Biology subjects

Chou, A.

Publications and source records attributed to Chou, A..

10 recordsLinked to original sources

bioRxiv2026

Hydraulic fracturing-induced delamination and extravasation extends medial damage beyond the false lumen in aortic dissection

Aortic dissection is life-threatening due to continued loss of medial integrity that may culminate in secondary rupture within hours to days. While pre-existing defects or hemodynamic loads compound structural deterioration of the aorta, pathological progression from symptomatic dissection channel to lethal transmural tear is poorly understood. We examined the structure of referent and acutely dissected ascending aortas by microscopy. Elastic, collagen, and cellular components of non-dissected media were intricately interconnected. Medial damage in dissection lesions was traced from ingress to central to peripheral areas. Entry tears broke cleanly through successive laminae leading to cavernous false lumens in which medial structure was destroyed. Nearby laminae with widening between flanking elastic lamellae (termed minor delaminations) were filled with blood and showed severe medial damage. Farther laminae without delamination but containing red blood cells (termed blood extravasation) displayed moderate medial damage. More distant, non-delaminated laminae with accumulation of albumin but not red blood cells (termed plasma extravasation) exhibited mild medial damage. Varying medial hemorrhage with scattered sloughing of laminae was observed along the entire false lumen. We conclude that hydraulic fracturing of residual dissected media by pressurized blood via communications from the false lumen contributes to further structural weakening of the aortic wall.

pathology↗

bioRxiv2026

Increased medial collagen enhances aortic resilience against mural delamination from hydraulic fracturing

The aorta, normally resilient to hemodynamic stresses, becomes vulnerable to structural failure due to diverse conditions that weaken the wall. We injected fluid into excised specimens of human ascending aorta with pressure monitoring to quantify the impact of clinical and histological factors on mural damage. Two modes of medial injury emerged with distinct pressure tracings. Extravasation was characterized by diffuse infiltration of fluid with widespread damage of smooth muscle cells and collagen fibers but limited separation of elastic lamellae. By contrast, delamination was characterized by marked separation of elastic lamellae along a single plane with damage to cells and fibrillar matrix restricted to adjacent laminae. Aging, aortic dilatation, and family history associated with lower pressures causing delamination, whereas a diagnosis of hypertension associated with higher pressures suggesting resilience to dissection. Collagen fraction adjacent to delamination correlated with higher pressures as did decreased smooth muscle cell density and increased glycosaminoglycan fraction, although several clinical and histological variables were interrelated. Protein cross-linking strengthened and enzymatic digestion of collagen weakened the aortic wall, while acute cell lysis with detergent had no effect. We conclude that increased functional medial collagen has an adaptive protective role in aortic remodeling rather than signifying medial degeneration.

bioengineering↗

bioRxiv2025

Constitutive Androstane Receptor induces Ribonucleotide Reductase-M2 expression and maintains hepatocyte ploidy in mice

The nuclear receptor Constitutive Androstane Receptor (CAR/NR1i3) is known for regulating various liver functions, including detoxification, nutrient metabolism, and hepatocyte proliferation. While CAR activation has been previously linked to higher ploidy, the underlying mechanisms are not fully known. Here, we uncover a basal role for CAR in maintaining hepatocyte ploidy, such that CAR deletion increases the number of diploid (2c) hepatocytes with a concomitant reduction in tetraploid (4c) hepatocytes. We demonstrate that CAR controls the de novo dNTP synthesis by directly transactivating the Ribonucleotide Reductase-M2 (RRM2) gene, which encodes the rate-limiting catalytic subunit of the enzyme, ribonucleotide reductase. Further, we find that the ligand-dependent CAR activation is sufficient to induce several genes involved in the de novo dNTP synthesis pathways, resulting in higher hepatic dATP and dTTP levels within the liver. Importantly, overexpressing RRM2 levels in CAR knockouts led to increased DNA synthesis and tetraploid (4c) hepatocytes compared to the control mice. Importantly, we demonstrate that CAR-mediated DNA synthesis in liver cells is dependent on catalytically active RRM2 function. Taken together, these findings reveal that the CAR-mediated RRM2 regulation contributes towards DNA synthesis and thereby maintains hepatocyte ploidy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/651109v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1750110org.highwire.dtl.DTLVardef@98f579org.highwire.dtl.DTLVardef@1c0e87org.highwire.dtl.DTLVardef@1fdfda5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Host-derived oxidized phospholipids initiate effector-triggered immunity fostering lethality upon microbial encounter.

