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106 Publications

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    11/01/07 | Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice.
    Lasek AW, Janak PH, He L, Whistler JL, Heberlein U
    Genes, Brain, and Behavior. 2007 Nov;6(8):728-35. doi: 10.1111/j.1601-183X.2007.00303.x

    Pharmacological and genetic studies have implicated the mu opioid receptor (MOR) in the regulation of ethanol intake in animal models and humans. Non-specific antagonists of opioid receptors have been shown to affect ethanol consumption when infused directly into the ventral tegmental area (VTA) of rats. However, administration of MOR-selective antagonists into the VTA has yielded mixed results. We used RNA interference (RNAi) to specifically decrease levels of MOR messenger RNA in the VTA of mice and examined the effect on ethanol consumption in a two-bottle choice paradigm. Mice were injected in the VTA with lentivirus expressing either a small hairpin RNA (shRNA) targeting MOR or a control shRNA. One week after virus injection, mice were examined for ethanol consumption in a two-bottle choice experiment with increasing concentrations of ethanol over the course of 1 month. Expression of an shRNA targeting MOR in the VTA led to a significant reduction in ethanol consumption. These results strengthen the hypothesis that MOR in the VTA is one of the key brain substrates mediating alcohol consumption. The RNAi combined with lentiviral delivery can be used successfully in brain to effect a sustained reduction in expression of specific genes for behavioral analysis.

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    Pavlopoulos Lab
    10/31/07 | The DNA transposon Minos as a tool for transgenesis and functional genomic analysis in vertebrates and invertebrates.
    Pavlopoulos A, Oehler S, Kapetanaki MG, Savakis C
    Genome Biology. 2007 Oct 31;8 Suppl 1:S2. doi: 10.1186/gb-2007-8-s1-s2

    Transposons are powerful tools for conducting genetic manipulation and functional studies in organisms that are of scientific, economic, or medical interest. Minos, a member of the Tc1/mariner family of DNA transposons, exhibits a low insertional bias and transposes with high frequency in vertebrates and invertebrates. Its use as a tool for transgenesis and genome analysis of rather different animal species is described.

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    10/23/07 | Dendritic spikes induce single-burst long-term potentiation.
    Remy S, Spruston N
    Proceedings of the National Academy of Sciences of the United States of America. 2007 Oct 23;104(43):17192-7. doi: 10.1073/pnas.0707919104

    The hippocampus is essential for episodic memory, which requires single-trial learning. Although long-term potentiation (LTP) of synaptic strength is a candidate mechanism for learning, it is typically induced by using repeated synaptic activation to produce precisely timed, high-frequency, or rhythmic firing. Here we show that hippocampal synapses potentiate robustly in response to strong activation by a single burst. The induction mechanism of this single-burst LTP requires activation of NMDA receptors, L-type voltage-gated calcium channels, and dendritic spikes. Thus, dendritic spikes are a critical trigger for a form of LTP that is consistent with the function of the hippocampus in episodic memory.

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    10/19/07 | Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila.
    Bilen J, Bonini NM
    PLoS Genetics. 2007 Oct 19;3(10):1950-64. doi: 10.1371/journal.pgen.0030177

    Spinocerebellar ataxia type-3 (SCA3) is among the most common dominantly inherited ataxias, and is one of nine devastating human neurodegenerative diseases caused by the expansion of a CAG repeat encoding glutamine within the gene. The polyglutamine domain confers toxicity on the protein Ataxin-3 leading to neuronal dysfunction and loss. Although modifiers of polyglutamine toxicity have been identified, little is known concerning how the modifiers function mechanistically to affect toxicity. To reveal insight into spinocerebellar ataxia type-3, we performed a genetic screen in Drosophila with pathogenic Ataxin-3-induced neurodegeneration and identified 25 modifiers defining 18 genes. Despite a variety of predicted molecular activities, biological analysis indicated that the modifiers affected protein misfolding. Detailed mechanistic studies revealed that some modifiers affected protein accumulation in a manner dependent on the proteasome, whereas others affected autophagy. Select modifiers of Ataxin-3 also affected tau, revealing common pathways between degeneration due to distinct human neurotoxic proteins. These findings provide new insight into molecular pathways of polyQ toxicity, defining novel targets for promoting neuronal survival in human neurodegenerative disease.

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    10/15/07 | Ambient mass spectrometry with a handheld mass spectrometer at high pressure.
    Keil A, Talaty N, Janfelt C, Noll RJ, Gao L, Ouyang Z, Cooks RG
    Analytical Chemistry. 2007 Oct 15;79(20):7734-9. doi: 10.1364/AO.50.001792

    The first coupling of atmospheric pressure ionization methods, electrospray ionization (ESI) and desorption electrospray ionization (DESI), to a miniature hand-held mass spectrometer is reported. The instrument employs a rectilinear ion trap (RIT) mass analyzer and is battery-operated, hand-portable, and rugged (total system: 10 kg, 0.014 m(3), 75 W power consumption). The mass spectrometer was fitted with an atmospheric inlet, consisting of a 10 cm x 127 microm inner diameter stainless steel capillary tube which was used to introduce gas into the vacuum chamber at 13 mL/min. The operating pressure was 15 mTorr. Ions, generated by the atmospheric pressure ion source, were directed by the inlet along the axis of the ion trap, entering through an aperture in the dc-biased end plate, which was also operated as an ion gate. ESI and DESI sources were used to generate ions; ESI-MS analysis of an aqueous mixture of drugs yielded detection limits in the low parts-per-billion range. Signal response was linear over more than 3 orders of magnitude. Tandem mass spectrometry experiments were used to identify components of this mixture. ESI was also applied to the analysis of peptides and in this case multiply charged species were observed for compounds of molecular weight up to 1200 Da. Cocaine samples deposited or already present on different surfaces, including currency, were rapidly analyzed in situ by DESI. A geometry-independent version of the DESI ion source was also coupled to the miniature mass spectrometer. These results demonstrate that atmospheric pressure ionization can be implemented on simple portable mass spectrometry systems.

