RESUMO
Fasciola hepatica, the liver fluke, is a trematode parasite that causes disease of economic importance in livestock. As a zoonosis this parasite also poses a risk to human health in areas where it is endemic. Population genetic studies can reveal the mechanisms responsible for genetic structuring (non-panmixia) within parasite populations and provide valuable insights into population dynamics, which in turn enables theoretical predictions of evolutionary dynamics such as the evolution of drug resistance. Here we genotyped 320 F. hepatica collected from 14 definitive hosts from four provinces in Argentina. STRUCTURE analysis indicated three population clusters, and principal coordinate analysis confirmed this, showing population clustering across provinces. Similarly, pairwise FST values amongst all four provinces were significant, with standardised pairwise FST (F'ST) ranging from 0.0754 to 0.6327. Therefore, population genetic structure was evident across these four provinces in Argentina. However, there was no evidence of deviation from Hardy-Weinberg equilibrium, so it appears that within these sub-populations there is largely random mating. We identified 263 unique genotypes, which gave a clonal diversity of 82%. Parasites with identical genotypes, clones, accounted for 26.6% of the parasites studied and were found in 12 of the 14 hosts studied, suggesting some clonemate transmission.
Assuntos
Fasciola hepatica , Fasciolíase , Animais , Argentina/epidemiologia , Fasciola hepatica/genética , Fasciolíase/epidemiologia , Fasciolíase/veterinária , Variação Genética , Genética Populacional , Genótipo , HumanosRESUMO
In the present study, molecular characterization of Fasciola flukes from Spain was performed to reveal the relation with the previously reported Peruvian F. hepatica population. The nuclear DNA markers, phosphoenolpyruvate carboxykinase (pepck) and DNA polymerase delta (pold), were used for species identification of Fasciola flukes. A total of 196 Fasciola flukes were identified as F. hepatica by pepck and pold, and 26 haplotypes were detected in mitochondrial NADH dehydrogenase subunit 1 (nad1). Only one of them was previously found in Spanish samples; which indicates the existence of high genetic diversity and population structure in F. hepatica from Spain. Three haplotypes were identical to those from Peruvian F. hepatica. The pairwise fixation index value confirmed a relatively close relationship between the Spanish and Peruvian F. hepatica samples. The Spanish samples showed clearly higher genetic variability than the Peruvian population. These results are discussed in relation with the hypothesis of the introduction of the parasite in America from Europe and recent evidence of pre-Hispanic F. hepatica from Argentina revealed by ancient DNA.
Assuntos
Doenças dos Bovinos/parasitologia , Fasciola hepatica/genética , Fasciolíase/veterinária , Variação Genética , Doenças dos Ovinos/parasitologia , Animais , Carboxiliases/análise , Bovinos , DNA Polimerase III/análise , Fasciolíase/parasitologia , Proteínas Fúngicas/análise , Peru , Filogenia , Análise de Sequência de DNA , Ovinos , EspanhaRESUMO
BACKGROUND: Complex network approach allows the representation and analysis of complex systems of interacting agents in an ordered and effective manner, thus increasing the probability of discovering significant properties of them. In the present study, we defined and built for the first time a complex network based on data obtained from Immune Epitope Database for parasitic organisms. We then considered the general topology, the node degree distribution, and the local structure (triadic census) of this network. In addition, we calculated 9 node centrality measures for observed network and reported a comparative study of the real network with three theoretical models to detect similarities or deviations from these ideal networks. RESULT: The results obtained corroborate the utility of the complex network approach for handling information and data mining within the database under study. CONCLUSION: They confirm that this type of approach can be considered a valuable tool for preliminary screening of the best experimental conditions to determine whether the amino acid sequences being studied are true epitopes or not.
Assuntos
Bases de Dados Factuais , Epitopos/química , Epitopos/imunologia , Redes Neurais de Computação , Parasitos/química , Parasitos/imunologia , Sequência de Aminoácidos , Animais , Mineração de DadosRESUMO
In the last years, the encryption of system structure information with different network topological indices has been a very active field of research. In the present study, we assembled for the first time a complex network using data obtained from the Immune Epitope Database for fungi species, and we then considered the general topology, the node degree distribution, and the local structure of this network. We also calculated eight node centrality measures for the observed network and compared it with three theoretical models. In view of the results obtained, we may expect that the present approach can become a valuable tool to explore the complexity of this database, as well as for the storage, manipulation, comparison, and retrieval of information contained therein.
Assuntos
Epitopos/imunologia , Fungos/imunologia , Mineração de Dados , Bases de Dados Factuais , Humanos , Modelos Teóricos , Redes Neurais de ComputaçãoRESUMO
Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).
Assuntos
Alcaloides/farmacologia , Aporfinas/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Aciltransferases/metabolismo , Animais , DNA Topoisomerases Tipo I/metabolismo , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Several pathogen parasite species show different susceptibilities to different antiparasite drugs. Unfortunately, almost all structure-based methods are one-task or one-target Quantitative Structure-Activity Relationships (ot-QSAR) that predict the biological activity of drugs against only one parasite species. Consequently, multi-tasking learning to predict drugs activity against different species by a single model (mt-QSAR) is vitally important. In the two previous works of the present series we reported two single mt-QSAR models in order to predict the antimicrobial activity against different fungal (Bioorg. Med. Chem.2006, 14, 5973-5980) or bacterial species (Bioorg. Med. Chem.2007, 15, 897-902). These mt-QSARs offer a good opportunity (unpractical with ot-QSAR) to construct drug-drug similarity Complex Networks and to map the contribution of sub-structures to function for multiple species. These possibilities were unattended in our previous works. In the present work, we continue this series toward other important direction of chemotherapy (antiparasite drugs) with the development of an mt-QSAR for more than 500 drugs tested in the literature against different parasites. The data were processed by Linear Discriminant Analysis (LDA) classifying drugs as active or non-active against the different tested parasite species. The model correctly classifies 212 out of 244 (87.0%) cases in training series and 207 out of 243 compounds (85.4%) in external validation series. In order to illustrate the performance of the QSAR for the selection of active drugs we carried out an additional virtual screening of antiparasite compounds not used in training or predicting series; the model recognized 97 out of 114 (85.1%) of them. We also give the procedures to construct back-projection maps and to calculate sub-structures contribution to the biological activity. Finally, we used the outputs of the QSAR to construct, by the first time, a multi-species Complex Networks of antiparasite drugs. The network predicted has 380 nodes (compounds), 634 edges (pairs of compounds with similar activity). This network allows us to cluster different compounds and identify on average three known compounds similar to a new query compound according to their profile of biological activity. This is the first attempt to calculate probabilities of antiparasitic action of drugs against different parasites.