Biology subjects

Chen, Y.

Publications and source records attributed to Chen, Y..

At least 199 records · Page 11Linked to original sources

bioRxiv2026

A specific computational role for early-life unpredictability, and not lifelong stressful experience, in decision-making under uncertainty.

It has been shown that early-life adversity (ELA) shapes how individuals learn, remember, and make decisions, yet the precise computations altered by these experiences remain unclear. Here, we combine a structured foraging task with computational modeling to test a recently developed theory for how a particular kind of ELA, early-life unpredictability (ELU), specifically influences choice under uncertainty. Adult participants (N=297) performed a sequential foraging task requiring continuous trade-offs between exploiting depleting resources and exploring alternatives. Subsets also completed assessments of early-life unpredictability (QUIC) and for trauma symptoms arising from lifelong stressors (PCL). We fit participants behavior with a Bayesian learning-and-planning model in which uncertainty modulates the valuation of leaving a current resource patch. Critically, the subjective influence of local uncertainty was allowed to vary freely between participants. Consistent with theoretical proposals, computational model fits and mediation analyses revealed a robust indirect pathway: ELU predicted increased discounting in the face of uncertainty, which in turn predicted greater overharvesting. This pattern was consistent across environmental conditions, indicating that early-life unpredictability primarily influences behavior through a general influence on uncertainty processing. Importantly, although PCL scores were also correlated with uncertainty adaptation, these effects were fully accounted for by shared variance with ELU, offering a clear dissociation between developmental unpredictability and lifelong traumatic experience. Together, our results show that early-life unpredictability causes long-lasting changes in decision-making by amplifying the subjective experience of uncertainty.

neuroscience↗

bioRxiv2026

Characterizations of Antibacterial and Anti-biofilm Properties of Dendrimers G6 and G9

Dendrimers are nanosized molecules with potential antimicrobial applications. This study evaluates the antibacterial and anti-biofilm properties of two cationic dendrimers, NVX-G6 (G6) and NVX-G9 (G9), against clinically relevant bacterial pathogens. Minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC99) were determined for Escherichia coli, Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus (MSSA), and methicillin-resistant Staphylococcus aureus (MRSA). The synergy of dendrimers with ceftazidime and vancomycin was evaluated using checkerboard assays. Furthermore, biofilm formation inhibition assays and fluorescent microscopy were performed to assess dendrimer interactions with bacterial biofilms. The results indicate that G6 and G9 exhibit limited direct antibacterial activity at high concentrations (MIC > 1024 {micro}g/mL) but demonstrate synergistic effects when combined with ceftazidime against E. coli and P. aeruginosa (FIC < 0.5). Notably, both dendrimers penetrated and colocalized within established biofilms, with time-dependent reductions in biomass observed after extended incubation, suggesting a role in progressive biofilm disruption rather than acute inhibition of formation, although significant biomass reduction was not observed under standard assay conditions. These findings contribute to the understanding of dendrimer-antibiotic interactions and their implications in antimicrobial and nanomedicine therapy.

microbiology↗

bioRxiv2026

A phage-encoded small RNA that mimics chimeric guide to inhibit CRISPR-Cas9

CRISPR-Cas9 relies on a dual crRNA-tracrRNA guide, yet whether RNA-based anti-CRISPRs exist for this system has remained unknown. Here we identify a phage-encoded small non-coding RNA, rAcrIIA1, that adopts an unexpected chimeric crRNA-tracrRNA architecture, faithfully recapitulating the entire single-guide RNA (sgRNA) of Cas9. Cryo-EM structures of the Cas9-rAcrIIA1 binary complex and the Cas9-rAcrIIA1-DNA ternary complex reveal that rAcrIIA1 engages Cas9 nearly identically to the native sgRNA, competitively blocking crRNA and tracrRNA loading and thereby abolishing DNA interference. Strikingly, beyond its natural inhibitory function, rAcrIIA1 is fully reprogrammable: with variable guide sequences, it directs Cas9 for sequence-specific DNA cleavage with efficiency comparable to the canonical sgRNA, and it activates trans-cleavage more potently. Thus, rAcrIIA1 provides the first experimentally validated, mechanistically resolved RNA-based inhibitor of CRISPR-Cas9, reveals a distinct anti-CRISPR mechanism through complete sgRNA mimicry, and serves as a versatile bifunctional scaffold for genome editing and diagnostics.

