Búsqueda de un conjunto óptimo de descriptores moleculares para la modelación QSAR

Search for an optimal subset of molecular descriptors for QSAR modeling

Luis Antonio García González (2023, [Tesis de doctorado])

En la actualidad, se estima que más de 10 millones de vertebrados son utilizados cada año en estudios toxicológicos. Dadas estas circunstancias, varias agencias regulatorias están impulsando activamente a la comunidad científica para el desarrollo de una alternativa a la experimentación con animales. Entre las alternativas existentes se pueden encontrar los estudios in-silico, especialmente los métodos de Relación Cuantitativa Estructura-Actividad (QSAR por sus siglas en inglés), los cuales se destacan como uno de los más utilizados. Los estudios QSAR se basan en la hipótesis de que compuestos estructuralmente similares presentan una actividad similar, lo que permite predecir la actividad de nuevos compuestos en función de compuestos estructuralmente similares, para los cuales se definió su actividad de forma experimental. Estudios han demostrado que la selección del subconjunto “óptimo” de las variables (descriptores moleculares) que caracterizan estructuralmente los compuestos tiene mayor importancia para la construcción de un modelo QSAR robusto que la estrategia de modelación utilizada. Actualmente, los descriptores moleculares (DMs) utilizados para la modelación QSAR son calculados con herramientas computacionales que no tienen en cuenta si estos caracterizan bien la actividad que se quiere modelar y los compuestos que se están analizando. En este trabajo se describen las limitaciones del enfoque actual, teniendo en cuenta que, si se sigue este enfoque, se puede pasar por alto información relevante al suponer que el conjunto de DMs calculado caracteriza bien las estructuras químicas que se están analizando, cuando en realidad puede que esto no suceda. Estas limitaciones se deben principalmente a que dichas herramientas limitan el número de DMs que calculan, restringiendo el dominio de los parámetros en los que se definen los algoritmos que calculan los DMs, parámetros que definen el Espacio de Configuración de Descriptores (DCS por sus siglas en inglés). En este trabajo se propone relajar estas restricciones en un enfoque DCS abierto, de manera que se pueda considerar inicialmente un universo más amplio de DMs y que estos caractericen de manera adecuada las estructuras a modelar. La generación de DMs se aborda entonces como un problema de optimización multicriterio, y para darle solución, dos algoritmos evolutivos son propuestos. Estos algoritmos incluyen conceptos de coevolución cooperativa para medir la sinergia entre descriptores moleculares ...

Currently, it is estimated that more than 10 million vertebrates are used per year for toxicological studies. Numerous regulatory agencies are actively advocating for the development of alternative methods to avoid unnecessary experimentation on animals. Among the existing alternatives in silico studies, especially Quantitative Structure Activity Relationships (QSAR) methods, stands out as one ofthe most widely used approaches. QSAR Methods are based on the premise that molecules with similar structures presents similar activities, which makes it possible to predict the activity of new compounds based on structurally similar compounds, for which their activity has been defined experimentally. Studies have demonstrated that the selection of the “optimal” set of molecular descriptors (MDs) is more important to build a robust QSAR models than the choice of the learning algorithm. Nowadays, the molecular descriptors (MD) used for QSAR modeling are calculated using computational tools that do not consider whether they accurately characterize the activity to be modeled and the compounds being analyzed. We demonstrate here that this approach may miss relevant information by assuming that the initial universe of MDs codifies, when it does not, all relevant aspects for the respective learning task. We argue that the limitation is mainly because of the constrained intervals of the parameters used in the algorithms that compute the MDs, parameters that define the Descriptor Configuration Space (DCS). We propose to relax these constraints in an open CDS approach, so that a larger universe of MDs can initially be considered, and these descriptors can adequately characterize the structures to be modeled. We model the MD generation as a multicriteria optimization problem, and two genetic algorithms-based approaches are proposed to solve it. These algorithms include cooperative-coevolutionary concepts to consider the synergism between theoretically different MDs during the evolutionary process. As a novel component, the individual fitness function is computed by aggregating four criteria via the Choquet Integral using a fuzzy non-additive measure. Experimental outcomes on benchmarking chemical datasets show that models created from an “optimized” sets of MDs present greater probability to achieve better performances than models created from sets of MDs obtained without optimizing their DCSs. Therefore, it can be concluded that the proposed algorithms are more suitable ..

algoritmos genéticos, descriptores moleculares QuBiLS-MAS, QSAR, DILI, cooperación coevolutiva genetics algorithms, QuBiLS-MAS molecular descriptors, QSAR, DILI, cooperativecoevolutionary algorithms INGENIERÍA Y TECNOLOGÍA CIENCIAS TECNOLÓGICAS TECNOLOGÍA DE LOS ORDENADORES DISEÑO CON AYUDA DE ORDENADOR DISEÑO CON AYUDA DE ORDENADOR

Solanum tuberosum Microtuber Development under Darkness Unveiled through RNAseq Transcriptomic Analysis

ELIANA VALENCIA LOZANO LISSET HERRERA ISIDRON Osiel Salvador Recoder-Meléndez Aarón Barraza Celis JOSE LUIS CABRERA PONCE (2022, [Artículo])

"Potato microtuber (MT) development through in vitro techniques are ideal propagules for producing high quality potato plants. MT formation is influenced by several factors, i.e., photoperiod, sucrose, hormones, and osmotic stress. We have previously developed a protocol of MT induction in medium with sucrose (8% w/v), gelrite (6g/L), and 2iP as cytokinin under darkness. To understand the molecular mechanisms involved, we performed a transcriptome-wide analysis. Here we show that 1715 up- and 1624 down-regulated genes were involved in this biological process. Through the protein–protein interaction (PPI) network analyses performed in the STRING database (v11.5), we found 299 genes tightly associated in 14 clusters. Two major clusters of up-regulated proteins fundamental for life growth and development were found: 29 ribosomal proteins (RPs) interacting with 6 PEBP family members and 117 cell cycle (CC) proteins. The PPI network of up-regulated transcription factors (TFs) revealed that at least six TFs–MYB43, TSF, bZIP27, bZIP43, HAT4 and WOX9–may be involved during MTs development. The PPI network of down-regulated genes revealed a cluster of 83 proteins involved in light and photosynthesis, 110 in response to hormone, 74 in hormone mediate signaling pathway and 22 related to aging."

transcriptome-wide analysis, microtubers, potato, Solanum tuberosum, darkness, cell cycle, ribosomal proteins, PEBP family genes, cytokinin BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA GENÉTICA GENÉTICA MOLECULAR DE PLANTAS GENÉTICA MOLECULAR DE PLANTAS

Phylogenetic relationships of Pseudo-nitzschia subpacifica (Bacillariophyceae) from the Mexican Pacific, and its production of domoic acid in culture

Sonia Quijano (2020, [Artículo])

Pseudo-nitzschia is a cosmopolitan genus, some species of which can produce domoic acid (DA), a neurotoxin responsible for the Amnesic Shellfish Poisoning (ASP). In this study, we identified P. subpacifica for the first time in Todos Santos Bay and Manzanillo Bay, in the Mexican Pacific using SEM and molecular methods. Isolates from Todos Santos Bay were cultivated under conditions of phosphate sufficiency and deficiency at 16°C and 22°C to evaluate the production of DA. This toxin was detected in the particulate (DAp) and dissolved (DAd) fractions of the cultures during the exponential and stationary phases of growth of the cultures. The highest DA concentration was detected during the exponential phase grown in cells maintained in P-deficient medium at 16°C (1.14 ± 0.08 ng mL-1 DAd and 4.71 ± 1.11 × 10−5 ng cell-1 of DAp). In P-sufficient cultures DA was higher in cells maintained at 16°C (0.25 ± 0.05 ng mL-1 DAd and 9.41 ± 1.23 × 10−7 ng cell-1 of DAp) than in cells cultured at 22°C. Therefore, we confirm that P. subpacifica can produce DA, especially under P-limited conditions that could be associated with extraordinary oceanographic events such as the 2013–2016 "Blob" in the northeastern Pacific Ocean. This event altered local oceanographic conditions and possibly generated the presence of potential harmful species in areas with economic importance on the Mexican Pacific coast. © 2020 Quijano-Scheggia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

domoic acid, domoic acid, kainic acid, Article, cell growth, controlled study, diatom, Mexico, morphology, nonhuman, Pacific Ocean, phylogeny, plant cell, plant growth, Pseudo nitzschia, toxin analysis, cell culture technique, classification, diatom, CIENCIAS FÍSICO MATEMÁTICAS Y CIENCIAS DE LA TIERRA CIENCIAS DE LA TIERRA Y DEL ESPACIO OCEANOGRAFÍA OCEANOGRAFÍA

Maintenance of Coastal Surface Blooms by Surface Temperature Stratification and Wind Drift

MARY CARMEN RUIZ DE LA TORRE (2013, [Artículo])

Algae blooms are an increasingly recurrent phenomenon of potentially socio-economic impact in coastal waters globally and in the coastal upwelling region off northern Baja California, Mexico. In coastal upwelling areas the diurnal wind pattern is directed towards the coast during the day. We regularly found positive Near Surface Temperature Stratification (NSTS), the resulting density stratification is expected to reduce the frictional coupling of the surface layer from deeper waters and allow for its more efficient wind transport. We propose that the net transport of the top layer of approximately 2.7 kilometers per day towards the coast helps maintain surface blooms of slow growing dinoflagellate such as Lingulodinium polyedrum. We measured: near surface stratification with a free-rising CTD profiler, trajectories of drifter buoys with attached thermographs, wind speed and direction, velocity profiles via an Acoustic Doppler Current Profiler, Chlorophyll and cell concentration from water samples and vertical migration using sediment traps. The ADCP and drifter data agree and show noticeable current shear within the first meters of the surface where temperature stratification and high cell densities of L. polyedrum were found during the day. Drifters with 1m depth drogue moved towards the shore, whereas drifters at 3 and 5 m depth showed trajectories parallel or away from shore. A small part of the surface population migrated down to the sea floor during night thus reducing horizontal dispersion. The persistent transport of the surface bloom population towards shore should help maintain the bloom in favorable environmental conditions with high nutrients, but also increasing the potential socioeconomic impact of the blooms. The coast wise transport is not limited to blooms but includes all dissolved and particulate constituents in surface waters. © 2013 Ruiz-de la Torre et al.

chlorophyll, algal bloom, article, cell count, cell density, coastal waters, controlled study, dinoflagellate, Lingulodinium polyedrum, meteorological phenomena, Mexico, near surface temperature stratification, nonhuman, nutrient concentration, popul CIENCIAS FÍSICO MATEMÁTICAS Y CIENCIAS DE LA TIERRA CIENCIAS DE LA TIERRA Y DEL ESPACIO OCEANOGRAFÍA OCEANOGRAFÍA

Estudios de genética en poblaciones de abulón y sus aplicaciones en ordenamiento pesquero

RICARDO PEREZ ENRIQUEZ NOE DIAZ VILORIA JOSE LUIS GUTIERREZ GONZALEZ ALEJANDRA ARCINIEGA DE LOS SANTOS ADRIANA MAX AGUILAR Pedro Cruz Hernández Fernando Aranceta Garza (2016, [Artículo])

