Modeling the peptide-T cell receptor interaction by the comparative molecular similarity indices analysis-soft independent modeling of class analogy technique

A set of 38 epitopes and 183 non-epitopes, which bind to alleles of the HLA-A3 supertype, was subjected to a combination of comparative molecular similarity indices analysis (CoMSIA) and soft independent modeling of class analogy (SIMCA). During the process of T cell recognition, T cell receptors (TCR) interact with the central section of the bound nonamer peptide; thus only positions 4−8 were considered in the study. The derived model distinguished 82% of the epitopes and 73% of the non-epitopes after cross-validation in five groups. The overall preference from the model is for polar amino acids with high electron density and the ability to form hydrogen bonds. These so-called “aggressive” amino acids are flanked by small-sized residues, which enable such residues to protrude from the binding cleft and take an active role in TCR-mediated T cell recognition. Combinations of “aggressive” and “passive” amino acids in the middle part of epitopes constitute a putative TCR binding motif

A comparative molecular similarity indices (CoMSIA) study of peptide binding to the HLA-A3 superfamily

Epitope identification is the basis of modern vaccine design. The present paper studied the supermotif of the HLA-A3 superfamily, using comparative molecular similarity indices analysis (CoMSIA). Four alleles with high phenotype frequencies were used: A*1101, A*0301, A*3101 and A*6801. Five physicochemical properties—steric bulk, electrostatic potential, local hydro-phobicity, hydrogen-bond donor and acceptor abilities—were considered and ‘all fields’ models were produced for each of the alleles. The models have a moderate level of predictivity and there is a good correlation between the data. A revised HLA-A3 supermotif was defined based on the comparison of favoured and disfavoured properties for each position of the MHC bound peptide. The present study demonstrated that CoMSIA is an effective tool for studying peptide–MHC interactions.

Molecular quantum similarity in QSAR: applications in computer-aided molecular design

La present tesi està centrada en l'ús de la Teoria de Semblança Quàntica per a calcular descriptors moleculars. Aquests descriptors s'utilitzen com a paràmetres estructurals per a derivar correlacions entre l'estructura i la funció o activitat experimental per a un conjunt de compostos. Els estudis de Relacions Quantitatives Estructura-Activitat són d'especial interès per al disseny racional de molècules assistit per ordinador i, en particular, per al disseny de fàrmacs. Aquesta memòria consta de quatre parts diferenciades. En els dos primers blocs es revisen els fonaments de la teoria de semblança quàntica, així com l'aproximació topològica basada en la teoria de grafs. Ambdues teories es fan servir per a calcular els descriptors moleculars. En el segon bloc, s'ha de remarcar la programació i implementació de programari per a calcular els anomenats índexs topològics de semblança quàntica. La tercera secció detalla les bases de les Relacions Quantitatives Estructura-Activitat i, finalment, el darrer apartat recull els resultats d'aplicació obtinguts per a diferents sistemes biològics.

fuzzySim: Fuzzy similarity in species distributions

fuzzySim is an R package for calculating fuzzy similarity in species occurrence patterns. It includes functions for data preparation, such as converting species lists (long format) to presence-absence tables (wide format), obtaining unique abbreviations of species names, or transposing (parts of) complex data frames; and sample data sets for providing practical examples. It can convert binary presence-absence to fuzzy occurrence data, using e.g. trend surface analysis, inverse distance interpolation or prevalence-independent environmental favourability modelling, for multiple species simultaneously. It then calculates fuzzy similarity among (fuzzy) species distributions and/or among (fuzzy) regional species compositions. Currently available similarity indices are Jaccard, Sørensen, Simpson, and Baroni-Urbani & Buser.

Novel Biginelli dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study

Novel Biginelli dihydropyrimidines of biological interest were prepared using p-toluene sulphonic acid as an efficient catalyst. All the thirty-two synthesised dihydropyrimidines were evaluated for their in vitro antioxidant activity using DPPH method. Only, compounds 28 and 29 exhibited reasonably good antioxidant activity. Furthermore, the synthesised Biginelli compounds were subjected for their in vitro anticancer activity against MCF-7 human breast cancer cells. The title compounds were tested at the concentration of 10 μg. Compounds exhibited activity ranging from weak to moderate and, from moderate to high in terms of percentage cytotoxicity. Among them, compounds 10 and 11 exhibited significant anticancer activity. In order to elucidate the three-dimensional structure–activity relationships (3D QSAR) towards their anticancer activity, we subjected them for comparative molecular similarity indices analysis (CoMSIA). Illustration regarding their synthesis, analysis, antioxidant activity, anticancer activity and 3D QSAR study is described.

