Identification of Synaptic Targets of Drosophila Pumilio

Drosophila Pumilio (Pum) protein is a translational regulator involved in embryonic patterning and germline development. Recent findings demonstrate that Pum also plays an important role in the nervous system, both at the neuromuscular junction (NMJ) and in long-term memory formation. In neurons, Pum appears to play a role in homeostatic control of excitability via down regulation of para, a voltage gated sodium channel, and may more generally modulate local protein synthesis in neurons via translational repression of eIF-4E. Aside from these, the biologically relevant targets of Pum in the nervous system remain largely unknown. We hypothesized that Pum might play a role in regulating the local translation underlying synapse-specific modifications during memory formation. To identify relevant translational targets, we used an informatics approach to predict Pum targets among mRNAs whose products have synaptic localization. We then used both in vitro binding and two in vivo assays to functionally confirm the fidelity of this informatics screening method. We find that Pum strongly and specifically binds to RNA sequences in the 3′UTR of four of the predicted target genes, demonstrating the validity of our method. We then demonstrate that one of these predicted target sequences, in the 3′UTR of discs large (dlg1), the Drosophila PSD95 ortholog, can functionally substitute for a canonical NRE (Nanos response element) in vivo in a heterologous functional assay. Finally, we show that the endogenous dlg1 mRNA can be regulated by Pumilio in a neuronal context, the adult mushroom bodies (MB), which is an anatomical site of memory storage

Architects of the genome: CHD dysfunction in cancer, developmental disorders and neurological syndromes

Chromatin is vital to normal cells, and its deregulation contributes to a spectrum of human ailments. An emerging concept is that aberrant chromatin regulation culminates in gene expression programs that set the stage for the seemingly diverse pathologies of cancer, developmental disorders and neurological syndromes. However, the mechanisms responsible for such common etiology have been elusive. Recent evidence has implicated lesions affecting chromatin-remodeling proteins in cancer, developmental disorders and neurological syndromes, suggesting a common source for these different pathologies. Here, we focus on the chromodomain helicase DNA binding chromatin-remodeling family and the recent evidence for its deregulation in diverse pathological conditions, providing a new perspective on the underlying mechanisms and their implications for these prevalent human diseases

Query Translation Optimization and Mathematical Modeling for English-Chinese Cross-Language Information Retrieval

The basic theory of the neural network model used in this research is particle swarm optimization, applied to English-Chinese translation retrieval and model optimization. The decoded form obtains the translation task sequence. This topic uses TensorFlow to complete the construction of the translation system. This research solves the typical lack of semantic information in the hierarchical model. The demonstration of examples shows that the neural network model based on particle swarm optimization can significantly improve the quality of machine translation

Gamma Neurons Mediate Dopaminergic Input during Aversive Olfactory Memory Formation in Drosophila

Summary Mushroom body (MB)-dependent olfactory learning in Drosophila provides a powerful model to investigate memory mechanisms. MBs integrate olfactory conditioned stimulus (CS) inputs with neuromodulatory reinforcement (unconditioned stimuli, US) [1, 2], which for aversive learning is thought to rely on dopaminergic (DA) signaling [3–6] to DopR, a D1-like dopamine receptor expressed in MBs [7, 8]. A wealth of evidence suggests the conclusion that parallel and independent signaling occurs downstream of DopR within two MB neuron cell types, with each supporting half of memory performance. For instance, expression of the Rutabaga (Rut) adenylyl cyclase in γ neurons is sufficient to restore normal learning to rut mutants [9], whereas expression of Neurofibromatosis 1 (NF1) in α/β neurons is sufficient to rescue NF1 mutants [10, 11]. DopR mutations are the only case where memory performance is fully eliminated [7], consistent with the hypothesis that DopR receives the US inputs for both γ and α/β lobe traces. We demonstrate, however, that DopR expression in γ neurons is sufficient to fully support short- and long-term memory. We argue that DA-mediated CS-US association is formed in γ neurons followed by communication between γ and α/β neurons to drive consolidation

TDP-43 binding to TEs is selectively lost in FTLD patients.

<p>(<b>A</b>) In the human CLIP-seq data from FTLD versus healthy control, 38 repeat elements showed significant (<i>p</i>-value< = 1e-5 and fold changes> = 2) differential binding. Log2 fold binding differences are shown for significantly enriched/depleted elements. (<b>B,C,D</b>) Peaks are shown in genome browser for one RefGene control (<b>B</b>) and two differentially targeted TEs (<b>C,D</b>) in Healthy (<b>top</b>) versus FTLD (<b>bottom</b>). (<b>E</b>) Enrichment for the UGUGU motif relative to its prevalence in the genome is shown across a 51-nt window surrounding binding sites (−25 nt, 25 nt). Healthy samples (<b>Blue</b>) show similar enrichment for the UGUGU pentamer motif among RefGene (<b>solid</b>) and repeat (<b>dashed</b>) sequences (RefGene/repeat motif enrichment ratio ≈1.3). In contrast, motif enrichment in FTLD samples (<b>Red</b>) is significantly reduced among repeat (<b>dashed</b>) annotations relative to RefGene (<b>solid</b>; <i>p</i>-value< = 0.01; RefGene/repeat motif enrichment ratio ≈2.0).</p

TDP-43 binds broadly to transposable element (TE)-derived transcripts.

<p>Magnitude (log2-fold) of enrichments (<b>up</b>) or depletions (<b>down</b>) are shown (<b>A</b>, rat; <b>B</b>, mouse) for significantly bound repeat elements grouped by class. <b>MULTI</b> method (see text) was used for <b>A</b> and <b>B</b>. (<b>C</b>) The majority of rat TE targets identified with <b>MULTI</b> also are identified (<b>Left Panel, Rat</b>) when analysis is restricted to reads that map uniquely (<b>UNIQ</b>) or when both uniquely mapped and multi-mapped reads that map to the same TE were included (<b>UNIQ+SameEle</b>). These conclusions also hold for TE targets whose binding is reduced in FTLD samples from human tissue relative to healthy controls (<b>Left panel, Human</b>). Most rat TE targets and differentially bound human TE targets identified from uniquely mapped reads are intergenic (<b>Right panel</b>). (<b>D</b>) For TDP-43, peaks (UNIQ+SameEle) over TE targets are tall and sharp with mean peak height of 158 counts/peak. In contrast, peak heights are lower for FUS (mean peak height of 17).</p

Concordance between mis-regulated TE transcripts upon TDP-43 manipulation and TDP-43 bound TE transcripts.

<p>(A,B) Over-expression <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044099#pone.0044099-Shan1" target="_blank">[20]</a> of TDP-43 in transgenic mice and depletion <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044099#pone.0044099-Polymenidou1" target="_blank">[19]</a> of TDP-43 in mouse striatum each result in elevated expression of many TE derived transcripts. The majority of over-expressed TEs also were detected (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044099#pone.0044099.s004" target="_blank">Table S3</a>) as binding targets by CLIP-seq (RED). A few showed elevated expression but were not detected as binding targets (BLUE).</p