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58 Publications

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    09/01/03 | Design, synthesis, and development of novel caprolactam anticonvulsants.
    Grimm JB, Stables JP, Brown ML
    Bioorganic & Medicinal Chemistry. 2003 Sep 1;11(18):4133-41

    Epilepsy afflicts 1-2% of the world’s population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment. Therefore, there is great demand for the design of novel, effective anticonvulsants to combat epilepsy in its numerous forms. Previously, alpha-hydroxy-alpha-phenylcaprolactam was found to have rather potent antiepileptic activity [anti-maximal electroshock (MES) ED(50)=63 mg/kg and anti-subcutaneous Metrazol (scMet) ED(50)=74 mg/kg] when administered intraperitoneally in mice. We focused our attention on the development of this compound through traditional medicinal chemistry techniques-including the Topliss approach, isosteric replacement, methylene insertion, and rigid analogue approach-in the hopes of determining the effect of caprolactam alpha-substitution and other structural modifications on anticonvulsant activity. A number of the desired targets were successfully synthesized and submitted to the Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke (NINDS). Phase I results were quite promising for at least three of the compounds: alpha-ethynyl-alpha-hydroxycaprolactam (10), alpha-benzyl-alpha-hydroxycaprolactam (11), and alpha-hydroxy-alpha-(phenylethynyl)caprolactam (13). Phase II results for 11 strongly suggested it as a new structural class for further development, as it exhibited an anti-MES T.I. in excess of 4.0. Further, the potent activity of 13 in all models also pointed to the substituted alkynylcaprolactams as a new anticonvulsant structural class.

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    08/29/03 | Crystal structure of Pyrococcus furiosus phosphoglucose isomerase. Implications for substrate binding and catalysis.
    Berrisford JM, Akerboom J, Turnbull AP, de Geus D, Sedelnikova SE, Staton I, McLeod CW, Verhees CH, van der Oost J, Rice DW, Baker PJ
    The Journal of Biological Chemistry. 2003 Aug 29;278(35):33290-7. doi: 10.1074/jbc.M305170200

    Phosphoglucose isomerase (PGI) catalyzes the reversible isomerization between d-fructose 6-phosphate and d-glucose 6-phosphate as part of the glycolytic pathway. PGI from the Archaea Pyrococcus furiosus (Pfu) was crystallized, and its structure was determined by x-ray diffraction to a 2-A resolution. Structural comparison of this archaeal PGI with the previously solved structures of bacterial and eukaryotic PGIs reveals a completely different structure. Each subunit of the homodimeric Pfu PGI consists of a cupin domain, for which the overall structure is similar to other cupin domain-containing proteins, and includes a conserved transition metal-binding site. Biochemical data on the recombinant enzyme suggests that Fe2+ is bound to Pfu PGI. However, as catalytic activity is not strongly influenced either by the replacement of Fe2+ by a range of transition metals or by the presence or absence of the bound metal ion, we suggest that the metal may not be directly involved in catalysis but rather may be implicated in substrate recognition.

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    08/28/03 | Power-law for axon diameters at branch point.
    Chklovskii DB, Stepanyants A
    BMC Neuroscience. 2003 Aug 28;4:18. doi: 10.1016/j.tins.2005.05.006

    Axon calibers vary widely among different animals, neuron classes, and even within the same neuron. What determines the diameter of axon branches?

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    08/21/03 | Regulatory evolution of shavenbaby/ovo underlies multiple cases of morphological parallelism.
    Sucena E, Delon I, Jones I, Payre F, Stern DL
    Nature. 2003 Aug 21;424(6951):935-8. doi: 10.1038/nature01768

    Cases of convergent evolution that involve changes in the same developmental pathway, called parallelism, provide evidence that a limited number of developmental changes are available to evolve a particular phenotype. To our knowledge, in no case are the genetic changes underlying morphological convergence understood. However, morphological convergence is not generally assumed to imply developmental parallelism. Here we investigate a case of convergence of larval morphology in insects and show that the loss of particular trichomes, observed in one species of the Drosophila melanogaster species group, has independently evolved multiple times in the distantly related D. virilis species group. We present genetic and gene expression data showing that regulatory changes of the shavenbaby/ovo (svb/ovo) gene underlie all independent cases of this morphological convergence. Our results indicate that some developmental regulators might preferentially accumulate evolutionary changes and that morphological parallelism might therefore be more common than previously appreciated.

