Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a rare genetic disorder characterised by numerous renal cysts, the progressive expansion of which can impact kidney function and lead eventually to renal failure. Tolvaptan is the only disease-modifying drug approved for the treatment of ADPKD, however its poor side effect and safety profile necessitates the need for the development of new therapeutics in this area. Using a combination of transcriptomic and machine learning computational drug discovery tools, we predicted that a number of existing drugs could have utility in the treatment of ADPKD, and subsequently validated several of these drug predictions in established models of disease. We determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity. These findings demonstrate the utility of combining computational approaches to identify and understand potential new treatments for traditionally underserved rare diseases.

Ten facts about land systems for sustainability.

Land use is central to addressing sustainability issues, including biodiversity conservation, climate change, food security, poverty alleviation, and sustainable energy. In this paper, we synthesize knowledge accumulated in land system science, the integrated study of terrestrial social-ecological systems, into 10 hard truths that have strong, general, empirical support. These facts help to explain the challenges of achieving sustainability in land use and thus also point toward solutions. The 10 facts are as follows: 1) Meanings and values of land are socially constructed and contested; 2) land systems exhibit complex behaviors with abrupt, hard-to-predict changes; 3) irreversible changes and path dependence are common features of land systems; 4) some land uses have a small footprint but very large impacts; 5) drivers and impacts of land-use change are globally interconnected and spill over to distant locations; 6) humanity lives on a used planet where all land provides benefits to societies; 7) land-use change usually entails trade-offs between different benefits-"win-wins" are thus rare; 8) land tenure and land-use claims are often unclear, overlapping, and contested; 9) the benefits and burdens from land are unequally distributed; and 10) land users have multiple, sometimes conflicting, ideas of what social and environmental justice entails. The facts have implications for governance, but do not provide fixed answers. Instead they constitute a set of core principles which can guide scientists, policy makers, and practitioners toward meeting sustainability challenges in land use.

Invited review: Intergovernmental Panel on Climate Change, agriculture, and food-A case of shifting cultivation and history.

Since 1990, the Intergovernmental Panel on Climate Change (IPCC) has produced five Assessment Reports (ARs), in which agriculture as the production of food for humans via crops and livestock have featured in one form or another. A constructed database of the ca. 2,100 cited experiments and simulations in the five ARs was analyzed with respect to impacts on yields via crop type, region, and whether adaptation was included. Quantitative data on impacts and adaptation in livestock farming have been extremely scarce in the ARs. The main conclusions from impact and adaptation are that crop yields will decline, but that responses have large statistical variation. Mitigation assessments in the ARs have used both bottom-up and top-down methods but need better to link emissions and their mitigation with food production and security. Relevant policy options have become broader in later ARs and included more of the social and nonproduction aspects of food security. Our overall conclusion is that agriculture and food security, which are two of the most central, critical, and imminent issues in climate change, have been dealt with an unfocussed and inconsistent manner between the IPCC five ARs. This is partly a result of not only agriculture spanning two IPCC working groups but also the very strong focus on projections from computer crop simulation modeling. For the future, we suggest a need to examine interactions between themes such as crop resource use efficiencies and to include all production and nonproduction aspects of food security in future roles for integrated assessment models.

Effects and relationships of grazing intensity on multiple ecosystem services in the Inner Mongolian steppe.

Grassland ecosystems are one of the most important terrestrial ecosystems in the world, producing essential both goods and ecosystem services (ES) for human beings. The Inner Mongolian steppe is a major grassland ecosystem in Northern China, covering 13.5% of the northern Chinese grassland area, and playing important ecological roles for the adjacent region of the capital Beijing-Tianjin-Hebei. Quantification of grassland ES under the different utilization patterns is vital for the maintenance of multiple ES and mitigation against ES loss in this region. We made a manipulative experiment with four grazing intensities (grazing exclusion, GE; light grazing intensity, LG; medium grazing intensity, MG; heavy grazing intensity, HG). We then quantified the intensities of eight different grassland ES (1. herbage intake, HT; 2. biodiversity conservation, BI; 3. soil nutrient retention, SN; 4 soil carbon stocks SC; 5. soil erosion prevention, SEP; 6. soil water storage, SWC; 7. potential nutrient recycling, PNC; 8. carbon sequestration from atmosphere. CS) and total ES via a series of field measurements. Pearson coefficients and trade-offs index were used to access the above ES relationships and degree of trade-offs between ES. Grazing intensities significantly (p < 0.05) affected the grassland intensities of 'regulating', 'culture' and 'provisioning' services, but the 'supporting' services. We found three types of relationships (trade-offs, synergy or neutral) have been found in this study. Trade-offs occurred between 'provisioning' and 'regulating' services. Although GE management presented significantly higher intensity of total ES (0.64) than LG (0.52), LG management significantly weakened the trade-offs between 'provisioning' and 'regulating' services (Trade-offs index 0.22) in comparison with GE (Trade-offs index 11.02). Our study suggests, therefore, that LG is the most suitable grassland utilization practice in the Inner Mongolian steppe.

Climate change impact and adaptation for wheat protein.

Wheat grain protein concentration is an important determinant of wheat quality for human nutrition that is often overlooked in efforts to improve crop production. We tested and applied a 32-multi-model ensemble to simulate global wheat yield and quality in a changing climate. Potential benefits of elevated atmospheric CO2 concentration by 2050 on global wheat grain and protein yield are likely to be negated by impacts from rising temperature and changes in rainfall, but with considerable disparities between regions. Grain and protein yields are expected to be lower and more variable in most low-rainfall regions, with nitrogen availability limiting growth stimulus from elevated CO2 . Introducing genotypes adapted to warmer temperatures (and also considering changes in CO2 and rainfall) could boost global wheat yield by 7% and protein yield by 2%, but grain protein concentration would be reduced by -1.1 percentage points, representing a relative change of -8.6%. Climate change adaptations that benefit grain yield are not always positive for grain quality, putting additional pressure on global wheat production.

Global wheat production with 1.5 and 2.0°C above pre-industrial warming.

Efforts to limit global warming to below 2°C in relation to the pre-industrial level are under way, in accordance with the 2015 Paris Agreement. However, most impact research on agriculture to date has focused on impacts of warming >2°C on mean crop yields, and many previous studies did not focus sufficiently on extreme events and yield interannual variability. Here, with the latest climate scenarios from the Half a degree Additional warming, Prognosis and Projected Impacts (HAPPI) project, we evaluated the impacts of the 2015 Paris Agreement range of global warming (1.5 and 2.0°C warming above the pre-industrial period) on global wheat production and local yield variability. A multi-crop and multi-climate model ensemble over a global network of sites developed by the Agricultural Model Intercomparison and Improvement Project (AgMIP) for Wheat was used to represent major rainfed and irrigated wheat cropping systems. Results show that projected global wheat production will change by -2.3% to 7.0% under the 1.5°C scenario and -2.4% to 10.5% under the 2.0°C scenario, compared to a baseline of 1980-2010, when considering changes in local temperature, rainfall, and global atmospheric CO2 concentration, but no changes in management or wheat cultivars. The projected impact on wheat production varies spatially; a larger increase is projected for temperate high rainfall regions than for moderate hot low rainfall and irrigated regions. Grain yields in warmer regions are more likely to be reduced than in cooler regions. Despite mostly positive impacts on global average grain yields, the frequency of extremely low yields (bottom 5 percentile of baseline distribution) and yield inter-annual variability will increase under both warming scenarios for some of the hot growing locations, including locations from the second largest global wheat producer-India, which supplies more than 14% of global wheat. The projected global impact of warming <2°C on wheat production is therefore not evenly distributed and will affect regional food security across the globe as well as food prices and trade.

Simulation of Soil Organic Carbon Effects on Long-Term Winter Wheat (Triticum aestivum) Production Under Varying Fertilizer Inputs.

