Biology subjects

Anderson, S. T.

Publications and source records attributed to Anderson, S. T..

4 recordsLinked to original sources

bioRxiv2026

Single-cell transcriptomics reveals cell-type-specific circadian rhythms and their disruption by acute misalignment in mouse aorta

The circadian molecular clock is a 24 hour cellular timekeeper that influences many features of cardiovascular function. Disruption of the circadian clock via misalignment with the light dark cycle is associated with a higher incidence of cardiovascular disease and raises cardiovascular risk factors in humans. Nonetheless, the cell type specific molecular basis for how misalignment affects the vasculature remains poorly understood. To address this, we performed single cell RNA sequencing from whole mouse aorta at ZT0, ZT6, ZT12, and ZT18 under aligned and acutely misaligned (6 hour phase advance) light dark cycles in both male and female mice. Leveraging Bayesian variational inference, we estimated posterior waveforms for 141,752 cells across four major cell types and identified hundreds of cycling genes in vascular smooth muscle cells (SMCs) and fibroblasts. Pathway and transcription factor enrichment analyses revealed coordinated circadian activity in cholesterol biosynthesis, smooth muscle contraction, and extracellular matrix organization. Notably, SMC genes implicated in phenotypic switching showed coordinated temporal patterns, with genes promoting switching peaking at dusk and genes restraining switching peaking at dawn. Comparing males and females, we found that female SMCs are broadly more rhythmic, with higher amplitudes and nearly twice as many cycling genes after controlling for cell counts and library sizes, a sex difference that was cell type specific and not observed in fibroblasts. After acute misalignment, cycling genes showed reduced amplitudes, and peak times showed limited adaptation to the new light dark cycle. Given that the central clock is known to adapt near completely during this timeframe, these observations suggest internal misalignment between central and peripheral rhythms. Moreover, altered relative timing of core clock genes within cells indicates that misalignment is created at the intracellular level as well. In SMCs, gene expression patterns were consistent with proteostatic stress, including broad downregulation of protein chaperones and stress response genes, which cells appear to cope with by upregulating protein degradation pathways. In parallel, in vivo vascular phenotyping showed increased vascular permeability in both sexes, reduced urinary nitrate in males, and increased microvascular thrombus formation in males following acute misalignment. This atlas provides a resource for understanding how circadian misalignment disrupts vascular homeostasis and may contribute to cardiovascular disease risk.

genomics↗

bioRxiv2020

Sex dependent compensatory mechanisms to preserve blood pressure homeostasis in PGI2 receptor deficient mice

Inhibitors of microsomal prostaglandin E synthase-1 (mPges-1) are in the early phase of clinical development. Deletion of mPges-1 confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing prostaglandin (PG) E2, but increasing biosynthesis of prostacyclin (PGI2). In hyperlipidemic mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. To address how differential effects on PGE2 and PGI2 might modulate salt-evoked BP responses in the absence of mPges-1, we generated mice lacking the I prostanoid (Ipr) receptor or mPges-1 on a hyperlipidemic background caused by deletion of the low density lipoprotein receptor (Ldlr KOs). Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr KO mice, whereas, despite the direct vasodilator properties of PGI2, Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1 KO mice. Suppression of PGE2 biosynthesis was enough to explain the exaggerated BP response to salt loading by either mPges-1/Ldlr depletion or by an MPGES-1 inhibitor in mice expressing human mPGES-1. However, the lack of a hypertensive response to salt in Ipr-deficient mice was attributable to reactive activation of the atrial natriuretic peptide pathway. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr KO mice and in Ipr /Ldlr DKOs. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.

pharmacology and toxicology↗

bioRxiv2019

Viral and bacterial infection elicit distinct changes in plasma lipids in febrile children

Fever is the most common reason that children present to Emergency Departments in the UK. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. As a result, many children are prescribed antibiotics often unnecessarily, while others with life-threatening bacterial infections can remain untreated. The omics approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection elicit distinct changes in the host lipidome. Glycerophosphoinositol, sphingomyelin, lysophosphotidylcholine and cholesterol sulfate were increased in the confirmed virus infected group, while fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were increased in cases with confirmed bacterial infection. A combination of three lipids achieved the area under the receiver operating characteristic (ROC) curve of 0.918 (95% CI 0.835 to 1). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.

systems biology↗

bioRxiv2019

Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification

Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate the development of diagnostic tests.\n\nTo identify minimal transcript signatures, we applied a novel transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were validated using reverse transcriptase (RT) - digital PCR (dPCR).\n\nA four-transcript signature (GBP6, TMCC1, PRDM1, ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2 - 100%). A three-transcript signature (FCGR1A, ZNF296, C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3 - 100%), regardless of HIV.\n\nThese signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.

molecular biology↗