Development of Selective TGR5 Ligands Based on the 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene Skeleton

TGR5, a G-protein-coupled receptor (GPCR), plays an important role in several physiological functions. TGR5 activation through bile acids induces an increase in energy expenditure. Therefore, synthetic TGR5 ligands could be useful for the treatment of obesity or dyslipidemia. In this study, we designed and synthesized a set of TGR5 ligands with a 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (TMN) skeleton, and evaluated their TGR5 agonistic activity. We also investigated the selectivity of the synthesized compounds for TGR5 relative to the farnesoid X receptor (FXR) and retinoic acid receptor (RAR). Our results show that compound 4 b [N-(2-chlorophenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxamide] exhibited potent TGR5 agonist activity with an IC₅₀ value of 8.4 nM without significant cytotoxicity. In addition, compound 4 b showed only slight agonistic activity toward FXR and RAR at 1 μM treatment. These data indicate that compound 4 b is a selective TGR5 agonist, and could be a promising therapeutic agent for dyslipidemia.     

Completing causal networks by meta-level abduction

Meta-level abduction is a method to abduce missing rules in explaining observations. By representing rule structures of a problem in a form of causal networks, meta-level abduction infers missing links and unknown nodes from incomplete networks to complete paths for observations. We examine applicability of meta-level abduction on networks containing both positive and negative causal effects. Such networks appear in many domains including biology, in which inhibitory effects are important in several biological pathways. Reasoning in networks with inhibition involves nonmonotonic inference, which can be realized by making default assumptions in abduction. We show that meta-level abduction can consistently produce both positive and negative causal relations as well as invented nodes. Case studies of meta-level abduction are presented in p53 signaling networks, in which causal relations are abduced to suppress a tumor with a new protein and to stop DNA synthesis when damage has occurred. Effects of our method are also analyzed through experiments of completing networks randomly generated with both positive and negative links.     

Development of Millimeter Wave Fabry-Pérot Resonator for Simultaneous Electron-Spin and Nuclear Magnetic Resonance Measurement

We report a Fabry-Pérot resonator with spherical and flat mirrors to allow simultaneous electron-spin resonance (ESR) and nuclear magnetic resonance (NMR) measurements that could be used for double magnetic resonance (DoMR). In order to perform simultaneous ESR and NMR measurements, the flat mirror must reflect millimeter wavelength electromagnetic waves and the resonator must have a high Q value (Q?>?3000) for ESR frequencies, while the mirror must simultaneously let NMR frequencies pass through. This requirement can be achieved by exploiting the difference of skin depth for the two frequencies, since skin depth is inversely proportional to the square root of the frequency. In consideration of the skin depth, the optimum conditions for conducting ESR and NMR using a gold thin film are explored by examining the relation between the Q value and the film thickness. A flat mirror with a gold thin film was fabricated by sputtering gold on an epoxy plate. We also installed a Helmholtz radio frequency coil for NMR and tested the system both at room and low temperatures with an optimally thick gold film. As a result, signals were obtained at 0.18 K for ESR and at 1.3 K for NMR. A flat-mirrored resonator with a thin gold film surface is an effective way to locate NMR coils closer to the sample being examined with DoMR.     

Holographic femtosecond laser processing using optimal-rotation-angle method with compensation of spatial frequency response of liquid crystal spatial light modulator

Holographic femtosecond laser processing performs high-speed parallel processing using a computer-generated hologram (CGH) displayed on a liquid crystal spatial light modulator. A critical issue is to precisely control the intensities of the diffraction peaks of the CGH. We propose a method of compensating for the spatial frequency response in the design of CGH using the optimal-rotation-angle method. By applying the proposed method, the uniformity of the diffraction peaks was improved. We demonstrate holographic femtosecond laser processing with two-dimensional and three-dimensional parallelism.     

Helical Antimicrobial Peptide Foldamers Containing Non-proteinogenic Amino Acids

Antimicrobial peptides (AMPs) are potential novel therapeutic drugs against microbial infections. Most AMPs function by disrupting microbial membranes because of their amphipathic properties and ordered secondary structures. In this minireview, we describe recent efforts to develop helical AMP foldamers containing non-proteinogenic amino acids, such as α,α-disubstituted α-amino acids, β-amino acids, γ-amino acids, side-chain stapling and N-alkyl glycines.     

Behaviour of bismuth during simulated processing of model aluminium capacitor foils

The production of high specification, aluminium-based, electrolytic capacitors requires optimization of material composition and heat and surface treatments in order to maximize the area available for formation of the dielectric, anodic film. Commercial foils contain low additions of copper and lead in order to achieve this goal. The present study examines the effects of heat and surface treatments on aluminium foil containing either 50 or 1000 ppm bismuth, as a replacement for lead, by a combination of Rutherford backscattering spectroscopy and scanning electron microscopy. Heat treatment at 823 K results in segregation of bismuth to the surface regions of the foils, with enrichments in the range 4–8 × 10¹⁴ Bi atoms cm^–2, localized mainly just beneath the thermal oxide, for the selected treatment conditions. The enrichment reduces following alkaline etching, to the range 1–4 × 10¹⁴ Bi atoms cm^–2. This level of enrichment is maintained during subsequent anodizing, with the enrichment partitioned between the metal and the outermost layers of the anodic films. The enrichment of the metal is about 4 × 10¹³ Bi atoms cm^–2. Electropolishing in perchloric acid solution eliminates the enrichment developed during the heat treatment, probably due to activation during the polishing process. The enrichment remains very low or negligible during subsequent anodizing. The general behaviours of bismuth and lead are similar in aluminium foils subject to the selected heat and surface treatments. However, additional studies are needed of tunnel etching to determine the feasibility of substitution of lead by bismuth in commercial foils.     

