Biology subjects

Liu, X.

Publications and source records attributed to Liu, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

DYNAMIC CONFORMATIONS IN THE ACTIVATION OF PINK1 KINASE

Under mitochondrial stress, the mitochondrial kinase PINK1 is activated to phosphorylate ubiquitin, which in turn recruits the E3 ligase Parkin, thereby initiating clearance of damaged mitochondria. Dysregulation of the PINK1-Parkin signaling pathway is associated with early-onset autosomal recessive Parkinson's disease. However, the mechanisms governing PINK1 conformational dynamics and activation in response to mitochondrial stress remain poorly understood. Here, we report that Tribolium castaneum PINK1 (TcPINK1) forms specific symmetric dimers via interactions between the kinase N-lobe and the regulatory C-terminal domain. These dimers undergo dynamic conformational transitions across distinct states, including an autoinhibited state, an inactive intermediate state, a primed-activation state and an active state. Moreover, TcPINK1 undergoes lateral trans-phosphorylation through dimer-dimer interactions. Notably, symmetric dimer formation is essential for Parkin recruitment during mitophagy. These findings provide a framework for understanding the conformational plasticity and allosteric regulation of PINK1 in mitophagy.

biophysics↗

bioRxiv2026

MOLECULAR BASIS FOR PINK1 MATURATION

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a key regulator of mitophagy, has been linked to the pathogenesis of Parkinson's disease (PD). PINK1 recruits Parkin, an E3 ubiquitin ligase, triggering mitophagy in response to mitochondrial damage. During mitophagy, the quantity, stability, and activity of PINK1 must be strictly regulated; however, the mechanisms governing these parameters under cellular stress are still unclear. Herein, we determined the structural basis for PINK1 maturation mediated by heat shock protein 90/cell division cycle 37/FK506-binding protein 51 (HSP90/CDC37/FKBP51) chaperone complex. We identified PINK1-associated proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and determined the structures of the complexes using Cryo-Electron Microscopy (Cryo-EM). Results showed that FKBP51 potentially interacts with a conserved leucine-proline-phenylalanine (LPF) motif on the activation loop of PINK1 and negatively regulates PINK1 functions in mitophagy. A PINK1 mutation located at the FKBP51 recognition site is linked to mitophagy deficiency, which can be partially rescued by specific inhibition of FKBP51. These findings reveal a general mechanism for PINK1 recognition by the HSP90/CDC37/FKBP51 chaperone complex and suggest a potential approach for upregulating PINK1 activity, which is impaired in PD.

biophysics↗

bioRxiv2026

AFilter: Improved Antibody Epitope Prediction by Machine Learning-Optimized Interface Energy Filtering of AlphaFold3-Predicted Complex

AlphaFold3 (AF3) predicts protein-complex structures from sequence with near-experimental accuracy on many targets, substantially lowering the cost of mechanistic and therapeutic discovery. However, application to antibody epitope prediction is hampered by an approximately 63% failure rate. Comparing successful and failed AF3 predictions across antibody-antigen and nanobody-antigen complexes, we found that failed predictions share a distinctive energetic signature: distorted CDR-loop geometries and elevated van der Waals strain at the interface. Building upon these observations, we developed a machine learning-based interface energy filtering framework, designated AFilter, capable of eliminating over 90% of erroneous predictions while retaining >90% of true positives. Compared with ipTM-based filtering, AFilter improved accuracy from 82.7% to 97.7% for nanobody-antigen complexes and from 79.4% to 96.3% for antibody-antigen complexes, while simultaneously raising the true positive rate from 69.8% to 96.4% and from 63.1% to 92.5%, respectively. When applied to NeuroMab antibodies of unknown structure, AFilter prioritized high-confidence epitope predictions that AF3 sampling alone could not reliably surface. As a lightweight post-hoc filter (<5% computational overhead) that requires no re-docking, AFilter is directly compatible with existing AF3 prediction pipelines and, in principle, transferable to other diffusion-based complex predictors, providing a practical quality-assurance layer for antibody epitope mapping in early-stage drug discovery.