biochemistry↗

bioRxiv2026

The Drosophila IR20a Integrates L-arginine and Salt Signals via Distinct Subunit Assemblies

Amino acids and sodium salt are essential nutrients that frequently occur together in natural food sources. While animals typically employ distinct receptor subfamilies for specific taste modalities, the molecular mechanisms that integrate these concurrent nutritional signals at the peripheral level remain poorly understood. Here, we identify the Drosophila Ionotropic Receptor IR20a as a multimodal tuning receptor required for the detection of both the amino acid arginine and low NaCl salt. We find that IR20a is expressed in a subset of IR76b-positive gustatory receptor neurons (GRNs) distinct from GRNs dedicated to sweet or bitter taste. Mutation analysis and heterologous expression experiments demonstrate that IR20a functions combinatorially: it pairs with the core receptor IR25a to detect arginine, whereas the additional recruitment of IR76b is required to confer sensitivity to low salt. Crucially, we establish that IR20a/IR25a complex mediates synergistic responses to arginine-salt mixtures, thereby enhancing feeding preference. Furthermore, we reveal that IR20a provides a tonic, state-independent nutrient signal that operates in parallel to the starvation-modulated IR56b pathway to regulate NaCl feeding. Together, our studies uncover a molecular logic in which combinatorial assembly of receptor complexes enables the peripheral integration of complex nutritional signals.

neuroscience↗

bioRxiv2026

TRACE: a graph-based workflow for TCR-epitope prioritization and tumor-reactive T-cell identification

Accurate prioritization of T-cell receptor (TCR)-epitope interactions and identification of tumor-reactive T cells are important but difficult steps in immunotherapy-oriented bioinformatics workflows. Existing methods typically address these tasks separately and either model TCR-epitope pairs as independent observations or rely primarily on transcriptomic signatures. In this study, we present DUET (Dual Unified Evaluation of TCR-Epitopes and Tumor-reactive T cells), a graph-based computational workflow that unifies both applications within a single heterogeneous graph framework. The protocol represents TCRs, epitopes, and T cells as typed nodes connected by similarity and association edges, and combines pretrained sequence embeddings with edge-aware graph attention, Laplacian positional encoding, and bidirectional cross-domain attention. Applied to the IEDB and VDJdb benchmarks, DUET achieved AUROC/AUPR values of 0.937/0.922 and 0.992/0.990, respectively, outperforming five state-of-the-art algorithms. In addition, on a single-cell RNA-seq dataset, the workflow achieved an AUROC of 0.984 and an AUPR of 0.984, substantially exceeding transcriptomic signature-based baselines for tumor-reactive T-cell identification. Ablation analysis showed that Laplacian positional encoding provided the largest performance gain, particularly in sparse graph settings. These results suggest that heterogeneous graph modeling can serve as a practical protocol for integrating receptor sequence, antigen context, and cellular phenotype in computational immunology.

bioinformatics↗

bioRxiv2026

GAPVD1 regulates CSNK1D-dependent PER2 FASP phosphorylation

The mammalian circadian clock relies on precisely timed transcriptional and post-translational events to generate [~]24-hour rhythms. A key post-translational mechanism is phosphorylation of PER2 by CSNK1D, governed by a phosphoswitch that integrates stabilizing and destabilizing phosphorylation marks at the FASP and Degron sites to control PER2 stability and circadian period. Here, a novel role for the PER complex protein GAPVD1 in regulating CSNK1D-mediated FASP site phosphorylation is revealed. GAPVD1 associates with PER2 and CSNK1D via a distinct helical bundle domain, weakening PER2-CSNK1D association and attenuating PER2 FASP phosphorylation in cells and in vitro. Mechanistically, this helical bundle interacts with the PER2 casein kinase binding domain and is contacted by the adjacent VPS9 region in GAPVD1, providing a structural explanation for how flanking GAPVD1 domains can control access of binding proteins to the helical bundle. Notably, a minimal GAPVD1 helical bundle fragment is sufficient for binding to PER2 and CSNK1D but not for robust attenuation of PER2 FASP phosphorylation, indicating that additional regions of GAPVD1 are required. GAPVD1-mediated inhibition of PER2 FASP phosphorylation also turned out to be independent of the CSNK1D C-terminal tail, pointing to mechanisms such as displacement of PER2 FASP from the CSNK1D active site or allosteric regulation of CSNK1D substrate engagement. Together, these findings identify GAPVD1 as a PER-complex scaffold that modulates the PER2-CSNK1D control node and introduce an additional regulatory layer into the circadian phosphoswitch. A GAPVD1 helical bundle domain binds the PER2 CKBD and CSNK1D to weaken PER2-CSNK1D interaction and attenuate PER2 FASP phosphorylation.

