Reaction rate sensitivity of 44Ti production in massive stars and implications of a thick target yield measurement of 40Ca(alpha,gamma)44Ti

We evaluate two dominant nuclear reaction rates and their uncertainties that affect 44Ti production in explosive nucleosynthesis. Experimentally we develop thick-target yields for the 40Ca(alpha,gamma)44Ti reaction at E(alpha) = 4.13, 4.54, and 5.36 MeV using gamma-ray spectroscopy. At the highest beam energy, we also performed an activation measurement that agrees with the thick target result. From the measured yields a stellar reaction rate was developed that is smaller than current statistical-model calculations and recent experimental results, which would suggest lower 44Ti production in scenarios for the alpha-rich freeze out. Special attention has been paid to assessing realistic uncertainties of stellar rates produced from a combination of experimental and theoretical cross sections, which we use to develop a re-evaluation of the 44Ti(alpha,p)47V reaction rate. Using these we carry out a sensitivity survey of 44Ti synthesis in eight expansions representing peak temperature and density conditions drawn from a suite of recent supernova explosion models. Our results suggest that the current uncertainty in these two reaction rates could lead to as large an uncertainty in 44Ti synthesis as that produced by different treatments of stellar physics.Comment: Comments: 45 pages, 19 postscript figures Minor corrections from Referee and Proof Editors Figs 9 & 10 now in colo

Cellular Active N-Hydroxyurea FEN1 Inhibitors Block Substrate Entry to the Active Site

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the first crystal structure of inhibitor-bound hFEN1 and show a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein– substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the unpairing of substrate DNA necessary for reaction. Other compounds were more competitive with substrate. Cellular thermal shift data showed engagement of both inhibitor types with hFEN1 in cells with activation of the DNA damage response evident upon treatment. However, cellular EC50s were significantly higher than in vitro inhibition constants and the implications of this for exploitation of hFEN1 as a drug target are discussed

Site-selective protein-modification chemistry for basic biology and drug development.

Nature has produced intricate machinery to covalently diversify the structure of proteins after their synthesis in the ribosome. In an attempt to mimic nature, chemists have developed a large set of reactions that enable post-expression modification of proteins at pre-determined sites. These reactions are now used to selectively install particular modifications on proteins for many biological and therapeutic applications. For example, they provide an opportunity to install post-translational modifications on proteins to determine their exact biological roles. Labelling of proteins in live cells with fluorescent dyes allows protein uptake and intracellular trafficking to be tracked and also enables physiological parameters to be measured optically. Through the conjugation of potent cytotoxicants to antibodies, novel anti-cancer drugs with improved efficacy and reduced side effects may be obtained. In this Perspective, we highlight the most exciting current and future applications of chemical site-selective protein modification and consider which hurdles still need to be overcome for more widespread use.We thank FCT Portugal (FCT Investigator to G.J.L.B.), the EU (Marie-Curie CIG to G.J.L.B. and Marie-Curie IEF to O.B.) and the EPSRC for funding. G.J.L.B. is a Royal Society University Research Fellow.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.239

Thick target measurement of the 40Ca(alpha,gamma)44Ti reaction rate

The thick-target yield for the {sup 40}Ca({alpha},{gamma}){sup 44}Ti reaction has been measured for E{sub beam} = 4.13, 4.54, and 5.36 MeV using both an activation measurement and online {gamma}-ray spectroscopy. The results of the two measurements agree. From the measured yield a reaction rate is deduced that is smaller than statistical model calculations. This implies a smaller {sup 44}Ti production in supernova compared to recently measured {sup 40}Ca({alpha},{gamma}){sup 44}Ti reaction rates