bioinformatics↗

bioRxiv2026

TEAD1 signaling modulates adrenal chromaffin maturation

Chromaffin cells synthesize and secrete catecholamines to coordinate systemic stress responses and regulate diverse neuroendocrine and metabolic functions. However, the molecular mechanisms governing chromaffin-cell differentiation and their disruption in pheochromocytoma (PC) remain incompletely understood. Here, through integrated analyses of human developmental atlases, patient-derived transcriptomic datasets, genetically engineered mouse models, and chromaffin organoids, we identify TEAD1 signaling as a critical regulator of chromaffin-cell differentiation and function. In vivo studies using a chromaffin cell-specific TEAD1 overexpression mouse model demonstrated that suppression of TEAD signaling markedly compromises chromaffin-cell differentiation and endocrine function. Additionally, compared with other TEAD family members, TEAD1 transcriptional activities are readily affected by sequences near the binding motif. To identify therapeutically actionable regulators of TEAD1 signaling, we established a TEAD activity-based screening platform and identified the serotonin receptor HTR5A antagonist SB699551 as a potent modulator of chromaffin-cell state. SB699551 suppressed PC-cell proliferation in vivo, and remodeled catecholamines synthesis in primary human PC cells. Additionally, application of SB699551 to human PC tumor revealed a subpopulation of primary chromaffin cells sensitive to this compound. Mechanistically, CXXC5 and L1CAM were identified as downstream SB699551-TEAD1 signaling effectors mediating chromaffin-cell proliferation and differentiation. Overall, we demonstrate that TEAD1 signaling is a fundamental mechanism regulating chromaffin cell differentiation and that modulation of TEAD1 signaling via SB699551 offers a new area of investigation in chromaffin cell biology.

molecular biology↗

bioRxiv2026

What do satellite vegetation indices actually measure? Photosynthetic capacity rather than transient physiological function across 328 global FLUXNET sites

A direct empirical relationship between gross primary productivity (GPP) estimated by the eddy covariance method and satellite vegetation indices (VIs) has been widely observed across diverse ecosystems globally. Building on this observed covariation, VIs are frequently utilized as critical parameters - such as the fraction of absorbed photosynthetically active radiation (fPAR) - within light use efficiency (LUE) and greenness-based models for carbon cycle monitoring. However, actual canopy carbon assimilation is jointly governed by slowly evolving structural parameters and highly dynamic functional traits, such as physiological efficiency. The extent to which the macro-scale VI-GPP covariance is driven by structural scaffolding, and how this structural signal decouples from physiological function under environmental stress, remains to be systematically quantified. Here, we synthesized half-hourly eddy covariance measurements from 328 globally distributed sites and paired them with a rigorously angle-normalized Enhanced Vegetation Index (nadir view and fixed solar zenith angle at 30 degrees, EVI_SZA30). By applying a nonlinear light-response curve model across 54,720 high-frequency temporal windows, we mechanistically disentangled observed actual GPP (GPP_EC) into baseline photosynthetic capacity (P_c) and intrinsic quantum yield (alpha). Our results demonstrate that the macroscopic covariance between EVI_SZA30 and GPP_EC (R^2=0.554) is primarily driven by the index's robust ability to track structural capacity (P_c, R^2=0.538). In contrast, EVI_SZA30 exhibits limited sensitivity to high-frequency variations in functional traits like physiological efficiency (alpha, R^2=0.038). Particularly in water-limited biomes (e.g., open shrublands and woody savannas), intense environmental stress triggers rapid stomatal regulation while the physical canopy structure remains relatively stable. Consequently, the correlation between EVI and P_c becomes notably stronger than its correlation with actual GPP_EC, highlighting a pronounced structural-physiological decoupling. Because discrete overpasses by sun-synchronous polar-orbiting satellites face intrinsic temporal constraints in capturing sub-daily physiological down-regulation (e.g., midday photosynthetic depression), future monitoring paradigms could greatly benefit from the continuous, high-frequency observations provided by next-generation geostationary (GEO) satellites to bridge the gap between structural parameters and transient ecosystem function.

ecology↗

bioRxiv2026

Context-dependent variant interpretation from Mendelian disease to genetic predisposition: a proof-of-concept using LPL