Macrophages detect invading microorganisms via pattern recognition receptors that recognize pathogen-associated molecular patterns, or via sensing the activity of virulence factors that initiates effector-triggered immunity (ETI). Tissue damage that follows pathogen encounter leads to the release of host-derived factors that participate to inflammation. How these self-derived molecules are sensed by macrophages and their impact on immunity remain poorly understood. Here we demonstrate that, in mice and humans, host-derived oxidized phospholipids (oxPLs) are formed upon microbial encounter. oxPL blockade restricts inflammation and prevents the death of the host, without affecting pathogen burden. Mechanistically, oxPLs bind and inhibit AKT, a master regulator of immunity and metabolism. AKT inhibition potentiates the methionine cycle, and epigenetically dampens Il10, a pluripotent anti-inflammatory cytokine. Overall, we found that host-derived inflammatory cues act as "self" virulence factors that initiate ETI and that their activity can be targeted to protect the host against excessive inflammation upon microbial encounter.

immunology↗

bioRxiv2023

Improving rigor and reproducibility in western blot experiments with the blotRig analysis software

Western blot is a popular biomolecular analysis method for measuring the relative quantities of independent proteins in complex biological samples. However, variability in quantitative western blot data analysis poses a challenge in designing reproducible experiments. The lack of rigorous quantitative approaches in current western blot statistical methodology may result in irreproducible inferences. Here we describe best practices for the design and analysis of western blot experiments, with examples and demonstrations of how different analytical approaches can lead to widely varying outcomes. To facilitate best practices, we have developed the blotRig tool for designing and analyzing western blot experiments to improve their rigor and reproducibility. The blotRig application includes functions for counterbalancing experimental design by lane position, batch management across gels, and analytics with covariates and random effects.

neuroscience↗

bioRxiv2023

Sexually dimorphic differences in angiogenesis markers predict brain aging trajectories

Aberrant angiogenesis could contribute to cognitive impairment, representing a therapeutic target for preventing dementia. However, most angiogenesis studies focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in two deeply phenotyped human cohorts (n=435, age 74+9) with longitudinal cognitive assessments, biospecimens, structural brain imaging, and clinical data. Machine learning and traditional statistics revealed sex dimorphic associations of plasma angiogenic growth factors with brain aging outcomes. Specifically, angiogenesis is associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reverses around age 75. Higher levels of basic fibroblast growth factor, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories. This work demonstrates the relevance of angiogenesis to brain aging with important therapeutic implications for vascular cognitive impairment and dementia.

neuroscience↗

bioRxiv2022

Neuroanatomy of stomatopod central complexes offers putative neural substrate for oriented behaviors in crustaceans

All insects studied to date possess a centrally located group of neuropils, known collectively as the central complex, that has been implicated in sensory integration and motor action selection. Among the functions prescribed to the central complex, none is perhaps as intriguing as its role in orientation and navigation. Neurobiological correlates of both current and desired headings have been described in insect CXs. Despite the diversity of arthropods, understanding of the CX as a navigational center originates entirely from terrestrial insects. Stomatopod crustaceans, commonly referred to as mantis shrimps, form an order of predatory marine crustaceans with intricate and diverse visual systems that maintain the distinction of being the only fully aquatic animal known to utilize the navigational strategy of path integration. They utilize idiothetic, celestial, and landmark cues to orient in the benthos. Here, we investigate the neuroanatomy of adult and developing mantis shrimp central complexes and associated neuropils to begin understanding this brain region in a sensorially and behaviorally complex crustacean.

neuroscience↗

bioRxiv2021

Expert-integrated automated machine learning uncovers hemodynamic predictors in spinal cord injury

Automated machine learning (AutoML) is positioned to democratize artificial intelligence (AI) by reducing the amount of human input and ML expertise needed to create prediction models. However, successful translation of ML in biomedicine requires moving beyond optimizing only for prediction accuracy and towards discovering reproducible clinical and biological inferences. Here, we present a model-agnostic framework to reinforce AutoML using strategies and tools of explainable and reproducible AI, including novel metrics for performance precision and feature instability. The framework enables clinicians to interpret AutoML-generated models for clinical and biological verifiability and consequently integrate domain expertise during model development. We applied the framework towards spinal cord injury prognostication and identified a detrimental relationship between intraoperative hypertension and patient outcome. Furthermore, our analysis captured evolving clinical practices such as faster time-to-surgery and blood pressure management that affected clinical model validation. Altogether, we illustrate how augmenting AutoML for inferential reproducibility empowers biomedical discovery and builds trust in AI processes towards effective clinical integration.

bioinformatics↗

bioRxiv2020

A Single-Cell Tumor Immune Atlas for Precision Oncology

The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system for a harmonized interpretation. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying striking spatial immune cell patterns in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immuno-therapy.

cancer biology↗

bioRxiv2020

Blood RNA Profiles are Diagnostic for Severity in Human Acute Spinal Cord Injury

Biomarkers of spinal cord injury (SCI) could help determine the severity of the injury and facilitate early critical care decision making. We analyzed global gene expression in peripheral white blood cells during the acute injury phase and identified 197 genes whose expression changed after SCI compared to healthy and trauma controls and in direct relation to SCI severity. Unsupervised co-expression network analysis identified several gene modules that predicted injury severity (AIS grades) with an overall accuracy of 72.7% and included signatures of immune cell subtypes. Our findings indicate that global transcriptomic changes in peripheral blood cells have diagnostic and potentially prognostic value for SCI severity.

neuroscience↗