Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae

The benzylisoquinoline alkaloids (BIAs) are a diverse class of metabolites that exhibit a broad range of pharmacological activities and are synthesized through plant biosynthetic pathways comprised of complex enzyme activities and regulatory strategies. We have engineered yeast to produce the key intermediate reticuline and downstream BIA metabolites from a commercially available substrate. An enzyme tuning strategy was implemented that identified activity differences between variants from different plants and determined optimal expression levels. By synthesizing both stereoisomer forms of reticuline and integrating enzyme activities from three plant sources and humans, we demonstrated the synthesis of metabolites in the sanguinarine/berberine and morphinan branches. We also demonstrated that a human P450 enzyme exhibits a novel activity in the conversion of (R)-reticuline to the morphinan alkaloid salutaridine. Our engineered microbial hosts offer access to a rich group of BIA molecules and associated activities that will be further expanded through synthetic chemistry and biology approaches

A Multi-Host Agent-Based Model for a Zoonotic, Vector-Borne Disease. A Case Study on Trypanosomiasis in Eastern Province, Zambia

Background: This paper presents a new agent-based model (ABM) for investigating T. b. rhodesiense human African trypanosomiasis (rHAT) disease dynamics, produced to aid a greater understanding of disease transmission, and essential for development of appropriate mitigation strategies. Methods: The ABM was developed to model rHAT incidence at a fine spatial scale along a 75 km transect in the Luangwa Valley, Zambia. The method offers a complementary approach to traditional compartmentalised modelling techniques, permitting incorporation of fine scale demographic data such as ethnicity, age and gender into the simulation. Results: Through identification of possible spatial, demographic and behavioural characteristics which may have differing implications for rHAT risk in the region, the ABM produced output that could not be readily generated by other techniques. On average there were 1.99 (S.E. 0.245) human infections and 1.83 (S.E. 0.183) cattle infections per 6 month period. The model output identified that the approximate incidence rate (per 1000 person-years) was lower amongst cattle owning households (0.079, S.E. 0.017), than those without cattle (0.134, S.E. 0.017). Immigrant tribes (e.g. Bemba I.R. = 0.353, S.E.0.155) and school-age children (e.g. 5–10 year old I.R. = 0.239, S.E. 0.041) were the most at-risk for acquiring infection. These findings have the potential to aid the targeting of future mitigation strategies. Conclusion: ABMs provide an alternative way of thinking about HAT and NTDs more generally, offering a solution to the investigation of local-scale questions, and which generate results that can be easily disseminated to those affected. The ABM can be used as a tool for scenario testing at an appropriate spatial scale to allow the design of logistically feasible mitigation strategies suggested by model output. This is of particular importance where resources are limited and management strategies are often pushed to the local scale. © 2016 Alderton et al

Measurement of vortex motion in a type II superconductor: a novel use of the spinecho technique

We have used the neutron spin-echo technique to measure the small energy change of neutrons which are diffracted by a moving vortex lattice in a low-pinning Nb-Ta superconducting sample. A transport current was passed in the mixed state to cause flux line movement. In the case of uniform motion, the flux velocity v(L) was given as expected by the values of electric and magnetic fields, via E = -v(L) boolean AND B. We show that with a nonuniformly moving vortex lattice, one can measure the dispersion of the velocities, opening up new possibilities for investigating moving vortex lines.</p

Vortex motion in type-II superconductors probed by muon spin rotation and small-angle neutron scattering

We report muon spin rotation (μSR) measurements on the moving vortex lattice (VL) in the type-II superconductor Pb-In, backed up by small-angle neutron scattering (SANS) observations on the same sample. We observe a motional narrowing of the μSR lineshape p(B) and by SANS, alignment of the VL to the direction of vortex motion. We have calculated the μSR lineshape expected with a range of orientations of the moving VL. We demonstrate how the new μSR results give information on the moving VL which is complementary and consistent with the SANS data