"Se presenta la integración de más de 10 años de investigación científica en genética de las poblaciones de abulón en México realizada en el CIBNOR. Esta investigación muestra cómo se pueden aplicar los marcadores genéticos tanto en estudios de genética poblacional como en identificación forense con la finalidad de contribuir al conocimiento aplicado para manejo de la pesquería. Se desarrollaron marcadores genéticos tipo microsatélites de ADN enfocados tanto al abulón azul Haliotis fulgens como amarillo Haliotis corrugata para diferenciación de poblaciones y análisis de parentesco. Un análisis de estructura genética de las poblaciones silvestres de ambas especies de abulón mostró homogeneidad genética en la costa del Pacífico en la región centro-sur de la Península de Baja California, México, pero con diferenciación genética en localidades distantes debido a un flujo genético limitado producto del aislamiento reproductivo. Por ello, no existen elementos que den soporte a un manejo pesquero delimitado por bancos en ambas especies. De manera particular, el abulón amarillo mostró una menor de diversidad genética que el azul, posiblemente debido a una mayor explotación pesquera histórica. Los resultados obtenidos en pruebas de parentesco han indicado que la retención larvaria en bancos específicos es reducida, por lo que ni la agregación de reproductores ni la liberación de larvas han mostrado ser estrategias eficientes para favorecer el incremento de reclutas en bancos definidos. Un análisis de perfiles genéticos con el gen de la lisina permitió la identificación de las especies de abulón que se capturan y enlatan en México. El análisis comparativo de perfi les genéticos, basado en el gen nuclear 18S de abulón y otros moluscos, detectó producto enlatado conteniendo especies de moluscos comercializadas falsamente como abulón, lo que puede constituirse como una herramienta forense en futuras disputas legales. Este tipo de aplicación es potencialmente utilizable con otros productos comestibles en los cuales se sospecha de prácticas fraudulentas, ya sea por captura o comercialización ilegal o por sustitución de contenidos en productos procesados."

"This is an integrative work of more than 10 years of research in population genetics of abalone in Mexico performed at CIBNOR. It shows how molecular tools have the potential to support abalone fisheries management through population genetics and forensic analyses. Microsatellite DNA markers were developed on blue (green for its name in English) Haliotis fulgens and yellow abalone (pink for its name in English) H. corrugata to be used for genetic differentiation on populations and for parentage analysis. The analysis of genetic structure on wild populations of both species revealed genetic homogeneity in the Pacific coast of the central region of the Baja California Peninsula, Mexico, with genetic differentiation on distant localities due to a limited gene flow as a result of reproduction isolation. From this result we suggest that no evidences were found supporting the management of the fishery based on individual abalone beds. Pink abalone shows lower genetic diversity than green abalone, possibly due to higher historical fishery exploitation. The parentage analysis suggested that larval retention within beds is reduced, indicating that neither broodstockaggregation nor the release of abalone larvae for stock enhancement are efficient strategies to increase recruitment in specific beds.

An analysis of the genetic profiles with the lysine gene allowed the identification of abalone species captured and processed in Mexico. The comparative analysis, based on the 18S gene, among abalone and other mollusks, detected canned product containing mollusks that are commercialized allegedly as abalone or ‘abalone type’, which could constitute a forensic tool in future legal disputes. This type of application can also be used with other edible products in which fraudulent practices are suspected either because of illegal catch or commercialization or substitution in processed products."

Análisis forense, diversidad genética, gen 18S, genética de poblaciones, marcadores genéticos, retención larvaria Forensic analysis, genetic diversity, 18S gene, genetic markers, population genetics, larval retention BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA GENÉTICA GENÉTICA DE POBLACIONES GENÉTICA DE POBLACIONES

Comparative live-cell imaging analyses of SPA-2, BUD-6 and BNI-1 in Neurospora crassa reveal novel features of the filamentous fungal polarisome

Alexander Lichius (2012, [Artículo])

A key multiprotein complex involved in regulating the actin cytoskeleton and secretory machinery required for polarized growth in fungi, is the polarisome. Recognized core constituents in budding yeast are the proteins Spa2, Pea2, Aip3/Bud6, and the key effector Bni1. Multicellular fungi display a more complex polarized morphogenesis than yeasts, suggesting that the filamentous fungal polarisome might fulfill additional functions. In this study, we compared the subcellular organization and dynamics of the putative polarisome components BUD-6 and BNI-1 with those of the bona fide polarisome marker SPA-2 at various developmental stages of Neurospora crassa. All three proteins exhibited a yeast-like polarisome configuration during polarized germ tube growth, cell fusion, septal pore plugging and tip repolarization. However, the localization patterns of all three proteins showed spatiotemporally distinct characteristics during the establishment of new polar axes, septum formation and cytokinesis, and maintained hyphal tip growth. Most notably, in vegetative hyphal tips BUD-6 accumulated as a subapical cloud excluded from the Spitzenkörper (Spk), whereas BNI-1 and SPA-2 partially colocalized with the Spk and the tip apex. Novel roles during septal plugging and cytokinesis, connected to the reinitiation of tip growth upon physical injury and conidial maturation, were identified for BUD-6 and BNI-1, respectively. Phenotypic analyses of gene deletion mutants revealed additional functions for BUD-6 and BNI-1 in cell fusion regulation, and the maintenance of Spk integrity. Considered together, our findings reveal novel polarisome-independent functions of BUD-6 and BNI-1 in Neurospora, but also suggest that all three proteins cooperate at plugged septal pores, and their complex arrangement within the apical dome of mature hypha might represent a novel aspect of filamentous fungal polarisome architecture. © 2012 Lichius et al.