Soil organic carbon (SOC) has a vital role to enhance agricultural productivity and for mitigation of climate change. To quantify SOC effects on productivity, process models serve as a robust tool to keep track of multiple plant and soil factors and their interactions affecting SOC dynamics. We used soil-plant-atmospheric model viz. DAISY, to assess effects of SOC on nitrogen (N) supply and plant available water (PAW) under varying N fertilizer rates in winter wheat (Triticum aestivum) in Denmark. The study objective was assessment of SOC effects on winter wheat grain and aboveground biomass accumulation at three SOC levels (low: 0.7% SOC; reference: 1.3% SOC; and high: 2% SOC) with five nitrogen rates (0-200 kg N ha-1) and PAW at low, reference, and high SOC levels. The three SOC levels had significant effects on grain yields and aboveground biomass accumulation at only 0-100 kg N ha-1 and the SOC effects decreased with increasing N rates until no effects at 150-200 kg N ha-1. PAW had significant positive correlation with SOC content, with high SOC retaining higher PAW compared to low and reference SOC. The mean PAW and SOC correlation was given by PAW% = 1.0073 × SOC% + 15.641. For the 0.7-2% SOC range, the PAW increase was small with no significant effects on grain yields and aboveground biomass accumulation. The higher winter wheat grain and aboveground biomass was attributed to higher N supply in N deficient wheat production system. Our study suggested that building SOC enhances agronomic productivity at only 0-100 kg N ha-1. Maintenance of SOC stock will require regular replenishment of SOC, to compensate for the mineralization process degrading SOC over time. Hence, management can maximize realization of SOC benefits by building up SOC and maintaining N rates in the range 0-100 kg N ha-1, to reduce the off-farm N losses depending on the environmental zones, land use and the production system.

Circulating Microvesicles Are Elevated Acutely following Major Burns Injury and Associated with Clinical Severity.

Microvesicles are cell-derived signaling particles emerging as important mediators and biomarkers of systemic inflammation, but their production in severe burn injury patients has not been described. In this pilot investigation, we measured circulating microvesicle levels following severe burns, with severe sepsis patients as a comparator group. We hypothesized that levels of circulating vascular cell-derived microvesicles are elevated acutely following burns injury, mirroring clinical severity due to the early onset and prevalence of systemic inflammatory response syndrome (SIRS) in these patients. Blood samples were obtained from patients with moderate to severe thermal injury burns, with severe sepsis, and from healthy volunteers. Circulating microvesicles derived from total leukocytes, granulocytes, monocytes, and endothelial cells were quantified in plasma by flow cytometry. All circulating microvesicle subpopulations were elevated in burns patients on day of admission (day 0) compared to healthy volunteers (leukocyte-microvesicles: 3.5-fold, p = 0.005; granulocyte-microvesicles: 12.8-fold, p<0.0001; monocyte-microvesicles: 20.4-fold, p<0.0001; endothelial- microvesicles: 9.6-fold, p = 0.01), but decreased significantly by day 2. Microvesicle levels were increased with severe sepsis, but less consistently between patients. Leukocyte- and granulocyte-derived microvesicles on day 0 correlated with clinical assessment scores and were higher in burns ICU non-survivors compared to survivors (leukocyte MVs 4.6 fold, p = 0.002; granulocyte MVs 4.8 fold, p = 0.003). Mortality prediction analysis of area under receiver operating characteristic curve was 0.92 (p = 0.01) for total leukocyte microvesicles and 0.85 (p = 0.04) for granulocyte microvesicles. These findings demonstrate, for the first time, acute increases in circulating microvesicles following burns injury in patients and point to their potential role in propagation of sterile SIRS-related pathophysiology.

Food and nutritional security requires adequate protein as well as energy, delivered from whole-year crop production.