Hypoalbuminemia is an important risk factor of hypotension during hemodialysis

Hypotension during hemodialysis (HD) is an important problem in patients on HD. To investigate the risk factors that contribute to the hypotension during HD, we compared background factors of hypotensive (HP) patients during HD. Among 58 patients undergoing HD in Tamura Memorial Hospital, 12 patients could not continue full HD because of hypotension. We compared the data of ultrafiltration volume, cardiothoracic ratio (CTR), total protein (TP), serum albumin, blood urea nitrogen (BUN), serum creatinine, total cholesterol (TC), hemoglobin (Hb), blood glucose (BS), brain natriuretic peptide (BNP), and cardiac function between HP patients (HP group; n=12) and sex- and age-matched control patients (NP group; n=12). There were no significant differences of age, sex, and duration of HD between the 2 groups. Cardiothoracic ratio is bigger and BNP is higher in the HP group compared with the NP group (CTR: HP 55.8+/-2.9% vs. NP 47.7+/-1.1%, p=0.0165; BNP: HP 602+/-171 vs. NP 147+/-38, p=0.0167). Serum albumin in the HP group is significantly lower compared with the NP group (HP 3.2+/-0.1 g/dL vs. NP 3.5+/-0.1 g/dL, p=0.0130). However, there were no significant differences of ultrafiltration rate (UFR), BS, TC, Hb, and cardiac function between the 2 groups. There is a significant negative correlation between changes of systolic blood pressure (delta systolic blood pressure) and serum albumin in these patients (r=-0.598, p=0.0016). From these data, we conclude that hypoalbuminemia is a major risk factor of hypotension during HD.     

Enrichment behaviour of gallium in heat and surface treatments of Al–Ga foils

The behaviour of gallium is examined after heat and surface treatments of aluminium foils containing either 120 or 1300 ppm gallium, with low enrichments of gallium at the surfaces arising from foil manufacture. Vacuum heat treatment at 823 K for 20 ks caused negligible additional enrichment, probably associated with the high solubility of gallium in aluminium. Subsequent alkaline etching in 0.25 M sodium hydroxide for 60 s at 348 K increased significantly enrichments, to about 3.2×10¹⁴ and 3.6×10¹⁵ Ga atoms cm⁻² for the foils containing 120 and 1300 ppm gallium respectively. The enrichments were probably located in both the metal and the overlying etching products. In contrast, electropolishing in perchloric acid/ethanol eliminated pre-existing enrichments, probably due to activation of the foil, with no enrichment developing during the electropolishing procedure. Barrier-type anodic films formed on the alkaline-etched foils contained gallium species, with increased concentrations at the film surface. Gallium enriched the metal region immediately beneath the anodic film during anodizing and led eventually to detachment of the growing film from the etched foil, followed by growth of a second film beneath the detached film. The combined amounts of gallium in the anodic film and enriched metal layer were similar to the levels at the surface regions of the etched foils. The anodic films formed on the electropolished foils, with no pre-existing enrichment, were free of gallium species and remained attached to the foils, since insufficient gallium could enrich in the metal beneath the anodic film during the relatively short period of anodizing.     

DNA adsorption characteristics of hollow spherule allophane nano-particles

To understand the propensity of natural allophane to adsorb the DNA molecules, the adsorption characteristics were assessed against natural allophane (AK70), using single-stranded DNA (ss-DNA) and adenosine 5′-monophosphate (5′-AMP) as a reference molecule. The adsorption capacity of ss-DNA on AK70 exhibited one order of magnitude lower value as compared with that of 5′-AMP. The adsorption capacity of ss-DNA decreased with increasing pH due to the interaction generated between phosphate groups of ss-DNA and functional Al–OH groups on the wall perforations through deprotonating, associated with higher energy barrier for the adsorption of ss-DNA. The adsorption morphologies consisting of the individual ss-DNA with mono-layer coverage of the clustered allophane particle were observed successfully through transmission electron microscopy analysis.     

DNA-lipid complexes carrying carbazole and triphenylamine moieties: Synthesis, and chiroptical and photoelectronic properties

Novel DNA-lipid complexes carrying carbazole and triphenylamine moieties were prepared by substituting the sodium counter cation with cationic amphiphilic lipids, namely lipid(Cz) and lipid(TPA), in which the actual mole ratios of phosphate to lipid were 1:1.10 and 1:0.83, respectively. The DNA-lipid(Cz) and DNA-lipid(TPA) complexes were soluble in common organic solvents including CHCl₃, CH₂Cl₂, methanol and ethanol, while insoluble in THF, toluene, and aqueous solutions. CD spectroscopy revealed that the DNA-lipid complexes took a predominantly double helical structure in CHCl₃ and methanol and that the helical structure was fairly stable against heating. Solutions of DNA-lipid(Cz) and DNA-lipid(TPA) complexes emitted fluorescence in 5.7 and 76.4% quantum yields, which were higher than those of the corresponding lipid(Cz) and lipid(TPA) (4.4 and 55.3%). The cyclic voltammograms of the complexes indicated that the oxidation potentials of DNA-lipid(Cz) and DNA-lipid(TPA) were 0.95 and 0.85 V, respectively. The onset temperatures of weight loss of the DNA-lipid complexes were both 220 °C according to TGA in air.