p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1.We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins

The outcome of acute schistosomiasis infection in adult mice with postnatal exposure to maternal malnutrition

Maternal malnutrition during the lactation period in early development may have long-term programming effects on adult offspring. We evaluated the combined effects of parasitological behaviour and histopathological features and malnutrition during lactation. Lactating mice and their pups were divided into a control group (fed a normal diet of 23% protein), a protein-restricted group (PR) (fed a diet containing 8% protein) and a caloric-restricted group (CR) (fed according to the PR group intake). At the age of 60 days, the offspring were infected with Schistosoma mansoni cercariae and killed at nine weeks post-infection. Food intake, body and liver masses, leptinaemia, corticosteronaemia, collagen morphometry and neogenesis and the cellular composition of liver granulomas were studied. PR offspring showed reduced weight gain and hypophagia, whereas CR offspring became overweight and developed hyperphagia. The pre-patent period was longer (45 days) in both programmed offspring as compared to controls (40 days). The PR-infected group had higher faecal and intestinal egg output and increased liver damage. The CR-infected group showed a lower number of liver granulomas, increased collagen neogenesis and a higher frequency of binucleate hepatocytes, suggesting a better modulation of the inflammatory response and increased liver regeneration. Taken together, our findings suggest that neonatal malnutrition of offspring during lactation affects the outcome of schistosomiasis in mice

Estimating the life cycle greenhouse gas emissions of Australian ambulance services

Emergency medical services, or 'ambulance services', are a vehicle-intense component of the health sector that could contribute to that sector's emissions reduction efforts. This analysis uses data from an inventory of ambulance service Scope 1 (arising from direct energy consumption) and Scope 2 (arising from purchased energy consumption) emissions, along with publicly available expenditure data and emissions multipliers derived from economy-wide input-output tables, to estimate the life cycle greenhouse gas emissions of Australian ambulance services. Total emissions are estimated at between 216,369 and 546,688 t CO2e annually, and represent between 1.8% and 4.4% of total Australian health sector emissions. Approximately 20% of ambulance service emissions arise from direct consumption of vehicle fuels (diesel and petrol) and aircraft fuels, with 22% arising from electricity consumption, and 58% arising from Scope 3 (e.g., supply chain; waste disposal) processes. Incorporating alternative fuels and higher efficiency vehicles into Australian ambulance services' vehicle fleets could reduce their direct greenhouse emissions, but broader efforts targeting reduced electricity consumption, greener electricity generation, and environmentally friendly purchasing practices will be required to substantially reduce their total carbon footprint. © 2012 Elsevier Ltd. All rights reserved

The carbon footprint of Australian ambulance operations

Objective: To determine the greenhouse gas emissions associated with the energy consumption of Australian ambulance operations, and to identify the predominant energy sources that contribute to those emissions. Methods: A two-phase study of operational and financial data from a convenience sample of Australian ambulance operations to inventory their energy consumption and greenhouse gas emissions for 1 year. State- and territory-based ambulance systems serving 58% of Australia's population and performing 59% of Australia's ambulance responses provided data for the study. Results: Emissions for the participating systems totalled 67390 metric tons of carbon dioxide equivalents. For ground ambulance operations, emissions averaged 22kg of carbon dioxide equivalents per ambulance response, 30kg of carbon dioxide equivalents per patient transport and 3kg of carbon dioxide equivalents per capita. Vehicle fuels accounted for 58% of the emissions from ground ambulance operations, with the remainder primarily attributable to electricity consumption. Emissions from air ambulance transport were nearly 200 times those for ground ambulance transport. Conclusion: On a national level, emissions from Australian ambulance operations are estimated to be between 110000 and 120000 tons of carbon dioxide equivalents each year. Vehicle fuels are the primary source of emissions for ground ambulance operations. Emissions from air ambulance transport are substantially higher than those for ground ambulance transport. © 2012 The Authors. EMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine