Biology subjects

Mitchell, K.

Publications and source records attributed to Mitchell, K..

3 recordsLinked to original sources

bioRxiv2018

A comprehensive analysis of the usability and archival stability of omics computational tools and resources

Developing new software tools for analysis of large-scale biological data is a key component of advancing modern biomedical research. Scientific reproduction of published findings requires running computational tools on data generated by such studies, yet little attention is presently allocated to the installability and archival stability of computational software tools. Scientific journals require data and code sharing, but none currently require authors to guarantee the continuing functionality of newly published tools. We have estimated the archival stability of computational biology software tools by performing an empirical analysis of the internet presence for 36,702 omics software resources published from 2005 to 2017. We found that almost 28% of all resources are currently not accessible through URLs published in the paper they first appeared in. Among the 98 software tools selected for our installability test, 51% were deemed \"easy to install,\" and 28% of the tools failed to be installed at all due to problems in the implementation. Moreover, for papers introducing new software, we found that the number of citations significantly increased when authors provided an easy installation process. We propose for incorporation into journal policy several practical solutions for increasing the widespread installability and archival stability of published bioinformatics software.

bioinformatics↗

bioRxiv2017

SOD1A4V aggregation alters ubiquitin homeostasis in ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving the selective death of upper and lower motor neurons in the primary motor cortex and spinal cord. A hallmark of ALS pathology is the accumulation of ubiquitinated protein inclusions within motor neurons. Previous studies suggest the sequestration of ubiquitin (Ub) into inclusions reduces the availability of free Ub, which is essential for cellular function and survival. However, the dynamics of the Ub landscape in ALS have not yet been described. Here we show that Ub homeostasis is altered in a SOD1 cell model of ALS. Utilising fluorescently tagged Ub, we followed the distribution of Ub in living cells expressing SOD1 and show that Ub is present at the earliest stages of SOD1 aggregation. We also report that cells containing aggregates of mutant SOD1 have greater ubiquitin-proteasome system (UPS) dysfunction as measured by the accumulation of the fluorescent proteasome reporter tdTomatoCL1. Furthermore, SOD1 aggregation is associated with the redistribution of Ub and depletion of the free Ub pool. Ubiquitomics analysis indicates that mutant SOD1 is associated with a shift of Ub to a pool of supersaturated proteins including those associated with oxidative phosphorylation and metabolism, corresponding with altered mitochondrial morphology and function. Taken together, these results suggest misfolded SOD1 contributes to UPS dysfunction and that Ub homeostasis is an important target for monitoring pathological changes in ALS.

molecular biology↗

bioRxiv2017

Secretogranin-II Plays A Critical Role In Zebrafish Neurovascular Modeling

Summary statementNeurons expressing sgIIb align with central arteries in hindbrain. We show that sgIIb is critical for neurovascular modeling the larval zebrafish mediated by MAPK and PI3K/AKT signaling in vivo.\n\nAbstractSecretoneurin (SN) is a neuropeptide derived from specific proteolytic processing of the precursor secretogranin II (SgII). In zebrafish and other teleosts there are 2 paralogs we previously named sgIIa and sgIIb. Our results showed that neurons expressing sgIIb were aligned with central arteries in hindbrain, demonstrating a close neurovascular association. Both sgIIb-/- and sgIIa-/- /sgIIb-/- mutant embryos were defective in hindbrain central artery development, while artery development in sgIIa-/- mutant embryos was not affected. Hindbrain arterial and venous network identities were not affected in sgIIb-/- mutant embryos, and the mRNA levels of Notch and VEGF pathway-related genes were not altered. However, the activation of MAPK and PI3K/AKT pathways were inhibited in sgIIb-/- mutant embryos. Injection of a synthetic SNb mRNA or delivery of the protein kinase activator N-arachidonoyl-L-serine could partially rescue the central artery developmental defects in the sgIIb mutants. This study provides the first in vivo evidence that sgIIb plays a critical role in neurovascular modeling the hindbrain.

developmental biology↗