Molecular pharmacology of voltage-dependent calcium channels

Voltage-dependent Ca2+ channels serve as the only link to transduce membrane depolarization into cellular Ca(2+)-dependent reactions. A wide variety of chemical substances that have the ability to modulate Ca2+ channels have been demonstrated both for their clinic utility and for importance in elucidating the molecular basis of various biological responses. Recently, introduction of molecular biology to pharmacology has brought a great deal of information about the molecular basis of drug action in Ca2+ channels. In this review, we attempt to overview recent progress in understanding the interactions between Ca2+ channels and their blockers, namely Ca2+ antagonists, from a molecular and structural point of view.     

Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in Abeta-induced cytotoxicity

Endoplasmic reticulum-associated amyloid beta-peptide (Abeta)-binding protein (ERAB)/L-3-hydroxyacyl-CoA dehydrogenase type II (HADH II) is expressed at high levels in Alzheimer's disease (AD)-affected brain, binds Abeta, and contributes to Abeta-induced cytotoxicity. Purified recombinant ERAB/HADH II catalyzed the NADH-dependent reduction of S-acetoacetyl-CoA with a Km of approximately 68 microM and a Vmax of approximately 430 micromol/min/mg. The contribution of ERAB/HADH II enzymatic activity to Abeta-mediated cellular dysfunction was studied by site-directed mutagenesis in the catalytic domain (Y168G/K172G). Although COS cells cotransfected to overexpress wild-type ERAB/HADH II and variant beta-amyloid precursor protein (betaAPP(V717G)) showed DNA fragmentation, cotransfection with Y168G/K172G-altered ERAB and betaAPP(V717G) was without effect. We thus asked whether the enzyme might recognize alcohol substrates of which the aldehyde products could be cytotoxic; ERAB/HADH II catalyzed oxidation of a variety of simple alcohols (C2-C10) to their respective aldehydes in the presence of NAD+ and NAD-dependent oxidation of 17beta-estradiol. Addition of micromolar levels of synthetic Abeta(1-40) to purified ERAB/HADH II inhibited, in parallel, reduction of S-acetoacetyl-CoA (Ki approximately 1.6 microM), as well as oxidation of 17beta-estradiol (Ki approximately 3.2 microM) and (-)-2-octanol (Ki approximately 2.6 microM). Because micromolar levels of Abeta were required to inhibit ERAB/HADH II activity, whereas Abeta binding to ERAB/HADH II occurred at much lower concentrations (Km approximately 40-70 nM), the latter more closely simulating Abeta levels within cells, Abeta perturbation of ERAB/HADH II was likely to result from mechanisms other than the direct modulation of enzymatic activity. Cells cotransfected to overexpress ERAB/HADH II and betaAPP(V717G) generated malondialdehyde-protein and 4-hydroxynonenal-protein epitopes, which were detectable only at the lowest levels in cells overexpressing either ERAB/HADH II or betaAPP(V717G) alone. Generation of such toxic aldehydes was not observed in cells contransfected to overexpress Y168G/K172G-altered ERAB and betaAPP(V717G). We conclude that the generalized alcohol dehydrogenase activity of ERAB/HADH II is central to the cytotoxicity observed in an Abeta-rich environment.     

Two-Parameter Thermal Lattice BGK Model with a Controllable Prandtl Number

In this paper, two time relaxation parameters are introduce to a thermal lattice BGK, model to make its Prandtl number controllable. The dependency of the Prandtl number on the two parameters is derived. Numerical measurement of the transport coefficients is used to demonstrate the validity of the method. Furthermore, two examples of convective heat transfer are calculated, with one to show the effectiveness, and the other to show the breakdown of the two-parameter formulation under different conditions.     

Investigation of wall mass transfer characteristics downstream of an orifice

Numerical simulations were performed to determine the effect of Reynolds number and orifice to pipe diameter ratio (d_o/d) on the wall mass transfer rate downstream of an orifice. The simulations were performed for d_o/d of 0.475 for Reynolds number up to 70,000. The effect of d_o/d was determined by performing simulations at a Reynolds number of 70,000 for d_o/d of 0.375, 0.475 and 0.575. The momentum and mass transport equations were solved using the Low Reynolds Number (LRN) K-? turbulence model. The Sherwood number (Sh) profile downstream of the orifice was in relatively good agreement with existing experimental results. The Sh increases sharply downstream of the orifice, reaching a maximum within 1–2 diameters downstream of the orifice, before relaxing back to the fully developed pipe flow value. The Sh number well downstream of the orifice was in good agreement with results for fully developed pipe flow estimated from the correlation of Berger and Hau (1977). The peak Sh numbers from the simulations were higher than that predicted from Tagg et al. (1979) and Coney (1980).     

