Arf GTPase-activating proteins SMAP1 and AGFG2 regulate the size of Weibel-Palade bodies and exocytosis of von Willebrand factor.

Arf GTPase-Activating proteins (ArfGAPs) mediate the hydrolysis of GTP bound to ADP-ribosylation factors (Arfs), which are critical to form transport intermediates. ArfGAPs have been thought to be negative regulators of Arfs; however, accumulating evidence indicates that ArfGAPs are important for cargo sorting and promote membrane traffic. Weibel-Palade bodies (WPBs) are cigar-shaped secretory granules in endothelial cells that contain von Willebrand factor (vWF) as their main cargo. WPB biogenesis at the Golgi was reported to be regulated by Arf and their regulators, but the role of ArfGAPs has been unknown. In this study, we performed siRNA screening of ArfGAPs to investigate the role of ArfGAPs in the biogenesis of WPBs. We found two ArfGAPs, SMAP1 and AGFG2, to be involved in WPB size and vWF exocytosis, respectively. SMAP1 depletion resulted in small-sized WPBs, and the lysosomal inhibitor leupeptin recovered the size of WPBs. The results indicate that SMAP1 functions in preventing the degradation of cigar-shaped WPBs. On the other hand, AGFG2 downregulation resulted in the inhibition of vWF secretion upon Phorbol 12-myristate 13-acetate (PMA) or histamine stimulation, suggesting that AGFG2 plays a role in vWF exocytosis. Our study revealed unexpected roles of ArfGAPs in vWF transport.

Effect of Buffer Layer Capacitance on the Electrical Characteristics of Ferroelectric Polymer Capacitors and Field Effect Transistors.

We demonstrated the effect of a buffer layer on the electrical characteristics of ferroelectric polymer capacitors and field-effect transistors. Various polymer materials with a dielectric constant between 2 and 42 were used to form buffer layers with a similar thicknesses, but with different capacitances. In order to evaluate the characteristics of the ferroelectrics with a buffer layer, the polarization-voltage characteristics of the capacitor, the transfer characteristics, and the retention characteristics of the transistors were investigated. As the capacitance of the buffer layer increased, high remnant polarization (Pr), high hysteresis, and long retention times were observed. Exceptionally, when poly(methylmethacrylate) and rigid poly(aryl ether) (poly(9,9-bis(4-hydroxyphenyl)fluorene-co-decafluorobiphenyl)) were used as the buffer layer, Pr had a value close to 0 in the dynamic measurement polarization-voltage (P-V) characteristic, but the quasi-static measurement transfer characteristic and the static measurement retention characteristic showed relatively high hysteresis and long retention times. Our study provides a scientific and technical basis for the design of ferroelectric memory and neuromorphic devices.

Mechanochemical Drug Conjugation via pH-Responsive Imine Linkage for Polyether Prodrug Micelles.

Prodrug-type polymer-drug conjugates based on highly biocompatible functional polyethers are developed through mechanochemical post-polymerization modification. Herein, we design functional epoxide monomers of ethoxyethyl glycidyl ether (EEGE) and azidohexyl glycidyl ether (AHGE) and synthesize diblock copolyethers of PEEGE-b-PAHGE via sequential anionic ring-opening polymerization. Subsequent conversion of the functional monomers to the corresponding hydroxyl and amine groups allows for the preparation of double hydrophilic block copolyethers. Most notably, mechanochemical modification allows for the conjugation of these polymers with a highly hydrophobic and potent anticancer agent, cinnamaldehyde, through an imine linkage. The self-assembly of the resulting polymer-drug conjugates into polymeric micelles is characterized by dynamic light scattering and atomic force microscopy. The pH-responsive cleavage of the imine linkages under acidic conditions leads to the release of cinnamaldehyde with a concomitant disassembly of the polymeric micelles. The superior biocompatibility coupled with the solvent-less mechanochemical conjugation approach provides a convenient means to introduce various therapeutics for smart drug delivery.

Polyguanamine Derivative-Based Supramolecular Assemblies with Multiple Hydrogen Bonding and Their Metal-Scavenging Abilities.

Polyguanamine derivatives having cyclic moieties constituted by two phenyl and two triazine rings have been synthesized, and a supramolecular organization based on their multiple hydrogen-bonding ability was investigated. The obtained polyguanamine derivatives with cyclic moieties were transparent and amorphous in the bulk state and showed excellent mechanical strength emanating from multiple hydrogen bonds, owing to the abundant amino groups present in the structure. These polyguanamine derivatives formed stable monolayers at the air/water interface. The multilayers were transferred using the Langmuir-Blodgett method, and they formed highly periodic layered structures. To evaluate the metal scavenging ability of the cyclic moieties, the metal ions, Cd2+, Nd3+, and Pd2+, were introduced in the subphase. As a result, the cyclic moieties in the polyguanamine derivatives efficiently captured Cd2+, Nd3+, and Pd2+ metal ions. After the metal was captured, the layered structure of each organized film showed higher periodicity because of rearrangement. Moreover, the annular part had a cup-like structure, and the steric size effect of the ring influenced the metal scavenging.