As genomic sequencing evolves beyond rare disease diagnostics toward population screening and precision medicine, clinical variant interpretation is increasingly challenged by variants whose clinical consequences depend on biological context. Current frameworks, including the ACMG/AMP guidelines, generally assign a single classification to each variant regardless of inheritance state or genetic context, potentially failing to communicate context-dependent clinical consequences. Here, we address this issue using loss-of-function variants in LPL as a uniquely informative model system in which residual physiological LPL activity can be directly quantified in vivo. By systematically integrating published biallelic LPL genotypes, physiological measurements, functional studies, and clinical phenotypes, we identified a biologically meaningful transition at approximately 10% residual physiological LPL activity. Activity below this level was predominantly associated with classical childhood-onset familial chylomicronemia syndrome (FCS), whereas higher activity was associated with phenotypic attenuation and modifier-dependent clinical expression. Furthermore, heterozygous loss-of-function variants exhibited an estimated penetrance of 5-7% for severe hypertriglyceridemia. We therefore propose a context-dependent framework in which biallelic complete- or near-complete loss-of-function genotypes are interpreted as causative for FCS, whereas heterozygous variants are interpreted as predisposing to severe hypertriglyceridemia while retaining recognition of FCS carrier status. Together, our findings demonstrate that clinical variant interpretation should integrate available biological context--including, where relevant, allelic configuration, residual biological function, and penetrance--rather than rely on the intrinsic molecular consequence of the variant alone. More broadly, this framework provides a conceptual model for interpreting variants across the continuum from Mendelian disease to genetic predisposition in the era of precision medicine.

genetics↗

bioRxiv2026

Port of Protein-Protein Interactomes: An experiment-based protein-protein interactome database for rice

Protein-protein interactions (PPIs) play a crucial role in enabling proteins to carry out their functions within various biological processes (Hui et al., 2003). Since the introduction of the yeast two-hybrid (Y2H) method for PPI detection in 1989 (Fields and Song, 1989), the identification of PPIs has become a significant focus in modern biological research. PPI goes beyond examining individual proteins, allowing researchers to establish a comprehensive network that regulates biological processes. Rice, as a key model organism in plant biological studies, has been at the forefront of PPI research. In 2008, prominent rice scientists in China called for concerted efforts to define a comprehensive protein-protein interaction network experimentally, which aimed to facilitate the prediction of the functional mechanisms operating throughout a plants lifecycle (Zhang et al., 2008). With efforts for 2 decades, the experimentally identified rice PPIs have reached over ten thousand. Several public databases have been established to systematically collate and store PPIs, including STRING (Szklarczyk et al., 2019), BioGRID (Oughtred et al., 2020), IntAct (del Toro et al., 2022), PRIN (Gu et al., 2011), RicePPINet (Liu et al., 2017) and RiceNet v2 (Lee et al., 2015). However, most PPI datasets in rice stem from computational predictions, while experiment-based rice PPI datasets are fragmented due to the lack of systematic profiling at the rice PPIome level, which largely hinders information sharing in the rice research community. To bridge this gap, we constructed the Port of Protein-Protein Interactomes (POPPIN; https://riceome.hzau.edu.cn/poppin/), an integrated database dedicated to sharing experimentally verified PPIs and functional clues in rice. Empowered by high-throughput PPIome profiling technologies and text mining assisted by a large language model (Huang et al., 2025; Liu et al., 2025), POPPIN currently has deposited over 150,451 pieces of rice PPI-related information. Additionally, POPPIN provides detailed protein information, including GO annotations, subcellular localizations, domains, trait ontology (TO) information, and hyperlinks to external biological databases. Through offering a user-friendly web interface for search and dynamic network visualization, POPPIN serves as the first large-scale, experiment-based database for searchable PPIs in rice, and has the potential to be extended to other species under this structural framework.

systems biology↗

bioRxiv2026

Spatial cholesterol homeostasis gatekeeps T-cell development and activation by orchestrating signaling and fitness

Cholesterol is essential for T-cell immunity, and its spatial distribution is tightly regulated. Although cholesterol is synthesized in the endoplasmic reticulum (ER), it is predominantly transported to the plasma membrane (PM); however, the machinery mediating this anterograde transport in T cells remains unknown. Here, through a functional genetic screen, we identify oxysterol-binding protein (OSBP) as the principal mediator of ER-to-PM cholesterol transport in T cells. OSBP deficiency depletes accessible PM cholesterol while causing cholesterol accumulation in the ER, resulting in impaired T-cell receptor (TCR) signaling and disruption of ER homeostasis. Using stage-specific conditional knockout mice, we demonstrate that OSBP is required at multiple developmental checkpoints in the thymus, including {beta}-selection, positive selection, and post-selection maturation. Loss of OSBP during early thymocyte development causes a near-complete block in T-cell development, resulting in a profound absence of mature peripheral T cells. In mature T cells, activation markedly increases dependence on OSBP-mediated cholesterol transport, with its inhibition causing ER perturbation and extensive cell death. Finally, we show that disease-associated oxysterols disrupt OSBP-mediated cholesterol transport, leading to T-cell dysfunction and providing a mechanistic explanation for impaired T-cell immunity in pathological settings. Together, our findings identify OSBP as a central regulator of intracellular cholesterol transport that couples membrane cholesterol homeostasis to TCR signaling and ER integrity. These results establish the spatial distribution of cholesterol, rather than its abundance alone, as a fundamental metabolic determinant of thymocyte development and peripheral T-cell function.

