Changes in extracellular nitrite and nitrate levels after inhibition of glial metabolism with fluorocitrate

The role of glial cells in nitric oxide production in the cerebellum of conscious rats was investigated with a glial selective metabolic inhibitor, fluorocitrate. The levels of nitric oxide metabolites (nitrite plus nitrate) in the dialysate following in vivo microdialysis progressively increased to more than 2-fold the basal levels during a 2-h infusion of fluorocitrate (1 mM), and the increase persisted for more than 2 h after the treatment. Pretreatment with N(G)-nitro-L-arginine methyl ester attenuated the fluorocitrate-induced increase in nitric oxide metabolite levels. None of the glutamate receptor antagonists, including D(-)-2-amino-5-phosphonopentanoic acid, 6,7-dinitroquinoxaline-2,3-dione, and (+/-)-alpha-methyl-4-carboxyphenylglycine, inhibited the fluorocitrate-induced increase. The L-arginine-induced increase was significantly reduced by fluorocitrate treatment, while N-methyl-D-aspartate, (+)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and trans-(+/-)-1-amino-(1S,3R)-cyclopentane-dicarboxylic acid increased nitric oxide metabolites levels in the fluorocitrate-treated rats, as much as in control animals. These results suggest that glial cells play an important role in modulating nitric oxide production in the cerebellum by regulating L-arginine availability.     

On-line neuro-expert monitoring system for Borssele Nuclear Power Plant

A new method for an on-line monitoring system for the nuclear power plants has been developed utilizing the neural networks and the expert system. The integration of them is expected to enhance a substantial potential of the functionality as operators support.

The recurrent neural network and the feed-forward neural network with adaptive learning are selected for the plant modeling and anomaly detection because of the high capability of modeling for dynamic behavior. The expert system is used as a decision agent, which works on the information space of both the neural networks and the human operators. The information of other sensory signals is also fed to the expert system, together with the outputs that the neural networks generate from the measured plant signals. The expert system can treat almost all known correlation between plant status patterns and operation modes as a priori set of rules.

From the off-line test at Borssele Nuclear Power Plant (PWR 480 MWe) in the Netherlands, it was shown that the neuro-expert system successfully monitored the plant status. The expert system worked satisfactorily in diagnosing the system status by using the outputs of the neural networks and a priori knowledge base from the PWR simulator. The electric power coefficient is simultaneously monitored from the measured reactive and active electric power signals.     

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.     

Effects of dietary vegetable oils on behavior and drug responses in mice

Previously, we noted significant differences in the behavioral patterns of mice fed safflower oil with a very low alpha-linolenate/linoleate ratio and perilla oil with a high alpha-linolenate/linoleate ratio from mothers to offsprings. In this report, we compared the behavior and drug responses in mice fed diets containing six different vegetable oils-corn, rapeseed, soybean, safflower, perilla and a mixture of perilla and safflower oils- for a relatively short period: 8 months after weaning. Soybean oil is a component of most conventional diets and was used as a control. The alpha-linolenate/linoleate ratios of the oils appeared to affect the locomotor activities in a wheel cage: the activity decreased in the order of safflower, the mixture (1:1) and the perilla oil groups. However, the rapeseed oil group exhibited much higher locomotor activity than that expected from the alpha-linolenate/linoleate ratio. Additionally, the rapeseed oil group exhibited unusual behavior patterns, including higher ambulation and rearing activities, faster acquisition of the water maze task and slower habituation behavior as compared with the control group. Susceptibility to pentobarbital anesthesia tended to be higher in the rapeseed oil group. The differences in the alpha-linolenate/linoleate ratios of these oils alone do not account for the observed differences in the behavioral patterns among the six dietary groups. Although we cannot exclude the possibility that the observed behavioral anomaly is due to the unique fatty acid composition of rapeseed oil, we speculate that a factor(s) other than fatty acids in rapeseed oil affected nervous system functions.     

Temperature Dependence of the Velocity of Sound in Liquid Metals of Group XIV

The temperature dependences of the velocity of sound in liquid Pb, Sn, Ge, and Si have been measured by means of the pulse transmission technique over temperature ranges of 610–1078 K, 608–1463 K, 1215–1443 K, and 1723–1888 K, respectively. In both liquid Pb and Sn, the velocities of sound decrease linearly with increasing temperature, which is the same temperature dependence as shown in many other liquid metals. On the other hand, the velocities of sound in liquid Ge and Si exhibit anomalous temperature dependences. In Ge, the velocity of sound has a distinct maximum around 1280 K and decreases linearly at higher temperatures. In Si, the velocity of sound increases monotonically with increasing temperature in the temperature range investigated. It is considered that these results predict that the coordination numbers of liquid Ge and Si increase with increasing temperature.     

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.     

Stereospecific synthesis of ditactic polymers

Summary Polymerizations of t-butyl crotonate (E-TBC) and t-butyl isocrotonate (Z-TBC) were carried out in toluene at-78°C using t-BuMgBr as initiator. E-TBC gave polymers, whereas Z-TBC did not. The dimer of E-TBC isolated from the polymerization mixture by means of GPC contained predominatly one of the four possible diastereomers. X-ray crystallographic determination showed that the predominant dimer was the erythro-diisotactic isomer. t-BuLi/Et₃Al polymerized effectively both E-TBC and Z-TBC in toluene. The poly(E-TBC)s prepared with t-BuMgBr and t-BuLi/Et₃Al were insoluble in toluene, THF, and chloroform, but soluble in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). Stereostructure of the poly(TBC)s was analyzed by the one- and two-dimensional NMR spectra measured in HFIP. The poly(E-TBC) prepared with t-BuMgBr was a 1:1 mixture of the erythro- and threo-diisotactic polymers with high stereoregularity. The poly(E-TBC) and poly(Z-TBC) obtained from the polymerizations with t-BuLi/Et₃Al were rich in disyndiotactic structure. Polymerization of TBCs with t-BuLi in toluene and THF was also studied.

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Klotho protein protects against endothelial dysfunction

Viral respiratory infections cause acute airway abnormalities consisting of inflammation and physiological dysfunction in both animals and humans. It is likely that inflammatory cell products, such as cytokines, contribute substantially to viral-induced airway dysfunction. We hypothesized that imiquimod, an immune response enhancing agent that induces interferon-alpha, would attenuate the development of airway dysfunction during acute viral illness in rats. Adult Brown Norway rats were inoculated with parainfluenza type 1 (Sendai) virus or sterile vehicle, and treated with either imiquimod or water. Respiratory system resistance (Rrs), arterial oxygen tension (Pa,O2), lung viral titres and bronchoalveolar lavage (BAL) leucocyte counts were measured in anaesthetized, paralysed, ventilated rats. Virus-infected, water-treated rats had a significant decrease in Pa,O2 and had significant increases in leucocyte count and Rrs when compared to both the virus-infected, imiquimod-treated, (Pa,O2, p = 0.03; leucocyte count, p = 0.02; and Rrs, p = 0.009) and noninfected, water-treated rats (Pa,O2, p = 0.007; leucocyte count, p = 0.001; and Rrs, p = 0.01). In addition, imiquimod suppressed BAL eosinophils in both virus-infected (p = 0.02) and noninfected (p = 0.001) groups, and lowered overall virus titres (p = 0.03). Thus, both virus-induced airway inflammation and physiological dysfunction were attenuated significantly by imiquimod treatment in this animal model. By further delineating mechanisms by which infections induce airway dysfunction in animal models, more specific pharmacological interventions can be developed for the treatment of virus-induced asthma.