3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists: Part 1

We report the identification of a novel series of trisubstituted isoxazoles as PPAR activators from a high-throughput screen. A series of structural optimizations led to improved efficacy and excellent functional receptor selectivity for PPARdelta. The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif.     

Exploring the mechanism of β-amyloid toxicity attenuation by multivalent sialic acid polymers through the use of mathematical models

β-Amyloid peptide (Aβ), the primary protein component in senile plaques associated with Alzheimer's disease (AD), has been implicated in neurotoxicity associated with AD. Previous studies have shown that the Aβ-neuronal membrane interaction plays a role in the mechanism of Aβ toxicity. More specifically, it is thought that Aβ interacts with ganglioside rich and sialic acid rich regions of cell surfaces. In light of such evidence, we have used a number of different sialic acid compounds of different valency or number of sialic acid moieties per molecule to attenuate Aβ toxicity in a cell culture model. In this work, we proposed various mathematical models of Aβ interaction with both the cell membrane and with the multivalent sialic acid compounds, designed to act as membrane mimics. These models allow us to explore the mechanism of action of this class of sialic acid membrane mimics in attenuating the toxicity of Aβ. The mathematical models, when compared with experimental data, facilitate the discrimination between different modes of action of these materials. Understanding the mechanism of action of Aβ toxicity inhibitors should provide insight into the design of the next generation of molecules that could be used to prevent Aβ toxicity associated with AD.     

Short- and long-term consequences of individual and territory quality in a long-lived bird

Site-quality is a major determinant of fitness but its effect can be confounded by individual quality, a relationship that has been little studied in large, long-lived vertebrates. The fitness effects of quality estimates depend on the assumption of co-variation between individual and territory quality and can be framed as five working hypotheses: no effect on fitness, exclusive effect of individual quality, exclusive effect of site quality, and independent or interactive effects of the two. We explored such a framework using a medium-sized raptor, the black kite Milvus migrans, as a model species. Individual and territory quality co-varied, but the strength of the relationship varied across different estimates of individual quality (age, body size, or mass residuals). Short-term production of fledglings was related to the independent effects of both individual and territory quality. However, longer-term production of recruits was related solely to territory quality. The disappearance of individual quality effects over the long-term may be caused by antagonistic selective pressures acting during different stages of the life cycle. Our results contribute to a growing appreciation of the long-term fitness-benefits of advantages experienced in early life and highlight the importance of a long-term perspective in studies assessing the effects of individual and territory quality. In our case study, prioritizing sites for conservation on the basis of territory quality may be a feasible pathway to maintain the viability of the population. However, scenarios where such a method could be inefficient have been previously reported, suggesting caution in its application. More studies are needed to understand the generality of the efficiency of priority-setting approaches based on site quality.     

Aphid aerial density profiles are consistent with turbulent advection amplifying flight behaviours: abandoning the epithet 'passive'

Seminal field studies led by C. G. Johnson in the 1940s and 1950s showed that aphid aerial density diminishes with height above the ground such that the linear regression coefficient, b, of log density on log height provides a single-parameter characterization of the vertical density profile. This coefficient decreases with increasing atmospheric stability, ranging from -0.27 for a fully convective boundary layer to -2.01 for a stable boundary layer. We combined a well-established Lagrangian stochastic model of atmospheric dispersal with simple models of aphid behaviour in order to account for the range of aerial density profiles. We show that these density distributions are consistent with the aphids producing just enough lift to become neutrally buoyant when they are in updraughts and ceasing to produce lift when they are in downdraughts. This active flight behaviour in a weak flier is thus distinctly different from the aerial dispersal of seeds and wingless arthropods, which is passive once these organisms have launched into the air. The novel findings from the model indicate that the epithet 'passive' often applied to the windborne migration of small winged insects is misleading and should be abandoned. The implications for the distances traversed by migrating aphids under various boundary-layer conditions are outlined.     

