> cDNA. (C) Genomic location of the <i>ppr</i> (<i>CG14786</i>) gene, displaying the position of the molecular lesions associated with the different alleles. The genomic rescue construct spans a region from 0.3 kb upstream to 1.3 kb downstream of the <i>ppr</i> coding region. The genomic rescue-Green Fluorescent Protein (GFP) construct contains a GFP tag at the C-terminus of <i>ppr</i>. (D) The Ppr protein has 27% identity (I) and 44% similarity (S) to human LRPPRC. (E) The Ppr protein’s predicted mitochondrial localization signal and PPR repeats are shown. (F) Colocalization of the GFP-tagged Ppr protein (green) with mitochondrial complex V (ATP5A antibody, red) in larval muscle.</p

Cis elements associated with regulated pAs.

<p><b>(A)</b> Schematic showing the analysis method. As indicated, pAs were divided into proximal and distal pA groups, and pAs of regulated isoforms were compared only with other pAs in the same group. As such, proximal pAs were only compared with proximal pAs and so were distal pAs. pAs of upregulated and downregulated isoforms were analyzed separately. Only data of nuclear RNA samples were used for analysis, because they were expected to have less post-transcriptional effects than total RNA samples. <b>(B)</b> Number of 4-mers with significantly biased frequency of occurrence (<i>P</i> < 0.001, Fisher’s exact test) near regulated pAs. Regulated pAs were those with q-value < 0.05 (SAAP). Three regions around the pA were analyzed, including -100 to -41 nt, -40 to -1 nt and +1 to +100 nt. Data for all 4-mers and top 6-mers are shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005166#pgen.1005166.s018" target="_blank">S5 Table</a> and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005166#pgen.1005166.s019" target="_blank">S6 Table</a>, respectively. <b>(C)</b> Significant 4-mers enriched for or depleted from pAs regulated by siCFI-68. Only top five 4-mers for the regions with ≥5 significant 4-mers are shown. Numbers are significance score (SS), which was calculated by –log₁₀(<i>P</i>)*S, where <i>P</i> was based on the Fisher’s exact test and S = 1 for enrichment and -1 for depletion. <b>(D)</b> As in (C), significant 4-mers enriched for or depleted from pAs regulated by siFip1. <b>(E)</b> Regulation of different types of pAs by siFip1, as shown by Cumulative Distribution Function (CDF) curves of RED scores. Genes were divided into four groups based on i) distance between proximal and distal pAs (<120 nt or ≥120 nt), and 2) whether or not there was AAUAAA within 100 nt downstream of the proximal pA. These groups are also illustrated in the graph. The number of genes and the median RED score of each group are shown in a table. The differences between groups are indicated by p-values (Kolmogorov–Smirnov test).</p