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2496 Publications

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    10/01/11 | Accelerated profile HMM searches.
    Eddy SR
    PLoS Computational Biology. 2011 Oct;7(10):e1002195. doi: 10.1371/journal.pcbi.1002195

    Profile hidden Markov models (profile HMMs) and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the "multiple segment Viterbi" (MSV) algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as a heuristic filter. I also describe a 20-fold acceleration of the standard profile HMM Forward/Backward algorithms using a method I call "sparse rescaling". These methods are assembled in a pipeline in which high-scoring MSV hits are passed on for reanalysis with the full HMM Forward/Backward algorithm. This accelerated pipeline is implemented in the freely available HMMER3 software package. Performance benchmarks show that the use of the heuristic MSV filter sacrifices negligible sensitivity compared to unaccelerated profile HMM searches. HMMER3 is substantially more sensitive and 100- to 1000-fold faster than HMMER2. HMMER3 is now about as fast as BLAST for protein searches.

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    10/01/11 | Anisotropic path searching for automatic neuron reconstruction.
    Xie J, Zhao T, Lee T, Myers E, Peng H
    Medical Image Analysis. 2011 Oct;15:680-9. doi: 10.1016/j.media.2011.05.013

    Full reconstruction of neuron morphology is of fundamental interest for the analysis and understanding of their functioning. We have developed a novel method capable of automatically tracing neurons in three-dimensional microscopy data. In contrast to template-based methods, the proposed approach makes no assumptions about the shape or appearance of neurite structure. Instead, an efficient seeding approach is applied to capture complex neuronal structures and the tracing problem is solved by computing the optimal reconstruction with a weighted graph. The optimality is determined by the cost function designed for the path between each pair of seeds and by topological constraints defining the component interrelations and completeness. In addition, an automated neuron comparison method is introduced for performance evaluation and structure analysis. The proposed algorithm is computationally efficient and has been validated using different types of microscopy data sets including Drosophila’s projection neurons and fly neurons with presynaptic sites. In all cases, the approach yielded promising results.

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    10/01/11 | Optogenetics: potentials for addiction research.
    Cao ZF, Burdakov D, Sarnyai Z
    Addiction Biology. 2011 Oct;16(4):519-31. doi: 10.1111/j.1369-1600.2011.00386.x

    Research on the biology of addiction has advanced significantly over the last 50 years expanding our understanding of the brain mechanisms underlying reward, reinforcement and craving. Novel experimental approaches and techniques have provided an ever increasing armory of tools to dissect behavioral processes, neural networks and molecular mechanisms. The ultimate goal is to reintegrate this knowledge into a coherent, mechanistic framework of addiction to help identify new treatment. This can be greatly facilitated by using tools that allow, with great spatial and temporal specificity, to link molecular changes with altered activation of neural circuits and behavior. Such specificity can now be achieved by using optogenetic tools. Our review describes the general principles of optogenetics and its use to understand the links between neural activity and behavior. We also provide an overview of recent studies using optogenetic tools in addiction and consider some outstanding questions of addiction research that are particularly amenable for optogenetic approaches.

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    Sternson Lab
    09/16/11 | Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop.
    Yang Y, Atasoy D, Su HH, Sternson SM
    Cell. 2011 Sep 16;146:992-1003. doi: 10.1016/j.cell.2011.07.039

    Synaptic plasticity in response to changes in physiologic state is coordinated by hormonal signals across multiple neuronal cell types. Here, we combine cell-type-specific electrophysiological, pharmacological, and optogenetic techniques to dissect neural circuits and molecular pathways controlling synaptic plasticity onto AGRP neurons, a population that regulates feeding. We find that food deprivation elevates excitatory synaptic input, which is mediated by a presynaptic positive feedback loop involving AMP-activated protein kinase. Potentiation of glutamate release was triggered by the orexigenic hormone ghrelin and exhibited hysteresis, persisting for hours after ghrelin removal. Persistent activity was reversed by the anorexigenic hormone leptin, and optogenetic photostimulation demonstrated involvement of opioid release from POMC neurons. Based on these experiments, we propose a memory storage device for physiological state constructed from bistable synapses that are flipped between two sustained activity states by transient exposure to hormones signaling energy levels.

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    Sternson Lab
    09/08/11 | Metabolism: let them eat fat.
    Sternson SM
    Nature. 2011 Sep 8;477(7363):166-7. doi: 10.1038/477166a

    A specialist neuron uses an intriguing process to help control the body's response to hunger. A lipid pathway involving the breakdown of cellular components regulates the expression of a neuropeptide that affects feeding and body weight.

