Biology subjects

Garnett, M. R.

Publications and source records attributed to Garnett, M. R..

4 recordsLinked to original sources

bioRxiv2024

Synthetic augmentation of cancer cell line multi-omic datasets using unsupervised deep learning

Multi-omic characterization and integration remains a challenge due to data complexity and sparsity. Addressing this, our study introduces an unsupervised deep learning model, MOVE (Multi-Omic Variational Encoder), specifically designed to integrate and augment the Cancer Dependency Map (DepMap). Harnessing orthogonal multi-omic information, this model successfully generates molecular and phenotypic profiles, resulting in an increase of 32.7% in the number of multi-omic profiles and thereby generating a complete DepMap for 1,523 cancer cell lines. The synthetically enhanced data increases statistical power, uncovering less studied mechanisms associated with drug resistance, and refines the identification of genetic associations and clustering of cancer cell lines. By applying SHAP for model interpretation, MOVE reveals multi-omic features essential for cell clustering and biomarker identification related to drug and gene dependencies. This understanding is crucial for the development of much-needed, effective strategies in prioritizing cancer targets.

systems biology↗

bioRxiv2019

A map of transcriptional heterogeneity and regulatory variation in human microglia

Microglia, the tissue resident macrophages of the CNS, are implicated in a broad range of neurological pathologies, from acute brain injury to dementia. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single cell and bulk RNA sequencing, we defined distinct cellular populations of acutely in vivo-activated microglia, and characterised a dramatic switch in microglial population composition in patients suffering from acute brain injury. We mapped expression quantitative trait loci (eQTLs) in human microglia and show that many disease-associated eQTLs in microglia replicate well in a human induced pluripotent stem cell (hIPSC) derived macrophage model system. Using ATAC-seq from 95 individuals in this hIPSC model we fine-map candidate causal variants at risk loci for Alzheimers disease, the most prevalent neurodegenerative condition in acute brain injury patients. Our study provides the first population-scale transcriptional map of a critically important cell for neurodegenerative disorders.

genomics↗

bioRxiv2018

Validation of Davson’s equation in patients suffering from idiopathic Normal Pressure Hydrocephalus

IntroductionThe so called Davsons equation relates baseline intracranial pressure (ICP) to resistance to cerebrospinal fluid outflow (Rout), formation of cerebrospinal fluid (If) and sagittal sinus pressure (PSS) There is a controversy over whether this fundamental equation is applicable in patients with normal pressure hydrocephalus (NPH). We investigated the relationship between Rout and ICP and also other compensatory, clinical and demographic parameters in NPH patients.\n\nMethodWe carried out a retrospective study of 229 patients with primary NPH who had undergone constant-rate infusion studies in our hospital. Data was recorded and processed using ICM+ software. Relationships between variables were sought by calculating Pearson product correlation coefficients and p values.\n\nResultsWe found a significant, albeit weak, relationship between ICP and Rout (R=0.17, p=0.0049), Rout and peak-to-peak amplitude of ICP (AMP) (R=0.27, p=3.577e-05) and Rout and age (R=0.16, p=0.01306).\n\nConclusionsThe relationship found between ICP and Rout provides indirect evidence to support disturbed Cerebrospinal fluid circulation as a key factor in disturbed CSF dynamics in NPH. Weak correlation may indicate that other factors: variable Pss and formation of CSF outflow contribute heavily to linear model expressed by Davsons equation.

neuroscience↗

bioRxiv2017

Cerebral Autoregulation, CSF outflow resistance and outcome following CSF diversion in Normal Pressure Hydrocephalus.

IntroductionNormal pressure hydrocephalus (NPH) is not simply the result of a disturbance in cerebrospinal fluid (CSF) circulation, but often includes cardiovascular comorbidity and abnormalities within the cerebral mantle. In this study, we have examined the relationship between the global autoregulation pressure reactivity index (PRx), the profile of disturbed CSF circulation and pressure-volume compensation, and their possible effects on outcome after surgery.\n\nMaterials and methodsWe studied a cohort of 131 patients, investigated for possible NPH. Parameters describing CSF compensation and circulation were calculated during the cerebrospinal fluid (CSF) infusion test and PRx was calculated from CSF pressure and arterial pressure recordings. A simple scale was used to mark the patients outcome 6 months after surgery (improvement, temporary improvement, and no improvement).\n\nResultsPRx was negatively correlated with Rout (R=-0.18; p=0.044); patients with normal CSF circulation tended to have worse autoregulation. The correlation for patients who were surgically-managed (N=83) was: R=-0.28; p=0.03, and stronger in patients who improved after surgery (N=64; R=-0.36; p=0.03). In patients who did not improve, the correlation was not significantly different from zero (N= 19; R=0.17; p=0.15). There was a trend towards higher values for PRx in non-responders than in responders (PRx =0.16+/- 0.04 vs 0.09 +/-0.02 respectively; p=0.061), associated with higher MAP values (107.2+/-8.2 in non-responders vs 89.5+/-3.5 in responders; p=0.195). The product of MAP* (1+PRx), proposed as a measure of combined arterial hypertension and deranged autoregulation, showed a significant association with outcome (greater value in non-responders; p=0.013).\n\nConclusionAutoregulation proves to associate with cerebrospinal fluid circulation, and appears strongest in shunt responders. Outcome following CSF diversion is possibly most favorable when CSF outflow resistance is increased and global cerebral autoregulation is intact, in combination with arterial normotension.

neuroscience↗