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Now showing items 1 - 16 of 81

  • Structure and dynamics of the active human parathyroid hormone receptor-1

    Zhao, Li-Hua   Ma, Shanshan   Sutkeviciute, Ieva   Shen, Dan-Dan   Zhou, X. Edward   de Waal, Parker W.   Li, Chen-Yao   Kang, Yanyong   Clark, Lisa J.   Jean-Alphonse, Frederic G.   White, Alex D.   Yang, Dehua   Dai, Antao   Cai, Xiaoqing   Chen, Jian   Li, Cong   Jiang, Yi   Watanabe, Tomoyuki   Gardella, Thomas J.   Melcher, Karsten   Wang, Ming-Wei   Vilardaga, Jean-Pierre   Xu, H. Eric   Zhang, Yan  

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    A spark plug 1 has a cylindrical housing 2, a cylindrical insulator 3, a center electrode 4, a terminal bracket 7, a ground electrode 5, and a resistor 6. The insulator 3 is held inside the housing 2. The center electrode 4 is held inside the insulator 3 so that the distal end part is allowed to project. The terminal bracket 7 is held inside the insulator 3 so that the base end part is allowed to project. A spark discharge gap G is formed between the ground electrode 5 and the center electrode 4. The resistor 6 is disposed inside the insulator 3 so as to be located between the center electrode 4 and the terminal bracket 7. The resistor contains carbon. In the resistor 6, a first region 61 located on the distal end side with respect to the axial direction X of the spark plug 1 has a higher carbon content than a second region 62 located on the base end side.
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  • Receptor selectivity from minimal backbone modification of a polypeptide agonist.

    Liu, Shi   Cheloha, Ross W   Watanabe, Tomoyuki   Gardella, Thomas J   Gellman, Samuel H  

    Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share 51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1-34)-NH2 that contained a single beta-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1-34)-NH2 itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 activation. The beta-scan series allowed us to identify two homologs, each containing two alphabeta replacements, that were highly selective, one for PTHR1 and the other for PTHR2. These findings suggest that backbone modification of peptides may provide a general strategy for achieving activation selectivity among polypeptide-modulated receptors, and that success requires consideration of both beta2- and beta3-residues, which differ in terms of side-chain location.=20
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  • Complications of femtosecond laser-assisted cataract surgery combined with vitrectomy

    Kubota, Masaomi   Watanabe, Akira   Watanabe, Tomoyuki   Kono, Hideo   Hayashi, Takaaki   Nakano, Tadashi  

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    Light sources (18L, 18R) are respectively provided with light emitting surfaces (18a) from which lighting light (LEL, LER) is outputted merely to the condensing lens (20a, 31a) side, and condensing lenses (20a, 31a) and a refracting optical section (21 or 32) are integrally formed.
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    Disclosed is a lighting apparatus that is provided with: a socket (20) that is attached in a mounting hole (5) in a substrate (2A) having first and second electrode patterns (8, 9) formed thereon; a light emitting diode (70) that is attached to the socket (20); a first terminal plate (100), which is attached to the socket (20) for the purpose of electrically connecting the electrode pattern (9) and one terminal (72) of the light emitting diode (70) to each other; and a second terminal plate (110), which is attached to the socket (20) for the purpose of electrically connecting the second electrode pattern (8) of the substrate (2A) and the other terminal (71) of the light emitting diode (70) to each other. A resistor (80) for having the light emitting diode (70) emit light at predetermined luminance is disposed between the second terminal plate (110) and the terminal (71) of the light emitting diode (70), and a third terminal plate (90) that makes the terminal (71) of the light emitting diode (70) and the second terminal plate (110) sandwich the resistor (80) by means of an elastic force is provided, said third terminal plate making the terminal (71) and the second terminal plate (110) electrically connect to each other with the resistor (80) therebetween.
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  • Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist

    Cheloha, Ross W.   Watanabe, Tomoyuki   Dean, Thomas   Gellman, Samuel H.   Gardella, Thomas J.  