immunology↗

bioRxiv2026

A multi-agent molecular optimization framework leads to a rapid-recovery intravenous anesthetic candidate with an improved safety margin

Lead optimization, the systematic refinement of therapeutic compounds through iterative structural modification, faces a dual challenge in modern drug discovery: navigating astronomically vast molecular design spaces while balancing conflicting demands on potency, pharmacokinetics, and safety. We present MASCOT (Multi-Agent SearCh for molecular OpTimization), a role-specialized multi-agent framework for molecular optimization. Integrated with a chemically constrained graph-editing search, MASCOT coordinates three specialized agents: a trade-off agent that reprioritizes competing objectives, a strategy agent that adapts how molecular edits are proposed, and a reflection agent that distills lessons from previous decisions. Computational experiments showed that MASCOT achieved the best performance over competing methods on six benchmark settings. On the SARS-CoV-2 main protease task, its mean docking-score improvement was 3.6 times that of the strongest baseline. Applied to the clinically used anesthetic remimazolam (RM), MASCOT prioritized RM-1, which showed a shorter liver microsomal half-life, higher brain exposure, and a larger therapeutic index than RM. Subsequent derivative design yielded RM-7. Extensive animal studies established RM-7 as a rapid-recovery intravenous anesthetic candidate with greater potency, faster functional recovery, a wider safety margin, and preserved flumazenil reversibility. These results demonstrate that multi-agent coordination can link adaptive molecular search to medicinal chemistry and experimental pharmacology.

bioinformatics↗

bioRxiv2026

The HES1-SOD1 Antagonism Shapes Senescence Heterogeneity and Impacts Metastatic Relapse of Circulating Tumor Cells

Circulating tumor cells (CTCs) encounter multiple challenges within the blood microenvironment, including oxidative stress, flow shear forces, and immune surveillance, often leading to anoikis. Recently, a transitional state of CTC senescence has been identified, contributing to metastatic inefficiency. However, the molecular mechanisms linking senescent CTCs to disease relapse remain to be defined. By integrating a genetic model of cortactin knockdown-induced CTC senescence with single-cell multi-omic analyses, we revealed two distinct senescent CTC subpopulations marked by HES1 expression levels. These HES1low and HES1high subpopulations exhibited differential evolutionary trajectory dynamics and unique molecular and metabolic signatures, which were significantly correlated with adverse clinical outcome across several patient cohorts. HES1low senescent CTCs displayed enhanced mitochondrial fitness, oxidative phosphorylation, and ROS-detoxifying capabilities, resulting in more efficient tumor regrowth with a pro-inflammatory and thrombotic phenotype when compared to the HES1high group. Mechanistically, HES1 directly bound to the Sod1 promoter and repressed its expression, leading to redox imbalance and mitochondrial dysfunction that were linked to weakened tumor regrowth capacity. Both senescent CTC subpopulations were broadly resistant to cytotoxic and targeted therapies, yet they showed elevated dependency on anti-apoptosis programs that make them susceptible to dual blockade by SOD1 inhibitor and the anti-senolytic drug ABT737 in vivo. Finally, in a prospective cohort of on-treatment melanoma patients, HES1 senescent CTCs were highly enriched in patients with progressive disease. Thus, the HES1-SOD1 antagonism shapes CTC senescence heterogeneity and contributes to differential tumor relapse, which can be therapeutically explored for eliminating residual metastatic disease.

cancer biology↗

bioRxiv2026

REM Sleep Disengagement of β Oscillations Permits Rapid Dream Movements in Parkinsonism

