Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here, we report a systematic investigation of the structure–activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics

How the west was once: vegetation change in south-west Queensland from 1930 to 1995

Conflicting perceptions of past and present rangeland condition and limited historical data have led to debate regarding the management of vegetation in pastoral landscapes both internationally and in Australia. In light of this controversy we have sought to provide empirical evidence to determine the trajectory of vegetational change in a semi-arid rangeland for a significant portion of the 20th century using a suite of proxy measures. Ambathala Station, approximately 780 km west of Brisbane, in the semi-arid rangelands of south-western Queensland, Australia. We excavated stratified deposits of sheep manure which had accumulated beneath a shearing shed between the years 1930 and 1995. Multi-proxy data, including pollen and leaf cuticle analyses and analysis of historical aerial photography were coupled with a fine resolution radiocarbon chronology to generate a near annual history of vegetation on the property and local area. Aerial photography indicates that minor (< 5%) increases in the density of woody vegetation took place between 1951 and 1994 in two thirds of the study area not subjected to clearing. Areas that were selectively or entirely cleared prior to the 1950s (approximately 16% of the study area) had recovered to almost 60% of their original cover by the 1994 photo period. This slight thickening is only partially evident from pollen and leaf cuticle analyses of sheep faeces. Very little change in vegetation is revealed over the nearly 65 years based on the relative abundances of pollen taxonomic groups. Microhistological examination of sheep faeces provides evidence of dramatic changes in sheep diet. The majority of dietary changes are associated with climatic events of sustained above-average rainfall or persistent drought. Most notable in the dietary analysis is the absence of grass during the first two decades of the record. In contrast to prevailing perceptions and limited research into long-term vegetation change in the semi-arid areas of eastern Australia, the record of vegetation change at the Ambathala shearing shed indicates only a minor increase in woody vegetation cover and no decrease in grass cover on the property over the 65 years of pastoral activity covered by the study. However, there are marked changes in the abundance of grass cuticles in sheep faeces. The appearance and persistence of grass in sheep diets from the late 1940s can be attributed to the effects of periods of high rainfall and possibly some clearing and thinning of vegetation. Lower stock numbers may have allowed grass to persist through later drought years. The relative abundances of major groups of plant pollen have not changed significantly over the past 65 years

A standard protocol to report discrete stage‐structured demographic information

Stage-based demographic methods, such as matrix population models (MPMs), are powerful tools used to address a broad range of fundamental questions in ecology, evolutionary biology and conservation science. Accordingly, MPMs now exist for over 3000 species worldwide. These data are being digitised as an ongoing process and periodically released into two large open-access online repositories: the COMPADRE Plant Matrix Database and the COMADRE Animal Matrix Database. During the last decade, data archiving and curation of COMPADRE and COMADRE, and subsequent comparative research, have revealed pronounced variation in how MPMs are parameterized and reported. Here, we summarise current issues related to the parameterisation and reporting of MPMs that arise most frequently and outline how they affect MPM construction, analysis, and interpretation. To quantify variation in how MPMs are reported, we present results from a survey identifying key aspects of MPMs that are frequently unreported in manuscripts. We then screen COMPADRE and COMADRE to quantify how often key pieces of information are omitted from manuscripts using MPMs. Over 80% of surveyed researchers (n = 60) state a clear benefit to adopting more standardised methodologies for reporting MPMs. Furthermore, over 85% of the 300 MPMs assessed from COMPADRE and COMADRE omitted one or more elements that are key to their accurate interpretation. Based on these insights, we identify fundamental issues that can arise from MPM construction and communication and provide suggestions to improve clarity, reproducibility and future research utilising MPMs and their required metadata. To fortify reproducibility and empower researchers to take full advantage of their demographic data, we introduce a standardised protocol to present MPMs in publications. This standard is linked to www.compadre-db.org, so that authors wishing to archive their MPMs can do so prior to submission of publications, following examples from other open-access repositories such as DRYAD, Figshare and Zenodo. Combining and standardising MPMs parameterized from populations around the globe and across the tree of life opens up powerful research opportunities in evolutionary biology, ecology and conservation research. However, this potential can only be fully realised by adopting standardised methods to ensure reproducibility

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Orbital Influence on Precipitation, Fire, and Grass Community Composition From 1.87 to 1.38 Ma in the Turkana Basin, Kenya

The Turkana Basin in northern Kenya and southern Ethiopia has yielded hundreds of hominin fossils and is among the most important localities in the world for studying human origins. High resolution climate and vegetation reconstructions from this region can elucidate potential linkages between hominin evolution and environmental change. Microcharcoal and phytoliths were examined from a 216 m (1.87–1.38 Ma) drill core (WTK13), which targeted paleo-Lake Lorenyang sediments from the Nachukui Formation of the Turkana Basin. A total of 287 samples were analyzed at ∼32–96 cm intervals, providing millennial-scale temporal resolution. To better understand how basin sediments record fire and vegetation from the watershed, the paleorecord was compared with nine modern sediment samples collected from Lake Turkana along a transect of increasing distance from the 1978 to 1979 shoreline. This included vegetation surveys and phytolith production data for species from areas proximal to the basin. We found that phytolith and microcharcoal concentrations decreased predictably moving off shore. However, phytoliths from plants sourced in the Ethiopian Highlands increased moving off shore, likely the result of increased exposure to the Omo River sediment plume. In our down-core study, microcharcoal was well-preserved but phytolith preservation was poor below ∼60 m (∼1.50 Ma). Spectral analysis revealed that microcharcoal often varied at precessional (∼21 kyr) periodicities, and through a correlation with δDwax, linked orbitally forced peaks in precipitation with elevated fire on the landscape. Phytoliths revealed that alternating mesic C4 versus xeric C4 grass dominance likely varied at precessional periodicities as well, but that grass community composition was also mediated by basin geometry. Two high eccentricity intervals of particularly high amplitude and abrupt environmental change were centered at ∼1.72 and 1.50 Ma, with the intervening period experiencing high fire variability. With the switch from lacustrine to fluvial-deltaic deposition at the core site by 1.5 Ma, mesic C4 grasses dominated and fire activity was high. This upper interval correlated to the time interval from which Nariokotome Boy (Homo erectus/ergaster) was discovered 3 km east of our drill site. Phytoliths indicated a seasonally wet and open landscape dominated by xeric C4 grasses, sedges, and other herbaceous plants. © Copyright © 2021 Yost, Lupien, Beck, Feibel, Archer and Cohen.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]