Preparation of glycoside polymer micelles with antioxidant polyphenolic cores using alkylated poly(arbutin)s.

This paper describes the synthesis of long-chain-alkylated poly(arbutin)s (poly(Arb)-R x , where R = alkyl-chain length and x = degree of substitution (DS)) and their aqueous micelle formation. DS was controlled by tailoring the alkyl reagent/main-chain phenol substituent feed ratio. The critical micelle concentrations (CMCs) of poly(Arb)-R x were determined as 1.3-5.2 mg mL-1 by the surface tension method. Introduction of longer alkyl substituents decreased CMC and also decreased aqueous solubility. In DLS measurement, the average micelle diameters were 225-616 nm, and micelle size decreased with increasing DS because of increased stabilization by hydrophobic alkyl substituents. Transmission electron microscopy indicated that mainly wormlike cylindrical micelles were formed, even with highly hydrophilic polymers. The alkylated polymer exhibited no cytotoxicity, and their antioxidant abilities were evaluated by the ß-carotene bleaching method. Only 0.049 mol equivalents of poly(Arb)-C830 to linoleic acid was sufficient to preserve the ß-carotene.

Elucidation of the Origin of Thixotropic-Inducing Properties of Additive Amphiphiles and the Creation of a High-Performance Triamide Amphiphile.

The spontaneous growth of helical fibers of amphiphilic diamide derivatives containing hydrocarbons with asymmetric carbon centers in their constituent hydrocarbons was investigated. 12-Hydroxystearic acid and a gemini-type surfactant obtained by the bimolecular condensation of this compound with hexamethylenediamine both impart thixotropic ability to a solvent. Although this thixotropic behavior is based on the growth of hierarchical crystalline nanofibers in the solvents, the degree of fiber growth itself was not the origin of the thixotropy. In this study, it has adopted the methods of the Langmuir monolayer and Langmuir-Blodgett films as technique to selectively and individually evaluate the behavior of 12-hydroxyl stearyl and/or stearyl chains themselves. The ability to impart thixotropy to the solvent via fiber organization was related to the intermolecular hydrogen bonding between the added amphiphiles. Additionally, homogeneous right-handed helical fibers were formed in the spin-cast films of the diamide derivatives, and a positive Cotton effect was observed in their circular dichroism spectra. It is suggested that fibers that do not form helical arrangements cannot impart sufficient thixotropy to the solvent even when extensive fiber growth is achieved, and the structure-dependent development of chirality is the driving force. In addition, to further the development of highly functional thixotropic agents, a trefoil-like triamide derivative containing three chains was synthesized. By using this molecule, solvent gelation occurred at 78% as an addition to the diamide case, and a supramolecular assembly was formed in the corresponding two-dimensional film.

Control of Fine Structure in "Polymer Nanosphere Multilayered Organization" and Enhancement of Its Optical Property.

This paper reports on a new functionality exhibited by "polymer nanosphere multilayered organization", a new type of molecular organization, and the relationship between their structure and function. The polymer nanosphere multilayered organization is a fine structural material formed by the accumulation of single-particle layers of a hydrophobic polymer at the air/water interface; these single-particle layers have uniform height along the c-axis. By employing the "alternate compression-relaxation method", high-density, low-defect particle layers are formed with a clear increase in their crystallite sizes. In the case of a ternary comb copolymer containing a carbazole ring, one particle is formed by the assembly of approximately 60 units of collapsed monolayer-like double layers. This structure is stabilized by the formation of side-chain crystals in the interlayer, with oriented π-π stacking of carbazole rings, resulting in enhanced fluorescence emission intensity.

Fabrication and structure of "polymer nanosphere multilayered organization".

We constructed a multiparticle layered organization of aromatic polyamides with rigid main chains and flexible side chains by the Langmuir-Blodgett (LB) technique, which resulted in a highly regular arrangement along the c-axis. The particle arrangement was estimated by performing out-of-plane X-ray diffraction (XRD) analysis and atomic force microscopic (AFM) observation. The results suggest that a double-particle layered structure (Y-type) is formed by the LB technique, forming amphiphilic particles at the air/water interface. Copolymers with highly hydrophobic carbazole contents and both hydrogenated and fluorinated side-chains also formed a single-particle layer at the air/water interface and exhibited multiparticle layers by a LB technique. Therefore, it is possible to control the formation of single- and double-particle layered structure using these techniques. Further, it was found that multiparticle layered organization of polymer nanospheres and polymer nanosheets could be formed simultaneously with the same component material.

