Biology subjects

Chen, Y.

Publications and source records attributed to Chen, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2026

Expectation Shapes Neural Preparation for AI-generated and Real Image Processing: Evidence from EEG

AbstractAI-generated images, videos, and news have become an inseparable part of daily life, leading to increasing skepticism toward online information. Understanding how expectations about the presence of AI-generated content influence perception is crucial for elucidating the underlying neural mechanisms and facilitating the generation of naturalistic avatars. In this study, we analyzed an existing EEG dataset (N = 29) in which participants viewed emotional facial photographs of only real individuals while being informed that upcoming faces were either real ("REAL") or AI-generated ("FAKE"). We examined pre-stimulus oscillatory activities in the one-second EEG interval before stimulus onset and found significantly lower alpha power when participants expected "FAKE" compared to "REAL" faces. This effect was region-specific, particularly in right occipito-parietal and temporo-parietal regions, as identified by both sensor- and source- level analyses. In addition, the modulation effect between pre-stimulus alpha activity and post-stimulus event-related potentials (ERPs) was measured. A significant correlation between changes in late positive potential (LPP) amplitudes and pre-stimulus alpha power was observed exclusively for "FAKE" smiling faces, consistent with our previous findings. These results suggest that AI-related expectations modulate neural preparatory states, with lower alpha activity presumably reflecting increased attentional demands for stimuli believed to be artificially generated. This study demonstrates that top-down beliefs systematically shape both pre- and post-stimulus neural dynamics, providing new insights into how cognitive expectations bias perceptual processing, with implications for understanding human-AI interaction and improving the design and evaluation of AI- generated content in real-world contexts.

neuroscience↗

bioRxiv2026

PEPC Gene Family Evolution Across Arecaceae: Complete Five-Subfamily Evidence for a Two-Lock Model of Irreversible C4 Exclusion

BackgroundC4 photosynthesis has evolved more than sixty times across flowering plants, but never in palms. Over 2,500 palm species have spent more than 100 million years in high-light, water-stressed habitats where C4 physiology would be advantageous, yet none have taken this path. Phosphoenolpyruvate carboxylase (PEPC) is the enzyme that gates entry into the C4 pathway. In every C4 grass, a commelinid-specific paralog called PEPC1 drives the CO2-concentrating mechanism that defines the syndrome. Until this study, one of the five palm subfamilies -- Ceroxyloideae -- had never been examined for PEPC gene content. ResultsWe present a complete PEPC census across 13 palm species spanning all five subfamilies (Calamoideae, Nypoideae, Coryphoideae, Ceroxyloideae, Arecoideae). Ceroxyloideae was characterized for the first time, using deep tBLASTn screening of ten million whole-genome shotgun reads. PEPC1 is absent from every palm species examined. Copy numbers are tightly constrained to 5-7 per genome, in stark contrast with the 6-25 copies found in grasses. A phylogenetic analysis of 337 PEPC sequences places all 55 palm loci at basal positions relative to the PEPC1 clade, consistent with the palm lineage having diverged approximately 120 million years ago -- roughly 15 million years before the PEPC1 duplication that occurred within the commelinids. Birth-death modeling reveals long-term gene family stasis in palms. Codon substitution analyses yield a genome-wide {omega} of 0.0582, indicating pervasive purifying selection and no signature of C4-specific adaptation. Coconut PEPC promoters uniformly lack the mesophyll-specific MESP-1/GT-1/DOF regulatory module that is required for C4-type gene expression. ConclusionsWe propose a Two-Lock Model of irreversible C4 exclusion in palms. The first is a Gene Lock: PEPC1 is phylogenetically absent from all five subfamilies. The second is a Regulatory Lock: the ancestral promoter architecture of palm PEPC genes lacks the cis-elements needed for mesophyll-specific expression. Together, these two locks -- one phylogenetic, one regulatory -- explain why C4 photosynthesis has never arisen in one of the largest C4-absent plant families. The model provides a testable framework for investigating other lineages that have remained closed to the C4 path.