Neurofuzzy model-based predictive control of weld fusion zonegeometry

A closed-loop system is developed to control the weld fusion, which Is specified by the top-side and back-side bead widths of the weld pool. Because in many applications only a top-side sensor is allowed, which is attached to and moves with the welding torch, an image processing algorithm and neurofuzzy model have been incorporated to measure and estimate the top-side and back-side bead widths based on an advanced top-side vision sensor. The welding current and speed are selected as the control variables. It is found that the correlation between any output and input depends on the value of another input. This cross coupling implies that a nonlinearity exists in the process being controlled. A neurofuzzy model is used to model this nonlinear dynamic process. Based on the dynamic fuzzy model, a predictive control system has been developed to control the welding process. Experiments confirmed that the developed control system is effective in achieving the desired fusion state despite the different disturbances     

On symbolic manipulation and code generation of a hybrid three-dimensional solid element

A symbolic procedure is utilized to derive the analytical expressions of the component matrices resulting to the closed-form integration of a stiffness matrix of a hybrid finite element. In order to alleviate the expression growth problem, we employ special techniques, including the use of symmetry conditions, pattern search, and introduction of intermediate variables, so that the final form of the derived stiffness matrix is suitable for coding implementation. Application of the symbolic procedure is made on a hybrid three-dimensional 8-node solid element. The same procedure is equally applicable to other types of hybrid elements.     

Covariance Structure Maximum-Likelihood Estimates in Compound Gaussian Noise: Existence and Algorithm Analysis

Recently, a new adaptive scheme [Conte (1995), Gini (1997)] has been introduced for covariance structure matrix estimation in the context of adaptive radar detection under non-Gaussian noise. This latter has been modeled by compound-Gaussian noise, which is the product c of the square root of a positive unknown variable tau (deterministic or random) and an independent Gaussian vector x, c=radictaux. Because of the implicit algebraic structure of the equation to solve, we called the corresponding solution, the fixed point (FP) estimate. When tau is assumed deterministic and unknown, the FP is the exact maximum-likelihood (ML) estimate of the noise covariance structure, while when tau is a positive random variable, the FP is an approximate maximum likelihood (AML). This estimate has been already used for its excellent statistical properties without proofs of its existence and uniqueness. The major contribution of this paper is to fill these gaps. Our derivation is based on some likelihood functions general properties like homogeneity and can be easily adapted to other recursive contexts. Moreover, the corresponding iterative algorithm used for the FP estimate practical determination is also analyzed and we show the convergence of this recursive scheme, ensured whatever the initialization.     

Adaptive switching mean filter using conditional morphological noise detector

The adaptive switching mean (ASM) filter is proposed to remove impulse noise. The filter first identifies the corrupted pixels using conditional morphological noise detection and then removes the detected impulses using the adaptive mean filter. Simulation results indicate that the ASM filter can suppress impulse noise effectively while preserving the details in the image very well, thus providing better restoration performance than many other switching-based filters.     

Linewidth-tolerant 30 Gbit/s 8-PSK self-homodyne using single modulator and phase-noise cancelling technique

Linewidth-tolerant 8-ary phase-shift keying (8-PSK) self-homodyne modulation/demodulation at symbol rates of 10 Gsymbol/s (30 Gbit/s) and 1 Gsymbol/s (3 Gbit/s) using a distributed-feedback laser diode with a linewidth of 30 MHz and a single modulator is experimentally demonstrated. Owing to the phase-noise cancelling capability of the self-homodyne scheme based on a polarisation-multiplexed pilot-carrier, a floorless bit error rate performance of <10^-9 was achieved; this value was obtained even for the symbol rate of 1 Gsymbol/s, at which the required linewidth condition is stringent. Furthermore, the tolerances against differential group delays and dispersion at the symbol rate of 10 Gsymbol/s have been evaluated.