Human food security requires the production of sufficient quantities of both high-quality protein and dietary energy. In a series of case-studies from New Zealand, we show that while production of food ingredients from crops on arable land can meet human dietary energy requirements effectively, requirements for high-quality protein are met more efficiently by animal production from such land. We present a model that can be used to assess dietary energy and quality-corrected protein production from various crop and crop/animal production systems, and demonstrate its utility. We extend our analysis with an accompanying economic analysis of commercially-available, pre-prepared or simply-cooked foods that can be produced from our case-study crop and animal products. We calculate the per-person, per-day cost of both quality-corrected protein and dietary energy as provided in the processed foods. We conclude that mixed dairy/cropping systems provide the greatest quantity of high-quality protein per unit price to the consumer, have the highest food energy production and can support the dietary requirements of the highest number of people, when assessed as all-year-round production systems. Global food and nutritional security will largely be an outcome of national or regional agroeconomies addressing their own food needs. We hope that our model will be used for similar analyses of food production systems in other countries, agroecological zones and economies.

The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17.

UNLABELLED: Biliary atresia, the most common indication for pediatric liver transplantation, is a fibrotic disease of unknown etiology affecting the extrahepatic bile ducts of newborns. The recently described toxin biliatresone causes lumen obstruction in mouse cholangiocyte spheroids and represents a new model of biliary atresia. The goal of this study was to determine the cellular changes caused by biliatresone in mammalian cells that ultimately lead to biliary atresia and extrahepatic fibrosis. We treated mouse cholangiocytes in three-dimensional (3D) spheroid culture and neonatal extrahepatic duct explants with biliatresone and compounds that regulate glutathione (GSH). We examined the effects of biliatresone on SOX17 levels and determined the effects of Sox17 knockdown on cholangiocytes in 3D culture. We found that biliatresone caused disruption of cholangiocyte apical polarity and loss of monolayer integrity. Spheroids treated with biliatresone had increased permeability as shown by rhodamine efflux within 5 hours compared with untreated spheroids, which retained rhodamine for longer than 12 hours. Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α-smooth muscle actin and collagen, consistent with fibrosis. Biliatresone caused a rapid and transient decrease in GSH, which was both necessary and sufficient to mediate its effects in cholangiocyte spheroid and bile duct explant systems. It also caused a significant decrease in cholangiocyte levels of SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone. CONCLUSION: Biliatresone decreases GSH and SOX17 in mouse cholangiocytes. In 3D cell systems, this leads to cholangiocyte monolayer damage and increased permeability; in extrahepatic bile duct explants, it leads to disruption of the extrahepatic biliary tree and subepithelial fibrosis. This mechanism may be important in understanding human biliary atresia. (Hepatology 2016;64:880-893).

Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish.

UNLABELLED: Biliatresone is an electrophilic isoflavone isolated from Dysphania species plants that has been causatively linked to naturally occurring outbreaks of a biliary atresia (BA)-like disease in livestock. Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in zebrafish larvae. To better understand its mechanism of toxicity, we performed transcriptional profiling of liver cells isolated from zebrafish larvae at the earliest stage of biliatresone-mediated biliary injury, with subsequent comparison of biliary and hepatocyte gene expression profiles. Transcripts encoded by genes involved in redox stress response, particularly those involved in glutathione (GSH) metabolism, were among the most prominently up-regulated in both cholangiocytes and hepatocytes of biliatresone-treated larvae. Consistent with these findings, hepatic GSH was depleted at the onset of biliary injury, and in situ mapping of the hepatic GSH redox potential using a redox-sensitive green fluorescent protein biosensor showed that it was significantly more oxidized in EHCs both before and after treatment with biliatresone. Pharmacological and genetic manipulation of GSH redox homeostasis confirmed the importance of GSH in modulating biliatresone-induced injury given that GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic cholangiocytes to the toxin, whereas replenishing GSH level by N-acetylcysteine administration or activation of nuclear factor erythroid 2-like 2 (Nrf2), a transcriptional regulator of GSH synthesis, inhibited EHC injury. CONCLUSION: These findings strongly support redox stress as a critical contributing factor in biliatresone-induced cholangiocyte injury, and suggest that variations in intrinsic stress responses underlie the susceptibility profile. Insufficient antioxidant capacity of EHCs may be critical to early pathogenesis of human BA. (Hepatology 2016;64:894-907).