One-pot synthesis of linear-hyperbranched amphiphilic block copolymers based on polyglycerol derivatives and their micelles.

This paper describes the one-pot synthesis of a polyglycidol (PG)-based polymer, poly(ethoxyethyl glycidyl ether) (PEEGE)-b-[hyperbranched polyglycerol (hbPG)-co-PEEGE]x/y, its micelle formulation, and the ability to encapsulate a model therapeutic molecule. Amphiphilic block copolymers were prepared by the sequential addition of ethoxyethyl glycidyl ether (EEGE) to glycidol. The composition of the block copolymers varied from 62:38 to 92:8. Block copolymers with composition x:y≥66:34 were soluble only in organic solvents. Micelles were formulated by injection of deionized water into a tetrahydrofuran block copolymer solution with or without pyrene as a model hydrophobic molecule. The critical micelle concentration was 18.2-30.9 mg/L, and the micelle size was 100-250 nm. The pyrene-containing micelle rapidly collapsed on acidic exposure, allowing conversion of hydrophobic PEEGE to hydrophilic PG, thus, facilitating the release of the encapsulated pyrene. Cytotoxicity data showed high biocompatibility of PG-based block copolymers, suggesting their potential as a drug delivery carrier.

Hyperbranched double hydrophilic block copolymer micelles of poly(ethylene oxide) and polyglycerol for pH-responsive drug delivery.

We report the synthesis of a well-defined hyperbranched double hydrophilic block copolymer of poly(ethylene oxide)-hyperbranched-polyglycerol (PEO-hb-PG) to develop an efficient drug delivery system. In specific, we demonstrate the hyperbranched PEO-hb-PG can form a self-assembled micellar structure on conjugation with the hydrophobic anticancer agent doxorubicin, which is linked to the polymer by pH-sensitive hydrazone bonds, resulting in a pH-responsive controlled release of doxorubicin. Dynamic light scattering, atomic force microscopy, and transmission electron microscopy demonstrated successful formation of the spherical core-shell type micelles with an average size of about 200 nm. Moreover, the pH-responsive release of doxorubicin and in vitro cytotoxicity studies revealed the controlled stimuli-responsive drug delivery system desirable for enhanced efficiency. Benefiting from many desirable features of hyperbranched double hydrophilic block copolymers such as enhanced biocompatibility, increased water solubility, and drug loading efficiency as well as improved clearance of the polymer after drug release, we believe that double hydrophilic block copolymer will provide a versatile platform to develop excellent drug delivery systems for effective treatment of cancer.

Surface morphological changes in monolayers of aromatic polyamides containing various N-alkyl side chains.

We synthesized new aromatic polyamides (poly-(N-alkylated benzamides), abbrev. PABA(n)) having both a rigid main chain and a flexible side chain with different lengths. We investigated the solid-state structures, that is, the molecular orientation and surface morphology, of organized molecular films of PABA(n) by performing surface pressure-area (pi-A) isotherm, in-plane and out-of plane X-ray diffraction (XRD), polarized infrared spectroscopy, and atomic force microscopy (AFM) measurements. The solid-state structure of poly-(N-methyl benzamide) (PABA(1)) belonged to the monoclinic system, whereas PABA(3), PABA(4), and PABA(5) showed an orthorhombic packing pattern. PABA(7) and PABA(8) formed amorphous polymers. In the case of PABA(17), a two-dimensional hexagonal lattice was formed as a subcell consisting of side chains. These polymer monolayers were highly condensed on a water surface at 15 degrees C. Out-of-plane XRD measurement results showed that the PABA(1), PABA(3), PABA(4), and PABA(5) multilayers showed large periodicities of 50-60 A. From AFM observation results, it was found that these aromatic polyamides formed single particle layers of hydrophilic groups localized at the bottom of the particles. On the other hand, PABA(7) and PABA(8) monolayers showed irregularity and exhibited shapeless morphologies. In addition, an organized molecular film of PABA(17) formed a highly ordered layer structure (periodicity of 30 A) and a giant circular domain (diameter of 20 nm) made of a side chain crystal. The PABA(17) monolayer showed a hexagonal packing pattern formed due to van der Waals interaction between the flexible side chains. From these experimental findings, it was concluded that the polymer synthesis method employed in the present study can be directly used to control the crystal structure (the third order structure of polymers), molecular arrangement, and surface morphologies of polymer monolayers.

