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Publications (8) View all
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Article: Insights from the HuR-interacting transcriptome: ncRNAs, ubiquitin pathways, and patterns of secondary structure dependent RNA interactions.
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ABSTRACT: The HuR protein regulates the expression of thousands of cellular transcripts by modulating mRNA splicing, trafficking, translation, and stability. Although it serves as a model of RNA-protein interactions, many features of HuR's interactions with RNAs remain unknown. In this report, we deployed the cryogenic RNA immunoprecipitation technique to analyze HuR-interacting RNAs with the Affymetrix all-exon microarray platform. We revealed several thousand novel HuR-interacting RNAs, including hundreds of non-coding RNAs such as natural antisense transcripts from stress responsive loci. To gain insight into the mechanisms of specificity and sensitivity of HuR's interaction with its target RNAs, we searched HuR-interacting RNAs for composite patterns of primary sequence and secondary structure. We provide evidence that secondary structures of 66-75 nucleotides enhance HuR's recognition of its specific RNA targets composed of short primary sequence patterns. We validated thousands of these RNAs by analysis of overlap with recently published findings, including HuR's interaction with RNAs in the pathways of RNA splicing and stability. Finally, we observed a striking enrichment for members of ubiquitin ligase pathways among the HuR-interacting mRNAs, suggesting a new role for HuR in the regulation of protein degradation to mirror its known function in protein translation.MGG Molecular & General Genetics 10/2012; · 2.58 Impact Factor -
Thesis: The NeuroML C. elegans Connectome
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ABSTRACT: We have merged and extended the C. elegans connectome (Varshney et al., 2006) and a three-dimensional cellular anatomy model (Grove & Sternberg, 2011) in the context of the OpenWorm project, an open source project to build a data integration and simulation framework for the C. elegans. To do so, we have leveraged the NeuroML standard (Gleeson et al., 2010), a language for describing neuronal morphologies, ion channels, synapse models and position and network structure in a simulator independent format. It facilitates the exchange of these key model components between computational neuroscience applications. We have converted the neurons described as 3D objects into NeuroML multi-compartmental neuron models and populated the connection statements between these neurons with the Varshney et al. (2006) connection graph. We have used NeuroConstruct (Gleeson et al., 2007) as the rallying point for these data integration efforts and we have demonstrated a successful export from NeuroConstruct into a simulation engine. We have also made available a WebGL based browser that enables the neurons to be seen in the 3D context of the rest of the C. elegans anatomy (http://browser.openworm.org). While not yet sufficient to explain the activity of its neurons, we believe rthis is a necessary prerequisite for deep investigations into the non-linear dynamics and neuronal computation of the C. elegans neuronal network. -
Article: On the problems of biological neural networks simulations
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ABSTRACT: Nowadays a significant amount of neurobiological studies, including human neurobiology, is being performed using modern methods, technologies and equipment, but scientists are still unison in opinions that we are still far from understanding of fundamental mechanisms of brain and consciousness functioning. Many researchers also suppose that we are, moreover, still far from understanding of a single neuron. Until this challenging puzzle remains unsolved we can only expect the real amount of knowledge and technology level intercepting the humanity from the success. In this paper the analysis of actual situation in computational neuroscience will be peformed, particularly the brain inverse-engineering problem – study of mechanisms underlying principles of living organisms’ nervous systems functioning and reproduction of them in the form of computer simulations. Also we’ll try to identify the most principal problems and discuss the ways of solving them, as well as further perspectives. A part of the paper is devoted to authors’ work on development of computer simulation of C. elegans nematode including its neuromuscular model.Bulletin of the Novosibirsk State University, series "Information Technologies". 10/2012; 10(3):46-57. -
Article: Towards a virtual C . elegans : A framework for simulation and visualization of the neuromuscular system in a 3D physical environment
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ABSTRACT: The nematode C. elegans is the only animal with a known neuronal wiring diagram, or “connectome”. During the last three decades, extensive studies of the C. elegans have provided wide-ranging data about it, but few systematic ways of integrating these data into a dynamic model have been put forward. Here we present a detailed demonstration of a virtual C. elegans aimed at integrating these data in the form of a 3D dynamic model operating in a simulated physical environment. Our current demonstration includes a realistic flexible worm body model, muscular system and a partially implemented ventral neural cord. Our virtual C. elegans demonstrates successful forward and backward locomotion when sending sinusoidal patterns of neuronal activity to groups of motor neurons. To account for the relatively slow propagation velocity and the attenuation of neuronal signals, we introduced “pseudo neurons” into our model to simulate simplified neuronal dynamics. The pseudo neurons also provide a good way of visualizing the nervous system’s structure and activity dynamics.In Silico Biology 01/2012; 11:137-147. -
Article: AUG_hairpin: prediction of a downstream secondary structure influencing the recognition of a translation start site.
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ABSTRACT: The translation start site plays an important role in the control of translation efficiency of eukaryotic mRNAs. The recognition of the start AUG codon by eukaryotic ribosomes is considered to depend on its nucleotide context. However, the fraction of eukaryotic mRNAs with the start codon in a suboptimal context is relatively large. It may be expected that mRNA should possess some features providing efficient translation, including the proper recognition of a translation start site. It has been experimentally shown that a downstream hairpin located in certain positions with respect to start codon can compensate in part for the suboptimal AUG context and also increases translation from non-AUG initiation codons. Prediction of such a compensatory hairpin may be useful in the evaluation of eukaryotic mRNA translation properties. We evaluated interdependency between the start codon context and mRNA secondary structure at the CDS beginning: it was found that a suboptimal start codon context significantly correlated with higher base pairing probabilities at positions 13 - 17 of CDS of human and mouse mRNAs. It is likely that the downstream hairpins are used to enhance translation of some mammalian mRNAs in vivo. Thus, we have developed a tool, AUG_hairpin, to predict local stem-loop structures located within the defined region at the beginning of mRNA coding part. The implemented algorithm is based on the available published experimental data on the CDS-located stem-loop structures influencing the recognition of upstream start codons. An occurrence of a potential secondary structure downstream of start AUG codon in a suboptimal context (or downstream of a potential non-AUG start codon) may provide researchers with a testable assumption on the presence of additional regulatory signal influencing mRNA translation initiation rate and the start codon choice. AUG_hairpin, which has a convenient Web-interface with adjustable parameters, will make such an evaluation easy and efficient.BMC Bioinformatics 02/2007; 8:318. · 2.75 Impact Factor
