High-throughput cytochrome p450 inhibition assays by ultrafast gradient liquid chromatography with tandem mass spectrometry using monolithic columns

A generic method employing ultrafast liquid chromatography with tandem mass spectrometry (LC/MS/MS) was developed and employed for routine screening of drug candidates for inhibition of five major human cytochrome p450 (CYP) isozymes, CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2. The method utilized a monolithic silica rod column to allow fast flow rates to significantly reduce chromatographic run time. The major metabolites of six CYP-specific probe substrates for the five p450 isoforms were monitored and quantified to determine IC(50) values of five drug compounds against each p450 isozyme. Human liver microsomal incubation samples at each test compound concentration were combined and analyzed simultaneously by the LC/MS/MS method. Each pooled sample containing six substrates and an internal standard was separated and detected in only 24 seconds. The combination of ultrafast chromatography and sample pooling techniques has significantly increased sample throughput and shortened assay turnaround time, allowing a large number of compounds to be screened rapidly for potential p450 inhibitory activity, to aid in compound selection and optimization in drug discovery.     

Sc(OTf)3-catalyzed efficient synthesis of beta,beta-bis(indolyl) ketones by the double indolylation of acetic acid 2-methylene-3-oxobutyl ester

In the presence of 5 mol% Sc(OTf)3, double indolylation of acetic acid 2-methylene-3-oxo-butyl ester with differently substituted indoles readily afforded beta,beta-bis(indolyl) ketones. The reaction may proceed via a Sc(OTf)3-catalyzed SN2'-type substitution and subsequent conjugate addition.     

Structural Relationships between the Hemiporphyrazine Macrocyclic Ligand and its Metal Complexes. II.: Planar Neutral Ligand,C26H16N8, and Four Isomorphous Metal Complexes, [M(C26H16N8)(H2O)], M=Mn(II), Co(II), Cu(II), Zn(II)

Crystal and molecular structures of the planar neutral ligand, C₂₆H₁₆N₈, and the four isomorphous five-coordinated metal complexes, [M(C₂₆H₁₆N₈)(H₂O)], M = Mn(II), Co(II), Cu(II), Zn(II), have been determined from three-dimensional X-ray diffraction data. The free ligand hpH₂, C₂₆H₁₆N₈, belongs to the P 2₁/c space group with Z=2, a=4.142(3), b=23.736(6), c=10.338(3) Ä, β=94.66(6)°. The metal complexes monohydrate Mhp-H₂O all belong to the orthorhombic Pcab space group with Z=8. The dimensions are roughly 8.8×19.3×23.7 ų. In each structure, the macrocyclic ligand has an almost planar conformation which differs from the saddle shaped ligand hydrate (hpH₂·H₂O) and the nickel complex [Nihp]⁵. The distances from the center of the macrocyclic ring to the nitrogen atom of the free ligand are 1.907(6) and 2.245(6)Å. The coordination geometry in these four complexes is square pyramidal with a water molecule as an axial ligand. The bond distances of M(II)-O(H₂O), M(II)-N1 (imine), M(II)-N3 (pyridine) are: 2.19(1), 2.00(2), 2.27(2)Å respectively for the manganese complex; 2.08(1), 1.97(1), 2.23(1)Å for the cobalt complex; 2.33(1), 1.92(3), 2.18(1)Å for the copper complex; 2.110(5), 1.964(6), 2.252(6)Å for the zinc complex. The variation of metal-ligand distances can be correlated to the metal d orbital occupancy. A comparison with similar ligands will be presented.     

基于DFRFT水下动目标LFM回波检测算法

匹配滤波器作为高斯白噪声背景下线性调频信号的最优检测器,在水下声信号处理中得到了广泛的应用。根据匹配滤波器输出峰值位置可以获得目标距离的估计,但运动目标径向速度造成的回波和样本失配将导致匹配滤波器检测性能下降。利用分数阶傅里叶变换对线性调频信号的聚焦特性,提出了应用离散分数阶傅里叶变换的水下运动目标线性调频回波检测算法。仿真测试表明,该算法对于混响噪声背景下径向速度未知动目标的线性调频回波具有良好的检测性能。     

一种用于波长路由光网络的分布式快速波长预留协议

波长预留协议用于在光通道建立过程中预留和配置波长.目前已有的波长预留协议都把协议设计的目标定为降低网络阻塞率,没有一种协议设计把目标定为缩短光通道的建立时间和简化协议处理过程.然而更短的建立时间和更小的协议复杂度对于未来极其动态的光网络却是非常重要的.提出了一种新颖的用于波长路由光网络的分布式快速波长预留协议-目的端预留协议,它在保证网络阻塞率可以接受的前提下,不仅可以降低连接建立时间,还可以减少控制节点处理器需要处理的信令消息数量.仿真结果证明了这一点.     

非跟踪体制炮位侦察雷达目标自动识别技术的实现

非跟踪体制炮位侦察雷达要实现目标的自动识别,其关键技术是背景杂波的处理和对目标信号的识别。文中提出了采用脉冲积累技术,对非相参脉冲串信号处理进行视频积累,由门限判决器判断有无目标回波、抑制噪声和杂乱脉冲干扰,降低系统的虚警率;采用杂波存储技术存储全画面杂波,建立静态杂波图,有效地抑制地物杂波的影响;采用单片机主-从系统双机速度识别技术,对回波信号进行速度识别和相关处理,实现非跟踪体制炮位侦察雷达目标自动识别。     

次级源和误差传感器布放对带弹性障板的充液直管声振复合有源控制的影响*

针对充液管路系统噪声有源控制问题,研究了次级源和误差传感器布放对带弹性障板的充液直管管路系统有源消声与有源消振复合控制效果的影响。基于声固耦合方法建立了带弹性障板的充液直管管路系统的有限元模型,在声激励下对比了次级声源布放对系统有源消声性能的影响,并在组合激励下分析了次级力源、次级声源和误差传感器布放对系统复合有源控制的影响。结果表明,非对称分布的次级声源容易激起管壁振动,进而带动障板振动,导致有源消声效果不佳;采用对称分布的次级声源可使低频段的降噪量提高10 dB以上。复合有源控制可进一步提升全频段的控制效果。通过增加振动误差传感器数量,可使绝大多数频点的降噪量提高1~20 dB不等。此外,在管壁上布放的两圈次级力源的间距小于管壁振动波长的1/4,且都不位于管壁振动节点附近时控制效果更好。     

钝头机体用FADS-α的求解算法及精度研究

针对钝头机体用嵌入式大气数据传感(flush air data sensing,FADS)系统的4类攻角求解算法及算法的求解精度进行研究.针对典型的15°钝头体外形,在Mach数Ma=2.04,3.02,5.01,攻角α=-5°～30°,侧滑角β=0°的条件下,首先基于势流理论及修正的Newton流理论建立了钝头机体用...     

基于红外热成像技术的急性痛风性关节炎治疗效果评价研究

探讨了红外热成像技术是否可作为急性痛风性关节炎(Gout)治疗疗效的一种评价手段.基于多中心、随机、对照试验设计,选取Gout中医证型为湿热蕴结证的患者60例,并将其分为试验组和对照组(各30例).试验组予竹叶石膏汤配方颗粒剂口服,1袋/次,每 日3次;对照组予塞来昔布胶囊口服,200 mg/次,每日1次.两组均以7日...