Structure–Activity Relationship,Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent,Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist

The orexin system consists of two G‐protein‐coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB‐649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT‐462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non‐rapid eye movement (non‐REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT‐462206 shows anxiolytic‐like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.     

Evidence for a Substrate-Borne Sex Pheromone in the Parasitoid Wasp Trichogramma brassicae

While the use of chemical cues in host location is well known in parasitoid insects, little is known about their role in sexual communication. Sex pheromones were investigated in the egg parasitoid Trichogramma brassicae, and the evidence for a substrate-borne pheromone was demonstrated. Mated and unmated males concentrated their walking in an area where virgin females (<1 or 5 days old) had walked. Males were tested 15 min after females left the area. Male response decreased over time but was always significant during the 8 min of tracking. This suggests that females deposit chemicals on the substrate for mate finding. The pheromone is soluble in hexane, as shown by two kinds of extracts: female body rinsing and rinsing of the flask where females had walked. Hexane extracts resulted in a positive response by males. The response to different doses showed a saturation above a threshold of 4–8 female equivalents. The results do not exclude the possibility that a volatile part of the pheromone attracts males over long distances. Substrate-borne pheromones may increase mating chances for virgin females searching for oviposition sites, and may also increase mating chances on emergence sites by reducing male dispersion.     

Diffusion During the Supercritical Drying of Silica Gels

Drying is the most critical elaboration step of large monolithic and crack-free silica aerogel plates. In the present work, we are studying the supercritical CO₂ drying and more precisely the first step, here called the supercritical washing step. This phase consists of replacing the liquid phase contained in the nanopores with supercritical CO₂. Within this study, this step is governed by molecular diffusion through the gels. These phenomena were investigated experimentally in order to estimate the duration of the washing step. The experimental results were then fitted with an analytical mass transfer model to identify the effective diffusion coefficient.     

A global security architecture for intrusion detection on computer networks

Detecting all kinds of intrusions efficiently requires a global view of the monitored network. Built to increase the security of computer networks, traditional IDS's are unfortunately unable to give a global view of the security of a network. To overcome this situation, we are developing a distributed SOC (Security Operation Center) which is able to detect attacks occurring simultaneously on several sites in a network and to give a global view of the security of that network. In this article, we present the global architecture of our system, called DSOC as well as several methods used to test its accuracy and performance.     

Cross‐linking of polybutadiene: correlation between solid‐state 1H NMR spectroscopy,thermoporosimetry, densimetry and crystallinity measurements

T₂ proton NMR relaxation times were used to follow the changes in the macromolecular chain mobility of a chemically (by dicumyl peroxide) cross‐linked polybutadiene matrix. The same phenomenon was also studied by an investigation of the ability of the polymer to crystallize using DSC measurements. The solubility of the elastomer depends on the size of its macromolecular chains. Cross‐linking, leading to an increase in the size of macromolecules, provokes an insolubility of the elastomer. By densimetry measurements, it was possible to follow the changes in the solubility of the polymer up to its gel‐point. Beyond the gel‐point, the swelling solvent, cyclohexane, was used as a textural probe. Using the shift of its solid‐solid thermal transition points, it was possible to calculate the distribution of the distances between the cross‐links as a function of the curing times by thermoporosimetry analysis. Copyright © 2003 Society of Chemical Industry     

ANSWAPPS: Model for the Analysis of Grass Swale-Perforated Pipe Systems

A computer model for the analysis and design of grass swale perforated pipe systems is presented. The model, which was calibrated and validated using experimental as well as field data, performs detailed computations for flow through the system on a lot by lot basis (i.e., from one catchbasin to another). Several parameters affecting the system performance are considered in the modeling approach. These especially included lot size and imperviousness, grass swale dimensions and its infiltration capacity, pipe length, number of orifices and their configuration, trench dimensions, and native soil infiltration capacity. The model was used to simulate the minimum trench depth required to capture runoff from a 25?mm storm for different native soils and different lot imperviousness ratios. Trench depths varied from 0.3 to 1.4?mm depending on native soil infiltration capacity and lot imperviousness.     

Acute effects of dietary fatty acids on the fatty acids of human milk

1. Effects on 5-HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)-fenfluramine and (+)-amphetamine. 2. In vitro sibutramine weakly inhibited [3H]-5-HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [3H]-5-HT uptake inhibitors, whereas (+)-fenfluramine and (+)-amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [3H]-5-HT from brain slices at < or = 10(-5)M, (+)-fenfluramine and (+)-amphetamine concentration-dependently increased [3H]-5-HT release. 3. Sibutramine and fluoxetine had no effect on 5-hydroxytryptophan (5-HTP) accumulation in either frontal cortex or hypothalamus at doses < 10 mg kg(-1). In contrast, (+)-amphetamine ( > or = 3 mg kg(-1)) reduced 5-HTP in hypothalamus, whilst (+)-fenfluramine (> or =1 mg kg(-1)) decreased 5-HTP in both regions. 4. Sibutramine (10 mg kg(-1) i.p.) and fluoxetine (10 mg kg(-1) i.p.) produced slow, prolonged increases of extracellular 5-HT in the anterior hypothalamus. In contrast, (+)-fenfluramine (3 mg kg(-1) i.p.) and (+)-amphetamine (4 mg kg(-1) i.p.) induced rapid, short-lasting increases in extracellular 5-HT. 5. Only (+)-fenfluramine (10 mg kg(-1)) altered 5-HT2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity. 6. These results show that sibutramine powerfully enhances central 5-HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5-HT uptake inhibition. By contrast, (+)-fenfluramine enhances 5-HT function predominantly by increasing 5-HT release. (+)-Amphetamine, though weaker than (+)-fenfluramine, also enhances 5-HT function by release.