From UTP to AR-C118925, the discovery of a potent non nucleotide antagonist of the P2Y2 receptor

The G protein-coupled P2Y₂ receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y₂R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y₂ receptor discovered using the endogenous P2Y₂R agonist UTP as the chemical starting point.     

Dissecting adaptive clinal variation: markers, inversions and size/stress associations in Drosophila melanogaster from a central field population

Many organisms show latitudinal variation for quantitative traits that is assumed to be due to climatic adaptation. These clines provide an opportunity to study the genetics of the adaptive process both at the phenotypic and the underlying molecular levels. Yet researchers rarely try to link variation in quantitative traits to their underlying molecular genetic basis. We describe a novel approach for exploring the genetic basis for clinal variation in size and stress traits in Drosophila melanogaster. We look for associations between genetic markers and traits that exhibit clinal patterns on the east coast of Australia using a single, geographically central population. There are strong associations between markers found within In(3R)Payne and variation in size, suggesting that this inversion explains much of the clinal variation in this trait. We also find that development time is associated with the Adh allozyme locus, cold resistance is negatively associated with the In(3L)Payne inversion and a genetic marker for Hsp70, a heat‐shock protein, is associated with heat resistance. Finally we discuss the importance of inversions in clinal variation for quantitative traits and for identifying quantitative trait loci.     

Thermoregulation and the energetic significance of clustering behavior in the white-backed mousebird (Colius colius)

Thermoregulation and the energetic significance of clustering behavior were assessed in the white-backed mousebird Colius colius. Basal metabolic rate was 40% below the predicted allometric values. Rest-phase body temperature (T(b)) was highly labile and as low as 26 degrees C. Rest-phase T(b) was not regulated with respect to a constant set point temperature, as occurs typically in endotherms. Rather, we observed periods of linear decreases in rest-phase T(b) at a rate dependent on ambient temperature (T(a)) and the number of individuals in a cluster. The apparent inability of individual mousebirds to maintain rest-phase homeothermy suggests that clustering behavior is obligatory in the defense of a rest-phase set point T(b). The low rest-phase body temperatures exhibited by single C. colius hence appear to represent a normothermic state rather than typical avian facultative hypothermia. The birds were able to make significant energy savings by means of clustering behavior. These energy savings were dependent on T(a) and the number of birds in the cluster. At a T(a) of 15 degrees C, the mean energy expenditure of each bird in a cluster of six was 50% of that of a single bird. The metabolic traits of C. colius are likely be adaptive in the arid habitats that this species inhabits.     

Carbon debt repayment or carbon sequestration parity? Lessons from a forest bioenergy case study in Ontario,Canada

Forest bioenergy can contribute to climate change mitigation by reducing greenhouse gas (GHG) emissions associated with energy production. We assessed changes in GHG emissions resulting from displacement of coal with wood pellets for the Atikokan Generating Station located in Northwestern Ontario, Canada. Two contrasting biomass sources were considered for continuous wood pellet production: harvest residue from current harvest operations (residue scenario) and fibre from expanded harvest of standing live trees (stemwood scenario). For the stemwood scenario, two metrics were used to assess the effects of displacing coal with forest biomass on GHG emissions: (i) time to carbon sequestration parity, defined as the time from the beginning of harvest to when the combined GHG benefit of displacing coal with biomass and the amount of carbon in regenerating forest equalled the amount of forest carbon without harvest for energy production; and (ii) time to carbon debt repayment, defined as the time from the beginning of harvest to when the combined GHG benefit of displacing coal with biomass and the amount of carbon in the regenerating forest equalled forest carbon at the time of harvest. Only time to carbon sequestration parity was used for the residue scenario. In the residue scenario, carbon sequestration parity was achieved within 1 year. In the stemwood scenario, times to carbon sequestration parity and carbon debt repayment were 91 and 112 years, respectively. Sensitivity analysis showed that estimates were robust when parameter values were varied. Modelling experiments showed that increasing growth rates for regenerating stands in the stemwood scenario could substantially reduce time to carbon sequestration parity. We discuss the use of the two metrics (time to carbon sequestration parity and time to carbon debt repayment) for assessing the effects of forest bioenergy projects on GHG emissions and make recommendations on terminology and methodologies for forest bioenergy studies.     

Transforming Benzophenoxazine Laser Dyes into Chromophores for Dye‐Sensitized Solar Cells: A Molecular Engineering Approach

The refunctionalization of a series of four well‐known industrial laser dyes, based on benzophenoxazine, is explored with the prospect of molecularly engineering new chromophores for dye‐sensitized solar cell (DSC) applications. Such engineering is important since a lack of suitable dyes is stifling the progress of DSC technology. The conceptual idea involves making laser dyes DSC‐active by chemical modification, while maintaining their key property attributes that are attractive to DSC applications. This molecular engineering follows a stepwise approach. First, molecular structures and optical absorption properties are determined for the parent laser dyes: Cresyl Violet ( 1 ), Oxazine 170 ( 2 ), Nile Blue A ( 3 ), Oxazine 750 ( 4 ). These reveal structure‐property relationships which define the prerequisites for computational molecular design of DSC dyes; the nature of their molecular architecture (D‐π‐A) and intramolecular charge transfer. Second, new DSC dyes are computationally designed by the in silico addition of a carboxylic acid anchor at various chemical substitution points in the parent laser dyes. A comparison of the resulting frontier molecular orbital energy levels with the conduction band edge of a TiO₂ DSC photoanode and the redox potential of two electrolyte options I^?/I₃^? and Co^(II/III)tris(bipyridyl) suggests promise for these computationally designed dyes as co‐sensitizers for DSC applications.     