    A backbone-modified peptide derived from parathyroid hormone (PTH) is shown to function as an inhibitor and inverse agonist of parathyroid hormone receptor-1 (PTHR1) signaling. This receptor acts to regulate calcium and phosphate homeostasis, as well as bone turnover and development. PTH is a natural agonist of PTHR1, and PTH(1-34) displays full activity relative to the natural 84-residue hormone. PTH(1-34) is used clinically to treat osteoporosis. N-terminally truncated derivatives of PTH(1-34), such as PTH(7-34), are known to bind to PTHR1 without initiating intracellular signaling and can thus act as competitive antagonists of PTH-induced signaling at PTHR1. In some cases, N-terminally truncated PTH derivatives also act as inverse agonists of PTHR1 variants that display pathologically high levels of signaling in the absence of PTH. Many analogues of PTH, however, are rapidly degraded by proteases, which may limit biomedical application. We show that backbone modification via periodic replacement of a-amino acid residues with homologous beta-amino acid residues leads to an alpha/beta-PTH(7-34) peptide that retains the antagonist and inverse agonist activities of the prototype alpha-peptide while exhibiting enhanced stability in the presence of aggressive proteases. These findings highlight the value of backbone-modified peptides derived from PTH as tools for investigating determinants of PTH metabolism and provide guidance for designing therapeutic agents for diseases arising from excessive ligand-dependent or ligand-independent PTHR1 activity.
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  • Role of the imprinted allele of the Cdkn1c gene in mouse neocortical development

    Imaizumi, Yui   Furutachi, Shohei   Watanabe, Tomoyuki   Miya, Hiroaki   Kawaguchi, Daichi   Gotoh, Yukiko  

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  • Using Terahertz Reflectance Spectroscopy to Quantify Drug Substance in Tablets

    Hisazumi, Jin   Watanabe, Tomoyuki   Suzuki, Tatsuya   Wakiyama, Naoki   Terada, Katsuhide  

    The purpose of this research is to investigate the applicability of terahertz (THz) reflectance spectroscopy for quantification of drug substance in tablets, so as to demonstrate the feasibility for applying this technique to tableting process monitoring. In order to acquire a suitable absorbance spectrum for this purpose, it was necessary to enhance the reflection intensity. By using an aluminum plate as a mirror at the opposite surface of the tablet, a reasonable absorbance spectrum could be acquired to reflect the bulk information of the tablet. To assess the limit of tablet thickness, linearity between the tablet thickness and the absorbance value was investigated using lactose and mannitol tablets. Since linearity was found within 0.75-5.0 mm for both tablets using 0.4 and 0.8 THz region, it was confirmed that THz reflectance spectroscopy is applicable to tablets within at least 5.0 mm thickness. Mannitol tablets containing sodium salicylate as the model drug substance were used to investigate the quantitative performance of this technique. It was confirmed that the established calibration model was acceptable for this quantification because of the root-mean-squared error of cross-validation (RMSECV) being 1.95%. In order to evaluate the applicability of this technique, content quantitative performance in double layered tablets having active and placebo layers were assessed. Since this calibration model achieved the root-mean-squared error of prediction (RMSEP) of 1.42% for the double layered tablets, this technique was considered feasible even if the drug substance is localized in the tablets.
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    Provided are: a rotating drum DR for transportation at a prescribed speed in a transportation direction intersecting a width direction of a substrate P; a drawing device 11 having a plurality of drawing modules UW1-UW5 that scan drawing beams projected on the substrate P along drawing lines of the substrate P to draw prescribed patterns on the substrate P, and in which the drawing lines neighboring each other in the width direction are disposed with a prescribed space therebetween in the transportation direction such that the patterns drawn on the substrate P by each of the plurality of drawing modules UW1-UW5 are joined in the width direction; a rotating mechanism 24 that adjusts the relative inclination of the drawing lines with respect to the width direction of the substrate P; and a rotating-position detection mechanism that detects the transportation speed of the substrate P. The relative inclination of the drawing lines is adjusted by the rotating mechanism 24 on the basis of the transportation speed detected by the rotating-position detection mechanism.
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  • Harmonic structure design of Ti-6Al-4V alloy by High-pressure gas milling process

    Watanabe, Tomoyuki   Maeda, Ryo   Kurokawa, Kazuaki   Ota, Mie   Vajpai, Sanjay K.   Ameyama, Kei  

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  • Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells.