Decoupling of greenhouse gas emissions from global agricultural production: 1970-2050.

Since 1970 global agricultural production has more than doubled; contributing ~1/4 of total anthropogenic greenhouse gas (GHG) burden in 2010. Food production must increase to feed our growing demands, but to address climate change, GHG emissions must decrease. Using an identity approach, we estimate and analyse past trends in GHG emission intensities from global agricultural production and land-use change and project potential future emissions. The novel Kaya-Porter identity framework deconstructs the entity of emissions from a mix of multiple sources of GHGs into attributable elements allowing not only a combined analysis of the total level of all emissions jointly with emissions per unit area and emissions per unit product. It also allows us to examine how a change in emissions from a given source contributes to the change in total emissions over time. We show that agricultural production and GHGs have been steadily decoupled over recent decades. Emissions peaked in 1991 at ~12 Pg CO2 -eq. yr(-1) and have not exceeded this since. Since 1970 GHG emissions per unit product have declined by 39% and 44% for crop- and livestock-production, respectively. Except for the energy-use component of farming, emissions from all sources have increased less than agricultural production. Our projected business-as-usual range suggests that emissions may be further decoupled by 20-55% giving absolute agricultural emissions of 8.2-14.5 Pg CO2 -eq. yr(-1) by 2050, significantly lower than many previous estimates that do not allow for decoupling. Beyond this, several additional costcompetitive mitigation measures could reduce emissions further. However, agricultural GHG emissions can only be reduced to a certain level and a simultaneous focus on other parts of the food-system is necessary to increase food security whilst reducing emissions. The identity approach presented here could be used as a methodological framework for more holistic food systems analysis.

Reactivity of Biliatresone, a Natural Biliary Toxin, with Glutathione, Histamine, and Amino Acids.

In our previous work, we identified a natural toxin, biliatresone, from Dysphania glomulifera and D. littoralis, endemic plants associated with outbreaks of biliary atresia in Australian neonatal livestock. Biliatresone is a very rare isoflavonoid with an α-methylene ketone between two phenyls, 1,2-diaryl-2-propenone, along with methylenedioxy, dimethoxyl, and hydroxyl functional groups, that causes extrahepatic biliary toxicity in zebrafish. The toxic core of biliatresone is a methylene in the α-position relative to the ketone of 1,2-diaryl-2-propenone that serves as an electrophilic Michael acceptor. The α-methylene of biliatresone spontaneously conjugated with water and methanol (MeOH), respectively, via Michael addition in a reverse phase high-performance liquid chromatography (RP-HPLC) analysis. We here report the reactivity of biliatresone toward glutathione (GSH), several amino acids, and other thiol- or imidazole-containing biomolecules. LC-MS and HPLC analysis of the conjugation reaction showed the reactivity of biliatresone to be in the order histidine > N-acetyl-d-cysteine (D-NAC) = N-acetyl-l-cysteine (L-NAC) > histamine > glutathione ≥ cysteine ≫ glycine > glutamate > phenylalanine, while serine and adenine had no reactivity due to intramolecular hydrogen bonding in the protic solvents. The reactivity of ethyl vinyl ketone (EVK, 1-penten-3-one), an example of a highly reactive α,ß-unsaturated ketone, toward GSH gave a 6.7-fold lower reaction rate constant than that of biliatresone. The reaction rate constant of synthetic 1,2-diaryl-2-propen-1-one (DP), a core structure of the toxic molecule, was 10-fold and 1.5-fold weaker in potency compared to the reaction rate constants of biliatresone and EVK, respectively. These results demostrated that the methylenedioxy, dimethoxyl, and hydroxyl functional groups of biliatresone contribute to the stronger reactivity of the Michael acceptor α-methylene ketone toward nucleophiles compared to that of DP and EVK.