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    Looger LabSternson Lab
    09/02/11 | Chemical and genetic engineering of selective ion channel-ligand interactions.
    Magnus CJ, Lee PH, Atasoy D, Su HH, Looger LL, Sternson SM
    Science. 2011 Sep 2;333(6047):1292-6. doi: 10.1126/science.1206606

    Ionic flux mediates essential physiological and behavioral functions in defined cell populations. Cell type-specific activators of diverse ionic conductances are needed for probing these effects. We combined chemistry and protein engineering to enable the systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small-molecule effectors were able to activate a range of ionic conductances in genetically specified cell types. LGICs constructed for neuronal perturbation could be used to selectively manipulate neuron activity in mammalian brains in vivo. The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.

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    Svoboda Lab
    09/01/11 | DIADEMchallenge.org: a compendium of resources fostering the continuous development of automated neuronal reconstruction.
    Gillette TA, Brown KM, Svoboda K, Liu Y, Ascoli GA
    Neuroinformatics. 2011 Sep;9(2-3):303-4. doi: 10.1007/s12021-011-9104-3

    Concomitant with the publication of this Special Issue of Neuroinformatics, a substantially updated version of the DIADEM web site has been released at http://diademchallenge.org. This web site was originally designed to host the challenge for automating the digital reconstruction of axonal and dendritic morphology (hence the DIADEM acronym). This post-competition version features additional content for continued use as the access point for DIADEM-related material. From the very beginning, one of the spirits of DIADEM has been to share data and resources with the neuroscience research community at large. The resources available from or linked to the DIADEM website constitute a substantial scientific legacy of the 2009/2010 competition. The new content includes finalist algorithms, image stack data, gold standard reconstructions, an updated DIADEM metric, and a retrospective on the competition in text and images.

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    Eddy/Rivas Lab
    09/01/11 | Exploiting Oxytricha trifallax nanochromosomes to screen for non-coding RNA genes.
    Jung S, Swart EC, Minx PJ, Magrini V, Mardis ER, Landweber LF, Eddy SR
    Nucleic Acids Research. 2011 Sep 1;39:7529-47. doi: 10.1093/nar/gkr501

    We took advantage of the unusual genomic organization of the ciliate Oxytricha trifallax to screen for eukaryotic non-coding RNA (ncRNA) genes. Ciliates have two types of nuclei: a germ line micronucleus that is usually transcriptionally inactive, and a somatic macronucleus that contains a reduced, fragmented and rearranged genome that expresses all genes required for growth and asexual reproduction. In some ciliates including Oxytricha, the macronuclear genome is particularly extreme, consisting of thousands of tiny ’nanochromosomes’, each of which usually contains only a single gene. Because the organism itself identifies and isolates most of its genes on single-gene nanochromosomes, nanochromosome structure could facilitate the discovery of unusual genes or gene classes, such as ncRNA genes. Using a draft Oxytricha genome assembly and a custom-written protein-coding genefinding program, we identified a subset of nanochromosomes that lack any detectable protein-coding gene, thereby strongly enriching for nanochromosomes that carry ncRNA genes. We found only a small proportion of non-coding nanochromosomes, suggesting that Oxytricha has few independent ncRNA genes besides homologs of already known RNAs. Other than new members of known ncRNA classes including C/D and H/ACA snoRNAs, our screen identified one new family of small RNA genes, named the Arisong RNAs, which share some of the features of small nuclear RNAs.

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    09/01/11 | New tools for the analysis of glial cell biology in Drosophila.
    Awasaki T, Lee T
    Glia. 2011 Sep;59(9):1377-86. doi: 10.1002/glia.21133

    Because of its genetic, molecular, and behavioral tractability, Drosophila has emerged as a powerful model system for studying molecular and cellular mechanisms underlying the development and function of nervous systems. The Drosophila nervous system has fewer neurons and exhibits a lower glia:neuron ratio than is seen in vertebrate nervous systems. Despite the simplicity of the Drosophila nervous system, glial organization in flies is as sophisticated as it is in vertebrates. Furthermore, fly glial cells play vital roles in neural development and behavior. In addition, powerful genetic tools are continuously being created to explore cell function in vivo. In taking advantage of these features, the fly nervous system serves as an excellent model system to study general aspects of glial cell development and function in vivo. In this article, we review and discuss advanced genetic tools that are potentially useful for understanding glial cell biology in Drosophila.

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    09/01/11 | Proof-editing is the bottleneck of 3D neuron reconstruction: the problem and solutions.
    Peng H, Long F, Zhao T, Myers E
    Neuroinformatics. 2011 Sep;9:103-5. doi: 10.1007/s12021-010-9090-x