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 .     

基于双声表面波器件的引信加速度传感器

In view of the shortcomings of silicon micro acceleration sensor based on piezoresistive effect and capacitance principle, such as temperature drift, low resolution and poor anti-interference ability, a fuze acceleration sensor based on dual SAW devices is proposed. The sensor adopts a dual saw device structure, one is coated with a sensitive film for measurement, the other is an uncoat- ed reference channel for compensation of environmental temperature, pressure, humidity and other factors. The experimental results show that the maximum linear error is only 1.6%, the sensitivity is 54.3Hz/g, and the maximum hysteresis error is less than 1%. Compared with piezoresistive accelerometer and capacitive accelerometer, the linear error of the accelerometer is small, the sensitivi- ty is high, and it has strong anti-interference ability.     

Dual pH‐ and thermal‐responsive nanocomposite hydrogels for controllable delivery of hydrophobic drug baicalein

Hydrogels have been widely used as mild biomaterials due to their bio‐affinity, high drug loading capability and controllable release profiles. However, hydrogel‐based carriers are greatly limited for the delivery of hydrophobic payloads due to the lack of hydrophobic binding sites. Herein, nano‐liposome micelles were embedded in semi‐interpenetrating poly[(N‐isopropylacrylamide)‐co‐chitosan] (PNIPAAm‐co‐CS) and poly[(N‐isopropylacrylamide)‐co‐(sodium alginate)] (PNIPAAm‐co‐SA) hydrogels which were responsive to both temperature and pH, thereby establishing tunable nanocomposite hydrogel delivery systems. Nano‐micelles formed via the self‐assembly of phospholipid could serve as the link between hydrophobic drug and hydrophilic hydrogel due to their special amphiphilic structure. The results of transmission and scanning electron microscopies and infrared spectroscopy showed that the porous hydrogels were successfully fabricated and the liposomes encapsulated with baicalein could be well contained in the network. In addition, the experimental results of response release in vitro revealed that the smart hydrogels showed different degree of sensitiveness under different pH and temperature stimuli. The results of the study demonstrate that combining PNIPAAm‐co‐SA and PNIPAAm‐co‐CS hydrogels with liposomes encapsulated with hydrophobic drugs is a feasible method for hydrophobic drug delivery and have potential application prospects in the medical field. © 2018 Society of Chemical Industry     

车辆自组织网络中新型NP-CSMA随机多址协议研究分析

智能交通的出现使得车辆自组织网络受到越来越多的关注。车辆自组织网络的动态拓扑结构变化非常剧烈,这对网络的吞吐率、传输速率等性能提出了很高的要求。提出1种具有握手机制协议的自适应多通道双时钟NP-CSMA随机多址接入协议。该协议首先区分2种P-CSMA协议,握手机制成功解决了隐藏的终端问题,双时钟机制减少了平均空闲时间,多通道机制增加通道数量和划分用户优先级的同时提高了系统吞吐率,自适应机制能够使系统在高负载下保持稳定吞吐率。还对该协议的传输速率进行了分析,得出该协议的传输速率相对较高的结论。通过平均周期方法推导吞吐率和传输速率的计算公式,仿真结果与理论推导一致。     

Design of switchable band‐notched frequency selective absorber

An active band‐notched frequency selective absorber (BNFSA) with switchable notch band is proposed in this article. The BNFSA is a two‐layer structure composed of a lossy layer at the top and a ground plane at the bottom, separated by an air spacer. The element of the lossy layer is a lumped‐resistor‐loaded metallic dipole with a parallel LC resonance structure, which is realized by complementary n‐shaped resonator (CnR) inserted in the center, and PIN diode is welded at two arms of CnR. The bias circuit printed on the back of the substrate of the lossy layer connects to anode and cathode of the diode by via hole and isolates by the inductor. Simulation results show that the notch bands are located at 4.50 and 6.81 GHz when the diode sets to ON and OFF, respectively. To validate the performance of switchable BNFSA, the prototypes are fabricated and measured, reasonable agreement between simulated and measured results is obtained.     

A dual Newton strategy for tree‐sparse quadratic programs and its implementation in the open‐source software treeQP

This paper presents a dual Newton scheme for tree‐sparse quadratic programs as they may arise in the field of stochastic programming. Previous work suggests to introduce auxiliary variables to decompose the tree into scenarios and use Newton's method to solve a dual problem formulation. Following a different approach, we apply the same principle directly on the tree‐sparse problem, avoiding the increase in dimensionality. In combination with a tailored algorithm for the calculation of the step direction, which is typically the most expensive operation per iteration, the proposed algorithm achieves a linear complexity in the number of nodes and supports parallel processing of the tree branches in a stage‐wise fashion. An open‐source implementation of the presented dual Newton strategy is publicly available in treeQP , a toolbox of open‐source solvers for tree‐sparse quadratic programs.     

DP980高强钢连续退火后的组织与性能

研究了不同工艺参数对980 MPa级连续退火双相钢组织及力学性能的影响,利用光学显微镜、透射电镜(TEM)以及拉伸试验对双相钢的微观组织和力学性能进行测试及分析。结果表明:DP980钢的退火组织主要由铁素体、马氏体岛和少量的贝氏体组成,马氏体岛附近的位错密度较高。随着均热温度的升高,DP980钢的抗拉强度呈现先降低后升高的趋势,屈服强度与抗拉强度的趋势一致,伸长率先升高后降低。随着过时效温度的升高,DP980钢的抗拉强度和屈服强度降低,降低幅度较小,伸长率上升,但变化不明显,说明通过调整过时效温度来调控其力学性能的作用较小。     

高碳硅锰钢的动态力学性能

通过扫描电镜、霍普金森压杆和拉伸试验机等仪器研究了不同温度淬火高碳硅锰钢的组织、变形程度和动态力学性能。研究表明,随淬火温度提高,试验钢中残留碳化物数量减少,在880 ℃时,试验钢的残留碳化物全部溶解。动态力学试验后,880 ℃淬火试样因残留碳化物固溶,动态强度增幅较小,对应变速率不敏感,由均匀变形转为破碎。绝热剪切带内和远离绝热剪切带的区域均存在孔洞,远离剪切带区域的孔洞无序分布,且伴随有均匀分布的碳化物。靠近绝热剪切带区域的碳化物存在分布不均匀的情况,且绝热剪切带内部的孔洞沿着热量传播方向扩展,形成沿剪切带分布的裂纹。     

Strength and strain-hardening enhancement by generating hard delta-ferrite in twinning-induced plasticity steel

ABSTRACT

A dual-phase (12?vol.% delta-ferrite?+?78?vol.% austenite) high manganese twinning-induced plasticity (TWIP) steel was produced by hot rolled and annealing treatment. In comparison with the fully austenitic TWIP steel, both the yield and ultimate tensile strength of the dual-phase TWIP steel reinforced by hard delta-ferrite are significantly increased. It was found that the delta-ferrite in dual-phase steel exhibits a high hardness owing to the formed DO₃ structured intermetallic phase within ferrite. The presence of delta-ferrite dramatically improves the strain-hardening ability of TWIP steel. This is principally attributed to the effects of strain partitioning between hard delta-ferrite and softer austenite on the kinetics of deformation twinning and/or additional geometrical necessary dislocation (GND) during the deformation process.