Biology subjects

Morris, L.

Publications and source records attributed to Morris, L..

21 records · Page 2Linked to original sources

bioRxiv2019

Population genetics of the coral Acropora millepora: Towards a genomic predictor of bleaching

Although reef-building corals are rapidly declining worldwide, responses to bleaching vary both within and among species. Because these inter-individual differences are partly heritable, they should in principle be predictable from genomic data. Towards that goal, we generated a chromosome-scale genome assembly for the coral Acropora millepora. We then obtained whole genome sequences for 237 phenotyped samples collected at 12 reefs distributed along the Great Barrier Reef, among which we inferred very little population structure. Scanning the genome for evidence of local adaptation, we detected signatures of long-term balancing selection in the heat-shock co-chaperone sacsin. We further used 213 of the samples to conduct a genome-wide association study of visual bleaching score, incorporating the polygenic score derived from it into a predictive model for bleaching in the wild. These results set the stage for the use of genomics-based approaches in conservation strategies.

evolutionary biology↗

bioRxiv2019

Identification of a novel therapeutic agent for Inflammatory Bowel Disease guided by systems medicine

ObjectiveInflammatory bowel diseases cause significant morbidity and mortality. Aberrant NF-{kappa}B signalling is strongly associated with these conditions, and several established drugs influence the NF-{kappa}B signalling network to exert their effect. This study aimed to identify drugs which alter NF-{kappa}B signalling and may be repositioned for use in inflammatory bowel disease. DesignThe SysmedIBD consortium established a novel drug-repurposing pipeline based on a combination of in-silico drug discovery and biological assays targeted at demonstrating an impact on NF-kappaB signalling, and a murine model of IBD. ResultsThe drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic Clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. Clarithromycins effects were validated in several experiments: it influenced NF-{kappa}B mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-{kappa}B protein shuttling in murine reporter enteroids; it suppressed NF-{kappa}B (p65) DNA binding in the small intestine of mice exposed to LPS, and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-{kappa}B (p65) nuclear translocation in human intestinal enteroids. ConclusionsThese findings demonstrate that in-silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of inflammatory bowel disease; and that further clinical assessment of clarithromycin in the management of inflammatory bowel disease is required.

systems biology↗

bioRxiv2018

Ultra-high field MRI reveals mood-related circuit disturbances in depression: A systematic comparison between 3-Tesla and 7-Tesla

Ultra-high field 7-Tesla (7T) MRI has the potential to advance our understanding of neuropsychiatric disorders, including major depressive disorder (MDD). To date, few studies have quantified the advantage of resting state functional MRI (fMRI) at 7T compared to 3-Tesla (3T). We conducted a series of experiments that demonstrate the improvement in temporal signal-to-noise ratio (TSNR) of a multi-echo fMRI protocol with ultra-high field 7T, compared to 3T MRI in healthy controls (HC). We also directly tested the enhancement in ultra-high field 7T fMRI signal power by examining the ventral tegmental area (VTA), a small midbrain structure that is critical to the expected neuropathology of MDD but difficult to discern with standard 3T MRI. We demonstrate 200-300% improvement in TSNR and resting state functional connectivity coefficients provided by ultra-high field 7T fMRI compared to 3T, indicating enhanced power for detection of functional neural architecture. A multi-echo based acquisition protocol and signal denoising pipeline afforded greater gain in signal power at ultra-high field compared to classic acquisition and denoising pipelines. Furthermore, ultra-high field fMRI revealed mood-related neuro-circuit disturbances in patients with MDD compared to HC, which were not detectable with 3T fMRI. Ultra-high field 7T fMRI may provide an effective tool for studying functional neural architecture relevant to MDD and other neuropsychiatric disorders.

neuroscience↗