Research data from the University of British Columbia Michael Smith Laboratories
Dr. Paul Pavlidis
Dr. Paul Pavlidis
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Studies: 4 | Downloads: 51
Modeling sources of inter-laboratory variability in electrophysiological properties of mammalian neuronsby Tebaykin, Dmitry; Tripathy, Shreejoy J.; Binnion, Nathalie; Li, Brenna; Gerkin, Richard C.; Pavlidis, Paul
Description:

Patch-clamp electrophysiology is widely used to characterize neuronal electrical phenotypes. However, there are no standard experimental conditions for in vitro whole-cell patch-clamp electrophysiology, complicating direct comparisons between datasets. Here, we sought to understand how basic experimental conditions differ among labs and how these differences might impact measurements of electrophysiological parameters. We curated the compositions of external bath solutions (ACSF), internal pipette solutions, and other methodological details such as animal strain and age from 509 published neurophysiology articles studying rodent neurons. We found that very few articles used the exact same experimental solutions as any other and some solution differences stem from recipe inheritance from adviser to advisee as well as changing trends over the years. Next, we used statistical models to understand how the use of different experimental conditions impacts downstream electrophysiological measurements such as resting potential and action potential width. While these experimental condition features could explain up to 43% of the study-to-study variance in electrophysiological parameters, the majority of the variability was left unexplained. Our results suggest that there are likely additional experimental factors that contribute to cross-laboratory electrophysiological variability, and identifying and addressing these will be important to future efforts to assemble consensus descriptions of neurophysiological phenotypes for mammalian cell types.

Production Date:November 22, 2017
hdl:11272/10525
1 download
Last Released: Nov 23, 2017
Protease-inhibitor interaction predictions: Lessons on the complexity of protein-protein interactionsby Fortelny, Nikolaus; Butler, Georgina; Overall, Christopher; Pavlidis, Paul
Description:

Protein interactions shape proteome function and thus biology. Identification of protein interactions is a major goal in molecular biology, but biochemical methods, although improving, remain limited in coverage and accuracy. Whereas computational predictions can guide biochemical experiments, low validation rates of predictions remain a major limitation. Here, we investigated computational methods in the prediction of a specific type of interaction, the inhibitory interactions between proteases and their inhibitors. Proteases generate thousands of proteoforms that dynamically shape the functional state of proteomes. Despite the important regulatory role of proteases, knowledge of their inhibitors remains largely incomplete with the vast majority of proteases lacking an annotated inhibitor. To link inhibitors to their target proteases on a large scale, we applied computational methods to predict inhibitory interactions between proteases and their inhibitors based on complementary data including coexpression, phylogenetic similarity, structural information, co-annotation, and colocalization, and also surveyed general protein interaction networks for potential inhibitory interactions. In testing nine predicted interactions biochemically, we validated the inhibition of kallikrein 5 by serpin B12. Despite the use of a wide array of complementary data, we found a high false positive rate of computational predictions in biochemical follow-up. Based on a protease-specific definition of true negatives derived from the biochemical classification of proteases and inhibitors, we analyzed prediction accuracy of individual features. Thereby we identified feature-specific limitations, which also affected general protein interaction prediction methods. Interestingly, proteases were often not coexpressed with most of their functional inhibitors, contrary to what is commonly assumed and extrapolated predominantly from cell culture experiments. Predictions of inhibitory interactions were indeed more challenging than predictions of non-proteolytic and non-inhibitory interactions. In summary, we describe a novel and well-defined but difficult protein interaction prediction task, and thereby highlight limitations of computational interaction prediction methods.

Production Date:2017
hdl:11272/10472
18 downloads
Last Released: Apr 3, 2017
Transcriptomic correlates of neuron electrophysiological diversityby Tripathy, Shreejoy; Toker, Lilah; Li, Brenna; Crichlow, Cindy-Lee; Tebaykin, Dmitry; Mancarci, Ogan; Shreejoy Tripathy
Description:

How neuronal diversity emerges from complex patterns of gene expression remains poorly understood. Here we present an approach to understand electrophysiological diversity through gene expression by integrating pooled- and single-cell transcriptomics with intracellular electrophysiology. Using neuroinformatics methods, we compiled a brain-wide dataset of 34 neuron types with paired gene expression and intrinsic electrophysiological features from publically accessible sources, the largest such collection to date. We identified 420 genes whose expression levels significantly correlated with variability in one or more of 11 physiological parameters. We next trained statistical models to infer cellular features from multivariate gene expression. Such models were predictive of gene-electrophysiological relationships in an independent collection of 12 visual cortex cell types from the Allen Institute, suggesting that these correlations might reflect general principles relating expression patterns to phenotypic diversity across very different cell types. Many associations reported here have the potential to provide new insights into how neurons generate functional diversity, and correlations of ion channel genes like Gabrd and Scn1a (Nav1.1) with resting potential and spiking frequency are consistent with known causal mechanisms. Our work highlights the promise and inherent challenges in using cell type-specific transcriptomics to understand the mechanistic origins of neuronal diversity.

hdl:11272/10485
32 downloads
Last Released: Sep 11, 2017
Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Databy Mancarci, B. Ogan; Toker, Lilah; Tripathy, Shreejoy J; Li, Brenna; Rocco, Brad; Sibille, Etienne; Pavlidis, Paul
Description:

Establishing the molecular diversity of cell types is crucial for the study of the nervous system. We compiled a cross-laboratory database of mouse brain cell type-specific transcriptomes from 36 major cell types from across the mammalian brain using rigorously curated published data from pooled cell type microarray and single cell RNA-sequencing studies. We used these data to identify cell type-specific marker genes, discovering a substantial number of novel markers, many of which we validated using computational and experimental approaches. We further demonstrate that summarized expression of marker gene sets in bulk tissue data can be used to estimate the relative cell type abundance across samples. To facilitate use of this expanding resource, we provide a user-friendly web interface at Neuroexpresso.org.

Related Publications:Mancarci, B. Ogan, Lilah Toker, Shreejoy J. Tripathy, Brenna Li, Brad Rocco, Etienne Sibille, and Paul Pavlidis. “Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data.” eNeuro, November 20, 2017, ENEURO.0212-17.2017. https://doi.org/10.1523/ENEURO.0212-17.2017.
hdl:11272/10527
0 downloads
Last Released: Nov 23, 2017
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