Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate

The protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP(+) and the inhibitor determined at 2.2 Å resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the β6-α6 loop and α6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis

Back to the future : using long-term observational and paleo-proxy reconstructions to improve model projections of Antarctic climate

Quantitative estimates of future Antarctic climate change are derived from numerical global climate models. Evaluation of the reliability of climate model projections involves many lines of evidence on past performance combined with knowledge of the processes that need to be represented. Routine model evaluation is mainly based on the modern observational period, which started with the establishment of a network of Antarctic weather stations in 1957/58. This period is too short to evaluate many fundamental aspects of the Antarctic and Southern Ocean climate system, such as decadal-to-century time-scale climate variability and trends. To help address this gap, we present a new evaluation of potential ways in which long-term observational and paleo-proxy reconstructions may be used, with a particular focus on improving projections. A wide range of data sources and time periods is included, ranging from ship observations of the early 20th century to ice core records spanning hundreds to hundreds of thousands of years to sediment records dating back 34 million years. We conclude that paleo-proxy records and long-term observational datasets are an underused resource in terms of strategies for improving Antarctic climate projections for the 21st century and beyond. We identify priorities and suggest next steps to addressing this

Attitudes towards abortion in male and female adolescents with diverse sexual and pregnancy experiences: A cross-sectional study

© 2020 CSIRO. Background: Research focused on adolescents' attitudes towards abortion is limited, and validated scales are not routinely used. A greater understanding of adolescents' attitudes towards abortion could better inform the sexuality education strategies targeted at this age group. Methods: A cross-sectional survey was completed by 1470 adolescents (437 males, 1033 females) aged 12-19 years and living in Perth, Australia. Participants were recruited from secondary schools, antenatal clinics and termination clinics to capture varying experiences of sexual activity and pregnancy. Survey items investigated abortion attitudes, sexual behaviour and pregnancy history alongside other demographic and psychosocial factors. Analyses included comparative means and adjusted linear regressions. Results: Sexually active participants (n = 554) and females reporting a previous abortion (n = 196) held more supportive attitudes towards abortion (P < 0.001 for both). Among sexually active females, more supportive attitudes were held by those reporting a previous abortion (β = 2.60, 95% confidence interval 0.93-4.27, P = 0.002), later age (≥16 years) at first vaginal intercourse (P < 0.001), use of oral contraception at last sex (P = 0.029), previous condom use (P < 0.001) and/or three or more oral sex partners in the previous 12 months (P = 0.005). For sexually active males, more supportive attitudes were reported by those whose female partners had used oral contraception at last sex (P = 0.013) or ever (P = 0.017). Multivariable analyses indicated that other correlates, including risky sexual behaviour, had minimal or no effect on attitudes. Conclusions: Adolescents' attitudes towards abortion appear to be influenced by their ability to personalise and contextualise the effect of a pregnancy. Associations between less-effective contraceptive use and reduced support for abortion may be explained by a diminished perceived risk of parenthood. Educational strategies should acknowledge and respond to differences in abortion attitudes as adolescents commence and navigate sexual relationships

Police misconduct and minority citizens: Exploring key issues

This manuscript provides a review of the literature concerning key issues associated with acts of police misconduct and minority citizens in the United States. First, the issue of what types of behaviors are defined as ‘police misconduct’ is explored. Second, the level of police misconduct is discussed. Finally, the question of whether or not minority citizens are targeted for harassment and abuse is addressed