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    10/14/07 | Supervised Learning of Image Restoration with Convolutional Networks
    Jain V, Murray J, Roth F, Turaga S, Zhigulin V, Briggman K, Helmstaedter M, Denk W, Seung H
    IEEE 11th International Conference on Computer Vision, 2007. ICCV 2007. 2007-10:. doi: 10.1109/ICCV.2007.4408909

    Convolutional networks have achieved a great deal of success in high-level vision problems such as object recognition. Here we show that they can also be used as a general method for low-level image processing. As an example of our approach, convolutional networks are trained using gradient learning to solve the problem of restoring noisy or degraded images. For our training data, we have used electron microscopic images of neural circuitry with ground truth restorations provided by human experts. On this dataset, Markov random field (MRF), conditional random field (CRF), and anisotropic diffusion algorithms perform about the same as simple thresholding, but superior performance is obtained with a convolutional network containing over 34,000 adjustable parameters. When restored by this convolutional network, the images are clean enough to be used for segmentation, whereas the other approaches fail in this respect. We do not believe that convolutional networks are fundamentally superior to MRFs as a representation for image processing algorithms. On the contrary, the two approaches are closely related. But in practice, it is possible to train complex convolutional networks, while even simple MRF models are hindered by problems with Bayesian learning and inference procedures. Our results suggest that high model complexity is the single most important factor for good performance, and this is possible with convolutional networks.

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    10/14/07 | Supervised learning of image restoration with convolutional networks.
    Jain V, Murray JF, Roth F, Turaga S, Zhigulin V, Briggman KL, Helmstaedter MN, Denk W, Seung HS
    IEEE 11th International Conference on Computer Vision. 2007 Oct 14;2:1-8
    10/12/07 | A new strategy for the synthesis of benzylic sulfonamides: palladium-catalyzed arylation and sulfonamide metathesis.
    Grimm JB, Katcher MH, Witter DJ, Northrup AB
    The Journal of Organic Chemistry. 2007 Oct 12;72(21):8135-8. doi: 10.1021/jo701431j

    An efficient two-step strategy has been developed to access diversely functionalized benzylic sulfonamides. Execution of this strategy required the development of two reaction methods: the palladium-catalyzed cross-coupling of aryl halides with CH-acidic methanesulfonamides and a metathesis reaction between the resulting alpha-arylated sulfonamides and diverse amines. The broad scope of the cross-coupling process combined with a versatile sulfonamide metathesis constitutes an efficient strategy for the synthesis of various benzylic sulfonamides.

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    10/10/07 | Multiple memory traces for olfactory reward learning in Drosophila.
    Thum AS, Jenett A, Ito K, Heisenberg M, Tanimoto H
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2007 Oct 10;27(41):11132-8. doi: 10.1523/JNEUROSCI.2712-07.2007

    Physical traces underlying simple memories can be confined to a single group of cells in the brain. In the fly Drosophila melanogaster, the Kenyon cells of the mushroom bodies house traces for both appetitive and aversive odor memories. The adenylate cyclase protein, Rutabaga, has been shown to mediate both traces. Here, we show that, for appetitive learning, another group of cells can additionally accommodate a Rutabaga-dependent memory trace. Localized expression of rutabaga in either projection neurons, the first-order olfactory interneurons, or in Kenyon cells, the second-order interneurons, is sufficient for rescuing the mutant defect in appetitive short-term memory. Thus, appetitive learning may induce multiple memory traces in the first- and second-order olfactory interneurons using the same plasticity mechanism. In contrast, aversive odor memory of rutabaga is rescued selectively in the Kenyon cells, but not in the projection neurons. This difference in the organization of memory traces is consistent with the internal representation of reward and punishment.

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    10/07/07 | Reduced C(beta) statistical potentials can outperform all-atom potentials in decoy identification.
    Fitzgerald JE, Jha AK, Colubri A, Sosnick TR, Freed KF
    Protein science : a publication of the Protein Society. 2007 Oct;16(10):2123-39. doi: 10.1110/ps.072939707

    We developed a series of statistical potentials to recognize the native protein from decoys, particularly when using only a reduced representation in which each side chain is treated as a single C(beta) atom. Beginning with a highly successful all-atom statistical potential, the Discrete Optimized Protein Energy function (DOPE), we considered the implications of including additional information in the all-atom statistical potential and subsequently reducing to the C(beta) representation. One of the potentials includes interaction energies conditional on backbone geometries. A second potential separates sequence local from sequence nonlocal interactions and introduces a novel reference state for the sequence local interactions. The resultant potentials perform better than the original DOPE statistical potential in decoy identification. Moreover, even upon passing to a reduced C(beta) representation, these statistical potentials outscore the original (all-atom) DOPE potential in identifying native states for sets of decoys. Interestingly, the backbone-dependent statistical potential is shown to retain nearly all of the information content of the all-atom representation in the C(beta) representation. In addition, these new statistical potentials are combined with existing potentials to model hydrogen bonding, torsion energies, and solvation energies to produce even better performing potentials. The ability of the C(beta) statistical potentials to accurately represent protein interactions bodes well for computational efficiency in protein folding calculations using reduced backbone representations, while the extensions to DOPE illustrate general principles for improving knowledge-based potentials.

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