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    Tjian Lab
    08/15/03 | Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.
    Puig O, Marr MT, Ruhf ML, Tjian R
    Genes & Development. 2003 Aug 15;17(16):2006-20. doi: 10.1073/pnas.1100640108

    The Drosophila insulin receptor (dInR) regulates cell growth and proliferation through the dPI3K/dAkt pathway, which is conserved in metazoan organisms. Here we report the identification and functional characterization of the Drosophila forkhead-related transcription factor dFOXO, a key component of the insulin signaling cascade. dFOXO is phosphorylated by dAkt upon insulin treatment, leading to cytoplasmic retention and inhibition of its transcriptional activity. Mutant dFOXO lacking dAkt phosphorylation sites no longer responds to insulin inhibition, remains in the nucleus, and is constitutively active. dFOXO activation in S2 cells induces growth arrest and activates two key players of the dInR/dPI3K/dAkt pathway: the translational regulator d4EBP and the dInR itself. Induction of d4EBP likely leads to growth inhibition by dFOXO, whereas activation of dInR provides a novel transcriptionally induced feedback control mechanism. Targeted expression of dFOXO in fly tissues regulates organ size by specifying cell number with no effect on cell size. Our results establish dFOXO as a key transcriptional regulator of the insulin pathway that modulates growth and proliferation.

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    08/08/03 | Diapause in the pea aphid (Acyrthosiphon pisum) is a slowing but not a cessation of development.
    Shingleton AW, Sisk GC, Stern DL
    BMC Dev Biol. 2003 Aug 8;3:7. doi: 10.1186/1471-213X-3-7

    BACKGROUND: Many insects undergo a period of arrested development, called diapause, to avoid seasonally recurring adverse conditions. Whilst the phenology and endocrinology of insect diapause have been well studied, there has been comparatively little research into the developmental details of diapause. We investigated developmental aspects of diapause in sexually-produced embryos of the pea aphid, Acyrthosiphon pisum.

    RESULTS: We found that early stages of embryogenesis progressed at a temperature-independent rate, characteristic of diapause, whereas later stages of embryogenesis progressed at a temperature-dependent rate. However, embryos maintained at very high temperatures during the temperature-independent stage showed severe developmental abnormalities. Under no temperature regime did embryos display a distinct resting stage. Rather, morphological development progressed slowly but continuously throughout embryogenesis.

    CONCLUSION: Diapause in the pea aphid, and perhaps in many other insects, is a temperature-independent slowing but not a cessation of morphological development. This suggests that the mechanisms limiting developmental rate during diapause may be the same as those controlling developmental rate at other stages of growth.

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    07/23/03 | Striatal proenkephalin gene induction: coordinated regulation by cyclic AMP and calcium pathways.
    Konradi C, Macías W, Dudman JT, Carlson RR
    Brain Research. Molecular Brain Research. 2003 Jul 23;115(2):157-61. doi: 10.3389/fnana.2010.00147

    Enkephalin modulates striatal function, thereby affecting motor performance and addictive behaviors. The proenkephalin gene is also used as a model to study cyclic AMP-mediated gene expression in striatal neurons. The second messenger pathway leading to proenkephalin expression demonstrates how cyclic AMP pathways are synchronized with depolarization. We show that cyclic AMP-mediated regulation of the proenkephalin gene is dependent on the activity of L-type Ca2+ channels. Inhibition of L-type Ca2+ channels blocks forskolin-mediated induction of proenkephalin. The Ca2+-activated kinase, Ca2+/calmodulin kinase, as well as the cyclic AMP-activated kinase, protein kinase A (PKA), are both necessary for the induction of the proenkephalin promoter. Similarly, both kinases are needed for the L-type Ca2+ channel-mediated induction of proenkephalin. This synchronization of second messenger pathways provides a coincidence mechanism that gates proenkephalin synthesis in striatal neurons, ensuring that levels are increased only in the presence of activated PKA and depolarization.