Microbial communities and processes within a hypersaline gypsum crust in a saltern evaporation pond (Eilat,Israel)

Gypsum crusts containing multicolored, stratified microbial communities develop in the evaporation ponds of a commercial saltern in Eilat, Israel at salt concentrations between 190 and 240 g l⁻¹. The upper 0.5–2 cm of the crust is densely populated by orange-brown unicellular cyanobacteria. Below, a layer of green-colored filamentous cyanobacteria is found. Underneath, a bright purple layer of anoxygenic phototrophs is present, below which a reduced black layer is found. We have investigated the biological properties of this crust using a wide variety of techniques, and we here review the results of these interdisciplinary studies. The tests performed included microscopic examination of the biota, phylogenetic analyses based on 16S rRNA gene clone libraries and denaturing gradient gel electrophoresis, fatty acid analysis, light intensity and light quality measurements, microelectrode studies of oxygen profiles and oxygen evolution, determination of sulfate reduction using radioisotope methods, and measurement of methane evolution. The stable vertical stratification in the system enabled separate analyses of the different layers with a high spatial resolution. It was therefore possible to combine the different approaches and obtain information on the activities of the different types of oxygenic and anoxygenic phototrophs, dissimilatory sulfate reducers and methanogens in the different layers, as well as phylogenetic information on the nature of the microorganisms responsible for these processes. The gypsum crust thus becomes a paradigm for the study of a wide variety of microbial processes and their interrelationships in the presence of high salt concentrations. Guest Editors: J. John & B. Timms Salt Lake Research: Biodiversity and Conservation—Selected papers from the 9th Conference of the International Society for Salt Lake Research     

Quinolines as a novel structural class of potent and selective PDE4 inhibitors: Optimisation for oral administration

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD     

Ultraviolet and violet light: attractive orientation cues for the Indian meal moth, Plodia interpunctella

The Indian meal moth (IMM), Plodia interpunctella (Hübner) (Lepidoptera: Pyralidae), engages in long-distance or foraging flights in the twilight hours of the scotophase when blue light dominates the irradiance spectrum of the sky. We tested the hypothesis that IMM uses wavelengths of visible blue/violet light as orientation cues that trigger phototactic responses. In four-choice laboratory experiments, blue light (400–475 nm) was significantly more effective than green (475–600 nm), orange (575–700 nm), or red (590–800 nm) light in attracting males and mated females. In subsequent experiments that tested light emitting diodes (LEDs) emitting peak wavelengths in the blue/violet-light range, the 405-nm 'violet' LED was significantly more effective than the 435-, 450-, or 470-nm 'blue' LED in attracting males as well as virgin and mated females. In electroretinogram recordings, the 405-nm wavelength elicited significantly stronger receptor potentials from female and male eyes than the 350-nm (UV) wavelength, and in a behavioral experiment it significantly enhanced the known attractiveness of UV light. Equal attraction of IMMs to 405-nm LEDs at 600–700 µW/cm² with or without UV light, and significantly stronger attraction to a 405-nm LED than to a 350-nm LED at maximum light intensities, suggest that the deployment of violet instead of UV light could become one of several management tactics for control of IMMs.     

Quantifying Transmission of Campylobacter jejuni in Commercial Broiler Flocks

Since meat from poultry colonized with Campylobacter spp. is a major cause of bacterial gastroenteritis, human exposure should be reduced by, among other things, prevention of colonization of broiler flocks. To obtain more insight into possible sources of introduction of Campylobacter into broiler flocks, it is essential to estimate the moment that the first bird in a flock is colonized. If the rate of transmission within a flock were known, such an estimate could be determined from the change in the prevalence of colonized birds in a flock over time. The aim of this study was to determine the rate of transmission of Campylobacter using field data gathered for 5 years for Australian broiler flocks. We used unique sampling data for 42 Campylobacter jejuni-colonized flocks and estimated the transmission rate, which is defined as the number of secondary infections caused by one colonized bird per day. The estimate was 2.37 ± 0.295 infections per infectious bird per day, which implies that in our study population colonized flocks consisting of 20,000 broilers would have an increase in within-flock prevalence to 95% within 4.4 to 7.2 days after colonization of the first broiler. Using Bayesian analysis, the moment of colonization of the first bird in a flock was estimated to be from 21 days of age onward in all flocks in the study. This study provides an important quantitative estimate of the rate of transmission of Campylobacter in broiler flocks, which could be helpful in future studies on the epidemiology of Campylobacter in the field.