Peptide and protein mimetics inhibiting amyloid beta-peptide aggregation

Protein misfolding is related to some fatal diseases including Alzheimer's disease (AD). Amyloid beta-peptide (Abeta) generated from amyloid precursor protein can aggregate into amyloid fibrils, which are known to be a major component of Abeta deposits (senile plaques). The fibril formation of Abeta is typical of a nucleation-dependent process through self-recognition. Moreover, during fibrillization, several metastable intermediates such as soluble oligomers, including Abeta-derived diffusible ligands (ADDLs) and Abeta*56, are produced, which are thought to be the most toxic species to neuronal cells. Therefore, construction of molecules that decrease the Abeta aggregates, including soluble oligomers, protofibrils, and amyloid fibrils, might further our understanding of the mechanism(s) behind fibril formation and enable targeted drug discovery against AD. To this aim, various peptides and peptide derivatives have been constructed using the "Abeta binding element" based on the structural models of Abeta amyloid fibrils and the mechanisms of self-assembly. The central hydrophobic amino acid sequence, LVFF, of Abeta is a key sequence to self-assemble into amyloid fibrils. By combination of this core sequence with a hydrophobic or hydrophilic moiety, such as cholic acid or aminoethoxy ethoxy acetic acid units, respectively, good inhibitors of Abeta aggregation can be designed and synthesized. A peptide, LF, consisting of the sequence Ac-KQKLLLFLEE-NH 2, was designed based on the core sequence of Abeta but with a simplified amino acid sequence. The LF peptide can form amyloid-like fibrils that efficiently coassemble with mature Abeta1-42 fibrils. The LF peptide was also observed to immediately transform the soluble oligomers of Abeta1-42, which are thought to pose toxicity in AD, into amyloid-like fibrils. On the other hand, two Abeta-like beta-strands with a parallel orientation were embedded in green fluorescent protein (GFP), comprised of a beta-barrel structure, to make pseudo-Abeta beta-sheets on its surface. The GFP variant P13H binds to Abeta1-42 and inhibits Abeta1-42 oligomerization effectively in a substoichiometric condition. Thus, molecules capable of binding to Abeta can be designed based on structural similarities with the Abeta molecule. The peptide and protein mimetics based on the structural features of Abeta might lead to the development of drug candidates against AD.     

Hydrogen‐bonding interaction between poly(ε‐caprolactone) and low‐molecular‐weight amino compounds

The specific interactions between several low‐molecular‐weight diamino compounds and poly(ε‐caprolactone) (PCL) have been investigated by FT‐IR. It was found that PCL and 3,3′‐diaminodiphenylmethane (3,3′‐DADPM) interact through strong intermolecular hydrogen bonds in the blend. Thermal and mechanical properties of PCL/3,3′‐DADPM blends were investigated by DSC and tensile measurements, respectively. The glass transition temperature of the blend increases while both the melting point and the elongation‐at‐break of the blend decrease with the increase of 3,3′‐DADPM content. Besides 3,3′‐DADPM, several other low‐molecular‐weight compounds containing two amino groups, such as o‐phenylenediamine or 1,6‐diaminohexane, were also added into PCL and the corresponding blend systems were investigated by FT‐IR and DSC. The effect of the chemical structure of the additives on the properties of PCL is discussed. © 2001 Society of Chemical Industry     

Chemical Modification of Phage-Displayed Helix-Loop-Helix Peptides to Construct Kinase-Focused Libraries

Conformationally constrained peptides hold promise as molecular tools in chemical biology and as a new modality in drug discovery. The construction and screening of a target-focused library could be a promising approach for the generation of de novo ligands or inhibitors against target proteins. Here, we have prepared a protein kinase-focused library by chemically modifying helix-loop-helix (HLH) peptides displayed on phage and subsequently tethered to adenosine. The library was screened against aurora kinase A (AurA). The selected HLH peptide Bip - 3 retained the α-helical structure and bound to AurA with a K_D value of 13.7 μM. Bip - 3 and the adenosine-tethered peptide Bip - 3 - Adc provided IC₅₀ values of 103 μM and 7.7 μM, respectively, suggesting that Bip - 3 - Adc bivalently inhibited AurA. In addition, the selectivity of Bip - 3 - Adc to several protein kinases was tested, and was highest against AurA. These results demonstrate that chemical modification can enable the construction of a kinase-focused library of phage-displayed HLH peptides.     

Realization of an extremely low reflectance surface based on InP porous nanostructures for application to photoelectrochemical solar cells

Extremely low reflectance was obtained from InP porous nanostructures in UV, visible, and near-infrared ranges. Porous samples were electrochemically prepared on which 130-nm-diameter nanopores were formed in a straight, vertical direction and were laterally separated by 50-nm-thick InP nanowalls. The reflectance strongly depended on the surface morphology. The lowest reflectance of 0.1% in the visible light range was obtained after the irregular top layer had been completely removed. Superior photoelectrochemical properties were obtained on the InP porous structures due to two unique features: the large surface area inside pores, and the large photon absorption enhanced on the low reflectance surface.     

