mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis

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Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin,a DPPIV inhibitor,prevents progression of steatohepatitis in mice fed on a high trans-fat diet

Non-Alcoholic SteatoHepatitis (NASH) is the more severe form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, hepatocyte injury with or without fibrosis. Recently, GPR119 receptor has emerged as a novel therapeutic target for the treatment of dyslipidemia and non-alcoholic steatohepatitis. In the present study, we investigated the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor on the progression of steatohepatitis in mice fed on a high trans-fat diet. In this study, monotherapy with either APD668 or linagliptin caused a reduction in the levels of ALT, AST, glucose, cholesterol and epididymal fat mass but the effect was more pronounced upon treatment with combination of both drugs.On the other hand, combined treatment of APD668 with linagliptin demonstrated a non-significant additive effect in reduction of hepatic triglyceride (?78%) and cholesterol (?56%) compared to monotherapy groups. Moreover, co-administration of APD668 and linagliptin resulted in enhanced levels of active GLP-1 with additional benefit of significant synergistic decrease in body weight gain (?19%) in mice. We speculated that the enhanced effect observed with the combination treatment could be due to either 1) direct activation of GPR119 receptors present in liver and intestine or 2) enhanced active GLP-1 levels or 3) decreased degradation of GLP-1 in-vivo through DPPIV inhibition. Therefore, these findings clearly suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of non-alcoholic steatohepatitis.     

Miscanthus biomass productivity within US croplands and its potential impact on soil organic carbon

Interest in bioenergy crops is increasing due to their potential to reduce greenhouse gas emissions and dependence on fossil fuels. We combined process‐based and geospatial models to estimate the potential biomass productivity of miscanthus and its potential impact on soil carbon stocks in the croplands of the continental United States. The optimum (climatic potential) rainfed productivity for field‐dried miscanthus biomass ranged from 1 to 23 Mg biomass ha^?1 yr^?1, with a spatial average of 13 Mg ha^?1 yr^?1 and a coefficient of variation of 30%. This variation resulted primarily from the spatial heterogeneity of effective rainfall, growing degree days, temperature, and solar radiation interception. Cultivating miscanthus would result in a soil organic carbon (SOC) sequestration at the rate of 0.16–0.82 Mg C ha^?1 yr^?1 across the croplands due to cessation of tillage and increased biomass carbon input into the soil system. We identified about 81 million ha of cropland, primarily in the eastern United States, that could sustain economically viable (>10 Mg ha^?1 yr^?1) production without supplemental irrigation, of which about 14 million ha would reach optimal miscanthus growth. To meet targets of the US Energy Independence and Security Act of 2007 using miscanthus as feedstock, 19 million ha of cropland would be needed (spatial average 13 Mg ha^?1 yr^?1) or about 16% less than is currently dedicated to US corn‐based ethanol production.     

Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits

In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach.     

Sorghum biomass production in the continental United States and its potential impacts on soil organic carbon and nitrous oxide emissions

National scale projections of bioenergy crop yields and their environmental impacts are essential to identify appropriate locations to place bioenergy crops and ensure sustainable land use strategies. In this study, we used the process‐based Daily Century (DAYCENT) model with site‐specific environmental data to simulate sorghum (Sorghum bicolor L. Moench) biomass yield, soil organic carbon (SOC) change, and nitrous oxide emissions across cultivated lands in the continental United States. The simulated rainfed dry biomass productivity ranged from 0.8 to 19.2 Mg ha^?1 year^?1, with a spatiotemporal average of  Mg ha^?1 year^?1, and a coefficient of variation of 35%. The average SOC sequestration and direct nitrous oxide emission rates were simulated as  Mg CO₂e ha^?1 year^?1 and  Mg CO₂e ha^?1 year^?1, respectively. Compared to field‐observed biomass yield data at multiple locations, model predictions of biomass productivity showed a root mean square error (RMSE) of 5.6 Mg ha^?1 year^?1. In comparison to the multi State (n = 21) NASS database, our results showed RMSE of 5.5 Mg ha^?1 year^?1. Model projections of baseline SOC showed RMSE of 1.9 kg/m² in comparison to a recently available continental SOC stock dataset. The model‐predicted N₂O emissions are close to 1.25% of N input. Our results suggest 10.2 million ha of cultivated lands in the Southern and Lower Midwestern United States will produce >10 Mg ha^?1 year^?1 with net carbon sequestration under rainfed conditions. Cultivated lands in Upper Midwestern states including Iowa, Minnesota, Montana, Michigan, and North Dakota showed lower sorghum biomass productivity (average: 6.9 Mg ha^?1 year^?1) with net sequestration (average: 0.13 Mg CO₂e ha^?1 year^?1). Our national‐scale spatially explicit results are critical inputs for robust life cycle assessment of bioenergy production systems and land use‐based climate change mitigation strategies.     