REM sleep behavior disorder is a hallmark of prodromal -synucleinopathies, yet why patients with Parkinsons disease can generate rapid, coordinated movements during REM sleep despite daytime bradykinesia remains unknown. Here we combined recordings of eye movements, cortical electroencephalography, and basal ganglia-thalamic neuronal activity across vigilance states in non-human primates before and after MPTP-induced parkinsonism. Parkinsonism enhanced {beta} oscillations and impaired movement-related neural dynamics during wakefulness and NREM sleep, whereas both pathological {beta} activity and motor impairments were attenuated during REM sleep. {beta} suppression preceded the onset of REM sleep, indicating that network reconfiguration begins before REM becomes behaviorally apparent. These findings demonstrate that Parkinsonian network dysfunction is dynamically gated by brain state rather than continuously imposed by dopamine depletion. REM sleep is a natural physiological condition in which {beta} oscillations are disengaged, uncovering a latent capacity, normally masked by REM atonia, for rapid movement even in the dopamine-depleted motor network.

neuroscience↗

bioRxiv2026

TRACER navigates rearrangement-driven sesterterpene chemical space via multimodal enzyme-product representation learning

Skeletal rearrangement drives the immense structural complexity of terpene, yet predicting it remains a formidable challenge due to sequence-function decoupling in terpene synthases. Here, we established TRACER (terpene rearrangement annotation via co-attentive enzyme-product representation), a multimodal framework mapping the latent associations between sequence-derived enzyme representations and product chemotypes. Retrospective validation proved TRACERs exceptional precision in predicting compound classes and discriminating skeletal rearrangement (SR) from non-skeletal rearrangement (NSR) pathways. TRACER-guided genome mining characterized two bifunctional synthases, FsPS and AcPS, uncovering four unprecedented carbon skeletons. Density functional theory calculations deciphered these cyclization cascades, pinpointing a critical 5/6/11 tricyclic intermediate as the key branching node for scaffold diversification. Mutagenesis and molecular dynamics simulations suggested that E305 in FsPS enables rearrangement by maintaining active-site water exclusion, whereas its alanine mutation causes premature carbocation quenching. Collectively, this work establishes a predictive paradigm for the rational discovery and mechanistic elucidation of complex terpene architectures.

synthetic biology↗

bioRxiv2026

Antibiotic condensates activate magnesium signaling to drive drug tolerance

The spatial distribution of small molecules within cells shapes their biological activity, yet these distributions are generally assumed to be governed passively by reaction-driven electrochemical gradients. Here we show that aminoglycoside antibiotics actively control their own subcellular organization by undergoing phase separation with RNAs. Combining in vitro reconstitution, bacterial assays, and molecular dynamics simulations, we discovered that aminoglycosides coacervate with RNA through multivalent electrostatic interactions, displacing and releasing RNA-bound Mg2+. This condensate-dependent Mg2+ release remodels the cytosolic labile Mg2+ pool and activates magnesium signaling. This effect dampens the magnesium-starvation regulation, sustains ribosome activity, and shifts the cellular electrochemical state, promoting bacterial fitness. Because condensation occurs only above a defined concentration threshold, it generates a non-monotonic dose-response in which higher antibiotic concentrations paradoxically enhance bacterial survival. This antibiotic condensate-dependent Mg2+ signaling confers tolerance to multiple ribosome-targeting antibiotics simultaneously even in cells lacking resistance gene, while condensate dissolution restores antibiotic efficacy. Our findings establish antibiotic-driven phase separation as a previously unrecognized mechanism to encode cellular signaling and identify antibiotic condensates as a distinct functional unit underlying drug tolerance.

microbiology↗

bioRxiv2026

Virtual-cell verification enables self-auditing AI discovery for immune rejuvenation

Artificial-intelligence agents propose drug-discovery hypotheses faster than experiments can test them, yet their conclusions are rarely verified, against the underlying biology, the predicted perturbation, or the agent's own scoring logic. We close this verification gap with an agentic framework built on three verifiers. First, PACE, a phenotype verifier, resolves immune aging into ten directionally scored, cell-type-resolved gene-set modules, selected for cross-cohort stability across four PBMC cohorts, and outperforms five established aging clocks in an independent in-house aging cohort of 434 elderly donors. Second, CellQ, a virtual-cell verifier built with multi-modal LLM, compresses each single-cell transcriptome into eight discrete tokens aligned to a language model's vocabulary through residual vector quantization; it attains state-of-the-art perturbation prediction and uniquely resolves the weak, module-level shifts that differential-expression recovery misses. Third, an Analyzer-Planner-Auditor agent verifies its own scoring logic: screening 110 compounds in primary human PBMCs, it found aged-down modules more reversible than aged-up modules and revised its objective from an equal-weight mean to a balance-constrained minimum, a self-correction that generalized to an independent 13-compound T-cell assay. By verifying its predictions and its own objective against experiment, the framework points beyond hypothesis-generating AI toward self-correcting AI scientists whose objectives could continuously evolve.

