Biology subjects

Decker, S.

Publications and source records attributed to Decker, S..

3 recordsLinked to original sources

bioRxiv2021

phylogatR: Phylogeographic data aggregation and repurposing

Patterns of genetic diversity within species contain information about the history of that species, including how they have responded to historical climate change and how easily the organism is able to disperse across its habitat. More than 40,000 phylogeographic and population genetic investigations have been published to date, each collecting genetic data from hundreds of samples. Despite these millions of data points, meta-analyses are challenging because the synthesis of results across hundreds of studies, each using different methods and forms of analysis, is a daunting and time-consuming task. It is more efficient to proceed by repurposing existing data and using automated data analysis. To facilitate data repurposing, we created a database (phylogatR) that aggregates data from different sources and conducts automated multiple sequence alignments and data curation to provide users with nearly ready-to-analyze sets of data for thousands of species. Two types of scientific research will be made easier by phylogatR, large meta-analyses of thousands of species that can address classic questions in evolutionary biology and ecology and student- or citizen-science based investigations that will introduce a broad range of people to the analysis of genetic data. phylogatR enhances the value of existing data via the creation of software and web-based tools that enable these data to be recycled and reanalyzed and increase accessibility to big data for research labs and classroom instructors with limited computational expertise and resources.

bioinformatics↗

bioRxiv2021

NBI-921352, a First-in-Class, Na V 1.6 Selective, Sodium Channel Inhibitor That Prevents Seizures in Scn8a Gain-of- Function Mice, and Wild-Type Mice and Rats

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Moller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC50 0.051 {micro}M), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756X for NaV1.1, 134X for NaV1.2, 276X for NaV1.7, and >583X for NaV1.3, NaV1.4, and NaV1.5). NBI-921352 is a state-dependent inhibitor, preferentially inhibiting activated (inactivated or open) channels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse, as well as in wild-type mouse and rat seizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor antiseizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 was well tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

pharmacology and toxicology↗

bioRxiv2020

Comparison of motility of H. pylori in broth and mucin reveals the interplay of effect of acid on bacterium and the rheology of the medium it swims in.

To colonize on the gastric epithelium Helicobacter pylori bacteria have to swim across a gradient of pH from 2-7 in the mucus layer. Previous studies of H. pylori motility have shown that at pH below 4 do not swim in porcine gastric mucin (PGM) gels. To separately assess the influence of gelation of PGM and that of pH on motors and pH sensitive receptors of H. pylori, we used phase contrast microscopy to compare the translational and rotational motion of H. pylori in PGM versus Brucella broth (BB10) at different pHs. We observed that decreasing pH leads to decreased fraction of motile swimmers with a decrease in the contribution of fast swimmers to the distributions of swimming speeds and length of trajectories. At all pHs the bacteria swam faster with longer net displacement over the trajectory in BB10 as compared to PGM. While bacteria are stuck in PGM gels at low pH, they swim at low pH in broth, albeit with reduced speed. The body rotation rate and estimated cell body torque are weakly dependent on pH in BB10, whereas in PGM the torque increases with increasing viscosity and bacteria stuck in the low pH gel rotate faster than the motile bacteria. Our results show that H. pylori has optimal swimming under slightly acidic conditions, and exhibits mechanosensing when stuck in low pH mucin gels.

biophysics↗