Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia

Mitochondrial Release of Caspase-2 and -9 during the Apoptotic Process

The barrier function of mitochondrial membranes is perturbed early during the apoptotic process. Here we show that the mitochondria contain a caspase-like enzymatic activity cleaving the caspase substrate Z-VAD.afc, in addition to three biological activities previously suggested to participate in the apoptotic process: (a) cytochrome c; (b) an apoptosis-inducing factor (AIF) which causes isolated nuclei to undergo apoptosis in vitro; and (c) a DNAse activity. All of these factors, which are biochemically distinct, are released upon opening of the permeability transition (PT) pore in a coordinate, Bcl-2–inhibitable fashion. Caspase inhibitors fully neutralize the Z-VAD.afc–cleaving activity, have a limited effect on the AIF activity, and have no effect at all on the DNase activities. Purification of proteins reacting with the biotinylated caspase substrate Z-VAD, immunodetection, and immunodepletion experiments reveal the presence of procaspase-2 and -9 in mitochondria. Upon induction of PT pore opening, these procaspases are released from purified mitochondria and become activated. Similarly, upon induction of apoptosis, both procaspases redistribute from the mitochondrion to the cytosol and are processed to generate enzymatically active caspases. This redistribution is inhibited by Bcl-2. Recombinant caspase-2 and -9 suffice to provoke full-blown apoptosis upon microinjection into cells. Altogether, these data suggest that caspase-2 and -9 zymogens are essentially localized in mitochondria and that the disruption of the outer mitochondrial membrane occurring early during apoptosis may be critical for their subcellular redistribution and activation

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Livestock 2.0 – genome editing for fitter, healthier, and more productive farmed animals

Abstract The human population is growing, and as a result we need to produce more food whilst reducing the impact of farming on the environment. Selective breeding and genomic selection have had a transformational impact on livestock productivity, and now transgenic and genome-editing technologies offer exciting opportunities for the production of fitter, healthier and more-productive livestock. Here, we review recent progress in the application of genome editing to farmed animal species and discuss the potential impact on our ability to produce food

The Cost and Market Impacts of Slow-Growth Broilers

There has been substantial productivity growth in the broiler industry; however, high growth rates might adversely affect animal welfare, resulting in calls for slow-growth breeds. This research shows production costs are 11%'25% per pound higher for slower-growing breeds than for modern breeds, depending on the target endpoint. Breakeven wholesale price premiums needed equate net returns of slow- to fast-growth broilers range from $0.10/lb to$0.36/lb. Annual costs of an industry-wide conversion to slow growth are $450 million for consumers and$3.1 billion for producers. Consumer willingness-to-pay would need to increase 10.8% to offset the producer losses

Fungicides for Winter Wheat

Topic Relevance Foliar diseases often reduce grain yields of winter wheat in the southern Great Plains, with some individual year yield losses in excess of 10%. At current prices, the gross value of these losses for the region could exceed a quarter of a billion dollars annually. Historically, use of foliar fungicide applications to manage these diseases has not been common in the region. As a result, management of foliar diseases has largely relied on genetic resistance and other cultural practices such as planting date and crop rotations. However, in Europe, where wheat yields average more than twice the U.S. average, fungicides are applied to over 95% of the wheat area and are credited as one of the major factors influencing increases in European wheat yields since the 1970s (Gianessi and Williams 2011). Recent wheat prices and decreasing fungicide costs have generated interest among U.S. wheat farmers in evaluating the economics of fungicide treatments. Wheat grain yield response to fungicide treatment is variable, and depends on several factors including incidence and severity of specific foliar diseases, cultivar disease resistance, timing and leaf coverage achieved by fungicide application, yield potential, and environmental conditions. In addition, if a ground applicator is used to apply the fungicide, the wheel tracks or the use of tram lines may influence yield. Alternatively, if an aerial application is used, the cost consequence of applying a sufficient water volume to achieve adequate plant leaf coverage is critical. Some research has been conducted to determine the expected returns to fungicide treatment as part of a disease management strategy. However, variability of expected returns resulting from alternative management strategies has not been considered. The objective of this research is to determine the expected net returns to fungicide treatment on hard red winter wheat cultivars with differing levels of genetic resistance to foliar diseases in the southern Great Plains, and to determine if fungicide treatment is an economically optimal management strategy for several levels of risk aversion. Research Methods Hard red winter wheat grain yield data were produced in field experiments conducted at two locations during seven production seasons, from 2005 to 2012. Varietal resistance for each wheat cultivar was determined based on average disease resistance rating to leaf rust, stripe rust, and powdery mildew. Two fungicides were rotated between the two locations and applied at recommended rates at Feekes growth stage 9.5 to 10. SAS Proc Mixed was used to determine grain yield response to fungicide treatment, varietal resistance level, and their interaction. Least-square mean grain yields were estimated and compared for differences between fungicide treated and nontreated plots by varietal resistance level for each year and location. A partial budgeting approach was used to determine the expected net returns for each disease management strategy at both locations. Expected yields were adjusted for losses expected to occur from wheel tracking and/or tram lines required for ground application of fungicide. Given the lack of information about these losses, sensitivity analysis was done across various levels of yield losses. Fungicide treatment cost included the per acre cost of chemical as well as the per acre rental rate for ground application. Risk analysis was conducted using SIMETAR (Richardson, Schumann, and Feldman 2001). Assuming each season was equally likely, and the years of the study were representative of the entire distribution, cumulative distribution functions of net returns to alternative strategies were evaluated using stochastic efficiency with respect to a function (SERF). SERF was used to determine the fungicide treatment cost that would entice wheat producers to use fungicide for several levels of risk aversion. Potential for Generating Discussion Fungicide treatment on winter wheat is a timely topic that has the potential to generate discussion. Fungicides are not commonly used among U.S. wheat producers in the southern Great Plains. However, results of recent literature, including this analysis, suggest potential economic benefits to treating winter wheat with fungicides. In addition, results of this analysis suggest that the utility of risk averse decision makers would generally be increased by strategies that include fungicide treatment given its tendency to protect from the downside risk of large yield losses in years of high disease incidence and severity. These results may facilitate a discussion as to the role of fungicides in winter wheat production in particular and chemical use in production agriculture in general. Other facets of this research, such whether or not U.S. farmers could benefit from using tramlines, also have potential to stimulate discussion