Biology subjects

Williams, G.

Publications and source records attributed to Williams, G..

41 records · Page 3Linked to original sources

bioRxiv2020

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

INTRODUCTIONStroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events. METHODWhole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository. RESULTSAtherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection). CONCLUSIONThese findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events. COMPETING INTERESTSCB has received grants and personal fees from ACADIA Pharmaceuticals and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline and Pfizer. DAC is an employee of Eli Lilly and Company Ltd.

bioinformatics↗

bioRxiv2020

An in vivo Probabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field

Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinsons disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent with post mortem findings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structure in vivo at high-resolution (resolution 0.4x0.4x0.5 mm, duration seven minutes). Magnetisation transfer images from 53 healthy older volunteers (52-84 years) revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults, appropriate for clinical research. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance differences of the LC were observed, mirroring distinctive ex vivo spatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset is available for researchers, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies.

neuroscience↗

bioRxiv2019

Fractal Dimension of Cortical Functional Connectivity Networks Predicts Severity in Disorders of Consciousness

Recent evidence suggests that the quantity and quality of conscious experience may be a function of the complexity of activity in the brain, and that consciousness emerges in a critical zone on the axes of order/randomness and integration/differentiation. We propose fractal shapes as a measure of proximity to this critical point, as fractal dimension encodes information about complexity beyond simple entropy or randomness, and fractal structures are known to emerge in systems nearing a critical point. To validate this, we tested the several measures of fractal dimension on the brain activity from healthy volunteers and patients with disorders of consciousness of varying severity. We used a Compact Box Burning algorithm to compute the fractal dimension of cortical functional connectivity networks as well as computing the fractal dimension of the associated adjacency matrices using a 2D box-counting algorithm. To test whether brain activity is fractal in time as well as space, we used the Higuchi temporal fractal dimension on BOLD time-series. We found significant decreases in the fractal dimension between healthy volunteers (n=15), patients in a minimally conscious state (n=10), and patients in a vegetative state (n=8), regardless of the mechanism of injury. We also found significant decreases in adjacency matrix fractal dimension and Higuchi temporal fractal dimension, which correlated with decreasing level of consciousness. These results suggest that cortical functional connectivity networks display fractal character and that this is predictive of level of consciousness in a clinically relevant population, with more fractal (i.e. more complex) networks being associated with higher levels of consciousness. This supports the hypothesis that level of consciousness and system complexity are positively associated, and is consistent with previous EEG, MEG, and fMRI studies.

neuroscience↗

bioRxiv2019

MicroRNA-210 Knockout Alters Dendritic Density and Behavioural Flexibility

MicroRNAs exert post-transcriptional control over eukaryotic genomes and are integral for regulating complex functions in neurodevelopment, neuroplasticity and cognitive processing. The microRNA-210 (miR-210) is a highly-conserved, hypoxia-regulated miRNA that has been shown to be dysregulated in Alzheimers Disease. We have recently also identified a significant enrichment of neurodegenerative diseases among miR-210 targets within the human transcriptome. To further elucidate the role of miR-210 in neuronal function and cognitive behaviour, we utilised conditional miR-210 knockout mice to characterise miR-210 regulation and function in primary hippocampal neurons and measured visual discrimination and reversal learning using rodent touchscreen assays. We found that miR-210 expression was induced by neuronal activation and loss of neuronal miR-210 increased oxidative metabolism and ROS production as well as dendritic density and branching in vitro. We also found that loss of miR-210 in knockout mice increased behavioural flexibility and reduced perseverative responding during reversal learning which required updating of information and feedback. These data support a conserved, activity-dependent role for miR-210 in cognitive function through modulation of neuronal metabolism.

neuroscience↗

bioRxiv2019

Identifying Novel Candidates for Re-Purposing as Potential Therapeutic Agents for Alzheimer’s disease

The current paper describes the identification of novel candidate compounds for repositioning as treatments for Alzheimers disease (AD) from the CMAP library. Candidate compounds were identified based on inverse correlation with transcriptome signatures developed from meta-analyses of Alzheimer RNA expression studies using the SPIED platform. The 78 compounds with a significant inverse correlation were taken forward into an in vitro programme using 6 well validated screening assays relevant to potential treatment targets in AD. Nineteen pf the compounds were hits in at least 2 of these assays. A description of each of these compounds is presented.

neuroscience↗