bioinformatics↗

bioRxiv2026

Hyperlipidemia abolishes, but immune balancing by DNase-I restores neuroprotection by MSC-derived extracellular vesicles

BackgroundOwing to their potent immunomodulatory properties, mesenchymal stromal cell (MSC)-derived small extracellular vesicles (EVs) have emerged as promising neuroprotective treatments for ischemic stroke. Preclinical studies using MSC-EVs have mainly been performed in young, otherwise healthy rodents. Stroke patients frequently carry vascular risk factors and comorbidities. We herein investigated whether MSC-EVs retain neuroprotective activity in hyperlipidemic mice on cholesterol-rich Western diet. MethodsMale C57BL/6J mice were exposed to regular normal diet or Western diet for 6 weeks. At the age of 9-10 weeks, mice were exposed to transient intraluminal middle cerebral artery occlusion (MCAO). Vehicle or MSC-EVs (2x106 or 6x106 cell equivalents) were intravenously administered immediately after reperfusion, and vehicle or rosuvastatin (5 mg/kg/day) were intraperitoneally applied starting immediately after or seven days before MCAO. Neurological deficits, ischemic injury, and immune responses were evaluated up to 72 hours post-ischemia. To investigate the hyperlipidemia-associated immune dysregulation, mice received DNase-I before or immediately after MCAO. In defined subgroups, monocytes/ macrophages or neutrophils were additionally depleted by clodronate liposomes or anti-Ly6G antibodies, respectively. ResultsIn contrast to normolipidemic control mice, MSC-EVs failed to induce post-ischemic neuroprotection in hyperlipidemic mice. Neither MSC-EV dose escalation nor rosuvastatin co-treatment restored the therapeutic efficacy of MSC-EVs. Hyperlipidemia induced systemic innate immune dysregulation characterized by reduced monocyte/ macrophage activation, increased neutrophil activation, and elevated circulating cell-free DNA. DNase-I treatment before, but not after MCAO reversed these immune abnormalities and restored neuroprotection by MSC-EVs, decreasing neurological deficits, infarct volume and brain edema. Depletion of either monocytes/ macrophages or neutrophils abolished the neuroprotective effects of MSC-EVs in DNase-I-pretreated hyperlipidemic mice. ConclusionsImmune dysregulation abolishes MSC-EV-induced neuroprotection after ischemic stroke in hyperlipidemic mice. DNase-I priming restores MSC-EV responsiveness through mechanisms critically involving monocyte/ macrophage and neutrophil rebalancing. Our data highlight the host immune status as determinant of EV therapeutic efficacy.

neuroscience↗

bioRxiv2026

Closed-loop optical optimization enables patterned retinal stimulation in vivo at cellular scales

Visual neuroscience requires precise spatiotemporal projection of optical stimulation onto the retina, especially in experimental mouse models. However, in vivo patterned stimulation in mice is profoundly hindered by the extreme optical power and severe anatomical aberrations of the eye. Consequently, visual stimulation relies mainly on unverifiable, open-loop approximations that often lack spatial precision. Here, we introduce a closed-loop, spatially modulated stimulation platform that overcomes these barriers. By integrating a digital micromirror device (DMD) with electronically tunable lenses (ETLs) and a real-time, fundus camera-guided focus optimization module, we directly verify the location of patterned stimuli on the retina while dynamically correcting for chromatic and geometric defocus. This platform delivers quantitatively verified static and dynamic patterned stimuli to the living retina with lateral resolutions as fine as 6.7 {micro}m. Guided by ray-tracing optical analysis, our work establishes a technological foundation that enables highly reproducible, cellular-scale interrogations of the visual pathway.

bioengineering↗

bioRxiv2026

A Reduced Mechanobiological Framework for Platelet Priming: From Hemodynamic Shear to Mechanosensitive Calcium Entry