molecular biology↗

bioRxiv2026

Microbial Dynamics Across Commercial Spaceflights of Varying Duration

SummarySpaceflight introduces environmental stressors that can alter human microbiomes and immune responses. We analyzed 259 biospecimens from six astronauts across two commercial ISS missions: Axiom 2 (10-day mission) and Axiom 3 (21-day mission). Samples included saliva, stool, urine, and body swabs from 10 anatomical sites, profiled via 16S ribosomal RNA (rRNA) gene sequencing. Gut and oral microbiomes remained stable, while skin-associated communities exhibited transient diversity shifts post-flight. Taxonomic analysis revealed individual and site-specific patterns as well as a possible microbial acquisition from the ISS/space-flight environment and microbiome exclusivity. Cytokine profiling from single cell data indicated immune activation, with IL-32 and IL-16 elevated in Axiom 2 and Axiom 3, coinciding with microbial changes. These findings provide an integrated view of microbiome individuality, exclusivity and immune dynamics during two short-duration commercial spaceflights of three weeks, informing strategies for crew health on future long-duration missions.

microbiology↗

bioRxiv2026

Structural Lung Remodeling Precedes Functional Decline After Chronic Smoldering Douglas Fir Smoke Exposure in Apoe-/- Mice

Wildland firefighters experience repeated exposure to wildfire smoke, yet the pathophysiological mechanisms underlying chronic inhalation injury remain poorly understood. Although prior studies report parenchymal destruction following prolonged woodsmoke exposure, the temporal relationship between molecular, structural, and functional decline following inhalation of smoke from needles/leaves remains unclear. To address this gap, we characterized coordinated changes in lung structure, function, and underlying molecular disruptions using a dosimetry-based murine model approximating 7-14 years of firefighter service. Male apolipoprotein E-deficient mice were exposed to smoldering Douglas fir needle smoke (40 mg/m3, 2 h/day, 5 days/week) for 8 or 16 weeks. Immunofluorescence analyses revealed an early elastolytic response at 8 weeks, with increased neutrophil elastases and matrix metalloproteinases-9 and -12, accompanied by elevated surfactant protein-D, compared to air controls. These changes were resolved by 16 weeks despite progressive tissue injury. Airspace enlargement was evident at 8 weeks, progressed by 16 weeks, and included increased alveolar blunting and septal wall thickening at the later time point. Cleaved caspase-3 was elevated at 16 weeks, indicative of advanced parenchymal damage and apoptosis. Epithelial tight-junction protein ZO-1 intensity was reduced at both evaluation points, whereas the epithelial-to-mesenchymal marker N-cadherin remained undetectable in the alveolar epithelium. Functional impairment as evident by increased static compliance and upward shifts in pressure-volume curves was only significant after 16 weeks of exposure. Findings indicate that molecular and structural injury of tissue destruction preceded measurable functional decline, underscoring the need for early biomarkers to identify smoke-induced lung injury in wildland firefighters before function loss occurs.

physiology↗

bioRxiv2026

Autism associated Cntnap2 deletion disrupts vestibular sensory signaling and spatial cognition in mice