Baby Steps Text: Feasibility Study of an SMS-Based Tool for Tracking Children's Developmental Progress.

To help reach populations of children without consistent Internet access or medical care, we designed and implemented Baby Steps Text, an automated text message-based screening tool. We conducted preliminary user research via storyboarding and prototyping with target populations and then developed a fully functional system. In a one-month deployment study, we evaluated the feasibility of Baby Steps Text with fourteen families. During a one-month study, 13 out of 14 participants were able to learn and use the response structure (yielding 2.88% error rate) and complete a child development screener entirely via text messages. All post-study survey respondents agreed Baby Steps Text was understandable and easy to use, which was also confirmed through post-study interviews. Some survey respondents expressed liking Baby Steps Text because it was easy, quick, convenient to use, and delivered helpful, timely information. Our initial deployment study shows text messaging is a feasible tool for supporting parents in tracking and monitoring their child's development.

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis.

Podophyllotoxin (PPT) is a plant natural product that serves as a precursor for the synthesis of many well-known chemotherapeutic drugs. The limited availability and high demand for the source plants of PPT have led to the exploration of alternative sources for this compound. In this study, we utilized the endophytic fungus Phialocephala podophylli (strain PPE7) that we isolated from the rhizomes of Podophyllum peltatum and is known to produce detectable amounts of PPT in broth culture. To date, the complete PPT biosynthetic pathway has yet to be determined in any species. Since fungi are well known for clustering genes that belong to secondary metabolite pathways, use of a fungal system for investigation of the PPT biosynthesis genes may ultimately lead to elucidation of the entire pathway. In this study, we investigated the secoisolariciresinol dehydrogenase (SD) gene that facilitates the dehydrogenation of secoisolariciresinol to form matairesinol, a mid-pathway intermediate product in PPT biosynthesis. We utilized PCR amplification to acquire the complete SD gene sequence in PPE7 and opted to synthesize the P. peltatum SD sequence for expression. Through western blotting, we confirmed the expression of the recombinant SD (PpSD) and verified protein functionality with a bioconversion assay followed by HPLC and LC-MS analyses. Here, we report the identification of the SD gene in PPE7; this is the first report of the SD gene in an endophytic fungus. Additionally, we established the groundwork for the future expression of the complete PPT biosynthetic pathway in the heterologous host Pichia pastoris.

Biliatresone, a Reactive Natural Toxin from Dysphania glomulifera and D. littoralis: Discovery of the Toxic Moiety 1,2-Diaryl-2-Propenone.

We identified a reactive natural toxin, biliatresone, from Dysphania glomulifera and D. littoralis collected in Australia that produces extrahepatic biliary atresia in a zebrafish model. Three additional isoflavonoids, including the known isoflavone betavulgarin, were also isolated. Biliatresone is in the very rare 1,2-diaryl-2-propenone class of isoflavonoids. The α-methylene of the 1,2-diaryl-2-propenone of biliatresone spontaneously reacts via Michael addition in the formation of water and methanol adducts. The lethal dose of biliatresone in a zebrafish assay was 1 µg/mL, while the lethal dose of synthetic 1,2-diaryl-2-propen-1-one was 5 µg/mL, suggesting 1,2-diaryl-2-propenone as the toxic Michael acceptor.

An Isoflavone from Leiophyllum buxifolium and Its Antiproliferative Effect.

A new C-methylisoflavone, isosideroxylin (1), and a known C-methylflavone, sideroxylin (2), were isolated from the EtOAc extract of the leaves of Leiophyllum buxifolium. The two compounds were evaluated with the sulforhodamine B assay for their antiproliferative effects against ER(-) MDA-MB-231 and ER(+) MCF-7 breast cancer cell lines and the NIH3T3 mouse fibroblast cell line. Isosideroxylin (1) displayed a selective antiproliferative effect against MDA-MB-231 cells.