Biology subjects

Dunn, R.

Publications and source records attributed to Dunn, R..

5 recordsLinked to original sources

bioRxiv2018

The Utilization of Pharmacophore-based 3D QSAR Modeling and Virtual Screening in Safety Profiling: a Case Study to Identify Antagonistic Activities against Adenosince Receptor, A2aR, using 1,897 known drugs

ABSTRACTSafety pharmacology screening against a wide range of unintended vital targets using in vitro assays is crucial to understand off-target interactions with drug candidates. With the increasing demand for in vitro assays, ligand-and structure-based virtual screening approaches have been evaluated for potential utilization in safety profiling. Although ligand based approaches have been actively applied in retrospective analysis or prospectively within well-defined chemical space during the early discovery stage (i.e., HTS screening and lead optimization), virtual screening is rarely implemented in later stage of drug discovery (i.e., safety). Here we present a case study to evaluate ligand-based 3D QSAR models built based on in vitro antagonistic activity data against adenosine receptor 2A (A2aR). The resulting models, obtained from 268 chemically diverse compounds, were used to test a set of 1,897 chemically distinct drugs, simulating the real-world challenge of safety screening when presented with novel chemistry and a limited training set. Due to the unique requirements of safety screening versus discovery screening, the limitations of 3D QSAR methods (i.e., chemotypes, dependence on large training set, and prone to false positives) are less critical than early discovery screen. We demonstrated that 3D QSAR modelling can be effectively applied in safety assessment prior to in vitro assays, even with chemotypes that are drastically different from training compounds. It is also worth noting that our model is able to adequately make the mechanistic distinction between agonists and antagonists, which is important to inform subsequent in vivo studies. Overall, we present an in-depth analysis of the appropriate utilization and interpretation of pharmacophore-based 3D QSAR models for safety screening.

pharmacology and toxicology↗

bioRxiv2018

Ecological analyses of mycobacteria in showerhead biofilms and their relevance to human health

Bacteria within the genus Mycobacterium can be abundant in showerheads, and the inhalation of aerosolized mycobacteria while showering has been implicated as a mode of transmission in nontuberculous mycobacterial (NTM) lung infections. Despite their importance, the diversity, distributions, and environmental predictors of showerhead-associated mycobacteria remain largely unresolved. To address these knowledge gaps, we worked with citizen scientists to collect showerhead biofilm samples and associated water chemistry data from 656 households located across the U.S. and Europe. Our cultivation-independent analyses revealed that the genus Mycobacterium was consistently the most abundant genus of bacteria detected in residential showerheads, yet mycobacterial diversity and abundances were highly variable. Mycobacteria were far more abundant, on average, in showerheads receiving municipal versus well water, and in U.S. households as compared to European households, patterns that are likely driven by differences in the use of chlorine disinfectants. Moreover, we found that water source, water chemistry, and household location also influenced the prevalence of specific mycobacterial lineages detected in showerheads. We identified geographic regions within the U.S. where showerheads have particularly high abundances of potentially pathogenic lineages of mycobacteria and these hot spots generally overlapped with those regions where NTM lung disease is most prevalent. Together these results emphasize the public health relevance of mycobacteria in showerhead biofilms. They further demonstrate that mycobacterial distributions in showerhead biofilms are often predictable from household location and water chemistry, knowledge that advances our understanding of NTM transmission dynamics and the development of strategies to reduce exposures to these emerging pathogens.

