Asymmetric dearomatization/cyclization enables access to polycyclic chemotypes

Enantioenriched, polycyclic compounds were obtained from a simple acylphloroglucinol scaffold. Highly enantioselective dearomatization was accomplished using a Trost ligand-palladium(0) complex. A computational DFT model was developed to rationalize observed enantioselectivities and revealed a key reactant-ligand hydrogen bonding interaction. Dearomatized products were used in visible light-mediated photocycloadditions and oxidative free radical cyclizations to obtain novel polycyclic chemotypes including tricyclo[4.3.1.01,4]decan-10-ones, bicyclo[3.2.1]octan-8-ones and highly-substituted cycloheptanones.R24 GM111625 - NIGMS NIH HH

A versatile transposon-based technology to generate loss- and gain-of-function phenotypes in the mouse liver

Background Understanding the contribution of gene function in distinct organ systems to the pathogenesis of human diseases in biomedical research requires modifying gene expression through the generation of gain- and loss-of-function phenotypes in model organisms, for instance, the mouse. However, methods to modify both germline and somatic genomes have important limitations that prevent easy, strong, and stable expression of transgenes. For instance, while the liver is remarkably easy to target, nucleic acids introduced to modify the genome of hepatocytes are rapidly lost, or the transgene expression they mediate becomes inhibited due to the action of effector pathways for the elimination of exogenous DNA. Novel methods are required to overcome these challenges, and here we develop a somatic gene delivery technology enabling long-lasting high-level transgene expression in the entire hepatocyte population of mice. Results We exploit the fumarylacetoacetate hydrolase (Fah) gene correction-induced regeneration in Fah-deficient livers, to demonstrate that such approach stabilizes luciferase expression more than 5000-fold above the level detected in WT animals, following plasmid DNA introduction complemented by transposon-mediated chromosomal gene transfer. Building on this advancement, we created a versatile technology platform for performing gene function analysis in vivo in the mouse liver. Our technology allows the tag-free expression of proteins of interest and silencing of any arbitrary gene in the mouse genome. This was achieved by applying the HADHA/B endogenous bidirectional promoter capable of driving well-balanced bidirectional expression and by optimizing in vivo intronic artificial microRNA-based gene silencing. We demonstrated the particular usefulness of the technology in cancer research by creating a p53-silenced and hRas G12V-overexpressing tumor model. Conclusions We developed a versatile technology platform for in vivo somatic genome editing in the mouse liver, which meets multiple requirements for long-lasting high-level transgene expression. We believe that this technology will contribute to the development of a more accurate new generation of tools for gene function analysis in mice.Peer reviewe

Isolation of a Ru(IV) side-on peroxo intermediate in the water oxidation reaction

The electrons that nature uses to reduce CO2 during photosynthesis come from water oxidation at the oxygen-evolving complex of photosystem II. Molecular catalysts have served as models to understand its mechanism, in particular the O-O bond-forming reaction, which is still not fully understood. Here we report a Ru(IV) side-on peroxo complex that serves as a 'missing link' for the species that form after the rate-determining O-O bond-forming step. The Ru(IV) side-on peroxo complex (eta(2)-1(IV)-OO) is generated from the isolated Ru(IV) oxo complex (1(IV)=O) in the presence of an excess of oxidant. The oxidation (IV) and spin state (singlet) of eta(2)-1(IV)-OO were determined by a combination of experimental and theoretical studies. O-18- and H-2-labelling studies evidence the direct evolution of O-2 through the nucleophilic attack of a H2O molecule on the highly electrophilic metal-oxo species via the formation of eta(2)-1(IV)-OO. These studies demonstrate water nucleophilic attack as a viable mechanism for O-O bond formation, as previously proposed based on indirect evidence

Snow Chemistry Across Antarctica

An updated compilation of published and new data of major-ion (Ca, Cl, K, Mg, Na, NO3, SO4) and methylsulfonate (MS) concentrations in snow from 520 Antarctic sites is provided by the national ITASE (International Trans-Antarctic Scientific Expedition) programmes of Australia, Brazil, China, Germany, Italy, Japan, Korea, New Zealand, Norway, the United Kingdom, the United States and the national Antarctic programme of Finland. The comparison shows that snow chemistry concentrations vary by up to four orders of magnitude across Antarctica and exhibit distinct geographical patterns. The Antarctic-wide comparison of glaciochemical records provides a unique opportunity to improve our understanding of the fundamental factors that ultimately control the chemistry of snow or ice samples. This paper aims to initiate data compilation and administration in order to provide a framework for facilitation of Antarctic-wide snow chemistry discussions across all ITASE nations and other contributing groups. The data are made available through the ITASE web page (http:// www2.umaine.edu/itase/content/syngroups/snowchem.html) and will be updated with new data as they are provided. In addition, recommendations for future research efforts are summarized