Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

Slow-channel congenital myasthenic syndromes (SCCMSs) are rare genetic diseases caused by mutations in muscle nicotinic acetylcholine receptor (nAChR) subunits. Most of the known SCCMS-associated mutations localize at the transmembrane region near the ion pore. Only two SCCMS point mutations are at the extracellular domains near the acetylcholine binding site, α1(G153S) being one of them. In this work, a combination of molecular dynamics, targeted mutagenesis, fluorescent Ca²⁺ imaging and patch-clamp electrophysiology has been applied to G153S mutant muscle nAChR to investigate the role of hydrogen bonds formed by Ser 153 with C-loop residues near the acetylcholine-binding site. Introduction of L199T mutation to the C-loop in the vicinity of Ser 153 changed hydrogen bonds distribution, decreased acetylcholine potency (EC₅₀ 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca²⁺ rise (τ 14.2 ± 0.3 vs. 34.0 ± 0.4 s). These results shed light on molecular mechanisms of nAChR activation-desensitization and on the involvement of such mechanisms in channelopathy genesis.     

Optical properties of new organic conductors based on the BEDT-TSeF molecule (the κ-(BETS)4Hg2.84Br8 superconductor and κ-(BETS)4Hg3Cl8 Metal) in the range 300–15 K

Polarized reflectance and optical conductivity spectra of single crystals of two new isostructural organic conductors based on the BEDT-TSeF molecule, namely, the κ-(BETS)₄Hg_2.84Br₈ superconductor (T _c =2 K) and the κ-(BETS)₄Hg₃Cl₈ metal, which undergoes a smooth transition to the dielectric state near 35 K, have been obtained in the spectral region 700–6500 cm⁻¹ at temperatures of 300–15 K. At 300 K, the spectra of both compounds are nearly identical and differ from the Drude spectrum characteristic of metals. The nature of the observed difference is discussed, and the spectra are described in terms of a cluster approach with inclusion of electron-electron correlations in the Hubbard approximation combined with the Drude model. The parameters of the theory were determined, including the electron transfer integrals between molecules in a cluster. The spectra in the conducting plane of the crystals were found to be essentially anisotropic, which should be assigned to specific features of in-plane interaction between molecules. The spectra of the superconductor and the metal become increasingly different as the temperature is lowered. The spectra of the metal obtained for T<150 K exhibit splitting of the broad electronic maximum in the mid-IR region into two bands, which is accompanied by a splitting of a vibronic feature deriving from electron interaction with intramolecular BETS vibrations of ν₃(A _g ) symmetry. No such splitting is observed in the superconductor spectra with decreasing temperature. __________ Translated from Fizika Tverdogo Tela, Vol. 46, No. 11, 2004, pp. 1921–1929. Original Russian Text Copyright ? 2004 by Vlasova, Drichko, Petrov, Semkin, Zhilyaeva, Lyubovskaya, Olejniczak, A. Kobayashi, H. Kobayashi.     

Experimental study and mathematical modelling of a new of vibro-impact moling device

In this paper experimental study and mathematical modelling of newly designed vibro-impact moling rig are presented. The design is based on electro-mechanical interactions of a conductor with an oscillating magnetic field. The rig consists of a metal bar placed within a solenoid which is connected to an RLC circuit, and an obstacle block positioned nearby. Both the solenoid and the block are attached to a base board. Externally supplied alternating voltage causes the bar to oscillate and hit the block resulting in the forward motion of the base board mimicking a mole penetration through the soil. By varying the excitation voltage and the capacitance in the circuit, a variety of system responses can be obtained.In the paper the rig design and experimental procedure are explained in detail, and the mathematical modelling of the rig is described. Then the obtained coupled electro-mechanical equations of motion are integrated numerically, and a comparison between experimental results and numerical predictions is presented.     

The catalytic reactions of triethyl- and triethoxy-silane with unsaturated sulphides

The hydrosilylation of mono- and di-alkenyl sulphides of the type RS(CH₂)_nCH=CH₂ (R = C₂H₅, CH₂=CH, CH₂=CHCH₂, C₃H₇, n = 0, 1 and 4) by triethyl- and triethoxy-silane, catalyzed by H₂PtCl₆·6 H₂O, (Ph₃P)₃RhCl and (PhCN)₂PdCl₂·Ph₃P, has been studied. The addition of hydrosilane to the double bond of alkenyl sulphide leads to a mixture of two isomeric monoadducts. The hydrosilane can cleave the C---S bond of the initial sulphides giving the corresponding derivatives of thiosilanes, X₃SiS(CH₂)_nCH=CH₂ (X = C₂H₅, C₂H₅O). Hydrosilylation of alkenyl sulphides is accompanied by some side reactions such as dehydrocondensation, reduction and polymerization. The effect of the catalyst nature, the structure of hydrosilane and alkenyl sulphide on the reaction route has been investigated.     

