Sustained hyperglycemia in diabetes causes alteration of a large number of transcription factors and mRNA transcripts, leading to tissue damage. We investigated whether p300, a transcriptional coactivator with histone acetyl transferase activity, regulates glucose-induced activation of transcription factors and subsequent upregulation of vasoactive factors and extracellular matrix (ECM) proteins in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated in varied glucose concentrations and were studied after p300 small interfering RNA (siRNA) transfection, p300 overexpression, or incubation with the p300 inhibitor curcumin. Histone H2AX phosphorylation and lysine acetylation were examined for oxidative DNA damage and p300 activation. Screening for transcription factors was performed with the Luminex system. Alterations of selected transcription factors were validated. mRNA expression of p300, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and fibronectin (FN) and its splice variant EDB(+)FN and FN protein production were analyzed. HUVECs in 25 mmol/l glucose showed increased p300 production accompanied by increased binding of p300 to ET-1 and FN promoters, augmented histone acetylation, H2AX phosphorylation, activation of multiple transcription factors, and increased mRNA expression of vasoactive factors and ECM proteins. p300 overexpression showed a glucose-like effect on the mRNA expression of ET-1, VEGF, and FN. Furthermore, siRNA-mediated p300 blockade or chemical inhibitor of p300 prevented such glucose-induced changes. Similar mRNA upregulation was also seen in the organ culture of vascular tissues, which was prevented by p300 siRNA transfection. Data from these studies suggest that glucose-induced p300 upregulation is an important upstream epigenetic mechanism regulating gene expression of vasoactive factors and ECM proteins in endothelial cells and is a potential therapeutic target for diabetic complications.

Data from these studies demonstrate a novel glucose-induced mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes which is mediated through miR133a.

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Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leads to heart failure. We investigated the role of transcriptional coactivator p300 and its interaction with myocyte enhancer factor 2 (MEF2) in diabetes-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed to variable levels of glucose. Cardiomyocytes were analyzed with respect to their size. mRNA expression of p300, MEF2A, MEF2C, atrial natriuretic polypeptide (ANP), brain natriuretic polypeptide (BNP), angiotensinogen (ANG), cAMP-responsive element binding protein-binding protein (CBP), and protein analysis of MEF2 were done with or without p300 blockade. We investigated the hearts of STZ-induced diabetic rats and compared them with age- and sex-matched controls after 1 and 4 mo of followup with or without treatment with p300 blocker curcumin. The results were that cardiomyocytes, exposed to 25 mM glucose for 48 h, showed cellular hypertrophy and augmented mRNA expression of ANP, BNP, and ANG, molecular markers of cardiac hypertrophy. Glucose caused a duration-dependent increase of mRNA and protein expression in MEF2A and MEF2C and transcriptional coactivator p300. Curcumin, a p300 blocker, and p300 siRNA prevented these abnormalities. Similarly, ANP, BNP, and ANG mRNA expression was significantly higher in the hearts of diabetic rats compared with the controls, in association with increased p300, MEF2A, and MEF2C expression. Treatment with p300 blocker curcumin prevented diabetes-induced upregulation of these transcripts. We concluded that data from these studies demonstrate a novel glucose-induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes.

This paper presents a critical review of the physical impacts of decentralized water supply systems on existing centralized water infrastructures. This paper highlights the combination of centralized and decentralized systems, which is referred to as hybrid water supply systems. The system is hypothesized to generate more sustainable and resilient urban water systems. The basic concept is to use decentralized water supply options such as rainwater tanks, storm water harvesting and localized wastewater treatment and reuse in combination with centralized systems. Currently the impact of hybrid water supply technologies on the operational performance of the downstream infrastructure and existing treatment processes is yet to be known. The paper identifies a number of significant research gaps related to interactions between centralized and decentralized OPEN ACCESSWater 2015, 7 154 urban water services. It indicates that an improved understanding of the interaction between these systems is expected to provide a better integration of hybrid systems by improved sewerage and drainage design, as well as facilitate operation and maintenance planning. The paper also highlights the need for a framework to better understand the interaction between different components of hybrid water supply systems.

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Farmers and irrigation system operators make real-time irrigation decisions based on a range of factors including crop water requirement and short-term weather forecasts of rainfall and air temperature. Forecasts of reference crop evapotranspiration (ET O ) can be calculated from numerical weather prediction (NWP) forecasts and ET O has the advantage of being more directly relevant to crop water requirements than air temperature. This paper aims to discuss the forecasting ability of ET O using outputs from the Bureau of Meteorology's operational NWP forecasts derived from the Australian Community Climate and Earth System Simulator -Global (ACCESS-G). The daily ET O forecasts were evaluated for the Shepparton Irrigation Area in Victoria. Forecast performance for ET O was quantified using the root mean squared error (RMSE), coefficient of determination (r 2 ), anomaly correlation coefficient (ACC) and mean square skill score (MSSS). Lead times of daily ET O forecasts up to 9 days were compared against ET O calculated using hourly observations from the Shepparton airport automatic weather station. It was found that forecasting daily ET O was better than using the long-term monthly mean ET O for lead times up to 6 days and beyond that the longterm monthly mean was better. The average MSSS of ET O forecasts varied between 64% and 4 % for 1 to 6 day lead times, respectively. The most influential forecast weather variable for daily ET O forecasts was mean wind speed, air temperature and incoming solar radiation for 1, 2-3 and 4-9 day lead times respectively. Also, it was found that the forecast performance for incoming solar radiation and mean wind speed was relatively poor compared with the air and dew point temperatures.