Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein

Leukotrienes are proinflammatory products of arachidonic acid oxidation by 5-lipoxygenase that have been shown to be involved in respiratory and cardiovascular diseases. The integral membrane protein FLAP is essential for leukotriene biosynthesis. We describe the x-ray crystal structures of human FLAP in complex with two leukotriene biosynthesis inhibitors at 4.0 and 4.2 angstrom resolution, respectively. The structures show that inhibitors bind in membrane-embedded pockets of FLAP, which suggests how these inhibitors prevent arachidonic acid from binding to FLAP and subsequently being transferred to 5-lipoxygenase, thereby preventing leukotriene biosynthesis. This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases.     

A decision-analytic approach to the optimal allocation of resources for endangered species consultation

The resources available to support conservation work, whether time or money, are limited. Decision makers need methods to help them identify the optimal allocation of limited resources to meet conservation goals, and decision analysis is uniquely suited to assist with the development of such methods. In recent years, a number of case studies have been described that examine optimal conservation decisions under fiscal constraints; here we develop methods to look at other types of constraints, including limited staff and regulatory deadlines. In the US, Section Seven consultation, an important component of protection under the federal Endangered Species Act, requires that federal agencies overseeing projects consult with federal biologists to avoid jeopardizing species. A benefit of consultation is negotiation of project modifications that lessen impacts on species, so staff time allocated to consultation supports conservation. However, some offices have experienced declining staff, potentially reducing the efficacy of consultation. This is true of the US Fish and Wildlife Service’s Washington Fish and Wildlife Office (WFWO) and its consultation work on federally-threatened bull trout (Salvelinus confluentus). To improve effectiveness, WFWO managers needed a tool to help allocate this work to maximize conservation benefits. We used a decision-analytic approach to score projects based on the value of staff time investment, and then identified an optimal decision rule for how scored projects would be allocated across bins, where projects in different bins received different time investments. We found that, given current staff, the optimal decision rule placed 80% of informal consultations (those where expected effects are beneficial, insignificant, or discountable) in a short bin where they would be completed without negotiating changes. The remaining 20% would be placed in a long bin, warranting an investment of seven days, including time for negotiation. For formal consultations (those where expected effects are significant), 82% of projects would be placed in a long bin, with an average time investment of 15 days. The WFWO is using this decision-support tool to help allocate staff time. Because workload allocation decisions are iterative, we describe a monitoring plan designed to increase the tool’s efficacy over time. This work has general application beyond Section Seven consultation, in that it provides a framework for efficient investment of staff time in conservation when such time is limited and when regulatory deadlines prevent an unconstrained approach.     

Comparison of digital and optical hand-held refractometers for the measurement of feline urine specific gravity

Measuring urine specific gravity (USG) is an important component of urine analysis as it evaluates renal concentrating capability. The objective of this study was to quantify the difference in USG values between a hand-held optical analogue refractometer and a cat-specific digital instrument. Urine samples from 55 cats were assessed. There was a statistically significant difference between these two refractometers (P<0.001), with the optical refractometer (mean USG=1.031) consistently reading higher than the digital refractometer (mean USG=1.027). Results for a random subset of the samples (n=10) were compared with urine osmolality and both the optical and digital instruments demonstrated excellent correlation. While an accurate USG reading is important, it is unlikely that the statistical significance between the two instruments is clinically significant and, therefore, unlikely to result in a change in patient evaluation or treatment plans. While both the digital and optimal refractometers are highly correlated to the urine osmolality, making both devices valid for assessment of USG in clinical practice, this digital device is easier to read and eliminates the variability of subjective interpretation.     

Higher-tier assessment of the potential for groundwater issues due to the use of 1,3-D soil fumigant; evaluation of the active ingredient, metabolites and potentially related chlorinated compounds

BACKGROUND: 1,3‐Dichloropropene (1,3‐D, CAS No. 542‐75‐6) is a broad‐spectrum soil fumigant used to control numerous species of soilborne plant‐parasitic nematodes. 1,3‐D consists of two isomers, (Z)‐ and (E)‐1,3‐D. There are a number of low‐level chlorinated compounds that could potentially be produced as a part of the 1,3‐D manufacturing process. 1,3‐D and its metabolites, as well as potentially related chlorinated compounds, represent potential groundwater contaminants. RESULTS: This study has investigated the hydrolytic stability, under biotic and abiotic conditions in the laboratory, of an extensive representative list of 1,3‐D and potentially related chlorinated compounds in order to predict their environmental fate. All of these compounds showed intrinsic hydrolytic instability under both abiotic and biotic test conditions. Furthermore, a monitoring programme was carried out. Twenty‐five wells were monitored in five Italian regions characterised by historical and existing use of 1,3‐D. The parent compound, its two major metabolites and potentially related chlorinated compounds were not detected in the well water at > 0.1 µg L^?1 at any sampling location. CONCLUSION: The soil fumigant (E,Z)‐1,3‐D, its metabolites and potentially related chlorinated compounds constitute a low risk to groundwater. Copyright © 2011 Society of Chemical Industry