Biology subjects

Garner, T.

Publications and source records attributed to Garner, T..

3 recordsLinked to original sources

bioRxiv2018

Interactome comparison of human embryonic stem cell lines with the inner cell mass and trophectoderm

Human embryonic stem cells (hESCs) derived from the pluripotent Inner cell mass (ICM) of the blastocyst are fundamental tools for understanding human development, yet are not identical to their tissue of origin. To investigate this divergence we compared the transcriptomes of genetically paired ICM and trophectoderm (TE) samples with three hESC lines: MAN1, HUES3 and HUES7 at similar passage. We generated inferred interactome networks using transcriptomic data unique to the ICM or TE, and defined a hierarchy of modules (highly connected regions with shared function). We compared network properties and the modular hierarchy and show that the three hESCs had limited overlap with ICM specific transcriptome (6%-12%). However this overlap was enriched for network properties related to transcriptional activity in ICM (p=0.016); greatest in MAN1 compared to HUES3 (p=0.048) or HUES7 (p=0.012). The hierarchy of modules in the ICM interactome contained a greater proportion of MAN1 specific gene expression (46%) compared to HUES3 (28%) and HUES7 (25%) (p=9.0x10-4). These findings show that traditional methods based on transcriptome overlap are not sufficient to identify divergence of hESCs from ICM. Our approach also provides a valuable approach to the quantification of differences between hESC lines. And Manchester Academic Health Sciences Centre

developmental biology↗

bioRxiv2018

Direct Small Molecule Activation of Mitofusins

Mitochondrial fusion is a physiological process that is regulated by mitofusins on the outer mitochondrial membrane. Conformational plasticity between anti- and pro-tethering conformations of mitofusins permits mitochondrial tethering and subsequent fusion. Here we developed a pharmacophore-based model to rationally manipulate the conformational plasticity of mitofusin 2 and perfomed an in silico small-molecule screen. This enabled the discovery of a direct activator of mitofusins, MASM7, capable of potently promoting mitochondrial fusion. The specificity of the MASM7-mitofusin 2 interaction is highlighted by structure-activity relationships of MASM7 analogues, FRET, NMR and mitochondrial fusion studies using mitofusin mutants. Our study identified the first-in-class direct activator of mitofusins, demonstrating a new paradigm for chemical modulation of mitochondrial fusion and downstream processes.

biochemistry↗

bioRxiv2017

Host Microbiome Richness Predicts Resistance to Disturbance by Pathogenic Infection in a Vertebrate Host

Environmental heterogeneity is known to modulate the interactions between pathogens and hosts. However, the impact of environmental heterogeneity on the structure of host-associated microbial communities, and how these communities respond to pathogenic exposure remain poorly understood. Here we use an experimental framework to probe the links between environmental heterogeneity, skin microbiome structure and infection by the emerging pathogen Ranavirus in a vertebrate host, the European common frog (Rana temporaria). We provide evidence that environmental complexity directly influences the diversity and structure of the host skin microbiome, and that more diverse microbiomes are more resistant to perturbation associated with exposure to Ranavirus. Our data also indicate that host microbiome diversity covaries with survival following exposure to Ranavirus. Our study highlights the importance of extrinsic factors in driving host-pathogen dynamics in vertebrate hosts, and suggests that environment-mediated variation in the structure of the host microbiome may covary with observed differences in host susceptibility to disease in the wild.

ecology↗