Statistical analysis of unlabeled point sets: comparing molecules in chemoinformatics

We consider Bayesian methodology for comparing two or more unlabeled point sets. Application of the technique to a set of steroid molecules illustrates its potential utility involving the comparison of molecules in chemoinformatics and bioinformatics. We initially match a pair of molecules, where one molecule is regarded as random and the other fixed. A type of mixture model is proposed for the point set coordinates, and the parameters of the distribution are a labeling matrix (indicating which pairs of points match) and a concentration parameter. An important property of the likelihood is that it is invariant under rotations and translations of the data. Bayesian inference for the parameters is carried out using Markov chain Monte Carlo simulation, and it is demonstrated that the procedure works well on the steroid data. The posterior distribution is difficult to simulate from, due to multiple local modes, and we also use additional data (partial charges on atoms) to help with this task. An approximation is considered for speeding up the simulation algorithm, and the approximating fast algorithm leads to essentially identical inference to that under the exact method for our data. Extensions to multiple molecule alignment are also introduced, and an algorithm is described which also works well on the steroid data set. After all the steroid molecules have been matched, exploratory data analysis is carried out to examine which molecules are similar. Also, further Bayesian inference for the multiple alignment problem is considered.     

Classification of macroinvertebrate communities across drainage basins in Victoria, Australia: consequences of sampling on a broad spatial scale for predictive modelling

1. Spatial scale may influence the interpretation of environmental gradients that underlie classification and ordination analyses of lotic macroinvertebrate communities. This could have important consequences for the spatial scale over which predictive models derived from these multivariate analyses can be applied. 2. Macroinvertebrate community data (identified to genus or species) from edge and main-channel habitats were obtained for sites on rivers from 25 of the 29 drainage basins in Victoria. Trends in community similarity were analysed by carrying out separate multivariate analyses on data from the edge habitats (199 sites) and the main-channel habitats (163 sites). 3. Hierarchical classification (UPGMA) showed that the edge data could be placed into 11 site groups and the main-channel data into 12 site groups. 4. Ordination analysis (hybrid multidimensional scaling) showed no sharp disjunctions between site groups in either habitat; overlap was frequent. Correlation of the ordination patterns with environmental variables showed that edge communities varied longitudinally within a drainage basin and from the east to the west of Victoria. These two trends were superimposed on one another to form a single gradient on the ordination. The taxon richness of edge communities was also related to the species richness of macrophytes at a site. Main-channel communities also displayed a longitudinal and a geographic gradient, but these two gradients were uncorrelated on the ordination. 5. Community similarity only weakly reflected geographic proximity in either habitat. A preliminary subdivision of Victoria into a series of biogeographic regions did not match the pattern of distribution of site groups for the edge habitat, illustrating the difficulties of applying to lotic communities a priori regionalizations based on terrestrial features of the landscape. 6. The longitudinal gradients in the two data sets were commonly observed in data gathered at smaller spatial scales in Victoria. The other gradients (geographic, macrophyte), however, were either not consistently repeated or not evident at smaller spatial scales. At small spatial scales (i.e. within a single drainage basin) gradients were related to variables that varied over restricted ranges, e.g. mean particle size of the substratum. 7. Species richness was very variable when plotted against river slope or distance of site from source; both of these are measures of position on the longitudinal gradients. In contrast to suggestions in the literature, species richness did not show a unimodal trend on these gradients, or any other trend. 8. Environmental gradients (apart from longitudinal gradients) that underlie predictive models of macroinvertebrate distribution are reflections of the spatial scale on which the model has been constructed and cannot be extrapolated to different scales. Models must be suited to the spatial scale over which predictions are required.     

Characterization of a Fourth Adaptor-related Protein Complex

Adaptor protein complexes (APs) function as vesicle coat components in different membrane traffic pathways; however, there are a number of pathways for which there is still no candidate coat. To find novel coat components related to AP complexes, we have searched the expressed sequence tag database and have identified, cloned, and sequenced a new member of each of the four AP subunit families. We have shown by a combination of coimmunoprecipitation and yeast two-hybrid analysis that these four proteins (epsilon, beta4, mu4, and sigma4) are components of a novel adaptor-like heterotetrameric complex, which we are calling AP-4. Immunofluorescence reveals that AP-4 is localized to approximately 10-20 discrete dots in the perinuclear region of the cell. This pattern is disrupted by treating the cells with brefeldin A, indicating that, like other coat proteins, the association of AP-4 with membranes is regulated by the small GTPase ARF. Immunogold electron microscopy indicates that AP-4 is associated with nonclathrin-coated vesicles in the region of the trans-Golgi network. The mu4 subunit of the complex specifically interacts with a tyrosine-based sorting signal, indicating that, like the other three AP complexes, AP-4 is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs. AP-4 is of relatively low abundance, but it is expressed ubiquitously, suggesting that it participates in a specialized trafficking pathway but one that is required in all cell types.     

Synthesis and activity of N-cyanoguanidine-piperazine P2X7 antagonists

A novel series of cyanoguanidine-piperazine P2X₇ antagonists were identified and structure–activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X₇ receptors in addition to their ability to inhibit IL-1β release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 μM) in this latter assay and demonstrates moderate clearance in-vivo.     

Validation of ecological status concepts in UK rivers using historic diatom samples

We assessed the feasibility of using herbarium specimens to validate reference conditions in the UK by comparing diatom community composition of river sites with both recent and historic diatom samples. The question of substrate specificity was addressed by comparing epilithon (stone-derived) and epiphyton (plant-derived) samples from a number of rivers. No significant differences were found between the Trophic Diatom Index (TDI), species richness, species diversity, and percentage of motile valves between paired diatom samples (epilithic and epiphytic) from contemporary samples. Significant differences were recorded between a number of indices derived from analysis of the historic diatom samples on plant material sampled pre-1930 compared with diatoms from stones collected post-1990 from the same river location. The TDI, mean species richness, and species diversity and percentage of motile valves and nutrient tolerant valves were all significantly greater in the contemporary samples (p ≤ 0.05). The percentage of nutrient sensitive valves was significantly lower in the contemporary samples (p ≤ 0.05).The relative abundance of Achnanthidium minutissimum and Cocconeis placentula var. lineata was significantly greater on the herbarium material compared to matched contemporary samples. Calculated values for the TDI (43 ± 3) expected at reference conditions were similar to the observed TDI values derived from herbarium material (44 ± 12) showing no significant deviation in ecological status.