Nonlinear protein binding and enzyme heterogeneity: effects on hepatic drug removal

The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity.     

A dual-mode multiuser detector for DS-CDMA systems

We introduce a dual-mode multiuser detector that dynamically switches its detection mode between matched-filter and decorrelator operations based on the channel characteristics. This detector significantly reduces the overall computational requirement while maintaining similar performance as that of the decorrelator. The switching mechanism of our dual-mode detector is designed by exploiting the performance-complexity tradeoff between the decorrelator and the matched-filter. Extensions of this idea to other types of multiuser detectors are also proposed     

Phase transition of LCP fluids confined in nanochannels through MD simulation

Manipulation of molecular orientation alignment in MCTLCPs (main-chain thermotropic liquid crystalline polymers) by pure shear at nano scale has been investigated for the first time using molecular dynamics (MD) simulation. Results indicate that high planar shear induces long-range uniform orientation ordering (liquid crystalline phase) of initially randomly orientated molecules of MCTLCP fluid confined in a nanochannel, which is confirmed by analyzing the orientation order parameter and the snapshots of MCTLCP liquid in a nanochannel under different shear rates. Insights into the origin of the phase transition phenomena are given at molecular level through investigating the thermodynamic density distribution of MCTLCP molecules in the nanochannel, suggesting that the energy shift due to a radical jump of system density affects both the magnitude and the orientation of the molecular ordering. Simulation results also show that there is a critical shear rate for transforming isotropic phase into liquid crystalline phase. The critical shear rate is dependent on the temperature of the MCTLCP system. Findings in this paper may present useful information for processing TLCP molecules at nano scale and the understanding of nanoflow.     

Traveling-wave piezoelectric linear motor Part I: the stator design.

A new type of piezoelectric linear motor incorporating a traveling wave has been developed. The linear motor is comprised of a stator and a carriage. The stator design, which consists of a meander-line structure and gear teeth mounted on the meander-line structure, is the focus of this article. The meander-line structure is constructed with bimorph actuators arranged in a line. These actuators are driven by two phased sets of alternating current (ac) in order to generate a traveling wave. The traveling wave is transferred to the gear teeth, by which the carriage is driven. Modeling of the stator is derived by use of a strain energy method. The performance of various materials is evaluated by analytical and experimental methods. The analytical and the experimental results are quite approximate. Modal analysis is investigated using ANSYS. Appropriate modes associated with ultrasonic levels of resonant frequency are selected to obtain desired motion and to enhance the output performance. Surface speed for various applied input voltage are studied and indicate a nearly linear relationship. The stator in combination with the carriage makes up the linear motor.     

珠江口盆地开平凹陷油气聚集条件分析

珠江口盆地自新生代以来,曾先后受到不同方向张应力的作用,造成了不同时期构造体系的交叉叠合.中中新世以来构造运动强烈,并具有东强西弱的特点,对油气的运移与聚集产生了重要影响.开平凹陷的剧烈断裂和断陷活动始于始新世,并在同期沉积了巨厚的文昌组.晚渐新世以后,由于断裂活动非常微弱,在成熟的烃源岩与其上地层之间缺乏有效的油源断层,因而自生自储、近距离运移可能是开平凹陷油气聚集的基本特征.在凹陷内部,因重力滑动和欠压实泥岩共同作用所形成的KPll-1构造带可能是该区最具有油气远景的地区.     

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.     

鲁布革水电厂计算机监控系统的更新改造

鲁布革水电厂原Ｒ３０计算机监控系统更新改造过程中，重点研究了与原西门子ＲＴＵ的数据交换，机组功率调节和线路定功率调节的实现有关问题，在对３号机组计算机监控系统改造试验的基础上，成功地实现了计算机监控系统的整体改造，改造后采用的国产ＮＡＲＩＳＳＪ－３０００计算机监控系统实用可靠，功能完善，配置灵活，具有国际，国内领先水平。     

A novel method for elimination of line-current harmonics insingle-stage PFC switching regulators

This paper studies a particular single-stage power-factor-correction (PFC) switching regulator employing a discontinuous-conduction-mode (DCM) boost-input cell and a continuous-current-mode (CCM) forward output cell. Although this single-stage PFC regulator can provide a reasonably high power factor when its PFC stage is operating in discontinuous mode, substantial reduction in line-current harmonics is possible by applying a suitable frequency-modulation scheme. This paper derives a frequency-modulation scheme and proposes a practical implementation using a simple translinear analog circuit. A quantitative analysis on the total harmonic distortion (THD) of the line current when the circuit is subject to a limited range of frequency variations is presented along with some considerations for practical design. Experimental data obtained from a prototype confirms the effectiveness of the proposed frequency-modulation scheme. The proposed analog translinear circuit allows custom integrated circuit implementation, making it a viable low-cost solution to the elimination of line-current harmonics in switching regulators     

Representing context, cognition, and crew performance in a shutdown risk assessment

This paper presents a potentially practical treatment of dynamic operator-system interactions. The approach employs a dynamic event tree framework to explicitly address plant dynamics, system indications, crew-plant interactions, time available, crew cognition, errors of commission (mistakes), and multiple planning and diagnosis possibilities. The approach is applied in an analysis of a hypothesize medium break loss of coolant accident for a test reactor that occurs during plant shutdown. This transient was selected on the basis of: a significant cognitive component being present, high consequences being associated with operator actions, and the importance of event timing to scenario progression. The results presented show how quantitative risk predictions are affected by the treatment of dynamics, and demonstrate how non-proceduralized recovery actions and a number of performance shaping factors (e.g., crew experience, stress, and confidence) can be explicitly treated. Insights and lessons learned regarding the performance of a dynamic assessment are also presented.