Autism spectrum disorder (ASD) is frequently accompanied by sensory and motor abnormalities, including impaired balance, postural control, and spatial orientation, that are often attributed largely to altered central circuitry. Emerging evidence, however, suggests that peripheral sensory dysfunction can also shape ASD related behavioral phenotypes. Here, we tested whether loss of the ASD associated gene Cntnap2/Caspr2 alters vestibular signaling in Cntnap2-/- mice. Developmental transcriptomic analysis showed that Cntnap2 is expressed in vestibular sensory organs and increases during the first postnatal month, coincident with vestibular pathway maturation. Vestibular sensory evoked potentials revealed reduced response amplitudes and prolonged latencies in Cntnap2-/- mice, indicating impaired peripheral afferent responses to transient linear acceleration. Cntnap2-/- mice also showed delayed contact righting, reduced ocular counter roll, and increased hindlimb slips and compensatory tail excursions during balance beam walking, whereas rotational vestibulo-ocular reflex gain and phase were preserved. These vestibular and balance abnormalities were accompanied by reduced novel arm preference in the Y maze and severe impairment of Barnes maze acquisition, consistent with impaired spatial learning. Together, these findings identify Cntnap2/Caspr2 as a regulator of vestibular sensory signaling and support a model in which disrupted peripheral vestibular input, likely acting together with central effects of Cntnap2 loss, contributes to sensorimotor and spatial cognitive phenotypes relevant to ASD.

neuroscience↗

bioRxiv2026

Interplay of stability and dynamics in the optimization of a highly proficient de novo enzyme

The development of highly active de novo enzymes that catalyze new-to-nature reactions is becoming increasingly possible. Here, we identify the features underlying the catalytic efficiency of a highly proficient de novo enzyme, from the original computational design to an optimized catalyst obtained through two rounds of directed evolution. Computational, spectroscopic, and biochemical studies reveal successfully designed features, including precise alignment of catalytic residues, transition state stabilization, and environmental tuning. In the most evolved enzyme, binding of a transition state analog also led to widespread increases in backbone conformational stability throughout the protein, except within a helix near the active site entrance, where the introduction of Gly and Pro increased dynamics and catalytic activity. Thus, the entire protein contributes to catalysis in the most optimized enzyme. Also, the initial design considered only the transition state but not substrate binding, leading to a dynamic Michaelis complex prior to optimization. These studies show the multiple features that need to be optimized to achieve high activity in a designed enzyme.

biochemistry↗

bioRxiv2026

An AI-agent-orchestrated grey-box Transformer framework for sparse pharmacokinetic curve reconstruction and pharmacometric model initialization

Clinical pharmacokinetic (PK) modelling is constrained by sparse sampling, limited general-isability of single-drug models, and labour-intensive workflows, making it difficult to infer complete drug exposure from limited concentration observations. We present the Pharmacokinetic Foundation Model (PKFM), a grey-box Transformer framework pre-trained across 32 drugs that reconstructs concentration-time profiles from sparse concentration observations, dosing events, molecular descriptors, and physiological covariates while preserving output interpretability. In representative oral PK curves, three sparse input points recovered the principal absorption-elimination trajectory, achieving coefficient of determination (R2) = 0.992 for Midazolam oral and R2 = 0.990 for Verapamil oral. Using reconstructed curves in NONMEM (nonlinear mixed-effects modelling) improved covariance stability and individual prediction accuracy. Contrastive-learning embeddings supported Top-10 physiologically based pharmacokinetic (PBPK) candidate retrieval, with 75.6% of observations within the 2-fold range. A pharmacometrics-informed AI Agent (PM Agent) outperformed general-purpose programming tools in stability and pairwise win rate on a standardised modelling benchmark, with each run requiring human pharmaco-metrician confirmation before downstream use. These results support cross-drug pre-trained PK models as an information-completion layer for sparse PK evidence and a structured scaffold for the modelling workflow; clinical or regulatory use requires prospective validation, broader external benchmarking, and independent expert assessment.

pharmacology and toxicology↗

bioRxiv2026

Distinct and shared synergistic effects of high-fat and high-iron diets on liver tumorigenesis and transcriptomic remodeling in mice

