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1.
The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 .  相似文献   
2.
Scientometrics - This paper presents an analysis of the anti-vaccination movement’s referencing of research articles on the topic of vaccination in the social media network Twitter. Drawing...  相似文献   
3.
A fast method is proposed for determining the oxygen gas‐liquid diffusion coefficient from measurements of the fluorescence quenching behind a bubble. The approach consists of capturing pictures of the concentration field at micro‐scale in the laminar bubble wake. The Gaussian concentration profiles measured in the wake are demonstrated to be systematically equivalent to an instantaneous plane diffusion case. The approach permits to accurately evaluate the gas‐liquid diffusivity in a very short time of around one second.  相似文献   
4.
Mine Water and the Environment - Passive treatment is a promising, green technology that is increasingly being used for mine drainage treatment. However, several challenges remain concerning its...  相似文献   
5.
Co-doped ZnO-based ceramics using Al, Ti, and Mg ions in different ratios were synthesized with the objective to investigate the doping effects on the crystalline features, microstructure and the electrical behavior. For Al and Ti doping, a coexistence of crystalline phases was shown with a major wurtzite ZnO structure and secondary spinel phases (ZnAl2O4, Zn2TiO4, or ZnaTibAlcOd), while Mg doping did not alter significantly the structural features of the wurtzite ZnO phase. The electrical behavior induced by Al, Ti, and Mg co-doping in different ratios was investigated using Raman, electron paramagnetic resonance (EPR) and 27Al and 67Zn solid-state nuclear magnetic resonance (NMR). Al doping induces a high electrical conductivity compared to other doping elements. In particular, shallow donors from Zni-AlZn defect structures are inferred from the characteristic NMR signal at about 185 ppm; that is, quite far from the usual oxygen coordinated Al. The Knight shift effect emanating from a highly conducting Al-doped ZnO ceramics was considered as the origin of this observation. Oppositely, as Ti doping leads to the formation of secondary spinel phases, EPR analysis shows a high concentration of Ti3+ ions which limit the electrical conductivity. The correlation between the structural features at the local order, the involved defects and the electrical behavior as function of the doping process are discussed.  相似文献   
6.
Closed Circuit Television Inspection is used since decades as industry standard for sewer system inspection and structural performance evaluation. In current practice, inspection data are helpful to support asset management decisions. However, the quality and uncertainty of sewer condition assessment is rarely questioned. This article presents a methodology to determine the probability to underestimate, overestimate or accurately estimate the real condition of a pipe using visual inspection. The approach is based on the analysis of double inspections of the same sewer pipes and has been tested using the extensive data-set of the city of Braunschweig in Germany. Results indicate that the probability to inspect correctly a pipe in poor condition is close to 80%. The probability to overestimate the condition of a pipe in bad condition (false negative) is 20% whereas the probability to underestimate the condition of a pipe in good condition (false positive) is 15%. Finally, sewer condition evaluation can be used to assess the general condition of the network with an excellent accuracy probably because the respective effects of false positive and false negative are buffered.  相似文献   
7.
Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.  相似文献   
8.
9.
Inflammation and oxidative stress are thought to be involved in, or associated with, the development of obesity, dyslipidemia, hepatic steatosis, and insulin resistance. This work was designed to determine the evolution of inflammation and oxidative stress during onset and progression of hepatic steatosis and glucose intolerance. Seventy-five male Wistar rats were divided to control and high-fat high-fructose (HFHFr) groups. A subgroup of each group was sacrificed at 4, 8, 12, 16, and 20 weeks. HFHFr-fed rats exhibited overweight, glucose intolerance, and hepatic steatosis with increased contents of hepatic diacylglycerols and ceramides. The HFHFr diet increased hepatic interleukin 6 (IL-6) protein and adipose tissue CCL5 gene expression and hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity but not mitochondrial reactive oxygen species (ROS) production. The HFHFr diet decreased plasma and liver levels of isoprostanoid metabolites as well as plasma thiobarbituric acid-reactive substance (TBARS) levels. Hepatic glutathione content was decreased with a moderate decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) with the HFHFr diet. Overall, HFHFr diet led to hepatic lipid accumulation and glucose intolerance, which were accompanied by only moderate inflammation and oxidative stress. Most of these changes occurred at the same time and as early as 8 or 12 weeks of diet treatment. This implies that oxidative stress may be the result, not the cause, of these metabolic alterations, and suggests that marked hepatic oxidative stress should probably occur at the end of the steatotic stage to result in frank insulin resistance and steatohepatitis. These findings need to be further evaluated in other animal species as well as in human studies.  相似文献   
10.
Mine Water and the Environment - Acid mine drainage (AMD) is a major environmental challenge for the mining industry in northern climates. Laboratory-scale experiments were conducted to test...  相似文献   
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