BackgroundPlatelet activation in flowing blood is a multiscale process in which vessel-scale hemodynamics, red blood cell (RBC) mechanics, adhesive receptor interactions, and intracellular signalling jointly determine thrombotic risk. Individual components are well studied, but a single reduced description that carries each explicitly from vessel-scale flow to mechanosensitive calcium entry, with dimensionally consistent couplings, remains uncommon. ObjectivesWe develop and analyse a reduced, six-module mechanobiological framework for platelet priming spanning the cascade from hemodynamic shear to mechanosensitive calcium entry, and we delineate which elements are supported by existing evidence and which are new, testable hypotheses. MethodsThe framework comprises six coupled modules: (I) hemodynamic forcing from the incompressible Navier-Stokes equations, with an objective principal-strain-rate measure for extensional flow; (II) RBC-mediated platelet margination and near-wall delivery, closed by a near-wall arrival flux; (III) von Willebrand factor (VWF) activation with a bounded kernel and glycoprotein Ib (GPIb) catch-slip capture, resolved through an explicit contact area and a bond-dependent mobility that progressively immobilises wall-interacting platelets; (IV) a single-load membrane-stimulus formulation; (V) mechanosensitive gating and a dimensionally consistent cytosol-store calcium model with extracellular influx; and (VI) a phenomenological mechanical-memory state. We formally derive that the single-platelet stochastic dynamics and the continuum population balance form a Fokker-Planck pair, with the spatially varying diffusivity handled by an explicit drift correction. ResultsThe framework yields a family of mechanochemical dimensionless groups delineating priming regimes. Its central prediction is reformulated as a falsifiable, history-sensitive signature: in a conditioning-test protocol, a low-tension conditioning block charges the memory state, and a fixed sub-threshold test pulse then reports a delay-dependent calcium facilitation that decays on the memory time{tau} m and is distinguishable from no-memory gating, channel adaptation, and residual-calcium priming. We show explicitly that the previously proposed pulsatile-versus-monotone contrast is a nonlinear convexity/thresholding effect of the gating nonlinearity--its difference-in-differences is approximately zero-- and is therefore not a valid test of memory; the conditioning-test signature is. A second prediction links RBC stiffening to reduced near-wall delivery and captured-platelet calcium response, upstream of intrinsic platelet signalling. ConclusionsThe framework provides a dimensionally consistent, mechanistically grounded and hypothesis-generating description linking hemodynamic forcing to mechanosensitive calcium entry. It demonstrates how history-dependent platelet priming may arise from a phenomenological sensitisation state and proposes a conditioning-test protocol for comparison against adhesive, channel and intracellular-store persistence. The framework is calibratable rather than validated, and the quantitative outputs shown use representative uncalibrated parameters.

biophysics↗

bioRxiv2026

Aperiodic neural activity links electromagnetic and hemodynamic representations of domain-general cognitive demand across the cortical hierarchy

The human brain demonstrates remarkable flexibility and capacity for domain-general cognitive control, allowing us to perform diverse and complex tasks. Central to this ability is the multiple- demand (MD) network, a domain-general system that is robustly engaged during demanding tasks in fMRI studies. However, the electrophysiological signatures underlying these domain-general responses remain elusive. While recent research has implicated aperiodic neural activity as a promising candidate, the limited spatial resolution of non-invasive electrophysiology has left it unresolved how this aperiodic signal relates to demand-related activity within the MD network and whether this relationship reflects a broader organizational principle across the cortex. To address these questions, we used a multimodal fusion framework to integrate fMRI and magnetoencephalography (MEG) data acquired while participants performed a diverse set of cognitive control tasks. We found that raw MEG- fMRI correspondence was strongest in unimodal sensorimotor cortices and progressively decreased toward transmodal association cortex during cognitive control tasks, revealing a hierarchical decline in correspondence between the electromagnetic and hemodynamic signals measured by these technologies. However, the proportion of this variance that was attributable to cognitive demand and carried by aperiodic signals showed the reverse gradient, systematically increasing along the sensorimotor-association axis. In particular, in the MD network, aperiodic broadband power showed the strongest demand-specific cross-modal commonality, outperforming canonical oscillatory components. These findings reveal two opposing hierarchical gradients: overall MEG-fMRI correspondence across all electrophysiological signals decreased toward association cortex, whereas the proportion attributable to aperiodic signals associated with cognitive demand increased. Our results identify aperiodic neural activity as a key electrophysiological substrate of cognitive control and a bridge linking electromagnetic and hemodynamic representations across the cortical hierarchy.

neuroscience↗