Gapmer Antisense Oligonucleotides Containing 2′,3′-Dideoxy-2′-fluoro-3′-C-hydroxymethyl-β-d-lyxofuranosyl Nucleotides Display Site-Specific RNase H Cleavage and Induce Gene Silencing

Off-target effects remain a significant challenge in the therapeutic use of gapmer antisense oligonucleotides (AONs). Over the years various modifications have been synthesized and incorporated into AONs, however, precise control of RNase H-induced cleavage and target sequence selectivity has yet to be realized. Herein, the synthesis of the uracil and cytosine derivatives of a novel class of 2′-deoxy-2′-fluoro-3′-C-hydroxymethyl-β-d -lyxo-configured nucleotides has been accomplished and the target molecules have been incorporated into AONs. Experiments on exonuclease degradation showed improved nucleolytic stability relative to the unmodified control. Upon the introduction of one or two of the novel 2′-fluoro-3′-C-hydroxymethyl nucleotides as modifications in the gap region of a gapmer AON was associated with efficient RNase H-mediated cleavage of the RNA strand of the corresponding AON:RNA duplex. Notably, a tailored single cleavage event could be engineered depending on the positioning of a single modification. The effect of single mismatched base pairs was scanned along the full gap region demonstrating that the modification enables a remarkable specificity of RNase H cleavage. A cell-based model system was used to demonstrate the potential of gapmer AONs containing the novel modification to mediate gene silencing.     

Magnetic hyperfine fields of119Sn in vacancy-associated defect structures in 3d ferromagnets

Hyperfine Interactions - Defect structures associated with Sb or In impurity atoms in iron, cobalt, and nickel hosts have been detected by Sn-119 Mössbauer spectroscopy. With substitutional...     

Two photon-induced fluorescence intensity and anisotropy decays of diphenylhexatriene in solvents and lipid bilayers

We measured the fluorescence intensity and anisotropy decays of 1,6-diphenyl-1,3,5-hexatriene (DPH)-labeled membranes resulting from simultaneous two-photon excitation of fluorescence. Comparison of these two-photon data with the more usual one-photon measurements revealed that DPH displayed identical intensity decays, anisotropy decays, and order parameters for one- and two-photon excitation. While the anisotropy data are numerically distinct, they can be compared by use of the factor 10/7, which accounts for the two-photon versus one-photon photoselection. The increased time 0 anisotropy of DPH can result in increased resolution of complex anisotropy decays. Global analysis of the one- and two-photon data reveals consistency with a single apparent angle between the absorption and the emission oscillators. The global anisotropy analysis also suggests that, except for the photoselection factor, the anisotropy decays are the same for one-and two-photon excitation. This ideal behavior of DPH as a two-photon absorber, and its high two-photon cross section, makes DPH a potential probe for confocal two-photon microscopy and other systems where it is advantageous to use long-wavelength (680- to 760-nm) excitation.     

On the classification of all self-dual additive codes over GF(4) of length up to 12

We consider additive codes over GF(4) that are self-dual with respect to the Hermitian trace inner product. Such codes have a well-known interpretation as quantum codes and correspond to isotropic systems. It has also been shown that these codes can be represented as graphs, and that two codes are equivalent if and only if the corresponding graphs are equivalent with respect to local complementation and graph isomorphism. We use these facts to classify all codes of length up to 12, where previously only all codes of length up to 9 were known. We also classify all extremal Type II codes of length 14. Finally, we find that the smallest Type I and Type II codes with trivial automorphism group have length 9 and 12, respectively.     

New amorphous interface for precipitate nitrides in steel

According to classical theories precipitate interfaces are described by their degree of coherency with the matrix, which affects their strengthening contribution. Investigations of nitride precipitate interfaces in 12% Cr steels with transmission electron microscopy have shown the nitrides to be enveloped in an amorphous shell a few nm thick, thus leaving them without any coherency with the matrix. The amorphous nature of the shells could be ascertained with high resolution microscopy and dark field techniques. When extracted from the ferrite matrix the amorphous shells were observed to crystallize during electron beam exposure. The amorphous shells were observed around Ta- and Nb-based nitrides, which are considered to have a high interfacial energy with the ferrite matrix. They were not observed around V-based nitrides which have a Baker–Nutting relationship with low-misfit to the matrix.     