Background and AimsThe incidence of hepatocellular carcinoma (HCC) is increasingly driven by metabolic risk factors, including obesity and iron overload. Although high-fat and high-iron diets independently promote hepatocarcinogenesis, their shared and distinct molecular effects remain unclear. We sought to define how dietary fat and iron differentially shape HCC development. ApproachMale C3HeB/FeJ mice were exposed to long-term high-fat (HFD), high-iron (HID), or combined (HFD+HID) diets for 16.5 months. Tumor burden, hepatic iron distribution, mTOR signaling, oxidized phospholipid (OxPL) accumulation, and transcriptomic alterations across normal, adjacent non-tumor, and tumor liver tissues were analyzed using biochemical, histological, and RNA sequencing approaches. ResultsAll diets induced HCC with comparable tumor burden. HID increased iron levels in non-tumor liver tissue but resulted in relative iron depletion within tumors, indicating tumor-specific iron utilization. Tumors from all diet groups showed robust mTOR activation and increased OxPL accumulation, with stronger oxidative stress signatures in HFD and HFD+HID tumors. Transcriptomic analyses revealed conserved oncogenic programs alongside diet-specific signatures, with HFD exerting a dominant effect on metabolic reprogramming and gene dysregulation, whereas HID preferentially enhanced immune and inflammatory signaling. Progressive, monotonic changes in gene expression were observed across disease stages. Cross-species analyses linked diet-induced mouse tumors to immunologically "hot" human HCC subtypes. ConclusionsDietary fat and iron promote HCC through overlapping yet distinct molecular pathways, highlighting metabolic and immune mechanisms as key targets in diet-associated liver cancer.

cancer biology↗

bioRxiv2026

M1 macrophage-mediated lymphangiogenesis aggravates liver fibrosis via MDK/YAP signaling pathway

BackgroundLymphangiogenesis plays a critical role in various liver diseases, yet its function in liver fibrosis remains controversial. This study aimed to explore the role of lymphangiogenesis in liver fibrogenesis and its underlying regulatory mechanisms. MethodsLiver fibrotic mice were established by carbon tetrachloride (CCl4) or Thioacetamide (TAA)-induced injection or bile duct ligation. Lymphatic vessels were marked by podoplain (Pdpn) staining in mice and D2-40 staining in clinical samples. Lymphatic vessels area and density were measured to indicate lymphangiogenesis. Multiplexing immunohistochemistry was used to detect co-localization of proteins. ResultsIn the present study, we first verified increased lymphangiogenesis in human and murine fibrotic livers. Afterwards, we identified VEGFC rather than VEGFD as the primary driver of lymphangiogenesis in liver fibrosis. Furthermore, we demonstrated that M1 macrophages serve as the major source of VEGFC. Founctional studies revealed that VEGFC-mediated lymphangiogenesis exacerbates hepatic fibrosis, while its inhibition alleviated fibrosis. Bioinformatic analysis uncovered Midkine (MDK) as a key downstream of lymphangiogenesis. Both in vivo and in vitro studies confirmed that exogenous MDK promotes liver fibrosis via activating hepatic stellate cells (HSCs), whereas MDK inhibition counteracts the profibrotic effects of VEGFC-induced lymphangiogenesis. Importantly, we discovered that MDK activates HSCs through the Hippo/YAP signaling pathway. ConclusionsM1 macrophage-mediated lymphangiogenesis aggravates liver fibrosis via MDK secretion, which activates HSCs. These findings provide novel insights into coordinated crosstalk between macrophages, lymphatic endothelial cells and HSCs in liver fibrosis and suggest lymphangiogenesis and MDK as potential therapeutic targets for fibrotic liver diseases.

molecular biology↗

bioRxiv2026

Biosynthesis of bisbenzylisoquinoline alkaloids

Bisbenzylisoquinoline alkaloids (bisBIAs) are pharmacologically valuable plant metabolites with complex stereochemical architectures, yet the catalytic principles governing their assembly have remained largely unclear. Here, we elucidate the enzymatic pathway to cyclic bisBIAs and uncover a non-canonical redox-mediated mechanism for post-assembly stereochemical control. We identify cytochrome P450 enzymes that catalyze regioselective oxidative dimerization and macrocyclization of benzylisoquinoline monomers, establishing the macrocyclic scaffold. Subsequent stereochemical specification is achieved by a paired oxidase-reductase module that selectively epimerizes a single stereocenter through a transient imine formation, converting (R,S)-configured intermediates to (S,S)-products. Reconstitution of the pathway in yeast enabled production of both native bisBIAs and non-natural analogs, demonstrating pathway modularity and engineering potential. These results establish the biochemical principle underlying bisBIA biosynthesis and provide a framework for programmable biosynthesis of these complex natural products.

