Biosynthesis of 6-Hydroxymellein Requires a Collaborating Polyketide Synthase-like Enzyme

The polyketide synthase (PKS)-like protein TerB, consisting of inactive dehydratase, inactive C-methyltransferase, and functional ketoreductase domains collaborates with the iterative non reducing PKS TerA to produce 6-hydroxymellein, a key pathway intermediate during the biosynthesis of various fungal natural products. The catalytically inactive dehydratase domain of TerB appears to mediate productive interactions with TerA, demonstrating a new mode of trans-interaction between iterative PKS components

Estimating contact rates between Metarhizium anisopliae–exposed males with female Aedes aegypti

Introduction: Effective control of Aedes aegypti will reduce the frequency and severity of outbreaks of dengue, chikungunya, and Zika; however, control programs are increasingly threatened by the rapid development of insecticide resistance. Thus, there is an urgent need for novel vector control tools, such as auto-dissemination of the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana. The aim of this study was to estimate contact rates of M. anisopliae-exposed males with wild female Ae. aegypti. As a control the contact rates of untreated males with wild females was contrasted. Methods: The study was conducted in Reynosa, Mexico. The treatment and control households (n = 15 per group) were geographically separated by an arid and hot area that naturally prevented the flight of males between arms. In each control household, 40 M. anisopliae-exposed male Ae. aegypti were released per week for 8 weeks (specimens were exposed to a concentration of 5.96 × 107 conidia/cm2 for 24 h; n = 4,800 males). In each control household, 40 untreated males were released per week for 8 weeks (n = 4,800 males). All specimens were dust-marked prior to release. Mosquito abundance was monitored with human landing collections, and captured Ae. aegypti were examined for any dust-marking. Results: In the treatment households, the contact rate of Ae. aegypti females with marked, fungus-treated males was 14% (n = 29 females marked from 197). Where in the control households, the contact rate of females with marked, untreated males was only 6% (n = 22 marked from 365). In the treatment households the recapture rate of released males was at 5% and higher than that for the control households (which was 2%). Auto-dissemination of M. anisopliae from infected males to female Ae. aegypti was demonstrated through the recovery of an infected female from the floor of a household. Conclusions: Overall, the contact rate between M. anisopliae-infected males with the natural female population was 60% higher than for the control group of healthy males. The results provide further support to the release of fungus-exposed males as a potentially useful strategy against Ae. aegypti, though further research is required

Translating the efficacy of dapagliflozin in chronic kidney disease to lower healthcare resource utilization and costs: a medical care cost offset analysis

AIMS: Dapagliflozin was approved for use in patients with chronic kidney disease (CKD) based on results of the DAPA-CKD trial, demonstrating attenuation of CKD progression and reduced risk of cardio-renal outcomes and all-cause mortality (ACM) versus placebo, in addition to standard therapy. The study objective was to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes across 31 countries and regions. MATERIALS AND METHODS: A comparative cost-determination framework estimated outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year horizon based on the DAPA-CKD trial. Incidence rates of end-stage kidney disease (ESKD), hospitalizations for heart failure (HHF), acute kidney injury (AKI), and ACM were estimated for a treated population of 100,000 patients. Associated medical care costs for non-fatal events were calculated using sources from a review of publicly available data specific to each considered setting. RESULTS: Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7,221 vs 10,767; number needed to treat, NNT: 28), HHF (2,370 vs 4,684; NNT: 43), AKI (4,110 vs. 5,819; NNT: 58), and ACM (6,383 vs 8,874; NNT: 40) per 100,000 treated patients versus those treated with standard therapy alone. Across 31 countries/regions, reductions in clinical events were associated with a 33% reduction in total costs, or a cumulative mean medical care cost offset of $264 million per 100,000 patients over 3 years. LIMITATIONS AND CONCLUSIONS: This analysis is limited by the quality of country/region-specific data available for medical care event costs. Based on the DAPA-CKD trial, we show that treatment with dapagliflozin may prevent cardio-renal event incidence at the population level, which could have positive effects upon healthcare service delivery worldwide. The analysis was restricted to outcome-associated costs and did not consider the cost of drug treatments and disease management

Evaluating heterogeneity in cumulative meta-analyses

BACKGROUND: Recently developed measures such as I(2 )and H allow the evaluation of the impact of heterogeneity in conventional meta-analyses. There has been no examination of the development of heterogeneity in the context of a cumulative meta-analysis. METHODS: Cumulative meta-analyses of five smoking cessation interventions (clonidine, nicotine replacement therapy using gum and patch, physician advice and acupuncture) were used to calculate I(2 )and H. These values were plotted by year of publication, control event rate and sample size to trace the development of heterogeneity over these covariates. RESULTS: The cumulative evaluation of heterogeneity varied according to the measure of heterogeneity used and the basis of cumulation. Plots produced from the calculations revealed areas of heterogeneity useful in the consideration of potential sources for further study. CONCLUSION: The examination of heterogeneity in conjunction with summary effect estimates in a cumulative meta-analysis offered valuable insight into the evolution of variation. Such information is not available in the context of conventional meta-analysis and has the potential to lead to the development of a richer picture of the effectiveness of interventions

Evolutionary process of Bos taurus cattle in favourable versus unfavourable environments and its implications for genetic selection

The evolutionary processes that have enabled Bos taurus cattle to establish around the globe are at the core to the future success of livestock production. Our study focuses on the history of cattle domestication including the last 60 years of B. taurus breeding programmes in both favourable and unfavourable environments and its consequences on evolution and fitness of cattle. We discuss the emergence of ‘production diseases’ in temperate production systems and consider the evolutionary genetics of tropical adaptation in cattle and conclude that the Senepol, N'Dama, Adaptaur and Criollo breeds, among others with similar evolutionary trajectories, would possess genes capable of improving the productivity of cattle in challenging environments. Using our own experimental evidence from northern Australia, we review the evolution of the Adaptaur cattle breed which has become resistant to cattle tick. We emphasize that the knowledge of interactions between genotype, environment and management in the livestock systems will be required to generate genotypes for efficient livestock production that are both economically and environmentally sustainable. Livestock producers in the 21st century will have less reliance on infrastructure and veterinary products to alleviate environmental stress and more on the animal's ability to achieve fitness in a given production environment