    Furutachi, Shohei   Miya, Hiroaki   Watanabe, Tomoyuki   Kawai, Hiroki   Yamasaki, Norihiko   Harada, Yujin   Imayoshi, Itaru   Nelson, Mark   Nakayama, Keiichi I   Hirabayashi, Yusuke   Gotoh, Yukiko  

    The mechanism by which adult neural stem cells (NSCs) are established during development is unclear. In this study, analysis of cell cycle progression by examining retention of a histone 2B (H2B)-GFP fusion protein revealed that, in a subset of mouse embryonic neural progenitor cells (NPCs), the cell cycle slows between embryonic day (E) 13.5 and E15.5 while other embryonic NPCs continue to divide rapidly. By allowing H2B-GFP expressed at E9.5 to become diluted in dividing cells until the young adult stage, we determined that a majority of NSCs in the young adult subependymal zone (SEZ) originated from these slowly dividing embryonic NPCs. The cyclin-dependent kinase inhibitor p57 is highly expressed in this embryonic subpopulation, and the deletion of p57 impairs the emergence of adult NSCs. Our results suggest that a substantial fraction of adult SEZ NSCs is derived from a slowly dividing subpopulation of embryonic NPCs and identify p57 as a key factor in generating this embryonic origin of adult SEZ NSCs. =20
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    In this substrate-processing apparatus, a plurality of patterning units are arrayed in the widthwise direction of a substrate such that movement in the lengthwise direction of the substrate causes patterns formed on the substrate by pattern lines from the respective patterning units to join together. A control unit stores, in advance, calibration information regarding the positional relationships between the pattern lines formed on the substrate by the respective patterning units, and on the basis of said calibration information and movement information outputted by a movement-measuring device, the control unit adjusts the positions at which the patterns are formed on the substrate by patterning beams from the respective patterning units.
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  • Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment

    Sato, Haruhiko   Okamachi, Akira   Emura, Takashi   Ishizawa, Takenori   Kato, Tatsuya   Matsuura, Tetsu   Sato, Shigeo   Tamura, Tatsuya   Higuchi, Yoshinobu   Watanabe, Tomoyuki   Kitamura, Hidetomo   Asanuma, Kentaro   Yamazaki, Tadao   Ikemi, Masahisa   Kitagawa, Hironoshin   Morikawa, Tadashi   Ikeya, Hitoshi   Maeda, Kazuaki   Takahashi, Koichi   Nohmi, Kenji   Izutani, Noriyuki   Kanda, Makoto   Suzuki, Ryochi  

    Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis. (C) 2009 Elsevier Ltd. All rights reserved.
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  • Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase.

    Gidon, Alexandre   Al-Bataineh, Mohammad M   Jean-Alphonse, Frederic G   Stevenson, Hilary P   Watanabe, Tomoyuki   Louet, Claire   Khatri, Ashok   Calero, Guillermo   Pastor-Soler, Nuria M   Gardella, Thomas J   Vilardaga, Jean-Pierre  

    The PTH receptor is to our knowledge one of the first G protein-coupled receptor (GPCR) found to sustain cAMP signaling after internalization of the ligand-receptor complex in endosomes. This unexpected model is adding a new dimension on how we think about GPCR signaling, but its mechanism is incompletely understood. We report here that endosomal acidification mediated by the PKA action on the v-ATPase provides a negative feedback mechanism by which endosomal receptor signaling is turned off. =20
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  • Outcome of adolescent patients with acute myeloid leukemia treated with pediatric protocols.

    Tomizawa, Daisuke   Watanabe, Tomoyuki   Hanada, Ryoji   Horibe, Keizo   Horikoshi, Yasuo   Iwamoto, Shotaro   Kinoshita, Akitoshi   Moritake, Hiroshi   Nakayama, Hideki   Shimada, Akira   Taga, Takashi   Takahashi, Hiroyuki   Tawa, Akio   Terui, Kiminori   Hori, Hiroki   Kawano, Yoshifumi   Kikuta, Atsushi   Manabe, Atsushi   Adachi, Souichi  

    As past studies of adolescent and young adults (AYA) with acute myeloid leukemia (AML) reported conflicting results, we conducted a retrospective analysis using data from three Japanese pediatric AML studies. Among the 782 patients with de novo AML, 44 were classified as AYA (age =E2=89=A515 years at diagnosis), 164 as infants (0-1 year), 413 as younger children (2-11 years), and 161 as older children (12-14 years). While the 5-year event-free survival rate of AYA was not different among the groups, the five-year survival rate (54.7 %) was significantly lower than that of the other three groups (P =3D 0.019): 68.7 % for infants, 73.2 % for younger children, and 75.5 % for older children. No difference in the 5-year cumulative incidence of relapse was observed, but treatment-related death (TRD) of AYA was significantly higher (29.4 %) than that in infants (14.8 %), younger children (10.2 %), and older children (13.8 %). Multivariate analysis showed age =E2=89=A515 years old at diagnosis was associated with both poor survival rate and high TRD. Adolescents with AML had inferior survival due to a higher incidence of TRD, especially after failure of initial frontline treatment.=20
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