Biology subjects

Luong, D.

Publications and source records attributed to Luong, D..

4 recordsLinked to original sources

bioRxiv2026

Stochasticity in Metabolism: Oxidative Stress Response Phenotypes As Emergent Consequences of Network Topology

Reactive oxygen species (ROS) are ubiquitous yet elusive due to their reactivity and short half-lives, making simulation essential for mechanistic insight. Traditional ROS modeling has been confined to small ODE frameworks limited by kinetic-parameter scarcity. Here, we recast ROS dynamics as a flux-balance analysis (FBA) optimization problem using COBRA and CPLEX, augmenting the Escherichia coli iJO1366 genome-scale model with 84 spontaneous oxidation, 14 redox, and 9 detoxification reactions, targeting three ROS species: hydroxyl radicals, superoxide, and hydrogen peroxide (H2O2). We also formalize five fundamental rules of oxidation biology in the form of mixed-integer linear constraints, allowing us to dynamically incorporate reaction rate constants and let complex behavior emerge from first principles. Among these phenomena is the bimodal killing pattern under H2O2 stress, first announced over 40 years ago and never computationally recapitulated until now. We observe it by stochastically sampling our models with GapSplit, simulating bet-hedging and partitioning solutions into growers, persisters, and non-survivors. In our simulations, this killing effect arises solely from the metabolic network topology during random exploration of alternative metabolic configurations. The conservation of steady state creates a stochastic bias for detoxification when central carbon metabolism reaches its metabolic capacity to deal with ROS, causing the famous survival recovery phase. The recovery phase is thus part of Mode 1 metabolism, characterized by spare detoxification capacity and fulfilled by the Ahp reaction in E. coli. Mode 2 has no spare detoxification. We anticipate this to be an overlooked universal principle.

systems biology↗

bioRxiv2026

Iron export and lipid droplets shield deep-diving elephant seal cells from lipid peroxidation

Elephant seals are remarkable breath-hold divers, capable of remaining submerged for up to two hours during diving bouts. These dives entail repeated, extreme hypoxia/reoxygenation events that would induce severe lipid peroxidation and tissue dysfunction in most mammals. Here, we show that primary vascular endothelial cells derived from elephant seals possess an intrinsic resistance to lipid peroxidation. Comparative transcriptomic and lipidomic profiling across seal, human, and sheep cells identified ferroptosis - an iron-dependent, lipid peroxidation-driven cell death pathway - as uniquely regulated in seal cells following hydroperoxide exposure. Mechanistically, seal cells exhibit robust baseline expression of acyl-CoA synthetase long-chain family member 3 (ACSL3), alongside rapid, seal-specific induction of the sole mammalian iron exporter, ferroportin (SLC40A1). Functional validation using genetic and pharmacological approaches revealed that seal cells are naturally enriched in monounsaturated fatty acids and triglycerides and utilize lipid droplet biogenesis and active iron export as dual protective axes to evade lipid peroxidation. Together, these findings show that elephant seal cells employ a coordinated cytoprotective network of lipid remodeling and iron handling to withstand the severe challenges of deep diving. SIGNIFICANCE STATEMENTDeep-diving marine mammals repeatedly experience extreme hypoxia-reoxygenation events that would induce severe oxidative damage in most terrestrial mammals. However, vascular cells derived from seals naturally resist lipid peroxidation, a major driver of ischemia-reperfusion injury. Here, we show that elephant seal endothelial cells evade lipid peroxidation through two complementary mechanisms: lipid droplets that sequester peroxidation-prone phospholipids, and rapid iron export that limits lipid peroxide formation. These findings reveal naturally evolved cellular strategies that protect against vascular oxidative stress, offering new insights into physiological resilience against ischemia-reperfusion injury.

physiology↗

bioRxiv2025

Individual differences in fear memory expression engage distinct functional brain networks

Fearful stimuli elicit a mix of active (e.g., evasion) and passive (e.g., freezing) behaviors in a wide range of species, including zebrafish (Danio rerio). How these different responses are encoded in the brain, and the extent to which individuals vary in their fear responses, is not clear. To investigate this, we first developed a contextual fear conditioning paradigm in adult zebrafish where fish associate a specific tank with an aversive pheromone, conspecific alarm substance (CAS). We collected data from over 300 fish across four different strains (AB, TU, TL, and WIK) and both sexes finding that, as expected, fish exhibit a mix of active and passive responses during CAS exposure and during memory expression. We also found that behavior fell into four distinct groups: non-reactive, evaders, evading freezers, and freezers, with the evading freezer and freezer groups most clearly associated with memory formation. Background strain and sex also influenced how fish respond to CAS, with males more likely to increase evasive behaviors in response to CAS and the TU strain more likely to be non-reactive during recall. Finally, using whole-brain activity mapping, we identified the brain regions associated with active and passive fear responses during memory expression and how the functional brain networks of evading freezers and freezers differed. Freezing behavior was associated with widespread neural activity that was particularly strong in the cerebellum, reticular formation, and parts of the telencephalon associated with olfactory processing. Evasive behavior was associated with an increase in the activity of visual threat detection and a decrease in the activity of brain regions related to foraging and navigation. Network analysis revealed that animals with high freezing and low evasion (i.e., freezers) had strong interactions between the pallium and cerebellum as well as strong interconnectivity between visual (pretectal) and thalamic analog (preglomerular) nuclei. Animals that mix freezing with evasive behaviors (i.e., evading freezers) had higher subpallial connectivity to regions involved in autonomic function and stress responses such as the hypothalamus and preoptic areas.

neuroscience↗

bioRxiv2023

Domain-Invariant Brainstem Nuclei Segmentation and Signal Quantification

AO_SCPLOWBSTRACTC_SCPLOWBrainstem nuclei are hard to distinguish due to very few distinctive features which makes detecting them with high accuracy extremely difficult. We introduce StARQ that builds on SeBRe, a deep learning-based framework to segment regions of interest. StARQ provides new functionalities for automated segmentation of brainstem nuclei at high granularity, and quantification of underlying neural features such as axonal tracings, and synaptic punctae. StARQ will serve as a toolbox for generalized brainstem analysis, enabling reliable high-throughput computational analysis with open-source models.

neuroscience↗