Biology subjects

Christie, I. N.

Publications and source records attributed to Christie, I. N..

5 recordsLinked to original sources

bioRxiv2026

Opportunities and pitfalls in preclinical cerebral blood flow mapping using arterial spin labelling MRI: insights from multicentre data

Cerebral blood flow (CBF) is a quantitative metric for mapping perfusion. While the prototypical MRI approach arterial spin labelling (ASL) is well-validated in humans, the reproducibility of rodent ASL mapping remains poor, limiting translational impact. To address this gap, we used both newly acquired and analysis of previously published data to illustrate biological and physical sources of variation in CBF measured with ASL. Via a meta-analysis, we quantified the variation in CBF reported from the cortex of healthy rodents. A total of 23 mouse studies (343 data points) and 5 rat studies (41 data points) met the inclusion criteria. We demonstrate that reported CBF values exhibit a broad variability (50-400 ml/100g/min) driven primarily by experimental confounds rather than physiological differences. Our meta-analysis explores which factors cause variance in perfusion rates measured. Our experimental data highlight biological factors, particularly the choice of anaesthesia (e.g., isoflurane vs. medetomidine) and strain variations, that alter baseline CBF. Our work, reflecting both state-of-the-art and conventional practice in preclinical imaging, highlights the need to account for multiple sources of variability. Establishing community guidelines for rigorous ASL calibration and physiological monitoring will support improved study design and accelerate translational alignment between rodent and human perfusion measurements. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/733736v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1e94d5org.highwire.dtl.DTLVardef@1bd5718org.highwire.dtl.DTLVardef@1a0fafcorg.highwire.dtl.DTLVardef@1bde97d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

A novel role for UPF1 in safeguarding DNA replication in S phase and beyond.

Accurate DNA replication is essential for the faithful transmission of genetic information to daughter cells. Disruption of this process leads to replication stress, which can trigger mutagenesis, double-stranded DNA breaks, and genomic instability. Transcription is a well-established source of replication stress, contributing through altered chromatin dynamics, DNA structural changes, and direct transcription-replication collisions (TRCs). Here, we uncover a novel role for the RNA/DNA helicase UPF1 in maintaining replication fidelity and responding to replication stress. We show that cancer cells deficient in UPF1 exhibit elevated levels of spontaneous, transcription-dependent replication fork stalling and double-stranded breaks, along with heightened sensitivity to Rad51 and PARP1 inhibitors. Paradoxically, these cells also display resistance to exogenous replication stress, with reduced replication fork stalling, diminished mitotic delays, and decreased activation of mitotic DNA synthesis (MiDAS), a key salvage pathway under stress conditions. Low UPF1 expression has been previously linked to drug resistance in renal carcinoma and correlates with poor prognosis across multiple cancer types. Our findings position UPF1 as a critical guardian against transcription-associated replication stress and suggest that UPF1 deficiency may underlie mechanisms of cancer therapy resistance whilst leaving cells vulnerable to the depletion of key DNA repair pathways. Targeting this vulnerability could offer a promising avenue for therapeutic intervention in UPF1-low tumours.

cell biology↗

bioRxiv2022

Astrocyte mitochondria produce nitric oxide from nitrite to modulate cerebral blood flow during brain hypoxia

In low oxygen conditions, increases in cerebral blood flow maintain brain oxygen delivery but the mechanisms underlying hypoxia-induced dilations of cerebral vasculature are incompletely understood. Here we show that astrocytes accumulate nitrite and in response to hypoxia produce nitric oxide via mitochondrial reduction of nitrite by a molybdenum-containing enzyme sulfite oxidase. These data suggest that astrocytes can modulate cerebral blood flow in accord with brain tissue oxygenation via mitochondrial production of nitric oxide.

neuroscience↗

bioRxiv2021

CO2 signalling mediates neurovascular coupling in the cerebral cortex

The mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models that the neuronal activity-dependent increases in local cerebral blood flow in the somatosensory cortex are abolished by saturation of brain CO2-sensitive vasodilatory mechanism or disruption of brain HCO3-/CO2 transport, independently of baseline cerebral perfusion and brain tissue pH. These results suggest that increases in metabolic CO2 production and CO2 signalling play an important role in the development of neurovascular coupling response.

neuroscience↗

bioRxiv2020

Electrochemical carbon fiber-based technique for simultaneous recordings of brain tissue PO2, pH, and extracellular field potentials

A method for simultaneous electrochemical detection of brain tissue PO2 (PtO2) and pH changes together with neuronal activity using a modified form of fast cyclic voltammetry with carbon fiber electrodes is described. This technique has been developed for in vivo applications and recordings from discrete brain nuclei in experimental animals. The small size of the carbon fiber electrode (7m, length <100m) ensures minimal disruption of the brain tissue and allows recordings from small brain areas. Sample rate (up to 4 Hz) is sufficient to resolve rapid changes in PtO2 and pH that follow changes in neuronal activity and metabolism. Rapid switching between current and voltage recordings allows combined electrochemical detection and monitoring of extracellular action potentials. For simultaneous electrochemical detection of PtO2 and pH, two consecutive trapezoidal voltage ramps are applied with double differential-subtraction of the background current. This enables changes in current caused by protons and oxygen to be detected separately with minimal interference between the two. The profile of PtO2 changes evoked by increases in local neuronal activity recorded using the described technique was similar to that of blood oxygen level dependent responses recorded using fMRI. This voltammetric technique can be combined with fMRI and brain vessel imaging to study the metabolic mechanisms underlying neurovascular coupling response with much greater spatial and temporal resolution than is currently possible.

neuroscience↗