Adaptable night camouflage by cuttlefish

Cephalopods are well known for their diverse, quick-changing camouflage in a wide range of shallow habitats worldwide. However, there is no documentation that cephalopods use their diverse camouflage repertoire at night. We used a remotely operated vehicle equipped with a video camera and a red light to conduct 16 transects on the communal spawning grounds of the giant Australian cuttlefish Sepia apama situated on a temperate rock reef in southern Australia. Cuttlefish ceased sexual signaling and reproductive behavior at dusk and then settled to the bottom and quickly adapted their body patterns to produce camouflage that was tailored to different backgrounds. During the day, only 3% of cuttlefish were camouflaged on the spawning ground, but at night 86% (71 of 83 cuttlefish) were camouflaged in variations of three body pattern types: uniform (n=5), mottled (n=33), or disruptive (n=34) coloration. The implication is that nocturnal visual predators provide the selective pressure for rapid, changeable camouflage patterning tuned to different visual backgrounds at night.     

Bias and Sampling Error of the Estimated Proportion of Genotypic Variance Explained by Quantitative Trait Loci Determined From Experimental Data in Maize Using Cross Validation and Validation With Independent Samples.

Cross validation (CV) was used to analyze the effects of different environments and different genotypic samples on estimates of the proportion of genotypic variance explained by QTL (p). Testcrosses of 344 F(3) maize lines grown in four environments were evaluated for a number of agronomic traits. In each of 200 replicated CV runs, this data set was subdivided into an estimation set (ES) and various test sets (TS). ES were used to map QTL and estimate p for each run (p(ES)) and its median (p(ES)) across all runs. The bias of these estimates was assessed by comparison with the median (p(TS.ES)) obtained from TS. We also used two independent validation samples derived from the same cross for further comparison. The median p(ES) showed a large upward bias compared to p(TS.ES). Environmental sampling generally had a smaller effect on the bias of p(ES) than genotypic sampling or both factors simultaneously. In independent validation, p(TS.ES) was on average only 50% of p(ES). A wide range among p(ES) reflected a large sampling error of these estimates. QTL frequency distributions and comparison of estimated QTL effects indicated a low precision of QTL localization and an upward bias in the absolute values of estimated QTL effects from ES. CV with data from three QTL studies reported in the literature yielded similar results as those obtained with maize testcrosses. We therefore recommend CV for obtaining asymptotically unbiased estimates of p and consequently a realistic assessment of the prospects of MAS.     

Selection for cold resistance alters gene transcript levels in Drosophila melanogaster

Microarrays have been used to examine changes in gene expression underlying responses to selection for increased stress resistance in Drosophila melanogaster, but changes in expression patterns associated with increased resistance to cold stress have not been previously reported. Here we describe such changes in basal expression levels in replicate lines following selection for increased resistance to chill coma stress. We found significant up- or down-regulation of expression in 94 genes on the Affymetrix Genome 2.0 array. Quantitative RT-PCR was used to confirm changes in expression of six genes. Some of the identified genes had previously been associated with stress resistance but no previously identified candidate genes for cold resistance showed altered patterns of expression. Seven differentially expressed genes that form a tight chromosomal cluster and an unlinked gene AnnX may be potentially important for cold adaptation in natural populations. Artificial selection for chill coma resistance therefore altered basal patterns of gene expression, but we failed to link these changes to plastic changes in expression under cold stress or to previously identified candidate genes for components of cold resistance.     

Micro-evolution in a wine cellar population: An historical perspective

The population ofDrosophila melanogaster inside the wine cellar of Chateau Tahbilk of Victoria, Australia was found by McKenzie and Parsons (1974) to have undergone microevolution for greater alcohol tolerance when compared to the neighboring population outside the cellar. This triggered additional studies at Tahbilk, and at other wine cellars throughout the world. The contributions and interactions of researchers and the development of ideas on the ecology and genetics of this unique experimental system are traced. Although the ADH-F/ADH-S polymorphism was found to be maintained by selection in the Tahbilk populations, the selection is not significantly associated with alcohol tolerance. The environment inside the Tahbilk wine cellar is not as rich in ethanol as was originally anticipated, and selection that affects the alcohol dehydrogenase polymorphism may be more concerned with the relative efficiency with which ethanol is used as a nutrient byD. melanogaster. The synthesis and modification of lipids, particularly in membranes, appears to be important to alcohol tolerance. The studies of the Tahbilk population are at a crossroad. New experimental approaches promise to provide the keys to the selection that maintains the alcohol dehydrogenase polymorphism, and to factors that are important to alcohol tolerance and stress adaptation. From these research foundations at Tahbilk very significant contributions to our future understanding of the genetic processes of evolution can be made.