A Mapping of Drug Space from the Viewpoint of Small Molecule Metabolism

Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the “effect space” comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism

Annotation Error in Public Databases: Misannotation of Molecular Function in Enzyme Superfamilies

Due to the rapid release of new data from genome sequencing projects, the majority of protein sequences in public databases have not been experimentally characterized; rather, sequences are annotated using computational analysis. The level of misannotation and the types of misannotation in large public databases are currently unknown and have not been analyzed in depth. We have investigated the misannotation levels for molecular function in four public protein sequence databases (UniProtKB/Swiss-Prot, GenBank NR, UniProtKB/TrEMBL, and KEGG) for a model set of 37 enzyme families for which extensive experimental information is available. The manually curated database Swiss-Prot shows the lowest annotation error levels (close to 0% for most families); the two other protein sequence databases (GenBank NR and TrEMBL) and the protein sequences in the KEGG pathways database exhibit similar and surprisingly high levels of misannotation that average 5%–63% across the six superfamilies studied. For 10 of the 37 families examined, the level of misannotation in one or more of these databases is >80%. Examination of the NR database over time shows that misannotation has increased from 1993 to 2005. The types of misannotation that were found fall into several categories, most associated with “overprediction” of molecular function. These results suggest that misannotation in enzyme superfamilies containing multiple families that catalyze different reactions is a larger problem than has been recognized. Strategies are suggested for addressing some of the systematic problems contributing to these high levels of misannotation

Anuran responses to spatial patterns of agricultural landscapes in Argentina

Context: Amphibians are declining worldwide and land use change to agriculture is recognized as a leading cause. Argentina is undergoing an agriculturalization process with rapid changes in landscape structure. Objectives: We evaluated anuran response to landscape composition and configuration in two landscapes of east-central Argentina with different degrees of agriculturalization. We identified sensitive species and evaluated landscape influence on communities and individual species at two spatial scales. Methods: We compared anuran richness, frequency of occurrence, and activity between landscapes using call surveys data from 120 sampling points from 2007 to 2009. We evaluated anuran responses to landscape structure variables estimated within 250 and 500-m radius buffers using canonical correspondence analysis and multimodel inference from a set of candidate models. Results: Anuran richness was lower in the landscape with greater level of agriculturalization with reduced amount of forest cover and stream length. This pattern was driven by the lower occurrence and calling activity of seven out of the sixteen recorded species. Four species responded positively to the amount of forest cover and stream habitat. Three species responded positively to forest cohesion and negatively to rural housing. Two responded negatively to crop area and diversity of cover classes. Conclusions: Anurans within agricultural landscapes of east-central Argentina are responding to landscape structure. Responses varied depending on species and study scale. Life-history traits contribute to responses differences. Our study offers a better understanding of landscape effects on anurans and can be used for land management in other areas experiencing a similar agriculturalization process.Facultad de Ciencias ExactasCentro de Investigaciones del Medioambient

Nation related participation and performance trends in 'Ironman Hawaii' from 1985 to 2012

BACKGROUND: This study examined participation and performance trends in 'Ironman Hawaii' regarding the nationality of the finishers. METHODS: Associations between nationalities and race times of 39,706 finishers originating from 124 countries in the 'Ironman Hawaii' from 1985 to 2012 were analyzed using single and multi-level regression analysis. RESULTS: Most of the finishers originated from the United States of America (47.5%) followed by athletes from Germany (11.7%), Japan (7.9%), Australia (6.7%), Canada (5.2%), Switzerland (2.9%), France (2.3%), Great Britain (2.0%), New Zealand (1.9%), and Austria (1.5%). German women showed the fastest increase in finishers (r2=0.83, p0.05). For men, athletes from France showed the steepest increase (r2=0.85, p0.05) and New Zealand (r2=0.02, p>0.05) remained unchanged. Regarding female performance, the largest improvements were achieved by Japanese women (17.3%). The fastest race times in 2012 were achieved by US-American women. Women from Japan, Canada, Germany, Australia, and the United States of America improved race times. For men, the largest improvements were achieved by athletes originating from Brazil (20.9%) whereas the fastest race times in 2012 were achieved by athletes from Germany. Race times for athletes originating from Brazil, Austria, Great Britain, Switzerland, Germany, Australia, Canada, Japan, New Zealand and France decreased. Race times in athletes originating from Australia and the United States of America showed no significant changes. Regarding the fastest race times ever, the fastest women originated from the United States (546+/-7 min) followed by Great Britain (555+/-15 min) and Switzerland (558+/-8 min). In men, the fastest finishers originated from the United States (494+/-7 min), Germany (496+/-6 min) and Australia (497+/-5 min). CONCLUSIONS: The 'Ironman Hawaii' has been dominated by women and men from the United States of America in participation and performance