fungal protein, protein BNI 1, protein BUD 6, protein SPA 2, protein Spk, unclassified drug, actin binding protein, cytoskeleton protein, fungal protein, article, cell fusion, cellular distribution, comparative study, conidium, controlled study, cyto BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA MICROBIOLOGÍA MICROBIOLOGÍA

Functional characterization and cellular dynamics of the CDC-42 - RAC - CDC-24 module in neurospora crassa

CYNTHIA LIZZETH ARAUJO PALOMARES (2011, [Artículo])

Rho-type GTPases are key regulators that control eukaryotic cell polarity, but their role in fungal morphogenesis is only beginning to emerge. In this study, we investigate the role of the CDC-42 - RAC - CDC-24 module in Neurospora crassa. rac and cdc-42 deletion mutants are viable, but generate highly compact colonies with severe morphological defects. Double mutants carrying conditional and loss of function alleles of rac and cdc-42 are lethal, indicating that both GTPases share at least one common essential function. The defects of the GTPase mutants are phenocopied by deletion and conditional alleles of the guanine exchange factor (GEF) cdc-24, and in vitro GDP-GTP exchange assays identify CDC-24 as specific GEF for both CDC-42 and RAC. In vivo confocal microscopy shows that this module is organized as membrane-associated cap that covers the hyphal apex. However, the specific localization patterns of the three proteins are distinct, indicating different functions of RAC and CDC-42 within the hyphal tip. CDC-42 localized as confined apical membrane-associated crescent, while RAC labeled a membrane-associated ring excluding the region labeled by CDC42. The GEF CDC-24 occupied a strategic position, localizing as broad apical membrane-associated crescent and in the apical cytosol excluding the Spitzenkörper. RAC and CDC-42 also display distinct localization patterns during branch initiation and germ tube formation, with CDC-42 accumulating at the plasma membrane before RAC. Together with the distinct cellular defects of rac and cdc-42 mutants, these localizations suggest that CDC-42 is more important for polarity establishment, while the primary function of RAC may be maintaining polarity. In summary, this study identifies CDC-24 as essential regulator for RAC and CDC-42 that have common and distinct functions during polarity establishment and maintenance of cell polarity in N. crassa. © 2011 Araujo-Palomares et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

CDC24 protein, guanine nucleotide exchange factor, protein Cdc42, Rac protein, unclassified drug, cell cycle protein, fungal protein, membrane protein, multiprotein complex, protein Cdc42, Rac protein, allele, apical membrane, article, assay, cell me BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA MICROBIOLOGÍA MICROBIOLOGÍA

Synthetic libraries of shark vNAR domains with different cysteine numbers within the CDR3

OLIVIA CABANILLAS BERNAL (2019, [Artículo])

