Lysophosphatidic acid (LPA) stimulates Rho GTPase and its effector, the formin mDia, to capture and stabilize microtubules in fibroblasts. We investigated whether mammalian EB1 and adenomatous polyposis coli (APC) function downstream of Rho-mDia in microtubule stabilization. A carboxy-terminal APC-binding fragment of EB1 (EB1-C) functioned as a dominant-negative inhibitor of microtubule stabilization induced by LPA or active mDia. Knockdown of EB1 with small interfering RNAs also prevented microtubule stabilization. Expression of either full-length EB1 or APC, but not an APC-binding mutant of EB1, was sufficient to stabilize microtubules. Binding and localization studies showed that EB1, APC and mDia may form a complex at stable microtubule ends. Furthermore, EB1-C, but not an APC-binding mutant, inhibited fibroblast migration in an in vitro wounding assay. These results show an evolutionarily conserved pathway for microtubule capture, and suggest that mDia functions as a scaffold protein for EB1 and APC to stabilize microtubules and promote cell migration.

Abstract-Predicting user responses, such as clicks and conversions, is of great importance and has found its usage in many Web applications including recommender systems, web search and online advertising. The data in those applications is mostly categorical and contains multiple fields; a typical representation is to transform it into a high-dimensional sparse binary feature representation via one-hot encoding. Facing with the extreme sparsity, traditional models may limit their capacity of mining shallow patterns from the data, i.e. low-order feature combinations. Deep models like deep neural networks, on the other hand, cannot be directly applied for the high-dimensional input because of the huge feature space. In this paper, we propose a Product-based Neural Networks (PNN) with an embedding layer to learn a distributed representation of the categorical data, a product layer to capture interactive patterns between interfield categories, and further fully connected layers to explore high-order feature interactions. Our experimental results on two large-scale real-world ad click datasets demonstrate that PNNs consistently outperform the state-of-the-art models on various metrics.

A remarkable feature of development is its reproducibility, the ability to correct embryo-to-embryo variations and instruct precise patterning. In Drosophila, embryonic patterning along the anterior-posterior axis is controlled by the morphogen gradient Bicoid (Bcd). In this report, we describe quantitative studies of the native Bcd gradient and its target Hunchback (Hb). We show that the native Bcd gradient is highly reproducible and is itself scaled with embryo length. While a precise Bcd gradient is necessary for precise Hb expression, it still has positional errors greater than Hb expression. We describe analyses further probing mechanisms for Bcd gradient scaling and correction of its residual positional errors. Our results suggest a simple model of a robust Bcd gradient sufficient to achieve scaled and precise activation of its targets. The robustness of this gradient is conferred by its intrinsic properties of "self-correcting" the inevitable input variations to achieve a precise and reproducible output.

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The aim of the current study was to identify enteric 5-HT(4) splice variants, locate enteric 5-HT(4) receptors, determine the relationship, if any, of the 5-HT(4) receptor to 5-HT(1P) activity, and to ascertain the function of 5-HT(4) receptors in enteric neurophysiology. 5-HT(4a), 5-HT(4b), 5-HT(4e), and 5-HT(4f) isoforms were found in mouse brain and gut. The ratio of 5-HT(4) expression to that of the neural marker, synaptophysin, was higher in gut than in brain but was similar in small and large intestines. Submucosal 5-HT(4) expression was higher than myenteric. Although transcripts encoding 5-HT(4a) and 5-HT(4b) isoforms were more abundant, those encoding 5-HT(4e) and 5-HT(4f) were myenteric plexus specific. In situ hybridization revealed the presence of transcripts encoding 5-HT(4) receptors in subsets of enteric neurons, interstitial cells of Cajal, and smooth muscle cells. IgY antibodies to mouse 5-HT(4) receptors were raised, affinity purified, and characterized. Nerve fibers in the circular muscle and the neuropil in ganglia of both plexuses were highly 5-HT(4) immunoreactive, although only a small subset of neurons contained 5-HT(4) immunoreactivity. No 5-HT(4)-immunoreactive nerves were detected in the mucosa. 5-HT and 5-HT(1P) agonists evoked a G protein-mediated long-lasting inward current that was neither mimicked by 5-HT(4) agonists nor blocked by 5-HT(4) antagonists. In contrast, the 5-HT(4) agonists renzapride and tegaserod increased the amplitudes of nicotinic evoked excitatory postsynaptic currents. Enteric neuronal 5-HT(4) receptors thus are presynaptic and probably exert their prokinetic effects by strengthening excitatory neurotransmission.

We report the discovery of a class of abundant circular noncoding RNAs that are produced during metazoan tRNA splicing. These transcripts, termed tRNA intronic circular (tric)RNAs, are conserved features of animal transcriptomes. Biogenesis of tricRNAs requires anciently conserved tRNA sequence motifs and processing enzymes, and their expression is regulated in an agedependent and tissue-specific manner. Furthermore, we exploited this biogenesis pathway to develop an in vivo expression system for generating "designer" circular RNAs in human cells. Reporter constructs expressing RNA aptamers such as Spinach and Broccoli can be used to follow the transcription and subcellular localization of tricRNAs in living cells. Owing to the superior stability of circular vs. linear RNA isoforms, this expression system has a wide range of potential applications, from basic research to pharmaceutical science.

Summary The Spinal Muscular Atrophy (SMA) protein, survival motor neuron (SMN), functions in the biogenesis of small nuclear ribonucleoproteins (snRNPs). SMN has also been implicated in tissue-specific functions, however, it remains unclear which of these is important for the etiology of SMA. Smn null mutants are larval lethals and show significant locomotion defects as well as reductions in minor-class spliceosomal snRNAs. Despite these reductions, we found no appreciable defects in splicing of mRNAs containing minor-class introns. Transgenic expression of low levels of either wild-type or an SMA patient-derived form of SMN rescued the larval lethality and locomotor defects, however, snRNA levels were not restored. Thus, the snRNP biogenesis function of SMN is not a major contributor to the phenotype of Smn null mutants. These findings have major implications for SMA etiology because they show that SMN's role in snRNP biogenesis can be uncoupled from the organismal viability and locomotor defects.