Biology subjects

Hogan, M.

Publications and source records attributed to Hogan, M..

3 recordsLinked to original sources

bioRxiv2020

AGORA2: Large scale reconstruction of the microbiome highlights wide-spread drug-metabolising capacities.

The human microbiome influences the efficacy and safety of a wide variety of commonly prescribed drugs, yet comprehensive systems-level approaches to interrogate drug-microbiome interactions are lacking. Here, we present a computational resource of human microbial genome-scale reconstructions, deemed AGORA2, which accounts for 7,206 strains, includes microbial drug degradation and biotransformation, and was extensively curated based on comparative genomics and literature searches. AGORA2 serves as a knowledge base for the human microbiome and as a metabolic modelling resource. We demonstrate the latter by mechanistically modelling microbial drug metabolism capabilities in single strains and pairwise models. Moreover, we predict the individual-specific drug conversion potential in a cohort of 616 colorectal cancer patients and controls. This analysis reveals that some drug activation capabilities are present in only a subset of individuals, moreover, drug conversion potential correlate with clinical parameters. Thus, AGORA2 paves the way towards personalised, predictive analysis of host-drug-microbiome interactions.

systems biology↗

bioRxiv2020

Moderate and intensive mechanical loading differentially modulate the phenotype of tendon stem/progenitor cells in vivo

To examine the differential mechanobiological responses of specific resident tendon cells, we developed an in vivo model of whole-body irradiation followed by injection of either tendon stem/progenitor cells (TSCs) expressing green fluorescent protein (GFP-TSCs) or mature tenocytes expressing GFP (GFP-TNCs) into the patellar tendons of wild type C57 mice. Injected mice were subjected to moderate treadmill running (MTR) and intensive treadmill running (ITR). In MTR mice, both GFP-TSC and GFP-TNC injected tendons maintained normal cell morphology with elevated expression of tendon related markers collagen I and tenomodulin. In ITR mice injected with GFP-TNCs, cells also maintained an elongated shape similar to the shape found in normal/untreated control mice, as well as elevated expression of tendon related markers. However, ITR mice injected with GFP-TSCs showed typical tendinopathic changes, such as cell morphology transitioning to a round shape, elevated chondrogenic differentiation, and increased gene expression of non-tenocyte related genes LPL, Runx-2, and SOX-9. Increased gene expression data was supported by immunostaining showing elevated expression of SOX-9, Runx-2, and PPAR{gamma}. This study provides evidence that while MTR maintains tendon homeostasis by promoting the differentiation of TSCs into tenocytes, ITR may cause the development of tendinopathy by inducing non-tenocyte differentiation of TSCs, thus leading to the presence of non-tendinous tissues in tendon.

cell biology↗

bioRxiv2020

Peptide recognition and dephosphorylation by the vaccinia VH1 phosphatase

The VH1 protein encoded by the highly conserved H1 locus of orthopoxviruses is a dual-specificity phosphatase (DUSPs) that hydrolyzes phosphate groups from phosphorylated tyrosine, serine, and threonine residues of viral and host cell proteins. Because the DUSP activities are required for virus replication, VH1 is a prime target for the development of therapeutic inhibitors. However, the presentation of a shallow catalytic site has thwarted all drug development efforts. As an alternative to direct targeting of catalytic pockets, we describe surface contacts between VH1 and substrates that are essential for full activity and provide a new pathway for developing inhibitors of protein-protein interactions. Critical amino acid residues were manipulated by site-directed mutagenesis of VH1, and perturbation of peptide substrate interactions based on these mutations were assessed by high-throughput assays that employed surface plasmon resonance and phosphatase activities. Two positively-charged residues (Lys-20 and Lys-22) and the hydrophobic side chain of Met-60 appear to orient the polarity of the pTyr peptide on the VH1 surface, while additional amino acid residues that flank the catalytic site contribute to substrate recognition and productive dephosphorylation. We propose that the enzyme-substrate contact residues described here may serve as molecular targets for the development of inhibitors that specifically block VH1 catalytic activity and thus poxvirus replication.

biochemistry↗