Biology subjects

Duguid, A.

Publications and source records attributed to Duguid, A..

4 recordsLinked to original sources

bioRxiv2025

Metabolic modelling and time-resolved mapping of glucose oxidative metabolism in rats brain by indirect deuterium detection with 1H-FID-MRSI at 9.4T

ObjectThe present study exploits newly developed dynamic indirect 1H-[2H]-FID-MRSI at 9.4T, combined with a dedicated metabolic model, to enable regional and quantitative characterization of glucose oxidative metabolism flux in the rat brain with minimal metabolic assumptions, by measuring both 2H-labelled Glx turnover and pool size along a controlled 2H-Glc infusion protocol. Materials and MethodsSeven rats underwent dynamic 2D 1H-FID-MRSI during a 2-hour infusion of [6,6-2H2] glucose. Consecutive 13-min acquisitions quantified Glx-C4 1H-signal decay, converted to 2H-Glx concentrations using baseline metabolite pool sizes. A three-pool kinetic model including 2H-label loss was fitted to regional turnover curves to estimate oxidative flux (Vgt) and pyruvate dilution (Kdil). Model performance and parameter robustness were finally assessed with Monte-Carlo simulations. ResultsIn vivo 2H-Glx turnover showed a saturated exponential rise ([~]60 min), with a labelling plateau higher in striatum (1.85 mol/g) than hippocampus (1.55 mol/g). Metabolic modelling provided region-specific oxidative fluxes: Vgt = 0.27 {+/-} 0.07 mol/g/min (hippocampus) and Vgt = 0.40 {+/-} 0.06 mol/g/min (striatum), with consistent Kdil across regions. Simulations confirmed a good model robustness in retrieving Vgt over a large range of experimental conditions. DiscussionThis work shows the appropriateness of indirect dynamic 1H-[2H]-FID-MRSI for quantitative metabolic flux mapping of cerebral glucose oxidative metabolism.

neuroscience↗

bioRxiv2024

Leukaemia cell intrinsic and extrinsic factors cooperate to facilitate the survival and proliferation of KMT2A-rearranged B-ALL in the CNS niche.

Infant B-cell acute lymphoblastic leukaemia (B-ALL) is a rare, aggressive entity characterised by KMT2A rearrangements and poor outcomes. One of the unique features of KMT2A-rearranged infant ALL that contributes to these poor outcomes is a particularly high rate of central nervous system (CNS) involvement. There is a broad lack of understanding regarding the molecular processes and immune environment in CNS ALL. This hinders the development of targeted therapies for CNS ALL, which is increasingly essential given the potentially reduced efficacy of current immunotherapies in this specialised environment. In this study, we used an immune-competent KMT2A-AFF1+ infant B-ALL murine model to explore the cell-intrinsic and cell-extrinsic mechanisms that underpin this clinically significant complication. We show novel functional impacts on leukaemia propagating cells following exposure to the CNS niche which results in unique leukaemia repopulation dynamics. Transcriptomic and immune cell profiling by niche showed differences in the immune microenvironment between the CNS and bone marrow niches. The CNS niche demonstrates supressed T cell and macrophage activity which may be part of a wider CNS niche-specific immune escape mechanism. Our transcriptomic comparisons by niche also led us to explore the role of PI3K pathway activation in the propagation of leukaemia cells within the CNS niche. We identify miR-93 as a possible master regulator of this process. The importance of miR-93 is emphasised as it is shown to be upregulated in CNS leukaemia cells across multiple murine KMT2A-AFF1 B-ALL model systems and in primary KMT2A-AFF1 B-ALL patient samples. We conclude by showing impaired CNS engraftment of leukaemia cells upon miR-93 knockdown, cementing its importance in CNS leukaemia biology and opening up new CNS-specific therapeutic opportunities.

cancer biology↗

bioRxiv2023

Population genomics of harbour seal Phoca vitulina from northern British Columbia through California and comparison to the western Atlantic sub-species

The harbour seal Phoca vitulina is a ubiquitous pinniped species found throughout coastal waters of the Northern Hemisphere. Harbour seal impacts on ecosystem dynamics may be significant due to their high abundance and food web position. Two subspecies exist in North America, P. v. richardii in the Pacific Ocean, and P. v. vitulina in the Atlantic. Strong natal philopatry of harbour seals can result in fine-scale genetic structure and isolation-by-distance. Management of harbour seals is expected to benefit from improved resolution of seal population structure and dynamics. Here we use genotyping-by-sequencing to genotype 146 harbour seals from the eastern Pacific Ocean (i.e., British Columbia (BC), Oregon, and California) and the western Atlantic Ocean (i.e., Quebec, Newfoundland, and Labrador). Using 12,742 identified variants, we confirm the recently identified elevated genetic diversity in the eastern Pacific relative to the western Atlantic and greatest differentiation between the subspecies. Further, we demonstrate that this is independent of reference genome bias or other potential technical artefacts. Coast-specific analyses with 8,933 and 3,828 variants in Pacific and Atlantic subspecies, respectively, identify divergence between BC and Oregon-California, and between Quebec and Newfoundland-Labrador. Unexpected PCA outlier clusters were observed in two populations due to cryptic relatedness of individuals; subsequently, closely related samples were removed. Admixture analysis indicates an isolation-by-distance signature where Oregon seals contained some of the BC signature, whereas California did not. Additional sampling is needed in the central and north coast of BC to determine whether a discrete separation of populations exists within the region.

genomics↗

bioRxiv2023

A microRNA expression signature in infant t(4;11) MLL-AF4+ BCP-ALL uncovers novel therapeutic targets

Infants and children with MLL-AF4+ leukemia have an urgent need for more efficient and less aggressive therapy. In this study, we studied three microRNAs that are downregulated in MLL-AF4+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL): miR-194, miR-99b and miR-125a-5p. When overexpressed, all three microRNAs impaired the survival of MLL-AF4+ leukemic blasts and the maintenance of MLL-AF4+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in MLL-AF4+ BCP-ALL: CA5B, PPP3CA and PPP2R5C. Using CRISPR-Cas9 and specific inhibitors, we confirmed that CA5B, PPP3CA and PPP2R5C downregulation/inhibition severely compromised the proliferation and survival of MLL-AF4+ leukemic blasts. Importantly, CA5B, PPP3CA and PP2A inhibition by acetazolamide, tacrolimus and LB-100, respectively, showed high toxicity towards MLL-AF4+ leukemic blasts and reduced leukemia burden in vivo. This study highlights how the unique microRNA expression signature of patients with MLL-AF4+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. Statement of significanceThere is an urgent need to identify novel therapeutic avenues for patients with MLL-AF4+ BCP-ALL that are more effective and less aggressive. This study identified three clinically available drugs (acetazolamide, tacrolimus and LB-100) with high and selective toxicity towards MLL-AF4+ leukemic cells.

cancer biology↗