Octavio Martínez de la Vega

Unified QSAR approach to antimicrobials. Part 3: First multi-tasking QSAR model for Input-Coded prediction, structural back-projection, and complex networks clustering of antiprotozoal compounds

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.

Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug–drug complex networks

One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the model in practice, we develop a virtual screening recognizing the model as active 92.7%, 102 of 110 antivirus compounds. These compounds were never use in training or predicting series. Next, we obtained and compared the topology of the CNs and their respective GCs based on Euclidean, Manhattan, Chebychey, Pearson and other similarity measures. The GC of the Manhattan network showed the more interesting features for drug-drug similarity search. We also give the procedure for the construction of Back-Projection Maps for the contribution of each drug sub-structure to the antiviral activity against different species.

The Palomero Genome Suggests Metal Effects on Domestication

A-Maize-ing Maize is one of our oldest and most important crops, having been domesticated approximately 9000 years ago in central Mexico. Schnable et al. (p. 1112; see the cover) present the results of sequencing the B73 inbred maize line. The findings elucidate how maize became diploid after an ancestral doubling of its chromosomes and reveals transposable element movement and activity and recombination. Vielle-Calzada et al. (p. 1078) have sequenced the Palomero Toluqueño (Palomero) landrace, a highland popcorn from Mexico, which, when compared to the B73 line, reveals multiple loci impacted by domestication. Swanson-Wagner et al. (p. 1118) exploit possession of the genome to analyze expression differences occurring between lines. The identification of single nucleotide polymorphisms and copy number variations among lines was used by Gore et al. (p. 1115) to generate a Haplotype map of maize. While chromosomal diversity in maize is high, it is likely that recombination is the major force affecting the levels of heterozygosity in maize. The availability of the maize genome will help to guide future agricultural and biofuel applications (see the Perspective by Feuillet and Eversole). Genes involved in metal tolerance likely played a role in maize domestication. Maize domestication (Zea mays ssp. mays L.) resulted in a wide diversity of native landraces that represent an invaluable source of genetic information for exploring natural variation and genome evolution. We sequenced de novo the ~2-gigabase genome of the Mexican landrace Palomero Toluqueño (Palomero) and compared its features to those of the modern inbred line B73. We revealed differences concordant with its ancient origin and identified chromosomal regions of low nucleotide variability that contain domestication genes involved in heavy-metal detoxification. Our results indicate that environmental changes were important selective forces acting on maize domestication.

Jasmonic acid influences mycorrhizal colonization in tomato plants by modifying the expression of genes involved in carbohydrate partitioning

The role of jasmonic acid (JA) on mycorrhizal colonization by Glomus fasciculatum in tomato plants was examined using mutant plants overexpressing prosystemin (PS) or affected in the synthesis of JA (suppressor of prosystemin-mediated responses 2, spr2). The degree of mycorrhizal colonization was determined by measuring frequency (F%) and intensity (M%) of colonization and arbuscule abundance (A%). Gene expression and biochemical analyses were also performed in roots to detect changes in carbon (C) partitioning. Colonization was similar in mycorrhizal PS and wild-type roots, except for a higher A% in the former. Conversely, colonization was severely reduced in roots of spr2 mutants. No association was found between levels of expression of genes coding for systemic wound responsive proteins (or SWRPs) and other defense-related proteins in roots and mycorrhization levels in these plants. On the other hand, the degree of mycorrhizal colonization correlated with changes in the transcriptional regulation of a number of genes involved in sucrose hydrolysis and transport, cell wall invertase activity and mycorrhizal-specific fatty acid content in roots. The results obtained suggest that one of the mechanisms by which JA might operate to modulate the mycorrhization process could be through its influence on the regulation of C partitioning in the plant. The significant colonization increase observed in mycorrhizal spr2 plants supplied with exogenous methyl jasmonate supports its role as a positive regulator of the symbiosis.

The effect of exogenous jasmonic acid on induced resistance and productivity in amaranth (Amaranthus hypochondriacus) is influenced by environmental conditions.

Amaranthus hypochondriacus is a C4 pseudocereal crop capable of producing reasonable grain yields in adverse environmental conditions that limit cereal performance. It accumulates trypsin inhibitors and α-amylase inhibitors in seeds and leaves that are considered to act as insect feeding deterrents. Foliar trypsin and α-amylase inhibitors also accumulate by treatment with exogenous jasmonic acid (JA) in controlled laboratory conditions. Three field experiments were performed in successive years to test if two nonphytotoxic dosages of JA were capable of inducing inhibitor activity in A. hypochondriacus in agronomical settings, and if this induced response reduced insect herbivory and insect abundance in foliage and seed heads. The performance of JA-treated plants was compared to insecticide-treated plants and untreated controls. The effect of exogenous JA on the foliar levels of six additional putatively defence proteins was also evaluated. Possible adverse effects of JA induction on productivity were evaluated by measuring grain yield, seed protein content, and germination efficiency. The results present a complex pattern and were not consistent from year to year. To some extent, the yearly variability observed could have been consequence of growth under drought versus nondrought conditions. In a drought year, JA-treated plants had lower levels of insect herbivory-derived damage in apical leaves and panicle than control plants, whereas in nondrought years, there was an inconsistent effect on aphids, with no effect on lepidopteran larvae. JA treatments reduced the size of the insect community in seed heads. The effect varied with year. Exogenous JA did not adversely affect productivity, and in the absence of drought stress, the higher dosage enhanced grain yield. Induction of defensive proteins by JA, although sporadic, was more effective in nondrought conditions. The patterns of foliar protein accumulation observed suggest that they may be part of a constitutive, rather than inducible, chemical defense mechanism that is developmentally regulated and critically dependent on the environment. The results emphasize the difficulties that are often encountered when evaluating the performance of chemical elicitors of induced resistance in field settings.