biochemistry↗

bioRxiv2026

IRF7 deficiency increases disease severity independently of TLR7 recognition in Influenza A infection in mice

Influenza A virus (IAV) remains a major cause of respiratory morbidity and mortality, yet the role of Toll-like receptor 7 (TLR7), an RNA sensor, and its downstream signaling events, such as interferon regulatory factor 7 (IRF7), in IAV infection remain unclear. To address this question, we used single-cell RNA sequencing, genetic mouse models, and immunological analysis. Single -cell transcriptomic profiling of the infected lungs revealed robust upregulation of Tlr7 and genes associated with interferon pathways in dendritic cells and B cells, alongside widespread induction of Irf7 across immune and non-immune compartments. Tlr7-deficient mice exhibited normal viral control, lung pathology, and survival following IAV challenge. In contrast, Irf7 deficiency resulted in significantly increased disease severity, impaired early interferon responses, exacerbated bronchial epithelial hyperplasia, and defective early humoral priming. In assessing adaptive immunity, both Irf7-deficient andTlr7-deficient mice had reduced antihemagglutinin antibody production. Mechanistically, IRF7 protein expression and downstream signaling were largely preserved in TLR7-deficient mice, indicating that IRF7 activation during IAV infection occurs independently of TLR7. Collectively, these findings identify IRF7 as a non-redundant determinant of innate immunity and disease outcomes during IAV infection, while positioning TLR7 as a modulatory factor primarily influencing adaptive immune maturation. Our study refines current models of antiviral sensing by uncoupling receptor induction from functional necessity and highlights IRF7 as a critical downstream regulator dictating host defense against acute influenza A infection. ImportanceInfluenza A virus is a respiratory pathogen that remains a major threat to global health as a seasonal disease and a source of periodic pandemics. The outcomes of the infection can range from mild illness to severe pneumonia and death, particularly in vulnerable populations, yet the reasons why some individuals develop more severe disease are not fully understood. Early immune defenses in the lungs are critical for controlling the virus, but they can also contribute to harmful inflammation if not properly regulated. In particular, key sensors that detect viral genetic material and the signaling pathways that activate antiviral responses play an essential role in shaping these outcomes. The significance of our study lies in defining how these early immune mechanisms influence the course of influenza A infection, providing insight that may guide the development of improved therapies for influenza and related respiratory viruses.

immunology↗

bioRxiv2026

Aptamer charge-amplified field-effect transistor biosensors achieve picomolar detection limits for small-molecule biomarkers in complex biological matrices

Aptamers are attractive receptors for small-molecule biomarker detection in complex samples because of their high stability, affinity, and specificity, but aptamer-based sensors generally lack the sensitivity to detect low-abundance analytes. As a solution, we developed the charge-amplified FET (CAFET) aptamer biosensor, which is designed to amplify the net charge variation within the Debye length that occurs as a consequence of aptamer-target binding. Our sensor utilizes a strand-displacement aptamer switch, which releases an initially-hybridized displacement strand (DS) upon target binding and thus induces a measurable net charge variation within the Debye length that is amplified to a large FET current response as signal readout. This signal can be further enhanced by adding a charge label to the DS. As a consequence, our sensor can achieve far greater sensitivity than previously described aptamer-FET sensors, where the binding-induced local charge variation is modest. We demonstrate 3-hydroxykynurenine and progesterone detection with a picomolar limit of detection in undiluted human plasma--four orders of magnitude lower than the dissociation constant (KD) of the aptamer component. The CAFET sensor design is modular and should be adaptable for the detection of a wide range of clinically-informative low-abundance analytes in complex samples.

bioengineering↗

bioRxiv2026

Force-Gated Thrombosis (FGT): A Non-Equilibrium Mechanical Theory of Shear-Induced Blood Clot Initiation