Demonstration of an altered phenylalanyl-tRNA synthetase in an analogue-resistant mutant of Aspergillus nidulans

Summary We have isolated and characterized a new class of p-fluorophenylalanine (FPA)-resistant mutant in Aspergillus nidulans using a phenA strain as the wild type, by optimizing the conditions of growth. All four spontaneous mutants selected on a medium containing FPA were found to be recessive to their wild-type alleles in heterozygous diploids. Complementation analyses and linkage data showed that they were allelic and mapped at a single locus (fpaU) in the facA-riboD interval on the right arm of linkage group V. Partial purification and characterization of Phe-tRNA synthetase from wild-type and mutant strains revealed that the mutant enzyme had a greatly reduced ability to activate the analogue. It is suggested that mutation in the fpaU gene brings about a structural alteration in Phe-tRNA synthetase.Abbreviations FPA DL-p-fluorophenylalanine - phenA auxotroph of phenylalanine - Phe-tRNA synthetase phenylalanyl-transfer ribonucleic acid synthetase Current address: Department of Biological Sciences (M/C 066) The University of Illinois at Chicago, Box 4348, Chicago, IL 60680, USA     

Regulation of Acetate Metabolism and Acetyl Co-a Synthetase 1 (ACS1) Expression by Methanol Expression Regulator 1 (Mxr1p) in the Methylotrophic Yeast Pichia pastoris

Methanol expression regulator 1 (Mxr1p) is a zinc finger protein that regulates the expression of genes encoding enzymes of the methanol utilization pathway in the methylotrophic yeast Pichia pastoris by binding to Mxr1p response elements (MXREs) present in their promoters. Here we demonstrate that Mxr1p is a key regulator of acetate metabolism as well. Mxr1p is cytosolic in cells cultured in minimal medium containing a yeast nitrogen base, ammonium sulfate, and acetate (YNBA) but localizes to the nucleus of cells cultured in YNBA supplemented with glutamate or casamino acids as well as nutrient-rich medium containing yeast extract, peptone, and acetate (YPA). Deletion of Mxr1 retards the growth of P. pastoris cultured in YNBA supplemented with casamino acids as well as YPA. Mxr1p is a key regulator of ACS1 encoding acetyl-CoA synthetase in cells cultured in YPA. A truncated Mxr1p comprising 400 N-terminal amino acids activates ACS1 expression and enhances growth, indicating a crucial role for the N-terminal activation domain during acetate metabolism. The serine 215 residue, which is known to regulate the expression of Mxr1p-activated genes in a carbon source-dependent manner, has no role in the Mxr1p-mediated activation of ACS1 expression. The ACS1 promoter contains an Mxr1p response unit (MxRU) comprising two MXREs separated by a 30-bp spacer. Mutations that abrogate MxRU function in vivo abolish Mxr1p binding to MxRU in vitro. Mxr1p-dependent activation of ACS1 expression is most efficient in cells cultured in YPA. The fact that MXREs are conserved in genes outside of the methanol utilization pathway suggests that Mxr1p may be a key regulator of multiple metabolic pathways in P. pastoris.