Biology subjects

McQuade, R.

Publications and source records attributed to McQuade, R..

3 recordsLinked to original sources

bioRxiv2024

Food entrainment in mice leads to sex- and organ-specific responses in nutrient metabolism

Food intake is one of the main zeitgebers in the digestive system; however, little is known about organ- and sex-specific differences in food-driven regulation. We placed male and female C57Bl/6 mice on time-restricted feeding (TRF), limiting the food intake period to 8 hours. Food was added either at dark (ZT12) or light (ZT0) onset for 14 days. Afterwards, an additional 4-hour delay in the feeding period was introduced for half of the mice, and the TRF regime continued for another 14 days. TRF from ZT12 to ZT20 led to the highest weight gain in females but the lowest in males while improving intestinal transepithelial resistance (TEER) in both sexes. However, it also led to the disappearance of food-anticipatory response in several hepatic genes. Delaying the start of TRF until ZT16 led to an increase in weight gain and a decrease in fasting plasma glucose levels in male mice, as well as to strong entrainment of metabolism-related hepatic and duodenal genes in both sexes. The alignment of food intake with the early lights-on phase (ZT0-ZT8) caused only minor changes in physiological responses. However, it did lead to an overall downregulation of hepatic and an upregulation of duodenal and gastric genes, with additional loss of food-anticipatory gene expression in both sexes. Delaying the start of food intake until ZT4 was highly detrimental, causing an increase in fasting blood glucose levels, a decrease in TEER, and further disruptions in gene expression patterns in the stomach and liver. In contrast, the duodenum was able to restore its food-driven gene expression. These results demonstrate that the adjustment to food intake time in mice is highly sex- and organ-specific. Our chosen TRF regimes were not able to synchronize food-anticipatory responses between the liver and gut. Instead, we observed that organs entrain to food intake at different rates.

molecular biology↗

bioRxiv2023

Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) reporter mice (Nr4a3-Tocky-Ifng-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-{gamma} production decoupled from TCR signalling, decreased polyfunctionality and reduced TCM formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.

immunology↗

bioRxiv2020

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

The pathophysiology of the majority of neuropsychiatric disorders, including schizophrenia and mood disorders, involves synaptic dysfunction and/or loss, manifesting as lower levels of several presynaptic and postsynaptic marker proteins. Whether chronic exposure to antipsychotic drugs may contribute to this pattern of synaptic loss remains controversial. In contrast, the mood stabiliser lithium has shown to exhibit neurotrophic actions and is thought to enhance synapse formation. Whilst these data are not unequivocal, they suggest that antipsychotic drugs and lithium have contrasting effects on synapse density. We therefore investigated the effect of chronic exposure to lithium and to two different antipsychotics, haloperidol and olanzapine, on presynaptic Synaptic Vesicle glycoprotein 2A (SV2A) and postsynaptic Neuroligin (NLGN) clusters in the rat frontal cortex. Chronic exposure (28 days) to haloperidol (0.5 mg/kg/d) or olanzapine (7.5 mg/kg/d) had no effect on either SV2A or NLGN clusters and no overall effect on synaptic clusters. In contrast, chronic lithium exposure (2 mmol/L eq./d) significantly increased NLGN cluster density as compared to vehicle, but did not affect either SV2A or total synaptic clusters. These data are consistent with and extend our prior work, confirming no effect of either antipsychotics or lithium on SV2A clustering, but suggest contrasting effects of these drugs on the post-synapse. Although caution needs to be exerted when extrapolating results from animals to patients, these data provide clarity with regard to the effect of antipsychotics and lithium on synaptic markers, thus facilitating discrimination of drug from illness effects in human studies of synaptic pathology in psychiatric disorders.

neuroscience↗