The variable domain of New Antigen Receptors (vNAR) from sharks, present special characteristics in comparison to the conventional antibody molecules such as: small size (12–15 kDa), thermal and chemical stability and great tissue penetration, that makes them a good alternative source as therapeutic or diagnostic agents. Therefore, it is essential to improve techniques used for the development and selection of vNAR antibodies that recognize distinct antigens. The development of synthetic antibody libraries offers a fast option for the generation of antibodies with the desired characteristics. In this work three synthetic antibody libraries were constructed; without cysteines (Cys), with one Cys and with two Cys residues within its CDR3, with the objective of determining whether the presence or absence of Cys in the CDR3 favors the isolation of vNAR clones from a synthetic library. The libraries were validated selecting against six mammalian proteins. At least one vNAR was found for each of the antigens, and a clone coming from the library without Cys in the CDR3 was selected with all the antigens. In vitro angiogenesis assay with the isolated anti-VEGF antibodies, suggest that these vNARs are capable of inhibiting in vitro angiogenesis. In silico analysis of anti-VEGF antibodies showed that vNARs from synthetic libraries could rival antibodies with affinity maturation by in silico modeling. © 2019 Cabanillas-Bernal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

aquaporin 1, carcinoembryonic antigen, cysteine, fibroblast growth factor 2, glycophorin A, leukemia inhibitory factor, vasculotropin, vasculotropin antibody, angiogenesis inhibitor, antibody, cysteine, lymphocyte antigen receptor, vasculotropin A, a BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA BIOFÍSICA BIOFÍSICA

Multiple approaches to understanding the taxonomic status of an enigmatic new scorpion species of the genus Tityus (Buthidae) from the biogeographic island of Paraje Tres Cerros (Argentina)

Andres Alejandro Ojanguren Affilastro (2017, [Artículo])

Tityus curupi n. sp., belonging to the bolivianus complex, is described from the biogeographically distinct area of Paraje Tres Cerros in north-eastern Argentina. We also present a molecular species delimitation analysis between Tityus curupi n. sp. and its sister species Tityus uruguayensis Borelli 1901 to confirm species integrity. Furthermore, a cytogenetic analysis is presented for these two species which contain different multivalent associations in meiosis, as a consequence of chromosome rearrangements, and the highest chromosome numbers in the genus. © 2017 Ojanguren-Affilastro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Argentina, chromosome analysis, chromosome rearrangement, genus, human, meiosis, sister, species, anatomy and histology, animal, Argentina, chemistry, chromosome, classification, ecosystem, fluorescence in situ hybridization, genetics, geography, isl BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA BIOLOGÍA DE INSECTOS (ENTOMOLOGÍA) BIOLOGÍA DE INSECTOS (ENTOMOLOGÍA)

Coronin is a component of the endocytic collar of hyphae of neurospora crassa and is necessary for normal growth and morphogenesis

RAMON OSVALDO ECHAURI ESPINOSA (2012, [Artículo])

Coronin plays a major role in the organization and dynamics of actin in yeast. To investigate the role of coronin in a filamentous fungus (Neurospora crassa), we examined its subcellular localization using fluorescent proteins and the phenotypic consequences of coronin gene (crn-1) deletion in hyphal morphogenesis, Spitzenkörper behavior and endocytosis. Coronin-GFP was localized in patches, forming a subapical collar near the hyphal apex; significantly, it was absent from the apex. The subapical patches of coronin colocalized with fimbrin, Arp2/3 complex, and actin, altogether comprising the endocytic collar. Deletion of crn-1 resulted in reduced hyphal growth rates, distorted hyphal morphology, uneven wall thickness, and delayed establishment of polarity during germination; it also affected growth directionality and increased branching. The Spitzenkörper of Δcrn-1 mutant was unstable; it appeared and disappeared intermittently giving rise to periods of hyphoid-like and isotropic growth respectively. Uptake of FM4-64 in Δcrn-1 mutant indicated a partial disruption in endocytosis. These observations underscore coronin as an important component of F-actin remodeling in N. crassa. Although coronin is not essential in this fungus, its deletion influenced negatively the operation of the actin cytoskeleton involved in the orderly deployment of the apical growth apparatus, thus preventing normal hyphal growth and morphogenesis. © 2012 Echauri-Espinosa et al.

actin related protein 2-3 complex, F actin, fimbrin protein, fluorescent dye, fungal protein, fungal protein coronin, green fluorescent protein, unclassified drug, actin binding protein, coronin proteins, fungal protein, article, cell polarity, contr BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA MICROBIOLOGÍA MICROBIOLOGÍA