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    07/17/03 | Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration.
    Zhai Q, Wang J, Kim A, Liu Q, Watts R, Hoopfer E, Mitchison T, Luo L, He Z
    Neuron. 2003 Jul 17;39(2):217-25

    Local axon degeneration is a common pathological feature of many neurodegenerative diseases and peripheral neuropathies. While it is believed to operate with an apoptosis-independent molecular program, the underlying molecular mechanisms are largely unknown. In this study, we used the degeneration of transected axons, termed "Wallerian degeneration," as a model to examine the possible involvement of the ubiquitin proteasome system (UPS). Inhibiting UPS activity by both pharmacological and genetic means profoundly delays axon degeneration both in vitro and in vivo. In addition, we found that the fragmentation of microtubules is the earliest detectable change in axons undergoing Wallerian degeneration, which among other degenerative events, can be delayed by proteasome inhibitors. Interestingly, similar to transected axons, degeneration of axons from nerve growth factor (NGF)-deprived sympathetic neurons could also be suppressed by proteasome inhibitors. Our findings suggest a possibility that inhibiting UPS activity may serve to retard axon degeneration in pathological conditions.

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    Tjian Lab
    07/10/03 | Transcription regulation and animal diversity.
    Levine M, Tjian R
    Nature. 2003 Jul 10;424:147-51. doi: 10.1073/pnas.1100640108

    Whole-genome sequence assemblies are now available for seven different animals, including nematode worms, mice and humans. Comparative genome analyses reveal a surprising constancy in genetic content: vertebrate genomes have only about twice the number of genes that invertebrate genomes have, and the increase is primarily due to the duplication of existing genes rather than the invention of new ones. How, then, has evolutionary diversity arisen? Emerging evidence suggests that organismal complexity arises from progressively more elaborate regulation of gene expression.

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    07/01/03 | Functional properties of a brain-specific NH2-terminally spliced modulator of Kv4 channels.
    Boland LM, Jiang M, Lee SY, Fahrenkrug SC, Harnett MT, O’Grady SM
    American Journal of Physiology. Cell Physiology. 2003 Jul;285(1):C161-70. doi: 10.1152/ajpcell.00416.2002

    Kv4/K channel-interacting protein (KChIP) potassium channels are a major class of rapidly inactivating K channels in brain and heart. Considering the importance of alternative splicing to the quantitative features of KChIP gating modulation, a previously uncharacterized splice form of KChIP1 was functionally characterized. The KChIP1b splice variant differs from the previously characterized KChIP1a splice form by the inclusion of a novel amino-terminal region that is encoded by an alternative exon that is conserved in mouse, rat, and human genes. The expression of KChIP1b mRNA was high in brain but undetectable in heart or liver by RT-PCR. In cerebellar tissue, KChIP1b and KChIP1a transcripts were expressed at nearly equal levels. Coexpression of KChIP1b or KChIP1a with Kv4.2 channels in oocytes slowed K current decay and destabilized open-inactivated channel gating. Like other KChIP subunits, KChIP1b increased Kv4.2 current amplitude and KChIP1b also shifted Kv4.2 conductance-voltage curves by -10 mV. The development of Kv4.2 channel inactivation accessed from closed gating states was faster with KChIP1b coexpression. Deletion of the novel amino-terminal region in KChIP1b selectively altered the subunit’s modulation of Kv4.2 closed inactivation gating. The role of the KChIP1b NH2-terminal region was further confirmed by direct comparison of the properties of the NH2-terminal deletion mutant and the KChIP1a subunit, which is encoded by a transcript that lacks the novel exon. The features of KChIP1b modulation of Kv4 channels are likely to be conserved in mammals and demonstrate a role for the KChIP1 NH2-terminal region in the regulation of closed inactivation gating.

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