Structure,tautomerism, and transformations of β-(3-nitro-2-pyridyl)- and β-(3-nitro-4-pyridyl)pyruvic acid esters

It was shown by means of IR, UV, and PMR spectra that -(3-nitro-2-pyridyl)pyruvic acid esters are practically completely enolized in the crystal state and in solution; ethyl -(3-nitro-4-pyridyl)pyruvate has an enol structure in the crystalline state and in pyridine solution but exists as a mixture of keto and enol forms in low-polarity solvents.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 389–393, March, 1974.     

Influence of the reaction temperature and ph on the coordination modes of the 1,4-benzenedicarboxylate (BDC) ligand: a case study of the Ni(II)(BDC)/2,2'-bipyridine system

Three new Ni(BDC)/2,2'-bipy compounds, Ni2(BDC)(HBDC)2(2,2'-bipy)2 (2), Ni3(BDC)3(2,2'-bipy)2 (3), and Ni(BDC)(2,2-bipy)2.2H2O (5), in addition to the previously reported Ni(BDC)(2,2'-bipy).0.75H2BDC (1) and Ni(BDC)(2,2'-bipy)(H2O) (4) [BDC = 1,4-benzenedicarboxylate; 2,2'-bipy = 2,2'-bipyridine], have been synthesized by hydrothermal reactions. A systematic investigation of the effect of the reaction temperature and pH resulted in a series of compounds with different compositions and dimensionality. The diverse product slate illustrates the marked sensitivity of the structural chemistry of polycarboxylate aromatic ligands to synthesis conditions. Compound 1, which has a channel structure containing guest H2BDC molecules, is formed at the lowest pH. The guest H2BDC molecules are connected by hydrogen bonds and form extended chains. At a slightly higher pH, a dimeric molecular compound 2 is formed with a lower number of protonated carboxylate groups per nickel atom and per BDC ligand. Reactions at higher temperature and the same pH lead to the transformation of 1 and 2 into the two-dimensional, layered trinuclear compound 3. As the pH is increased, a one-dimensional polymer 4 is formed with a water molecule coordinated to Ni2+. Bis-monodentate and bischelating BDC ligands alternate along the chain to give a crankshaft rather than a regular zigzag arrangement. A further increase of the pH leads to the one-dimensional chain compound 5, which has two chelating 2,2'-bipy ligands. Crystal data: 2, triclinic, space group P, a = 7.4896(9) angstroms, b = 9.912(1) angstroms, c = 13.508(2) angstroms, alpha = 86.390(2) degrees , beta = 75.825(2) degrees, gamma = 79.612(2) degrees, Z = 2; 3, orthorhombic, space group Pbca, a = 9.626(2) angstroms, b = 17.980(3) angstroms, c = 25.131(5) angstroms, Z = 4; 5, orthorhombic, space group Pbcn, a = 14.266(2) angstroms, b = 10.692(2) angstroms, c = 17.171(2) angstroms, Z = 8.     

Convergence of series with respect to generalized Haar systems

. . . . , L _p[0, l], 1 >p <, .     

Efficient RNase H-directed cleavage of RNA promoted by antisense DNA or 2'F-ANA constructs containing acyclic nucleotide inserts

The ability of modified antisense oligonucleotides (AONs) containing acyclic interresidue units to support RNase H-promoted cleavage of complementary RNA is described. Manipulation of the backbone and sugar geometries in these conformationally labile monomers shows great benefits in the enzymatic recognition of the nucleic acid hybrids, while highlighting the importance of local strand conformation on the hydrolytic efficiency of the enzyme more conclusively. Our results demonstrate that the duplexes support remarkably high levels of enzymatic degradation when treated with human RNase HII, making them efficient mimics of the native substrates. Furthermore, interesting linker-dependent modulation of enzymatic activity is observed during in vitro assays, suggesting a potential role for this AON class in an RNase H-dependent pathway of controlling RNA expression. Additionally, the butyl-modified 2'F-ANA AONs described in this work constitute the first examples of a nucleic acid species capable of eliciting high RNase H activity while possessing a highly flexible molecular architecture at predetermined sites along the AON.