All-optical wavelength converters for optical switching applications

We present the latest results about all-optical wavelength conversion obtained within the European Union—funded RACE ATMOS project. In particular, solutions based on carrier depletion in Distributed Brag Reflector lasers have reached penalty-free polarization-insensitive operation at up to 2.5 Gbit/s, while solutions based on Semiconductor Optical Amplifiers (SOAS) under cross-gain modulation have been demonstrated at more than 20 Gbit/s. The study of cross-phase modulation in SOAs has also been performed, leading to the monolithic integration of SOAs within an interferometer, according to structures proposed by the project. Penalty-free operation at up to 10 Gbit/s as well as signal reshaping have been obtained with such devices. Besides the study of components, wavelength converters have been used in several demonstrators assessing their maturity and compatibility with photonic-switching applications.     

Analysis of perturbed angular correlation spectra of metal ions bound to proteins with rotational correlation times in the intermediate region

The formulation by Dattagupta of the strong-collision model, describing the effect on the perturbation function,G ₂(t) by the isotropic tumbling of an electric field gradient, is generalized to electric field gradients with no axial symmetry. The effect on the perturbation function by strong collisions is compared to the effect of rotational diffusion in the adiabatic limit. The comparison is carried out for decays with an intermediate state of spin 5/2 and for non-axially symmetric electric field gradients. It shows that the strong-collision model can be used for interpretation of PAC spectra of molecules with correlation times between the adiabatic and the fast relaxation limits. The strongcollision model is then used to determine the rotational diffusion of the cadmium substituted copper, zinc superoxide dismutase at 3°C and 25°C from^111mCd TDPAC spectra. For these analyses, the model is incorporated into a conventional least-squares fitting routine.     

THE PHOTOCHEMISTRY OF ADENOSINE: INTERMEDIATES CONTRIBUTING TO ITS PHOTODEGRADATION MECHANISM IN AQUEOUS SOLUTION AT 298 K AND CHARACTERIZATION OF THE MAJOR PRODUCT

Abstract— The steady-state (254 nm) photolysis of 9–(β-d-erythropentofuranosyl)adenine (adenosine) in aqueous solution was studied. Photodestruction yields on the order of 1.3 × 10⁻³⁾ were determined at room temperature by measuring the initial decrease in the absorption maximum as a function of irradiation time. The use of high performance liquid chromatography (HPLC) permitted a more exact determination of the yield (2.5 × 10³). The formation of photoproducts was also studied using HPLC. In the photolysis of 50 μ M aqueous solutions of adenosine under anaerobic conditions at least 11 stable photoproducts are formed that absorb at 260 nm, the wavelength of maximum absorption of adenosine. The major photoproduct was also isolated and characterized as adenine; its formation yield was determined to be 4.5 × 10⁴. This yield is affected by the presence of oxygen and by the initial concentration of adenosine employed. Fluorescence emission and excitation spectra were used to monitor the formation of highly fluorescent photoproducts that emit with maxima at 365, 398 , and 430 nm and absorb in the wavelength region of 240–380 nm.
The reactive species in the photodestruction mechanism were established using substrates that react selectively with the respective short-lived species. Photoionization is a primary photoprocess implied by these studies. The triplet state of adenosine also contributes to the photodestruction mechanism.     

Monte Carlo Simulations of PAC-Spectra as a General Approach to Dynamic Interactions

Time Dependent Perturbed Angular Correlations of -rays (PAC) can be used to study hyperfine interactions of a dynamic nature. However, the exact effect of the dynamic interaction on the PAC-spectrum is sometimes difficult to derive analytically. A new approach based on Monte Carlo simulations is therefore suggested, here implemented as a Fortran 90 program for simulating PAC spectra of dynamic electric field gradients of any origin. The program is designed for the most common experimental condition where the intermediate level has spin 5/2, but the approach can equally well be used for other spin states. Codes for 4 different situations have been developed: (1) Rotational diffusion by jumps; used as a test case. (2) Jumps between two states with different electric field gradients, different lifetimes and different orientations of the electric field gradient principal axes. (3) Relaxation of one state to another. (4) Molecules adhering to a surface with random rotational jumps around the axis perpendicular to the surface. To illustrate how this approach can be used to improve data-interpretation, previously published data on ^111mCd-plastocyanin and ¹¹¹Ag-plastocyanin are re-considered. The strength of this novel approach is its simplicity and generality so that other dynamic processes can easily be included by only adding new program units describing the random process behind the dynamics. The program is hereby made publicly available.