Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy

Herein we report the development and biological screening of a bioorthogonal palladium-labile prodrug of the nucleoside analogue floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast reduction of its biological activity (~6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chemistry both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy

Typhoid Fever and Its Association with Environmental Factors in the Dhaka Metropolitan Area of Bangladesh: A Spatial and Time-Series Approach

Typhoid fever is a major cause of death worldwide with a major part of the disease burden in developing regions such as the Indian sub-continent. Bangladesh is part of this highly endemic region, yet little is known about the spatial and temporal distribution of the disease at a regional scale. This research used a Geographic Information System to explore, spatially and temporally, the prevalence of typhoid in Dhaka Metropolitan Area (DMA) of Bangladesh over the period 2005-9. This paper provides the first study of the spatio-temporal epidemiology of typhoid for this region. The aims of the study were: (i) to analyse the epidemiology of cases from 2005 to 2009; (ii) to identify spatial patterns of infection based on two spatial hypotheses; and (iii) to determine the hydro-climatological factors associated with typhoid prevalence. Case occurrences data were collected from 11 major hospitals in DMA, geocoded to census tract level, and used in a spatio-temporal analysis with a range of demographic, environmental and meteorological variables. Analyses revealed distinct seasonality as well as age and gender differences, with males and very young children being disproportionately infected. The male-female ratio of typhoid cases was found to be 1.36, and the median age of the cases was 14 years. Typhoid incidence was higher in male population than female (χ2 = 5.88, p0.05). A statistically significant inverse association was found between typhoid incidence and distance to major waterbodies. Spatial pattern analysis showed that there was a significant clustering of typhoid distribution in the study area. Moran\u27s I was highest (0.879; p<0.01) in 2008 and lowest (0.075; p<0.05) in 2009. Incidence rates were found to form three large, multi-centred, spatial clusters with no significant difference between urban and rural rates. Temporally, typhoid incidence was seen to increase with temperature, rainfall and river level at time lags ranging from three to five weeks. For example, for a 0.1 metre rise in river levels, the number of typhoid cases increased by 4.6% (95% CI: 2.4-2.8) above the threshold of 4.0 metres (95% CI: 2.4-4.3). On the other hand, with a 1°C rise in temperature, the number of typhoid cases could increase by 14.2% (95% CI: 4.4-25.0)

Optical control of antibacterial activity

<p>Bacterial resistance is a major problem in the modern world, stemming in part from the build-up of antibiotics in the environment. Novel molecular approaches that enable an externally triggered increase in antibiotic activity with high spatiotemporal resolution and auto-inactivation are highly desirable. Here we report a responsive, broad-spectrum, antibacterial agent that can be temporally activated with light, whereupon it auto-inactivates on the scale of hours. The use of such a 'smart' antibiotic might prevent the build-up of active antimicrobial material in the environment. Reversible optical control over active drug concentration enables us to obtain pharmacodynamic information. Precisely localized control of activity is achieved, allowing the growth of bacteria to be confined to defined patterns, which has potential for the development of treatments that avoid interference with the endogenous microbial population in other parts of the organism.</p>