CXCR4 Stimulates Macropinocytosis: Implications for Cellular Uptake of Arginine-Rich Cell-Penetrating Peptides and HIV

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Highlights? CXCR4 was identified as a receptor to stimulate cellular uptake of R12 peptide ? Interaction with R12 stimulates internalization of CXCR4 via macropinocytosis ? SDF-1α and HIV-1 gp120 protein also induce macropinocytosis ? Macropinocytic uptake of HIV-1 diminished the infection of host cells     

Active Site Models for the Cu(A) Site of Peptidylglycine α-Hydroxylating Monooxygenase and Dopamine β-Monooxygenase

A mononuclear copper(II) superoxo species has been invoked as the key reactive intermediate in aliphatic substrate hydroxylation by copper monooxygenases such as peptidylglycine α-hydroxylating monooxygenase (PHM), dopamine β-monooxygenase (DβM), and tyramine β-monooxygenase (TβM). We have recently developed a mononuclear copper(II) end-on superoxo complex using a N-[2-(2-pyridyl)ethyl]-1,5-diazacyclooctane tridentate ligand, the structure of which is similar to the four-coordinate distorted tetrahedral geometry of the copper-dioxygen adduct found in the oxy-form of PHM (Prigge, S. T.; Eipper, B. A.; Mains, R. E.; Amzel, L. M. Science2004, 304, 864-867). In this study, structures and physicochemical properties as well as reactivity of the copper(I) and copper(II) complexes supported by a series of tridentate ligands having the same N-[2-(2-pyridyl)ethyl]-1,5-diazacyclooctane framework have been examined in detail to shed light on the chemistry dictated in the active sites of mononuclear copper monooxygenases. The ligand exhibits unique feature to stabilize the copper(I) complexes in a T-shape geometry and the copper(II) complexes in a distorted tetrahedral geometry. Low temperature oxygenation of the copper(I) complexes generated the mononuclear copper(II) end-on superoxo complexes, the structure and spin state of which have been further characterized by density functional theory (DFT) calculations. Detailed kinetic analysis on the O(2)-adduct formation reaction gave the kinetic and thermodynamic parameters providing mechanistic insights into the association and dissociation processes of O(2) to the copper complexes. The copper(II) end-on superoxo complex thus generated gradually decomposed to induce aliphatic ligand hydroxylation. Kinetic and DFT studies on the decomposition reaction have suggested that C-H bond abstraction occurs unimolecularly from the superoxo complex with subsequent rebound of the copper hydroperoxo species to generate the oxygenated product. The present results have indicated that a superoxo species having a four-coordinate distorted tetrahedral geometry could be reactive enough to induce the direct C-H bond activation of aliphatic substrates in the enzymatic systems.     

Molecular‐Complex Formation of Syndiotactic Polystyrene with Stable Radical Molecules

Summary: The formation of a molecular‐complex crystalline phase of syndiotactic polystyrene (sPS) that contains a stable nitroxide radical compound, 2,2,6,6‐tetramethylpiperidinyl‐N‐oxyl (TEMPO), is confirmed by IR and electron spin resonance (ESR) spectroscopy, X‐ray diffractometry, and thermogravimetric analysis. Through a guest exchange procedure assisted by a plasticizing agent, the original guest (chloroform) contained in the starting clathrate phase is completely replaced by TEMPO. Although the conformational regularity of the sPS helices in the resultant crystalline phase that contains TEMPO is similar to that in the starting clathrate phase, the host lattice expands in the 010 direction. The guest TEMPO molecules exhibit a significantly broadened ESR signal because of their highly concentrated state in the complex crystalline phase.

Thermogravimetric measurement of a powder sample of the sPS/TEMPO complex.     

Mixed Dimer Formation in Binary and Ternary Mixtures of Liquid Crystalline 4-Substituted Benzoic Acids

Mixed dimer formation is studied for a wide variety of 4-substituted benzoic acids that form liquid crystalline phases. The solid-mesophase transitions can show double eutectics when mixed dimer formation occurs, but in many cases the equilibrium constant for such a mixed dimer is extremely small. The mesophase-isotropic transitions are essentially linear over the entire phase diagram. Ternary mixtures can be created having nematic ranges of over 80° by virtue of eutectization.     

HPLC with fluorescence detection assay of perampanel,a novel AMPA receptor antagonist,in human plasma for clinical pharmacokinetic studies

Perampanel (Fycompa®), a novel α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, is registered for the adjunctive treatment of patients (aged ≥12 years) with refractory partial‐onset seizures. To support therapeutic drug monitoring, a simple high‐performance liquid chromatography (HPLC) assay with fluorescence detection was developed to determine perampanel concentrations in human plasma and validated to support clinical trials. Human plasma samples (1.0 mL) were processed by liquid extraction using diethyl ether, followed by chromatographic separation on a YMC Pack Pro C₁₈ column (150 × 4.6 mm i.d., 5 µm) with isocratic elution of acetonitrile–water–acetic acid–sodium acetate (840:560:3:1.8, v/v/v/w) at a flow rate of 1.0 mL/min. Column eluent was monitored at excitation and emission wavelengths of 290 and 430 nm, respectively. The assay was linear (range 1.0–500 ng/mL) and this could be extended to 25 µg/mL by 50‐fold dilution integrity. No endogenous peaks were detected in the elution of analytes in drug‐free blank human plasma from six individuals and no interference was observed with co‐medications tested. Intra‐ and inter‐batch reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. Validation data demonstrated that our assay is simple, selective, reproducible and suitable for therapeutic drug monitoring of perampanel. Copyright © 2015 John Wiley & Sons, Ltd.     

Design and Analysis of Compact Directionally Coupled Bistable Laser Diodes

A compact optical flip-flop with a directional coupler has been designed and analyzed. Using a narrow gap directional coupler, we have predicted the device length could be reduced down to 500 μm from 1300 μm.     

La2-xSrxCu1-yZnyO4: Tc and ns/m* correlations seen with muon spin rotation

We report the muon spin rotation experiments on Zn substituted La_1-x Sr_x CuO₄, for four zinc concentrations y=0.0,0.0025,0.005,0.01, at strontium concentrations x=0.15,0.20. We find that T_ c in the optimally doped (x=0.15) and overdoped (x=0.20) 2:1:4 decreases linearly with increasing zinc concentration. Plotted against the planar zinc concentration, the T_c’s of both series seem to fall on the same line. The superconducting carrier density/effective mass ratio, n_ s/m^*, at first decreases linearly, rising above this line for higher zinc concentrations. This behavior may result from the localization of carriers in an area \xi_ab around each zinc atom. This revised version was published online in August 2006 with corrections to the Cover Date.     

High-power CO(2) laser with a Gauss-core resonator for high-speed cutting of thin metal sheets

A novel resonator, the Gauss-core resonator, based on a stable resonator configuration designed to yield a highly focusing beam operating in a large-volume TEM(00) mode, is presented. A 6.2 kW linearly polarized output beam with an M(2) factor of 1.7 is obtained experimentally for a high-power cw CO(2) laser. The capability of the Gauss-core resonator to process laser materials is also studied. We can cut 1-mm-thick mild (soft) steel with a maximum cutting speed of 58 m/min at 5.6 kW and 0.2-mm-thick steel 145 m/min at 2.8 kW.