A stationary visual census technique for quantitatively assessing community structure of coral reef fishes

A new method is described and evaluated for visually sampling reef fish community structure in environments with highly diverse and abundant reef fish populations. The method is based on censuses of reef fishes taken within a cylinder of 7.5 m radius by a diver at randomly selected, stationary points. The method provides quantitative data on frequency of occnrrence, fish length, abundance, and community composition, and is simple, fast, objective, and repeatable. Species are accumulated rapidly for listing purposes, and large numbers of samples are easily obtained for statistical treatment. The method provides an alternative to traditional visual sampling methods. Observations showed that there were no significant differences in total numbers of species or individuals censused when visibility ranged between 8 and 30 m. The reefs and habitats sampled were significant sources of variation in number of species and individuals censused, but the diver was not a significant influence. Community similarity indices were influenced significantly by the specific sampling site and the reef sampled, but were not significantly affected by the habitat or diver (PDF file contains 21 pages.)

Analysis of three marine fish cell lines by RAPD assay

We tested the applicability of the random amplified polymorphic deoxyribonucleic acid (RAPD) analysis for identification of three marine fish cell lines FG. SPH, and RSBK and as a possible tool to detect cross-contamination. Sixth commercial 10-mer RAPD primers were tested on the cell lines and on samples collected from individual fish. The results obtained showed that the cell lines could be identified to the correspondent species on the basis of identical Patterns produced by 35-48% of the primers tested. the total mean similarity indices for cell lines versus correspondent species of individual fish ranged from 0.825 to 0.851. indicating the existence of genetic variation in these cell lines in relation to the species of their origin. Also, four primers, which gave a monomorphic hand pattern within species/line, but different among the species/line, were obtained. These primers can be useful for identification of these cell lines and for characterization of the genetic variation of these cell lines in relation to the species of their origin. This supported the use of RAPD analysis as an effective tool in species identification and cross-contamination test among different cell lines.

Patterns of synchrony in natterjack toad breeding activity and reproductive success at local and regional scales

Empirical studies of the spatiotemporal dynamics of populations are required to better understand natural fluctuations in abundance and reproductive success, and to better target conservation and monitoring programmes. In particular, spatial synchrony in amphibian populations remains little studied. We used data from a comprehensive three year study of natterjack toad Bufo calamita populations breeding at 36 ponds to assess whether there was spatial synchrony in the toad breeding activity (start and length of breeding season, total number of egg strings) and reproductive success (premetamorphic survival and production of metamorphs). We defined a novel approach to assess the importance of short-term synchrony at both local and regional scales. The approach employs similarity indices and quantifies the interaction between the temporal and spatial components of populations using mixed effects models. There was no synchrony in the toad breeding activity and reproductive success at the local scale, suggesting that populations function as individual clusters independent of each other. Regional synchrony was apparent in the commencement and duration of the breeding season and in the number of egg strings laid (indicative of female population size). Regional synchrony in both rainfall and temperature are likely to explain the patterns observed (e.g. Moran effect). There was no evidence supporting regional synchrony in reproductive success, most likely due to spatial variability in the environmental conditions at the breeding ponds, and to differences in local population fitness (e.g. fecundity). The small scale asynchronous dynamics and regional synchronous dynamics in the number of breeding females indicate that it is best to monitor several populations within a subset of regions. Importantly, variations in the toad breeding activity and reproductive success are not synchronous, and it is thus important to consider them both when assessing the conservation status of pond-breeding amphibians. © 2012 The Authors. Ecography © 2012 Nordic Society Oikos.

Measuring beta diversity for presence-absence data

1. Little consensus has been reached as to general features of spatial variation in beta diversity, a fundamental component of species diversity. This could reflect a genuine lack of simple gradients in beta diversity, or a lack of agreement as to just what constitutes beta diversity. Unfortunately, a large number of approaches have been applied to the investigation of variation in beta diversity, which potentially makes comparisons of the findings difficult.

2. We review 24 measures of beta diversity for presence/absence data (the most frequent form of data to which such measures are applied) that have been employed in the literature, express many of them for the first time in common terms, and compare some of their basic properties.

3. Four groups of measures are distinguished, with a fundamental distinction arising between 'broad sense' measures incorporating differences in composition attributable to species richness gradients, and 'narrow sense' measures that focus on compositional differences independent of such gradients. On a number of occasions on which the former have been employed in the literature the latter may have been more appropriate, and there are many situations in which consideration of both kinds of measures would be valuable.

4. We particularly recommend (i) considering beta diversity measures in terms of matching/mismatching components (usually denoted a , b and c) and thereby identifying the contribution of different sources of variation in species composition, and (ii) the use of ternary plots to express the relationship between the values of these measures and of the components, and as a way of understanding patterns in beta diversity.

The role of the seed bank in recovery of temperate heath and blanket bog following wildfires

Questions - Are the germinable seed banks of upland heath and blanket bog reduced following wildfires? Are some species at particular risk? Do the impacts of wildfires on seed banks differ between heathlands and blanket bog?

