Guanine-thymine intrastrand cross-linked lesion containing oligonucleotides: from chemical synthesis to in vitro enzymatic replication

An intrastrand cross-link lesion, in which two neighboring nucleobases are covalently tethered, has been site-specifically synthesized into defined sequence oligonucleotides in order to perform in vitro replication studies using either bacterial replicative or translesional synthesis polymerases. The investigated tandem base lesion that involves a cross-link between the methylene group of thymine and the C8 of an adjacent guanine residue has been prepared by UV-photolysis under anaerobic condition of the photolabile precursor 5-(phenylthiomethyl)-2'-deoxyuridine that has been site-specifically incorporated into a 9-mer oligonucleotide. After ligation, the lesion-containing modified oligonucleotide was used as a DNA template in primer extension reactions catalyzed by several DNA polymerases including the fragment Klenow exo-(Kf-) of E. coli polymerase I, the Thermus aquaticus polymerase (Taq pol) and the E. coli translesional DNA polymerase Pol IV (dinB). It was found that the primer extension reaction was stopped after the incorporation of the correct nucleotide dAMP opposite the 3'-thymine residue of guanine(C8-CH2) thymine lesion by Kf- and Pol IV; however it was noted that the efficiency of the nucleotide incorporation was reduced. In contrast, the Taq polymerase was totally blocked at the nucleotide preceding the tandem lesion. These results are strongly suggestive that the present intrastrand cross-link lesion, if not repaired, would constitute a blocking lesion for prokaryotic DNA polymerases, being likely lethal for the cell.     

Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors

We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.     

Unusual coordination behavior of Cr3+ in microporous aluminophosphates

A CrAPO-5 molecular sieve has been investigated with X-ray absorption spectroscopy (EXAFS-XANES) as dehydrated material and after loading with water and ammonia to unravel the coordination geometries of Cr3+ in the framework of a microporous crystalline aluminophosphate, more particularly of the AFI-type. A comparison of the XANES data, a preedge analysis with crystal field multiplet calculations and EXAFS data, pointed toward the presence of framework Cr3+ which, on dehydration, takes on a distorted tetrahedral coordination state. Due to the 3d3 configuration of Cr3+, this unusual tetrahedral coordination environment strongly tends to transform into the more stable 6-fold coordination geometry by binding two extraframework water molecules during hydration. In the presence of ammonia, tetrahedral Cr3+ readily transforms into a 5-fold coordination geometry by binding one ammonia molecule. Therefore, depending on the environmental conditions, the Cr3+ ions can occur in a 4-, 5-, or 6-fold coordination. This observation underlines the flexibility of transition metal ions, such as Cr3+, to cope with unusual coordination geometries in inorganic hosts, making them interesting as potential active sites in heterogeneous catalysis.     

New theoretical and experimental infrared results on formaldehyde in solution

An extension of our combined procedure to determine a complete quartic force field and to resolve a vibrational problem thanks to a variational treatment is proposed for quantitative calculations of vibrational spectra in solution. Energies and gradients are obtained through a polarizable continuum model (PCM), the so-called self-consistent isodensity (SCI)-PCM. We present in this paper new experimental results dealing with formaldehyde in solution in cyclohexane, chloroform, THF, acetonitrile, DMSO and water; the obtained vibrational spectra are then compared with CCSD(T)/cc-pVQZ calculations. In addition, density functional theory (DFT) calculations have been carried out with the aim of both anticipating and positioning these approaches for larger sized molecules.     

On well-posedness for some dispersive perturbations of Burgers' equation

We show that the Cauchy problem for a class of dispersive perturbations of Burgers' equations containing the low dispersion Benjamin–Ono equation

${?}_{t}u?D_x^{\alpha }{?}_{x}u={?}_x(u^2),0<\alpha \le 1,$

is locally well-posed in $H^s(\mathbb{R})$ when $s>s_{\alpha }:=\frac{3}{2}?\frac{5\alpha }{4}$. As a consequence, we obtain global well-posedness in the energy space $H^{\frac{\alpha }{2}}(\mathbb{R})$ as soon as $\frac{\alpha }{2}>s_{\alpha }$, i.e. $\alpha >\frac{6}{7}$.     

Detecting rigid convexity of bivariate polynomials

Given a polynomial x∈Rⁿ?p(x) in n=2 variables, a symbolic-numerical algorithm is first described for detecting whether the connected component of the plane sublevel set P={x:p(x)?0} containing the origin is rigidly convex, or equivalently, whether it has a linear matrix inequality (LMI) representation, or equivalently, if polynomial p(x) is hyperbolic with respect to the origin. The problem boils down to checking whether a univariate polynomial matrix is positive semidefinite, an optimization problem that can be solved with eigenvalue decomposition. When the variety C={x:p(x)=0} is an algebraic curve of genus zero, a second algorithm based on Bézoutians is proposed to detect whether P has an LMI representation and to build such a representation from a rational parametrization of C. Finally, some extensions to positive genus curves and to the case n>2 are mentioned.     

Quantum transport of slow charge carriers in quasicrystals and correlated systems

We show that the semiclassical model of conduction breaks down if the mean free path of charge carriers is smaller than a typical extension of their wave function. This situation is realized for sufficiently slow charge carriers and leads to a transition from a metalliclike to an insulatinglike regime when scattering by defects increases. This explains the unconventional conduction properties of quasicrystals and related alloys. The conduction properties of some heavy fermions or polaronic systems, where charge carriers are also slow, present a deep analogy.     

Simultaneous measurements of indoor radon and thoron and inhalation dose assessment in Douala City,Cameroon

ABSTRACT

Radon, thoron and associated progeny measurements have been carried out in 71 dwellings of Douala city, Cameroon. The radon–thoron discriminative detectors (RADUET) were used to estimate the radon and thoron concentration, while thoron progeny monitors measured equilibrium equivalent thoron concentration (EETC). Radon, thoron and thoron progeny concentrations vary from 31?±?1 to 436?±?12 Bq?m^–3, 4?±?7 to 246?±?5 Bq?m^–3, and 1.5?±?0.9 to 13.1?±?9.4 Bq?m^–3. The mean value of the equilibrium factor for thoron is estimated at 0.11?±?0.16. The annual effective dose due to exposure to indoor radon and progeny ranges from 0.6 to 9?mSv?a^–1 with an average value of 2.6?±?0.1?mSv?a^–1. The effective dose due to the exposure to thoron and progeny vary from 0.3 to 2.9?mSv?a^–1 with an average value of 1.0?±?0.4?mSv?a^–1. The contribution of thoron and its progeny to the total inhalation dose ranges from 7 to 60?% with an average value of 26?%; thus their contributions should not be neglected in the inhalation dose assessment.     

Kelvin–Helmholtz instability with a free surface

The well-posedness of the hydrostatic equations is linked to long wave stability criteria for parallel shear flows. We revisit the Kelvin--Helmholtz instability with a free surface. In the wall-bounded case, the flow is unstable to all wave lengths. Short wave instabilities are localized and independent of boundary conditions. On the other hand, long waves are shown to be stable if the upper boundary is a free surface and gravity is sufficiently small. We also consider smooth velocity profiles of the base flow rather than a velocity jump. We show that stability of long waves for small gravity generally holds for monotone profiles U(y). On the other hand, this need not be the case if U is not monotone.