Identification of Co-1 Anthracnose Resistance and Linked Molecular Markers in Common Bean Line A193

Phaseolus vulgaris line A193 has been shown to be widely resistant to Colletotrichum lindemuthianum, including race 1472, one of the most virulent races of C. lindemuthianum characterized. Resistance to C. lindemuthianum race 1472 in P. vulgaris line A193 was investigated in segregating F2 and F2.3 populations from a cross between A193 and Flor de Mayo Bajio (a commercial cultivar highly susceptible to C. lindemuthianum). Resistance to 1472 in A193 was determined to be conditioned by a single dominant gene. Inoculation of crosses between A193 and cultivars Michigan Dark Red Kidney and Perry Marrow with race 1472 suggest that resistance in A193 is conditioned by the Co-1 gene. Inoculation of the cross A193 × Perry Marrow with C. lindemuthianum race 2, demonstrated that resistance to race 2 in Perry Marrow is also conditioned by a single dominant gene and is distinct to resistance in A193 or Michigan Dark Red Kidney. Three AFLP markers (ECAG/MACC-1, EACA/MAGA-2, EAGG/MAAC-8) linked in repulsion to the Co-1 locus were identified by screening the A193 × Flor de Mayo F2 population with 314 random amplified polymorphic DNA, amplified fragment length polymorphism, and restriction fragment length polymorphism markers. The two most closely linked markers should be useful in marker-assisted selection for Co-1.

Transcriptional analysis of the Arabidopsis ovule by massively parallel signature sequencing

The life cycle of flowering plants alternates between a predominant sporophytic (diploid) and an ephemeral gametophytic (haploid) generation that only occurs in reproductive organs. In Arabidopsis thaliana, the female gametophyte is deeply embedded within the ovule, complicating the study of the genetic and molecular interactions involved in the sporophytic to gametophytic transition. Massively parallel signature sequencing (MPSS) was used to conduct a quantitative large-scale transcriptional analysis of the fully differentiated Arabidopsis ovule prior to fertilization. The expression of 9775 genes was quantified in wild-type ovules, additionally detecting >2200 new transcripts mapping to antisense or intergenic regions. A quantitative comparison of global expression in wild-type and sporocyteless (spl) individuals resulted in 1301 genes showing 25-fold reduced or null activity in ovules lacking a female gametophyte, including those encoding 92 signalling proteins, 75 transcription factors, and 72 RNA-binding proteins not reported in previous studies based on microarray profiling. A combination of independent genetic and molecular strategies confirmed the differential expression of 28 of them, showing that they are either preferentially active in the female gametophyte, or dependent on the presence of a female gametophyte to be expressed in sporophytic cells of the ovule. Among 18 genes encoding pentatricopeptide-repeat proteins (PPRs) that show transcriptional activity in wild-type but not spl ovules, CIHUATEOTL (At4g38150) is specifically expressed in the female gametophyte and necessary for female gametogenesis. These results expand the nature of the transcriptional universe present in the ovule of Arabidopsis, and offer a large-scale quantitative reference of global expression for future genomic and developmental studies.

Analysis of Pathotypes of Colletotrichum lindemuthianum Found in the Central Region of Mexico and Resistance in Elite Germ Plasm of Phaseolus vulgaris

The pathotypes of 17 isolates of Colletotrichum lindemuthianum from the central region of Mexico were characterized to determine the genetic relationship among isolates from this region and other regions of Mexico, and to evaluate the resistance present in the elite germ plasm collection of Phaseolus vulgaris at INIFAP. Eight pathotypes were identified, including pathotype 292, which is reported for the first time in Mexico. The lack of isolates infecting cultivar TU carrying the Co-5 resistance gene suggests that this cultivar is a useful source of resistance. Six pathotypes produced susceptible reactions on only differential cultivars of Middle American origin, one pathotype on a single cultivar of Andean origin, and one pathotype on cultivars of both Middle American and Andean origin. Comparison of amplified fragment length polymorphism (AFLP) genotypes of 21 isolates confirmed suggestions that populations of C. lindemuthianum are comprised of asexually reproducing clonal lineages. Analysis of five different pathotypes of C. lindemuthianum on 21 elite genotypes of P. vulgaris identified four genotypes from different races of P. vulgaris resistant to all five pathotypes. This information will allow breeders and farmers to select the resistant genotypes most suited to their needs.

An SSR-based approach incorporating a novel algorithm for identification of rare maize genotypes facilitates criteria for landrace conservation in Mexico

Abstract As maize was domesticated in Mexico around 9,000 years ago, local farmers have selected and maintained seed stocks with particular traits and adapted to local conditions. In the present day, many of these landraces are still cultivated; however, increased urbanization and migration from rural areas implies a risk that this invaluable maize germplasm may be lost. In order to implement an efficient mechanism of conservation in situ, the diversity of these landrace populations must be estimated. Development of a method to select the minimum number of samples that would include the maximum number of alleles and identify germplasm harboring rare combinations of particular alleles will also safeguard the efficient ex‐situ conservation of this germplasm. To reach this goal, a strategy based on SSR analysis and a novel algorithm to define a minimum collection and rare genotypes using landrace populations from Puebla State, Mexico, was developed as a “proof of concept” for methodology that could be extended to all maize landrace populations in Mexico and eventually to other native crops. The SSR‐based strategy using bulked DNA samples allows rapid processing of large numbers of samples and can be set up in most laboratories equipped for basic molecular biology. Therefore, continuous monitoring of landrace populations locally could easily be carried out. This methodology can now be applied to support incentives for small farmers for the in situ conservation of these traditional cultivars.