Location - Northern Ireland, United Kingdom.

Methods - Vegetation surveys and seed bank sampling were conducted in 2012 at burned and unburned areas within six upland sites where large wildfires had occurred during spring 2011. Differences in seedling abundance, species richness and Jaccard similarity indices between burned and unburned areas were compared using GLMMs. Differences in the community composition were examined using pRDA.

Results - In total, 24 of the 51 species in the vegetation were detected in the germinable seed bank. Species richness and the abundance of seedlings other than Calluna vulgaris were lower in areas where wildfires had occurred. Species composition of both germinable seed banks and vegetation differed between burned and unburned areas within sites; with negative associations between burned areas and some key indicator species including Drosera rotundifolia, Eriophorum vaginatum, Empetrum nigrum, Narthecium ossifragum and Trichophorum germanicum. We did not find any evidence of significant interactions between burning and habitat, suggesting that wildfires had similar impacts on each species regardless of the habitat in which they occurred.

Conclusions - This study differs from other UK studies in that it examines impacts of wildfires at sites that have not been previously intensively managed by burning. In particular, we highlight potential impacts on N. ossifragum and D. rotundifolia, which are key components of the upland flora and, to our knowledge, were not present in previous UK studies.

Estudi Qsar d'una família de Quinolones utilitzant índex de semblança i índex topològics de semblança i índexs topològics de semblanç

En aquest treball es presenta un exemple d'aplicació de la semblança molecular quàntica en l'àmbit de la determinació de relacions entre l'estructura i les propietats o activitats biològiques de molècules. La família estudiada està formada per un conjunt de divuit quinolones de les quals es coneixen dues propietats relacionades amb l'activitat biològica: la concentració mínima inhibitòria de la reproducció en E. Coli i I'escissió de l'ADN per la girasa, també en E. Coli. L'estudi s'ha realitzat emprant dues metodologies diferents, fonamentades ambdues en el desenvolupament de la semblança molecular quàntica. Aquestes dues metodologies es basen, respectivament, en el càlcul i l'aplicació dels índexs de semblança i dels índexs topològics de semblança

Synthesis and structure-activity relationship studies of CD4 down-modulating cyclotriazadisulfonamide (CADA) analogues

HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tail-group analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same major conformation of the central 12-membered ring. The solid-state structure of CADA was energy minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.

Investigation of the faecal microbiota of kittens: monitoring bacterial succession and effect of diet

Weaning is a stressful process for kittens, and is often associated with diarrhoea and the onset of infectious diseases. The gastrointestinal microbiota plays an essential role in host well-being, including improving homeostasis. Composition of the gastrointestinal microbiota of young cats is poorly understood, and the impact of diet on the kitten microbiota unknown. The aims of this study were to monitor the faecal microbiota of kittens and determine the effect(s) of diet on its composition. Bacterial succession was monitored in two groups of kittens (at 4 and 6 weeks, and 4 and 9 months of age) fed different foods. Age-related microbial changes revealed significantly different counts of total bacteria, lactic acid bacteria, Desulfovibrionales, Clostridium cluster IX and Bacteroidetes between 4-week- and 9-month-old kittens. Diet-associated differences in the faecal microbiota of the two feeding groups were evident. In general, fluorescence in situ hybridization analysis demonstrated bifidobacteria, Atopobium group, Clostridium cluster XIV and lactic acid bacteria were dominant in kittens. Denaturing gradient gel electrophoresis profiling showed highly complex and diverse faecal microbiotas for kittens, with age- and/or food-related changes seen in relation to species richness and similarity indices. Four-week-old kittens harboured more diverse and variable profiles than those of weaned kittens.

Quantitative structure-activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: Molecular modeling, CoMFA and CoMSIA studies

Human parasitic diseases are the foremost threat to human health and welfare around the world. Trypanosomiasis is a very serious infectious disease against which the currently available drugs are limited and not effective. Therefore, there is an urgent need for new chemotherapeutic agents. One attractive drug target is the major cysteine protease from Trypanosoma cruzi, cruzain. In the present work, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted on a series of thiosemicarbazone and semicarbazone derivatives as inhibitors of cruzain. Molecular modeling studies were performed in order to identify the preferred binding mode of the inhibitors into the enzyme active site, and to generate structural alignments for the three-dimensional quantitative structure-activity relationship (3D QSAR) investigations. Statistically significant models were obtained (CoMFA. r(2) = 0.96 and q(2) = 0.78; CoMSIA, r(2) = 0.91 and q(2) = 0.73), indicating their predictive ability for untested compounds. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the information gathered from the 3D CoMFA and CoMSIA contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of cruzain inhibitors, and should be useful for the design of new structurally related analogs with improved potency. (C) 2009 Elsevier Inc. All rights reserved.