Conditional transformation of immunoglobulin mutation pattern from gene conversion into point mutation by controlling XRCC3 expression in the DT40 B cell line

A hypermutating B cell line DT40 is useful for screening antibodies and improving affinity of the selected antibodies in vitro. To perform affinity maturation efficiently, we generated an engineered DT40 line whose immunoglobulin mutation pattern can be transformed from gene conversion into point mutation by conditional suppression of XRCC3 expression.     

Structure of effective catalyst layers around bubbles in a fluidized catalyst bed

In a fluidized catalyst bed, the reactant gas transfers from the bubble phase to the emulsion phase and reactions proceed in the emulsion phase. The catalyst particles around the bubbles should contact the gases containing a high concentration of the reactants. Therefore, the effect of the catalysts around the bubbles is very important for estimating the conversion and selectivity in the reactor. In order to study the role of these catalysts, the hydrogenation of carbon dioxide was carried out in a fluidized catalyst bed. Based on the results, the amount of the catalyst that was effective for the reaction was calculated. In addition, the shape of the bubbles ascending in the fluidized catalyst bed was observed using a fast X-ray computer tomography (CT) scanner. The structure of the bubbles in the fluidized catalyst bed was very complicated and the surface area of the bubbles was much greater than the obtained when assuming spherical shaped bubble. By assuming that effective catalysts existed around the bubbles, the thickness of catalyst layer was obtained. Finally, the 3-dimensional images of the catalyst layers around the bubbles were reconstructed.     

Influence of Bile Salts on the Permeability Through the Nasal Mucosa of Rabbits of Insulin in Comparison with Dextran Derivatives

The nasal drug absorption and the effect of absorption promoters have been studied in rabbits. Nasal mucosa excised from rabbits was mounted as a flat sheet in an in vitro chamber. The result indicates that the change in the porosity of the membrane by pretreatment with bile salts increased the permeability coefficient of sodium chloride in the nasal membrane. The permeabilities of dextran derivatives were enhanced by pretreatment with sodium glycocholate (GC). The permeability coefficient (P) of fluorescein isothiocyanate diethylaminoethyl dextran     

Improvement of strength distribution inside slab concrete by vacuum dewatering method

The strength and hardness of concrete slab surface is considered significantly affected by bleeding of concrete. It has been reported that dewatering by vacuum processing is quite effective to obtain high density of concrete. The method, however, has not been successfully used for the concrete work in the field of building construction, compared with that of civil engineering works in Japan. In the present study, firstly the state of the art concerning vacuum dewatering method is reviewed and the newly improved vacuum dewatering method is introduced. Then the effect of the proposed method on concrete properties of slab is examined by a series of experiments in order to find more reasonable and effective way in the application of the proposed method.     

Improved Filtration Performance of Continuous Alumina-fiber-reinforced Mullite Composites for Hot-Gas Cleaning

The effect of filtration layer morphology on filtration performance at 673 K was investigated for continuous alumina-fiber-reinforced mullite composite filters that capture fly ash on their outer surfaces. Two types of filtration layers were prepared on the outer surfaces: a mono-layer consisting of mullite agglomerated particulates and a bi-layer, with mullite whiskers formed by a vapor-phase reaction and strongly adhered to the particulates exposed on the outer surfaces. For filters with mono-filtration layers, the filtration efficiency was improved slightly by increasing the filtration layer thickness. However, the maximum differential pressure increased during the filtration tests. Adhesion of whiskers to the outer surface decreased the maximum differential pressure to about one-third less than that with the mono-filtration layer. This low differential pressure remained constant throughout the duration of the test, with corresponding increases in filtration efficiency.     

Titanium aluminide coating on titanium surface using three-dimensional microwelder

Feasibility of a new method of titanium aluminide coating on titanium surface based on a reaction between aluminum liquid beads and the surface of titanium substrate has been studied using a computer-aided three-dimensional microwelder (3DMW) designed by the present authors. A predetermined length of thin aluminum wire was fed onto the substrate surface, and a spark was stricken from a thin electrode of a W-Ce₂O₃ alloy to make a small aluminum liquid bead on the substrate surface and to simultaneously melt a small area of the substrate surface beneath the bead. All conditions including the length of the wire feeding, the position of the electrode, electric power, etc. had been programmed beforehand. The liquid bead containing aluminum and titanium rapidly solidified on the titanium substrate surface producing titanium aluminides on it. Repetition of the aluminum wire feeding, the electrode positioning and the spark striking produced a coating layer consisting of sub-layers of TiAl₃, TiAl and Ti₃Al from the surface side to the substrate side. Vickers hardness and wear resistance of the coated sample were remarkably improved.