Biology subjects

Ho, N.

Publications and source records attributed to Ho, N..

21 records · Page 2Linked to original sources

bioRxiv2020

A comprehensive proteomic SWATH-MS workflow for profiling blood extracellular vesicles: a new avenue for glioma tumour surveillance

There is a real need for biomarkers that can indicate glioma disease burden and inform clinical management, particularly in the recurrent glioblastoma (GBM; grade IV glioma) setting where treatment-associated brain changes can confound current and expensive tumour surveillance methods. In this regard, extracellular vesicles (EVs; 30-1000 nm membranous particles) hold major promise as robust tumour biomarkers. GBM-EVs encapsulate molecules that reflect the identity and molecular state of their cell-of-origin and cross the blood-brain-barrier into the periphery where they are readily accessible. Despite the suitability of circulating-EVs for GBM biomarker discovery, sample complexity has hindered comprehensive quantitative proteomic studies. Here, sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used in conjunction with a targeted data extraction strategy to comprehensively profile circulating-EVs isolated from plasma. Plasma-EVs sourced from pre-operative glioma II-IV patients (n=41) and controls (n=11) were sequenced by SWATH-MS, and the identities and absolute quantities of the proteins were extracted by aligning the SWATH-MS data against a custom glioma spectral library comprised of 8662 high confidence protein species. Overall, 4054 plasma-EV proteins were quantified across the cohorts, and putative circulating-EV biomarker proteins identified (adjusted p-value<0.05) included previously reported GBM-EV proteins identified in vitro and in neurosurgical aspirates. Principle component analyses showed that plasma-EV protein profiles clustered according to glioma subtype and WHO-grade, and plasma-EV proteins reflected the extent of glioma aggression. Using SWATH-MS, we describe the most comprehensive proteomic plasma-EV profiles for glioma and highlight the promise of this approach as an accurate and sensitive tumour monitoring method. Objective blood-based measurements of glioma tumour activity will support the implementation of next-generation, patient-centred therapies and are ideal surrogate endpoints for recurrent progression that would allow clinical trial protocols to be more dynamic and adapt to the individual patient and their cancer.

pathology↗

bioRxiv2019

ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated and is implicated in metabolic diseases when compromised. Using an engineered sensor that exclusively activates the unfolded protein response (UPR) during aberrant ER membrane lipid composition, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and are conserved in C. elegans. To systematically validate yeast mutants disrupting ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensing switch in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory pathway in which LBS and proteotoxic stress-induced UPR deploy divergent transcriptional programs. Together, these findings reveal the UPR program as the sum of two independent stress events and could be exploited for future therapeutic intervention.

cell biology↗

bioRxiv2019

Salient images: Evidence for a component process architecture for visual imagination.

The ability to visualise different people and places in imagination is a core element of human cognition. Contemporary neuroimaging research highlights regions of primary visual cortex as important in instantiating images in the minds eye. Here we combine task-based functional magnetic resonance imaging with measures of intrinsic brain organisation to show the ventral attention, or salience, network, also plays an important role in visual imagination. In a task-based study we replicated prior observations of regions of medial occipital cortex, including Brodmann Area 17, showing greater neural activity during imagination than when perceiving similar stimuli. In addition, we found regions of the ventral attention network, and in particular right dorsolateral prefrontal cortex (BA 9/46), were activated by the same acts of imagination. In a subsequent resting-state study, we demonstrated medial occipital cortex regions form a functional network with regions of the ventral attention network that were also active during imagination. Furthermore, this pattern was maximised in an overlapping region of right dorsolateral prefrontal cortex for individuals whose self-reported imagery had stronger negative affect. Together these data suggest visual imagination relies on functional interactions between regions of primary visual cortex with the ventral attention system, and in particular, with a region of right dorsolateral prefrontal cortex.

neuroscience↗