microbiology↗

bioRxiv2018

Expanded view of the ecological genomics of ant responses to climate change

Given the abundance, broad distribution, and diversity of roles that ants play in many ecosystems, they are an ideal group to serve as ecosystem indicators of climatic change. At present, only a few whole-genome sequences of ants are available (19 of > 16,000 species), mostly from tropical and sub-tropical species. To address this limited sampling, we sequenced genomes of temperate-latitude species from the genus Aphaenogaster, a genus with important seed dispersers. In total, we sampled seven colonies of six species: A. ashmeadi, A. floridana, A. fulva, A. miamiana, A. picea, and A. rudis. The geographic ranges of these species collectively span eastern North America from southern Florida to southern Canada, which encompasses a latitudinal gradient in which many climatic variables are changing rapidly. For the six genomes, we assembled an average of 271,039 contigs into 47,337 scaffolds. The mean genome size was 370.5 Mb, ranging from 310.3 to 429.7, which is comparable to that of other sequenced ant genomes (212.8 to 396.0 Mb) and flow cytometry estimates (210.7 to 690.4 Mb). In an analysis of currently sequenced ant genomes and the new Aphaenogaster sequences, we found that after controlling for both spatial autocorrelation and phylogenetics ant genome size was marginally correlated with sample site climate similarity. Of all examined climate variables, minimum temperature showed the strongest correlation with genome size, with ants from locations with colder minimum temperatures having larger genomes. These results suggest that temperature extremes could be a selective force acting on ant genomes and point to the need for more extensive sequencing of ant genomes.

genomics↗

bioRxiv2017

Linguistically deprived children: meta-analysis of published research underlines the importance of early syntactic language use for normal brain development

We analyzed all published reports of individuals not exposed to syntactic language until puberty: two feral children, who grew up without hearing any language, and eight deaf linguistic isolates, who grew up communicating to their families using homesign or kitchensign, a system of gestures which allows them to communicate simple commands but lacks much in the way of syntax. A common observation in these individuals is the lifelong difficulty understanding syntax and spatial prepositions, even after many years of rehabilitation. This debilitating condition stands in stark contrast to linguistic isolates performance on memory as well as semantic tests: they could easily remember hundreds of newly learned words and identify previously seen objects by name. The lack of syntactic language comprehension in linguistic isolates may stem from inability to understand words and/or grammar or inability to mentally synthesize known objects into novel configurations. We have previously shown that purposeful construction of novel mental images is the function of the lateral prefrontal cortex (LPFC) ability to dynamically control posterior cortex neurons 1. Here we have ranked all tests performed on linguistic isolates by their reliance on the LPFC control of the posterior cortex: a) the amount of posterior cortex territory that needs to be recruited by the LPFC and b) the number of disparate objects that have to be combined together by the LPFC in order to answer the test question. According to our analysis, linguistic isolates performed well in all tests that did not involve the LPFC control of the posterior cortex, showed decreasing scores in tests that involved greater recruitment of the posterior cortex by the LPFC, and failed in tests that involved greatest recruitment of posterior cortex necessary for mental synthesis of multiple objects. This pattern is consistent with inadequate frontoposterior connections in linguistic isolates. We discuss implications of these findings for the importance of early syntactic language exposure in formation of frontoposterior connections.

developmental biology↗

bioRxiv2017

Performance Of Children With Autism In Parent-Administered Cognitive And Language Exercises

There is a broad scientific consensus that early and intensive therapy has the greatest chance of positive impact on an individual with autism spectrum disorder (ASD). However, the availability, quality, and general funding for early intervention programs is often lacking, leaving newly diagnosed children without adequate and sufficient therapy during the most critical early period of their development. Parent-administered iPad-assisted therapy has the potential to reduce the gap between the amount of therapy recommended for children with ASD and the amount they receive. However it is unclear how ASD severity and age influence a childs ability to engage with and learn from computerized cognitive exercises. In this manuscript, we describe data from a tablet-based therapeutic application administered by parents to 1,514 young children with ASD over the course of four to twelve months. We report that older children and children with milder forms of ASD performed better and progressed faster in cognitive and language exercises. However, most children were able to engage with and learn from exercises independent of their age or ASD severity. This data confirm that tablet-based cognitive and language exercises can be successfully administered by parents to children as young as two years of age over the course of many months independent of ASD severity.

clinical trials↗