A zinc-containing compound, Polaprezinc, is effective for patients with taste disorders: randomized, double-blind, placebo-controlled, multi-center study.

CONCLUSIONS: The effect of a zinc-containing compound, Polaprezinc, was shown to clinically improve the disease conditions of idiopathic taste disorders with no serious side effects in a well controlled double-blinded clinical study. OBJECTIVES: The purpose of the present study was to evaluate the efficacy and safety of a zinc-containing compound in the treatment of patients with idiopathic taste disorders, including patients with low serum zinc, by a Good Clinical Practice (GCP)-compliant, randomized, placebo-controlled, double-blind, multi-center clinical study. SUBJECTS AND METHODS: A group of 109 patients suffering from taste disorders was assigned into placebo and three treatment groups. Each group of patients was given either placebo (n=28), or 17 mg (n=27), 34 mg (n=26) or 68 mg (n=28) of oral zinc, Polaprezinc preparations, daily for 12 weeks. RESULTS: The group of patients given 68 mg zinc showed a significant improvement in their gustatory sensitivity compared with the placebo group. The most common side effects observed were increase in serum triglyceride and serum alkaline phosphatase, decrease in serum iron, and some gastrointestinal incidents, although they were not serious.

Crosslinked, Glassy Styrenic Surfactants Stabilize Quantum Dots Against Environmental Extremes.

Semiconductor, quantum dot (QD) nanoparticles (including CdSe/ZnS, CdTe/ZnS, and CdSe) were encapsulated within cross-linked shells of amphiphilic polystyrene-block-poly(acrylic acid) block copolymer. Transmission electron microscopy revealed that each particle was surrounded by a uniform, layer of copolymer, and that the average diameter of the resulting QD-core micelles was between 25 and 50 nm, depending on the conditions of particle assembly. Overall, we found that aqueous suspensions of these QDs were substantially more stable to heat and pH than particles with other surface preparations; we argue that the enhanced stability is due to the uniform, hydrophobic coating of polystyrene around each particle and the reinforcement of this layer by shell-cross-linking. The biocompatibility of these particles was investigated by microinjection of particle suspension into live zebrafish embryos. The particles permanently stained the fish vasculature, but did not interfere with the normal development of the fish. We propose that QDs encapsulated in cross-linked block-copolymer shells allow QDs to be used in biological or biotechnological protocols requiring harsh reaction conditions.

Facile synthesis of amine-terminated aromatic polyamide dendrimers via a divergent method.

[structure: see text]. A novel, rapid, inexpensive, and highly efficient divergent approach for the synthesis of a 32-amine-terminated G4 polyamide dendrimer has been developed. Each generation dendrimer was successfully obtained by the condensation of the preceding generation dendrimer with the building block and the deprotection with hydrazine in one pot. All the dendrimers were easily purified by precipitation in alkaline water, and the purity was confirmed by NMR, MALDI-TOF mass spectra, and elemental analysis.

Facile synthesis of aryl ether dendrimer from unprotected AB2 building blocks using thionyl chloride as an activating agent.

[structure: see text] A novel, rapid, inexpensive, and highly efficient convergent approach for the synthesis of a Fréchet- type aryl ether dendrimer using thionyl chloride has been developed. In this method, the purification of each dendron and a dendrimer occurs by recrystallization, extraction, and precipitation. The MALDI-TOF MS spectrum supported the formation of the G2, G3, and G4 dendrons and the star-shaped G4 dendrimer.

Facile synthesis of polyamide dendrimers from unprotected AB2 building blocks.

[structure: see text]. A fast, inexpensive, and highly efficient synthesis of aromatic polyamide dendrimers without the need for protection and deprotection steps has been developed. Dendrons and third-generation polyamide dendrimers were easily prepared by a convergent approach involving activation of a focal point with thionyl chloride, followed by condensation with unprotected AB2 building blocks.

Rapid synthesis of polyamide dendrimers from unprotected AB2 building blocks.

A rapid synthetic method for the preparation of polyamide dendrimer without protection and deprotection steps has been developed. A symmetrically branched third-generation polyamide dendrimer was prepared by a convergent method involving activation of focal point with a condensing agent, diphenyl (2,3-dihydro-2-thioxo-3-benzoxazolyl)phosphonate (DBOP), followed by condensation of the active amide with the diaminocarboxylic acid 3,5-bis(4-aminophenoxy)benzoic acid as an AB2 building block.