Structural Insights into Differences in Drug-binding Selectivity between Two Forms of Human α1-Acid Glycoprotein Genetic Variants, the A and F1*S Forms

Human α1-acid glycoprotein (hAGP) in serum functions as a carrier of basic drugs. In most individuals, hAGP exists as a mixture of two genetic variants, the F1*S and A variants, which bind drugs with different selectivities. We prepared a mutant of the A variant, C149R, and showed that its drug-binding properties were indistinguishable from those of the wild type. In this study, we determined the crystal structures of this mutant hAGP alone and complexed with disopyramide (DSP), amitriptyline (AMT), and the nonspecific drug chlorpromazine (CPZ). The crystal structures revealed that the drug-binding pocket on the A variant is located within an eight-stranded β-barrel, similar to that found in the F1*S variant and other lipocalin family proteins. However, the binding region of the A variant is narrower than that of the F1*S variant. In the crystal structures of complexes with DSP and AMT, the two aromatic rings of each drug interact with Phe-49 and Phe-112 at the bottom of the binding pocket. Although the structure of CPZ is similar to those of DSP and AMT, its fused aromatic ring system, which is extended in length by the addition of a chlorine atom, appears to dictate an alternative mode of binding, which explains its nonselective binding to the F1*S and A variant hAGPs. Modeling experiments based on the co-crystal structures suggest that, in complexes of DSP, AMT, or CPZ with the F1*S variant, Phe-114 sterically hinders interactions with DSP and AMT, but not CPZ. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc

Clustering data by inhomogeneous chaotic map lattices

A new approach to clustering, based on the physical properties of inhomogeneous coupled chaotic maps, is presented. A chaotic map is assigned to each data-point and short range couplings are introduced. The stationary regime of the system corresponds to a macroscopic attractor independent of the initial conditions. The mutual information between couples of maps serves to partition the data set in clusters, without prior assumptions about the structure of the underlying distribution of the data. Experiments on simulated and real data sets show the effectiveness of the proposed algorithm.Comment: 8 pages, 6 figures. Revised version accepted for publication on Physical Review Letter

Characteristics of Japanese wrestlers with respect to function and structure of limbs

It is well known that hypertrophy and strength gain of the human skeletal muscle are induced by muscle training. It has also been shown that the training effect on size and strength of the skeletal muscle are altered the different athletic training protocols (1, 4). From these findings, it seems possible that wrestlers possess the hypertrophied muscle and stronger muscle strength by specific training. In the present study, we assess the functional and structural characteristics of the skeletal muscle in Japanese wrestlers

NMR Study on La and Tl-based High-T_c Cuprates (High Field Superconductors)

NMR study on three types of high-T_C cuprates TlBa_2CaCu_2O_ (Tl1212), La_Ba_xCuO_4 (LBCO) and (La_Y_y)_Ce_xCuO_4 (LYCCO) is reported. First the Knight shift in the superconducting state was investigated for the Zn-substituted TlBa_2Ca(Cu_Zn_z)_2O_, which belongs to the over-doped region. The temperature dependence of the Knight shift was successfully explained in terms of the partially closed d-wave model proposed by Kitaoka et al. The reduction in T_C by Zn-substitution was also consistent with Miyake\u27s theoretical calculation on the potential scattering of the unitarity limit in the d-wave superconductors. Next, the impurity effect on the anomalous suppression of the superconductivity in La_Ba_xCuO_4 (LBCO) around x≅1/8 was investigated by La-NMR and ultrasonic measurements. The transition temperatures of the magnetic order and of the structural phase transformation in Zn^ and Ce^-doped LBCO have shown that the main and direct force to the suppression in the superconductivity is the magnetic ordering, and that the role of the structural phase transformation is the enhancement of the suppression. Lastly, the new electron doped cuprate free from 4f-spins has been synthesized and studied by NMR. Observed spectra of ^Cu without quadrupolar splitting similar to other conventional electron-doped cuprates indicate that the doped carrier in this system is electron like

A Neuroeconomics Approach to Inferring Utility Functions in Sensorimotor Control

Making choices is a fundamental aspect of human life. For over a century experimental economists have characterized the decisions people make based on the concept of a utility function. This function increases with increasing desirability of the outcome, and people are assumed to make decisions so as to maximize utility. When utility depends on several variables, indifference curves arise that represent outcomes with identical utility that are therefore equally desirable. Whereas in economics utility is studied in terms of goods and services, the sensorimotor system may also have utility functions defining the desirability of various outcomes. Here, we investigate the indifference curves when subjects experience forces of varying magnitude and duration. Using a two-alternative forced-choice paradigm, in which subjects chose between different magnitude–duration profiles, we inferred the indifference curves and the utility function. Such a utility function defines, for example, whether subjects prefer to lift a 4-kg weight for 30 s or a 1-kg weight for a minute. The measured utility function depends nonlinearly on the force magnitude and duration and was remarkably conserved across subjects. This suggests that the utility function, a central concept in economics, may be applicable to the study of sensorimotor control

Analysis of calcium carbonate for differentiating between pigments using terahertz spectroscopy

Calcium carbonate that is used as an art pigment exhibits strong absorption at approximately 3 THz. In this study, the authors investigated the relationship between the absorption and the condition of calcium carbonate crystals. By employing terahertz time-domain spectroscopy (0.5–4 THz), they verified that terahertz absorption energy depended on the crystal direction and crystal shape of the powder sample due to large birefringence. Further, the authors observed the difference in the crystal structure (calcite or aragonite) and the presence of impurities in natural calcium carbonate such as shells through terahertz absorbance spectra. The absorbance peak value of calcite at around 3 THz was four times as large as the peak value of aragonite. The absorbance spectral width increased because of the presence of these impurities. From the above observation, this study demonstrated that a certain kind of calcium carbonate crystal could be distinguished by terahertz spectroscopy

A Simple Iterative Algorithm for Parsimonious Binary Kernel Fisher Discrimination

By applying recent results in optimization theory variously known as optimization transfer or majorize/minimize algorithms, an algorithm for binary, kernel, Fisher discriminant analysis is introduced that makes use of a non-smooth penalty on the coefficients to provide a parsimonious solution. The problem is converted into a smooth optimization that can be solved iteratively with no greater overhead than iteratively re-weighted least-squares. The result is simple, easily programmed and is shown to perform, in terms of both accuracy and parsimony, as well as or better than a number of leading machine learning algorithms on two well-studied and substantial benchmarks