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1.
Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging 下载免费PDF全文
Prof. Dr. Steven H. Liang Dr. Jinshan Michael Chen Prof. Dr. Marc D. Normandin Dr. Jeanne S. Chang Dr. George C. Chang Dr. Christine K. Taylor Dr. Patrick Trapa Dr. Mark S. Plummer Dr. Kimberly S. Para Dr. Edward L. Conn Dr. Lori Lopresti‐Morrow Dr. Lorraine F. Lanyon Dr. James M. Cook Dr. Karl E. G. Richter Dr. Charlie E. Nolan Dr. Joel B. Schachter Dr. Fouad Janat Dr. Ye Che Dr. Veerabahu Shanmugasundaram Dr. Bruce A. Lefker Dr. Bradley E. Enerson Prof. Dr. Elijahu Livni Lu Wang Dr. Nicolas J. Guehl Dr. Debasis Patnaik Florence F. Wagner Prof. Dr. Roy Perlis Dr. Edward B. Holson Prof. Dr. Stephen J. Haggarty Prof. Dr. Georges El Fakhri Dr. Ravi G. Kurumbail Prof. Dr. Neil Vasdev 《Angewandte Chemie (International ed. in English)》2016,55(33):9601-9605
Glycogen synthase kinase‐3 (GSK‐3) regulates multiple cellular processes in diabetes, oncology, and neurology. N‐(3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(3‐chloro‐4‐methoxyphenyl)oxazole‐4‐carboxamide (PF‐04802367 or PF‐367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK‐3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF‐367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF‐367 is ideal for discovery of radiopharmaceuticals for GSK‐3 in the central nervous system. A 11C‐isotopologue of PF‐367 was synthesized and preliminary PET imaging studies in non‐human primates confirmed that we have overcome the two major obstacles for imaging GSK‐3, namely, reasonable brain permeability and displaceable binding. 相似文献
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J?RG?FELDVOSSEmail author SALVATORE?SICILIANO THOMAS?WEIGEL 《Transformation Groups》2016,21(2):377-398
In this paper it is shown that the projective cover of the trivial irreducible module of a finite-dimensional solvable restricted Lie algebra is induced from the one dimensional trivial module of a maximal torus. As a consequence, the number of the isomorphism classes of irreducible modules with a fixed p-character for a finite-dimensional solvable restricted Lie algebra L is bounded above by p MT(L), where MT(L) denotes the maximal dimension of a torus in L. Finally, it is proved that in characteristic p > 3 the projective cover of the trivial irreducible L-module is induced from the one-dimensional trivial module of a torus of maximal dimension, only if L is solvable. 相似文献
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Xing L Kurumbail RG Frazier RB Davies MS Fujiwara H Weinberg RA Gierse JK Caspers N Carter JS McDonald JJ Moore WM Vazquez ML 《Journal of computer-aided molecular design》2009,23(1):13-24
Inducible, microsomal prostaglandin E synthase 1 (mPGES-1), the terminal enzyme in the prostaglandin (PG) biosynthetic pathway,
constitutes a promising therapeutic target for the development of new anti-inflammatory drugs. To elucidate structure–function
relationships and to enable structure-based design, an mPGES-1 homology model was developed using the three-dimensional structure
of the closest homologue of the MAPEG family (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism), mGST-1.
The ensuing model of mPGES-1 is a homo-trimer, with each monomer consisting of four membrane-spanning segments. Extensive
structure refinement revealed an inter-monomer salt bridge (K26-E77) as well as inter-helical interactions within each monomer,
including polar hydrogen bonds (e.g. T78-R110-T129) and hydrophobic π-stacking (F82-F103-F106), all contributing to the overall
stability of the homo-trimer of mPGES-1. Catalytic co-factor glutathione (GSH) was docked into the mPGES-1 model by flexible
optimization of both the ligand and the protein conformations, starting from the initial location ascertained from the mGST-1
structure. Possible binding site for the substrate, prostaglandin H2 (PGH2), was identified by systematically probing the refined molecular structure of mPGES-1. A binding model was generated by induced
fit docking of PGH2 in the presence of GSH. The homology model prescribes three potential inhibitor binding sites per mPGES-1 trimer. This was
further confirmed experimentally by equilibrium dialysis study which generated a binding stoichiometric ratio of approximately
three inhibitor molecules to three mPGES-1 monomers. The structural model that we have derived could serve as a useful tool
for structure-guided design of inhibitors for this emergently important therapeutic target. 相似文献
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ER Badman GE Patterson JM Wells RE Santini RG Cooks 《Journal of mass spectrometry : JMS》1999,34(8):889-894
Dual-detector differential non-destructive Fourier transform detection in a quadrupole ion trap is shown to improve signal intensity and reduce noise compared with spectra recorded using a single detector. A larger area detector in each end-cap electrode is machined to fit its hyperbolic shape and so minimize field imperfections on the z-axis. Argon, acetophenone and bromobenzene spectra were recorded to allow a comparison between single- and dual-detector (differential) modes of detection and to demonstrate the improvement achieved with differential detection. Copyright 1999 John Wiley & Sons, Ltd. 相似文献
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Darshan C Kundaliya Reeta Vij AA Tulapurkar U Vaidya R Pinto RG Kulkarni 《Pramana》2002,58(5-6):1041-1044
Electrical resistance (R) measurements of a bulk La0.33Nd0.33Ca0.33MnO3 perovskite in magnetic fields up to 40 kOe have revealed anomalous temperature hysteretic effects both in 0 Oe and 20 kOe
magnetic fields. The sharp peak observed in the R vs. T plot indicates the occurrence of metal-to-insulator (M-I) transition at a temperature of T
MI=110 K and 140 K, for cooling and warming paths, respectively. An applied magnetic field of 20 kOe reduces the resistance
and shifts T
MI to 160 K and 185 K for cooling and warming, respectively. We have observed a much higher resistance in the cooling path than
in the warming path leading to the hysteretic resistance ratio (R
cool/R
warm) of 200 at 110 K and 1.8 at 160 K for 0 Oe and 20 kOe, respectively. Record values of colossal magnetoresistance (CMR) have
been achieved. The CMR value reaches nearly 99% in the temperature ranges of 90 K to 140 K and 90 K to 170 K for 20 kOe and
40 kOe magnetic fields in the cooling mode, respectively. The observed unusual behavior is attributed to the co-existence
of La-rich and Nd-rich domains assumed to be distributed randomly in the compound. 相似文献
10.
ac Conductivity measurements are carried out across the metal to insulator transition in NiAl0.7Cr0.7Fe0.6O4. The low frequency data is analyzed using Summerfield scaling theory for hopping conductivity. The exponent of the scaling
behavior has significantly different values in the conducting and insulating regimes. The hopping frequency and the zero frequency
conductivity are found to increase with temperature, slowly in the metallic regime and rapidly in the insulating regime. 相似文献