Synthesis and properties of isobicyclo-DNA.

We present the synthesis of the isobicyclo-DNA building blocks with the nucleobases A, C, G and T, as well as biophysical and biological properties of oligonucleotides derived thereof. The synthesis of the sugar part was achieved in 5 steps starting from a known intermediate of the tricyclo-DNA synthesis. Dodecamers containing single isobicyclo-thymidine incorporations, fully modified A- and T-containing sequences, and fully modified oligonucleotides containing all four bases were synthesized and characterized. Isobicyclo-DNA forms stable duplexes with natural nucleic acids with a pronounced preference for DNA over RNA as complements. The most stable duplexes, however, arise by self-pairing. Isobicyclo-DNA forms preferentially B-DNA-like duplexes with DNA and A-like duplexes with complementary RNA as determined by circular dichroism (CD) spectroscopy. Self-paired duplexes show a yet unknown structure, as judged from CD spectroscopy. Biochemical tests revealed that isobicyclo-DNA is stable in fetal bovine serum and does not elicit RNaseH activity.

Position-dependent effects on stability in tricyclo-DNA modified oligonucleotide duplexes.

A series of oligodeoxyribonucleotides and oligoribonucleotides containing single and multiple tricyclo(tc)-nucleosides in various arrangements were prepared and the thermal and thermodynamic transition profiles of duplexes with complementary DNA and RNA evaluated. Tc-residues aligned in a non-continuous fashion in an RNA strand significantly decrease affinity to complementary RNA and DNA, mostly as a consequence of a loss of pairing enthalpy ΔH. Arranging the tc-residues in a continuous fashion rescues T(m) and leads to higher DNA and RNA affinity. Substitution of oligodeoxyribonucleotides in the same way causes much less differences in T(m) when paired to complementary DNA and leads to substantial increases in T(m) when paired to complementary RNA. CD-spectroscopic investigations in combination with molecular dynamics simulations of duplexes with single modifications show that tc-residues in the RNA backbone distinctly influence the conformation of the neighboring nucleotides forcing them into higher energy conformations, while tc-residues in the DNA backbone seem to have negligible influence on the nearest neighbor conformations. These results rationalize the observed affinity differences and are of relevance for the design of tc-DNA containing oligonucleotides for applications in antisense or RNAi therapy.

Russia's National Concept to Reduce Alcohol Abuse and Alcohol-Dependence in the Population 2010-2020: Which Policy Targets Have Been Achieved?

In the 2000s, Russia was globally one of the top 5 countries with the highest levels of alcohol per capita consumption and prevailing risky patterns of drinking, i.e., high intake per occasion, high proportion of people drinking to intoxication, and high frequency of situations where alcohol is consumed and tolerated. In 2009, in response to these challenges, the Russian government formed the Federal Service for Alcohol Market Regulation and published a national strategy concept to reduce alcohol abuse and alcohol-dependence at the population level for the period 2010-2020. The objectives of the present contribution are to analyze the evidence base of the core components of the concept and to provide a comprehensive evaluation framework of measures implemented (process evaluation) and the achievement of the formulated targets (effect evaluation). Most of the concept's measures were found to be evidence-based and aligned with eight out of 10 areas of the World Health Organization (WHO) policy portfolio. Out of the 14 tasks, 7 were rated as achieved, and 7 as partly achieved. Ten years after the concept's adoption, alcohol consumption seems to have declined by about a third and alcohol is conceptualized as a broad risk factor for the population's health in Russia.