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Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Helix-coil transitions of poly α-aspartic acid (PASP) were studied by dc polarography in the presence of Zn2+as a marker attached to the polymer. The diffusion current (id) of Zn2+declined markedly in the pH range of 3.5 – 7.4 due to a formation of metal ion-PASP macromolecular complexes. The complex formation also reflects on an increase of the magnitude at ca.222 nm of CD spectrum, suggesting that PASP forms the helix structure by coordination of Zn2+in the corresponding pH region. Helix content, determined by the decrease in idof Zn2+, corresponds favorably to that by CD measurements. In the lower acidic pH region, the coordination mode of Zn2+to PASP is different from that at neutral pH region. The decrease in idof Zn2+is independent of the further formation of helix structure. Zn2+coordinates with sparsely dissociated carboxylate groups of the helical part of PASP, which bring about an aggregation of polypeptide strands. The diffusion current of the ion attached to the polymer, therefore, is a parameter sensitive to conformational changes of PASP from acidic through neutral pH region.

To analyze a curing process of epoxy resin in terms of molecular motion, we adapted a pulsed NMR method. Three kinds of 1H spin-spin relaxation times (T2L(long), T2S(short) and T2M(intermediate)) were estimated from observed solid echo train signals as the curing process proceeded. A short T2Svalue below 20 ms suggests the existence of a motion-restricted chain, that is, cured elements of resin, and its fraction, PS, sigmoidally increased with the curing time. On the other hand, the fraction of T2L, PL, decreased with the reaction time reciprocally against PS, suggesting the disappearance of highly mobile molecules raised from pre-cured resin. The spin-lattice relaxation time, T1, was also measured to check another aspect of molecular motion in the process. T1of the mixed epoxy resin and curing agent gradually increased just after mixing both of them. This corresponds to an increment of a less-mobile fraction, of which the correction time is more than 10–6s, and also means that the occurrence of a network structure whose mobility is strongly restricted by chemically bonded bridges between the epoxy resin and curing agent. The time courses of these parameters coincided with those of IR peaks pertinent to the curing reaction. Therefore, pulsed NMR is a useful tool to monitor the hardening process of epoxy resin in real time non-distractively in terms of the molecular motion of protons.

The proton spin-spin relaxation time (T2) during the bulk polymerization of methyl acrylate was measured as a function of the reaction time at various temperatures. Three kinds of T2(T2L(long), T2S(short) and T2M(intermediate)) were obtained as the polymerization proceeded. The fraction of T2S(FS) increased sigmoidally at a certain reaction time, while that of T2L(FL) decreased reciprocally. The former corresponded to the amount of a polymer whose molecular weight was sufficiently high enough to cause a tight entanglement that produced a transient network structure; the latter reflected a decrease in the mixture of the monomer and the low molecular weight of the polymer. T2Mis considered to arise from a relatively mobile region of the entanglement. The relationship between the fractions of T2S+ T2Mand the polymer yield was found to be linear, which led us to monitor the polymer yield in real time during the polymerization in a non-distractive manner. 13C DD (dipolar decoupling)/MAS (magic angle spinning) NMR spectra were also measured to monitor the polymerization process in terms of the molecular motions between the main chain and the side chain in the formation of a network structure. The 13C DD/MAS NMR spectra show that the side chain motion became restricted as well as the main chain when the “Trommosdorff effect” (gel effect) was observed, and a part of the monomers were trapped in the network structure.

Interactions between poly α-L-glutamic acid (PGA) and metal ions Cd2+, Co2+were studied by direct current polarography. The diffusion currents of these ions decreased sharply in the presence of PGA in the pH region from 5.0 through neutral. A corresponding increase in the helix content of the PGA–metal ion complex was revealed by CD measurements on the same solutions. Helix contents determined by polarography were in good agreement with those by CD in the neutral pH region. On the contrary, the decrease of current in lower acidic pH regions was independent of helix formation and suggested that metal ions coordinate to sporadically-dissociated carboxylate groups to cause aggregation of the intra and/or inter polymer chains. The diffusion current of the ions, therefore, is a parameter sensitive to the conformational changes of PGA from acidic through neutral pH region.

The potential energy calculation for the hypothetical crystal structures of two chiral salts was carried out by using the program WMIN. The calculation revealed that the most stable structure of the chiral salts belonged to the space group P212121, which was in agreement with the real structure.

Molecular dynamics calculation was performed in order to obtain structural information about the complexes of a macrotricyclic receptor (1), which has crown ether and cyclophane subunits as binding sites, with organic substrates, ω-(phenylalkyl)ammonium picrates (2; the methylene number, n=4, 5, 7), taking account of solvent effect. The resulting equilibrium structures were in good agreement with experimental data; among the three complexes, the complex of 1with 2(n=5) gave the largest stability constant. Furthermore, the quantitative evaluation of the difference in Gibbs free energy between two complexes, calculated by the perturbation method, was also consistent with the experimental data.

α-Sulfenyl acetals reacted smoothly with silylated carbon nucleophiles such as silyl enol ether, ketene silyl acetal, and allylsilane in the presence of a catalytic amount of Lewis acid mainly to give anti-Cram adducts with high diastereoselectivity by the asymmetric induction of the α-sulfur atom of the acetals.

The Crystal structures of (+)-1-phenylethylamine·cinnamic acid salt and (+)-1-(4-isopropylphenyl)ethylamine·cinnamic acid salt were determined by X-ray analysis. The crystal structures of these two salts provided for the first time some insights into the mechanism of the formation of a conglomerate crystal. In each crytal, two amine components and two acid components form a helical column by hydrogen bonds. On the basis of this similarity in the molecular arrangements, the role of cinnamic acid, an achiral acid, is discussed, and the criteria for the choice of an achiral acid in the transformation of the racemic modification of an amine into a conglomerate crystal is proposed.

The structures of conglomerate crystals, p-chlorobenzenesulfonic acid salt of l-alanine, p-toluenesulfonic acid salt of l-serine, and benzenesulfonic acid salt of l-leucine, were determined by X-ray analysis. The crystals are built up of repeating units consisting of two amine components and two acid components to form a helical column by hydrogen bonds. The arrangements of the arenesulfonic acids are found to be similar to each other in these systems. Moreover, the arrangements have similarity to those of cinnamic acid in the crystals of cinnamic acid salts of (R)-1-phenylethylamine and of (R)-1-(4-isopropylphenyl)ethylamine, which are also conglomerates. These results suggest that our proposed criteria for the choice of an achiral derivatizing agent in the transformation of a racemic compound into a conglomerate crystal is appropriate.

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A novel chiral stationary phase, [(1R,2S)-2-hydroxy-1-methyl-2-phenylethylamino]acetic acid, was prepared from (-)-norephedrine, and its sodium salt was bound to silica gel pretreated with [3-(glycidyloxy)propyl]trimethoxysilane. The chiral stationary phase was found to be effective for the optical resolution of amino acids and their derivatives by ligand-exchange high-performance liquid chromatography using aq copper(II) sulfate solution as an eluent.

Ring-expansion of aryl gem-dichlorocyclopropyl ketones 1using Lawesson’s reagent afforded unsymmetrically and highly substituted 5-chloro and 3-chlorothiophenes 2and 3with excellent regioselectivity. The Suzuki–Miyaura coupling of 2and 3with PhB(OH)2was successfully performed to give 2-aryl-3-methyl-5-phenylthiophenes 4and 2-aryl-3-methyl-4,5-diphenylthiophenes 5, respectively.

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