Two-Dimensional Physical and Numerical Modeling of a Pile-Supported Earth Platform over Soft Soil

This paper focuses on the mechanisms occurring in a granular earth platform over soft ground improved by rigid piles. Two-dimensional physical model experiments were performed using the Schneebeli’s analogical soil to investigate the load transfer mechanisms by arching and the settlement reduction and homogenization. Experimental outputs are compared to results obtained on a numerical model using a plane strain continuum approach. The impact of the constitutive model complexity to simulate the platform material behavior was first assessed, but no large difference was recorded. As far as the proposed model, which takes the main features of the observed behavior satisfactorily into account, the numerical procedure could be validated and the parametric studies extended numerically. Both approaches of this study underlined the main geometrical and geotechnical parameters which should inevitably be taken into account in a simplified design method, namely the capping ratio, the platform height, and the platform material shear strength.     

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold‐hopping approach. Structure–activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time‐dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P‐glycoprotein (Pgp)‐mediated efflux. Compound 80 c [{(1S,6R)‐3‐(6,7‐difluoroquinoxalin‐2‐yl)‐3,8‐diazabicyclo[4.2.0]octan‐8‐yl}(4‐methyl‐[1,1′‐biphenyl]‐2‐yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium‐release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep‐promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.     

如何实现真实世界下的PC“绿色”能效

计算机原设备制造商（OEM）正面对商业、环保和法规等多方面的压力,需要体现他们产品的能效,提供更“绿色”的台式个人电脑（PC）和服务器。这使设计这些产品的工程师需要设计出符合诸如美国80 PLUS、“能源之星”（ENERGYSTAR）和计算产业拯救气候行动计划（CSCI）等能效标准的PC电源。     

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis,Structure–Activity Relationships,and Sleep-Promoting Properties in Rats

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone ( 3 ), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone ( 51 ), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.     

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

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 (f_u 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 .     

Seismic analysis of geosynthetic-reinforced retaining wall in cohesive soils

Although a cohesionless backfill is recommended for geosynthetic reinforced earth retaining walls, cohesive soil have been widely used in many regions across the globe for economic reasons. This type of backfill exposes the soil to the crack formation that leads to reduce the stability of the system. In this paper, to investigate the internal seismic stability of reinforced earth retaining walls with cracks, the discretization method combined with the upper bound theorem of limit analysis are used. The potential failure mechanism is generated using the point-to-point method. Two types of cracks are considered, a pre-existing crack and a crack formation as a part of the failure mechanism. The use of the discretization method allows the consideration of the vertical spatial variability of the soil properties. A pseudo-dynamic approach is implemented which allows the account of the dynamic characteristics of the ground shaking. The presented method is validated using the conventional limit analysis results of an existing study conducted under static conditions. Once the proposed technique to consider the cracks is validated, a parametric study is conducted to highlight the key parameters effects on the lower bound of the required reinforcement strength.     

Antiaversive effects of 5HT2C receptor agonists and fluoxetine in a model of panic-like anxiety in rats

Different techniques of stabilometric signal analysis have been used in order to study the adaptation of the fine postural control system to the wearing of corrective glasses with or without prisms. The comparison between the results obtained with conventional techniques and those obtained with non-linear dynamic methods demonstrates the better efficiency of the latter. These results confirm that the postural system behaves as a non-linear dynamical system and may explain the outstanding sensitivity of the fine postural system to small perturbations.