Arterial thrombosis is initiated when mechanical forces in flowing blood exceed the activation thresholds of platelets and von Willebrand factor (vWF). Despite extensive experimental characterization of shear-induced platelet aggregation, a unified theoretical framework that maps hemodynamic forcing onto clot nucleation is lacking. Here we present Force-Gated Thrombosis (FGT), a non-equilibrium mechanical theory that treats thrombus formation as a continuous phase transition driven by an effective mechanical forcing {Sigma} ={sigma} + |{nabla}{sigma}| + {beta}{varepsilon}, which combines local wall shear stress{sigma} , shear gradient |{nabla}{sigma}|, and extensional strain rate{varepsilon} . We introduce a dimensionless Thrombosis Number {Theta} = ({Sigma}/{Sigma}c)(P/P0)m(C/C0)n, which incorporates platelet concentration P and coagulation factor concentration C, and governs the transition between stable flow ({Theta} < 1) and active clot growth ({Theta} > 1). The thrombus density is represented by a scalar order parameter{varphi} whose dynamics follow a Ginzburg- Landau free energy functional. For a simplified stenosed artery we derive an analytic closed-form thrombosis onset criterion and a critical flow rate [Formula], where{delta} is stenosis severity. Linear stability analysis shows that perturbations grow at rate{omega} (k) = {Lambda}({Theta}) - D{varphi}k2, becoming unstable when {Theta} > 1. Near threshold the clot volume fraction scales as{varphi} [~] ({Theta} - 1)1/2, a mean-field critical exponent consistent with Ginzburg- Landau theory. Systematic comparison with fifteen published experimental and computational datasets spanning shear rates from 100 to 15,000 s-1 confirms that FGT correctly predicts the existence, location, and approximate severity of pathological thrombus formation across diverse vascular geometries. The theory provides a quantitative bridge between single-molecule mechanobiology and macroscale clinical thrombosis, and yields experimentally testable predictions distinguishing FGT from purely biochemical models.

biophysics↗

bioRxiv2026

Occupationally Relevant Wildfire Smoke Inhalation Impairs Nitric Oxide Signaling and Promotes Progressive Aortic Stiffening in Hypercholesterolemic Mice

BackgroundWildland firefighters experience repeated occupational exposure to wildfire smoke at high particulate matter (PM) concentrations, leading to elevated cardiovascular disease risk and hypertension prevalence. However, the pathophysiological processes linking cumulative smoke inhalation to vascular damage and blood pressure elevation remain poorly characterized. To evaluate these effects under controlled exposure conditions, we used a preclinical exposure model calibrated to match the cumulative PM burden deposited in wildland firefighter airways over 7-14 years of service. Male apolipoprotein E knockout (Apoe-/-) mice underwent whole-body inhalation of Douglas fir smoke or filtered air for 2 hours/day, 5 days/week, for 8 or 16 weeks at target PM concentrations of 40 mg/m3. ResultsProlonged smoke exposure induced sustained elevation of circulating tumor necrosis factor-alpha (TNF-), interleukin-1 beta (IL-1{beta}), and interleukin-6 (IL-6), coupled with diffused nuclear factor kappa B (NF-{kappa}B) activation throughout the aortic wall. Smoke inhalation disrupted endothelial adherens junctions, upregulated intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and promoted monocyte recruitment to aortic tissues, concurrent with enhanced monocyte chemoattractant protein-1 (MCP-1) expression. Oxidative stress was evidenced by increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 2 (NOX2) expression, elevated superoxide levels, and endothelial nitric oxide synthase (eNOS) uncoupling in the aorta, leading to lipid peroxidation and accompanied by intimal apoptosis. These inflammatory and oxidative perturbations occurred alongside a pro-fibrotic phenotypic shift characterized by transforming growth factor beta 1 (TGF-{beta}1) upregulation, myofibroblast differentiation, and progressive collagen accumulation in medial and adventitial compartments of the aortic wall. Functionally, smoke exposure progressively impaired aortic cyclic distensibility through combined wall thickening and circumferential tissue stiffening, while severely attenuating endothelium-dependent and nitric oxide (NO)-mediated vasodilation. These functional and structural shifts culminated in elevated systolic and diastolic blood pressures. While endothelial dysfunction reached maximal impairment by 8 weeks, aortic stiffening continued to worsen through 16 weeks of exposure, demonstrating differential temporal progression of vascular damage. ConclusionsThese findings demonstrate that occupationally relevant wildfire smoke exposure produces convergent inflammatory, oxidative, and profibrotic vascular remodeling with progressive loss of arterial compliance and impaired endothelium-dependent vasodilation, underscoring potential vascular targets for cardiovascular health surveillance and risk mitigation in wildland firefighters.

pharmacology and toxicology↗