Biology subjects

McQueen, J.

Publications and source records attributed to McQueen, J..

4 recordsLinked to original sources

bioRxiv2026

Higher-Order Organization Links Circulating Metabolites to Glucocorticoid Action in Human Adipose Tissue

Glucocorticoids (GCs) are regulators of metabolism, yet how physiological GC exposure remodels adipose metabolism and its relationship with circulating biomarkers remains poorly understood. In a randomised cross-over study of individuals with primary adrenal insufficiency, near-physiological GC exposure was compared to withdrawal using integrated serum metabolomics, abdominal subcutaneous microdialysis metabolomics, and adipose tissue transcriptomics. GC exposure induced coordinated changes in adipose lipid and amino-acid metabolism. Pathway-level entropy analysis revealed GC-state-dependent transcriptional reorganisation, with concentrated organisation during exposure and diffuse organisation during withdrawal. Integrative hypergraph and topological analyses revealed GC-state-dependent reorganisation of circulating metabolite-adipose tissue relationships, with greater higher-order coordination during exposure. The circulating phenylalanine/kynurenine ratio discriminated GC state, showed the strongest shared connectivity to GC-regulated adipose networks, persisted at midnight and in an independent dose-response study, and exhibited circadian rhythmicity. These findings reveal dynamic GC regulation of adipose metabolism and identify a circulating biomarker with potential to guide personalised GC therapy.

systems biology↗

bioRxiv2026

Mononuclear myeloid cells mount an adaptive protective response to intracerebral haemorrhage by activation of NRF2

Following intracerebral haemorrhage (ICH), secondary injury contributes to negative outcomes. Here, we describe inter-dependent injurious and adaptive-protective pathways that form a therapeutically modifiable ICH response. In perihaematomal tissue from post-mortem ICH patients, transcriptomic analysis pointed to concurrent perihaematomal activation of the cytoprotective stress-induced transcription factor NRF2 and activation of interferon responses, with mononuclear myeloid cells (microglia and monocyte-derived cells, MMCs) and astrocytes contributing to this signature. In vitro, microglia-astrocyte-neuron co-culture studies revealed that microglial NRF2 activation was induced by clot-conditioned medium and could influence the interferon pathway in both microglia themselves as well as astrocytes. In vivo, MMC-specific deletion of NRF2 inhibited NRF2 target-gene induction, exacerbated interferon pathway activation following ICH, and impaired functional recovery. Pharmacological NRF2 activation suppressed interferon pathway induction post-ICH, and direct interferon pathway antagonism rescued neurological recovery deficits caused by MMC-specific NRF2 deficiency. Thus, augmenting NRF2- or inhibiting interferon-signalling may improve outcomes after ICH.

neuroscience↗

bioRxiv2022

Neural tracking of speech does not unequivocally reflect intelligibility

During listening, brain activity tracks the rhythmic structures of speech signals. Here, we directly dissociated the contribution of neural tracking in the processing of speech acoustic cues from that related to linguistic processing. We examined the neural changes associated with the comprehension of Noise-Vocoded (NV) speech using magnetoencephalography (MEG). Participants listened to NV sentences in a 3-phase training paradigm: (1) pre-training, where NV stimuli were barely comprehended, (2) training with exposure of the original clear version of speech stimulus, and (3) post-training, where the same stimuli gained intelligibility from the training phase. Using this paradigm, we tested if the neural responses of a speech signal was modulated by its intelligibility without any change in its acoustic structure. To test the influence of spectral degradation on neural tracking independently of training, participants listened to two types of NV sentences (4-band and 2-band NV speech), but were only trained to understand 4-band NV speech. Significant changes in neural tracking were observed in the delta range in relation to the acoustic degradation of speech. However, we failed to find a direct effect of intelligibility on the neural tracking of speech in both theta and delta ranges. This suggests that acoustics greatly influence the neural tracking response to speech signals, and that caution needs to be taken when choosing the control signals for speech-brain tracking analyses, considering that a slight change in acoustic parameters can have strong effects on the neural tracking response.

neuroscience↗

bioRxiv2018

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimers disease (AD) is the lack of understanding of how amyloid beta (A{beta}) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human taus influence on human A{beta}-induced pathology. We find that A{beta} and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.\n\nHighlights- Expression of human familial Alzheimers associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function.\n- Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.\n- These data suggest that A{beta} and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

neuroscience↗