Ontologies in medicinal chemistry: current status and future challenges

[Abstract] Recent years have seen a dramatic increase in the amount and availability of data in the diverse areas of medicinal chemistry, making it possible to achieve significant advances in fields such as the design, synthesis and biological evaluation of compounds. However, with this data explosion, the storage, management and analysis of available data to extract relevant information has become even a more complex task that offers challenging research issues to Artificial Intelligence (AI) scientists. Ontologies have emerged in AI as a key tool to formally represent and semantically organize aspects of the real world. Beyond glossaries or thesauri, ontologies facilitate communication between experts and allow the application of computational techniques to extract useful information from available data. In medicinal chemistry, multiple ontologies have been developed during the last years which contain knowledge about chemical compounds and processes of synthesis of pharmaceutical products. This article reviews the principal standards and ontologies in medicinal chemistry, analyzes their main applications and suggests future directions.Instituto de Salud Carlos III; FIS-PI10/02180Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo; 209RT0366Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; CN2012/217Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; CN2011/034Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; CN2012/21

Investigating alternative life history trajectories in two species of Edwardsiid sea anemones using ecological, transcriptomic, and molecular approaches

Life histories unfold within the ecological context of an organism's environment, and thus are intimately linked to organismal fitness. The evolution of alternate life history strategies, either within or between taxa, can profoundly affect ontogeny, ecology, and population dynamics. Many cnidarians (sea anemones, corals, jellyfish, etc.) exhibit complex life histories involving sexual reproduction and multiple modes of asexual reproduction. Sea anemones of the family Edwardsiidae exemplify this complexity, and are therefore an attractive system for studying the developmental and ecological ramifications of life history evolution. I used intra- and interspecific comparisons of two Edwardsiid anemones, Edwardsiella lineata, and Nematostella vectensis to investigate alternative life histories using a multifaceted approach that included field-based ecological surveys, functional genetics, transcriptomics, and phylogenetics. Both anemones are capable of sexual and asexual reproduction. N. vectensis produces a rapidly maturing direct developing larva. By contrast, E. lineata has evolved a new larval stage that parasitizes the ctenophore, Mnemiopsis leidyi. Through fieldwork surveys and laboratory culture, I documented several life history traits, such as a previously un-characterized, pre-parasitic larval stage, and the developmental dynamics of early-stage parasitic infections, that augmented gaps in our knowledge of E. lineata's life history. To better understand how and when E. lineata evolved its novel, parasitic life history, I worked with collaborators in the Finnerty lab to sequence, assemble and annotate the transcriptome. Through a multigene molecular clock approach, enabled by the E. lineata transcriptome assembly, I estimated the divergence date for these two anemones between 215-364 million years ago, thereby establishing an upper bound for the innovation of E. lineata's derived, parasitic life history. Testing a hypothesis that Wnt signaling, which patterns the oral-aboral (OA) axis during embryogenesis, also patterns the OA axis during regeneration, I demonstrated that canonical Wnt signaling is sufficient for oral tissue fate across alternate life histories (embryogenesis and regeneration) of N. vectensis. Taken together, these dissertation research activities constitute an integrative approach to investigating the evolution of life histories, and are a step towards establishing E. lineata and N. vectensis as models for studying the evolutionary developmental mechanisms of parasitism and regeneration

Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation

While the catalog of mammalian transcripts and their expression levels in different cell types and disease states is rapidly expanding, our understanding of transcript function lags behind. We present a robust technology enabling systematic investigation of the cellular consequences of repressing or inducing individual transcripts. We identify rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90%–99% knockdown with minimal off-target effects, and activators (CRISPRa) to endogenous genes via endonuclease-deficient Cas9. Together they enable modulation of gene expression over a ∼1,000-fold range. Using these rules, we construct genome-scale CRISPRi and CRISPRa libraries, each of which we validate with two pooled screens. Growth-based screens identify essential genes, tumor suppressors, and regulators of differentiation. Screens for sensitivity to a cholera-diphtheria toxin provide broad insights into the mechanisms of pathogen entry, retrotranslocation and toxicity. Our results establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways