Biology subjects

Quach, A.

Publications and source records attributed to Quach, A..

7 recordsLinked to original sources

bioRxiv2022

Transcriptional drifts associated with environmental changes in endothelial cells

O_LIEnvironmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNA-seq and protein expression by LC-MS directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interations by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We identify novel flow depedent genes, as well as, genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information and physical forces. C_LI

cell biology↗

bioRxiv2021

The Human Milk Oligosaccharide 3-Sialyllactose Promotes Inflammation Resolution and Reduces Atherosclerosis Development in Mice.

Macrophages contribute to the induction and resolution of inflammation and play a central role in the chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3sialyllactose (3SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3SL attenuates a selected set of inflammatory gene expression and promotes activity of LXR and SREBP. These acute anti-inflammatory effects of 3SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CTCF, IRF2, BCL6, and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

immunology↗

bioRxiv2020

The human hippocampus plays a time-limited role in retrieving autobiographical memories

The necessity of the human hippocampus for remote autobiographical recall remains fiercely debated. The standard model of consolidation predicts a time-limited role for the hippocampus, but the competing multiple trace/trace transformation theories posit indefinite involvement. Lesion evidence remains inconclusive, and the inferences one can draw from fMRI have been limited by reliance on covert (silent) recall, which obscures dynamic, moment-to-moment content of retrieved memories. Here, we capitalized on advances in fMRI denoising to employ overtly spoken recall. Forty participants retrieved recent and remote memories, describing each for approximately two minutes. Details associated with each memory were identified and modeled in the fMRI timeseries data using a variant of the Autobiographical Interview procedure, and activity associated with the recall of recent and remote memories was then compared. Posterior hippocampal regions exhibited temporally-graded activity patterns (recent events > remote events), as did several regions of frontal and parietal cortex. Consistent with predictions of the standard model, recall-related hippocampal activity differed from a non-autobiographical control task only for recent, and not remote, events. Task-based connectivity between posterior hippocampal regions and others associated with mental scene construction also exhibited a temporal gradient, with greater connectivity accompanying the recall of recent events. These findings support predictions of the standard model of consolidation and demonstrate the potential benefits of overt recall in neuroimaging experiments.

neuroscience↗

bioRxiv2019

Neurocognitive development of inhibitory control and substance use vulnerability

Previous research indicates that risk for substance use is associated with poor inhibitory control. However, it remains unclear whether at risk youth use follow divergent patterns of inhibitory control development. As part of the longitudinal National Consortium on Adolescent Neurodevelopment and Alcohol (NCANDA) study, participants (N = 113, baseline age: 12-21) completed a rewarded antisaccade task during fMRI, with up to three time points. We examined whether substance use risk factors, including dimensional measures of psychopathology (externalizing, internalizing) and family history of substance use disorder, were associated with developmental differences in inhibitory control performance and BOLD activation at both the trial-level and within individual antisaccade epochs (cue, preparation, and response). Among substance use risk factors, only externalizing psychopathology predicted developmental differences in inhibitory control, where high externalizing predicted lower correct response rates and faster latencies were observed in early adolescence, but normalized by late adolescence. Neuroimaging results revealed high externalizing was associated with developmentally-stable hypo-activation in the left middle frontal gyrus (trial-level), but divergent developmental patterns of posterior parietal cortex activation (cue epoch). Developmental differences in inhibitory control associated with externalizing suggest early adolescence may be a unique period of substance use vulnerability via cognitive and phenotypic disinhibition.\n\nHighlightsO_LICharacterized inhibitory control development in adolescents at-risk for substance use.\nC_LIO_LIExternalizing psychopathology is associated with lower antisaccade correct response rate and faster latencies in early adolescence.\nC_LIO_LIExternalizing performance differences normalize by late adolescence.\nC_LIO_LIExternalizing is associated with prefrontal hypo-activation across development.\nC_LIO_LIExternalizing moderates age-related increases in posterior parietal cortex activity.\nC_LI

neuroscience↗

bioRxiv2018

An epigenetic biomarker of aging for lifespan and healthspan

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using a innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimers disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

epidemiology↗

bioRxiv2017

Striatal cholinergic receptor activation causes a rapid, selective, & state-dependent rise in corticostriatal β activity.

Cortico-basal ganglia-thalamic (CBT) {beta} oscillations (15-30 Hz) are elevated in Parkinsons disease and correlated with movement disability. To date, no experimental paradigm outside of loss of dopamine has been able to specifically elevate {beta} oscillations in the CBT loop. Here, we show that activation of striatal cholinergic receptors selectively increased {beta} oscillations in mouse striatum and motor cortex. In individuals showing simultaneous {beta} increases in both striatum and M1, {beta} partial directed coherence (PDC) increased from striatum to M1 (but not in the reverse direction). In individuals that did not show simultaneous {beta} increases, {beta} PDC increased from M1 to striatum (but not in the reverse direction), and M1 was characterized by persistent {beta}-HFO phase-amplitude coupling. Finally, the direction of {beta} PDC distinguished between {beta} subbands. This suggests: (1) striatal cholinergic tone exerts state-dependent and frequency-selective control over CBT {beta} power and coordination; (2) ongoing rhythmic dynamics can determine whether elevated {beta} oscillations are expressed in striatum and M1; (3) altered striatal cholinergic tone differentially modulates distinct {beta} subbands.

neuroscience↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