evolutionary biology↗

bioRxiv2026

Multidimensional atlas of RNA-regulated proteins revealed by RNA-dependent thermal proteome profiling

RNA and proteins interact pervasively in cellular processes, yet the functional relevance of most RNA-binding proteins remains unknown. To address this, we developed RNA-dependent thermal proteome profiling (RTPP), a method that identifies RNA-regulated proteins (RRPs) by detecting changes in a proteins structural stability upon RNA binding, without requiring crosslinking or enrichment. Applying RTPP in HEK293T cells revealed 1,664 RRPs, including 257 previously undetected RNA-binding "orphans". One such orphan, SGK3, binds the lncRNA CASC15, facilitating its PtdIns(3)P binding, endosomal recruitment and kinase activity. We further generated a tissue-specific RRP atlas, identifying interactions unique to particular organs, including hippocampus-specific RRPs dysregulated in Alzheimers disease. Integrating RTPP with proximity labeling resolved RNA-binding heterogeneities across subcellular compartments. Live-cell RNase treatment also uncovered proteins associated with cell surface RNA, revealing that RO60 form nanoscale clusters with glycoRNA. RTPP provides a powerful approach to decipher functional RNA-protein interactions across multiple biological dimensions.

molecular biology↗

bioRxiv2026

AMPKγ2 Deacetylation Drives Nuclear Translocation and Doxorubicin-Induced Cardiomyopathy via Nucleolar Stress Signaling

Doxorubicin (Dox)-induced cardiomyopathy (DIC), characterized by cardiomyocyte apoptosis, remains a major clinical challenge in chemotherapy. The regulatory {gamma}2 subunit of AMP-activated protein kinase (AMPK{gamma}2) plays a key role in cardiovascular diseases, but its function in DIC is poorly understood. Here, we report that Dox induces isoform-specific deacetylation and nuclear accumulation of {gamma}2, triggering nucleolar stress and p53-mediated apoptosis. Mechanistically, HDAC3 and TIP60 interact with {gamma}2 and modulate the acetylation of multiple lysine residues within its nuclear localization signal (NLS), controlling its nucleocytoplasmic shuttling. Dox enhances HDAC3-mediated {gamma}2 deacetylation, thereby driving nuclear accumulation of the {gamma}2-containing AMPK ({gamma}2-AMPK) while suppressing the cytosolic AMPK activity. Nuclear {gamma}2-AMPK phosphorylates and inactivates TIF-IA, a key RNA polymerase I-specific transcription initiation factor, leading to nucleolar stress through inhibition of rRNA transcription. rRNA deficit triggers release of free ribosomal proteins (RPs), which bind to and inhibit the E3 ubiquitin ligase MDM2, resulting in p53 stabilization and activation of apoptotic signaling. Using genetically engineered cardiomyocytes and a DIC mouse model, we found that a deacetyl-mimetic {gamma}2 mutant (6KR) exacerbated DIC, whereas an acetyl-mimetic mutant (6KQ) was cardioprotective. Collectively, our findings establish acetylation-driven nuclear translocation of {gamma}2 as a critical node linking Dox-induced nucleolar stress to p53-dependent apoptosis and suggest a promising cardio-oncology strategy that combines HDAC inhibitors with Dox to mitigate DIC. Significance statementDoxorubicin is an effective cancer drug, but its use is limited by cardiomyopathy. Our study reveals that doxorubicin drives HDAC3-mediated deacetylation of AMPK{gamma}2, exposing its nuclear localization signal and redirecting {gamma}2-containing AMPK from the cytoplasm to the nucleus. Nuclear AMPK{gamma}2 phosphorylates TIF-IA, suppresses ribosomal RNA synthesis, and activates a nucleolar stress pathway that stabilizes p53 and promotes cardiomyocyte apoptosis. In mice, a deacetylation-mimetic AMPK{gamma}2 mutant worsens doxorubicin-induced cardiomyopathy, whereas an acetylation-mimetic mutant is protective. These findings uncover an acetylation-controlled spatial switch in AMPK signaling and identify the AMPK{gamma}2 deacetylation-nucleolar stress axis as a potential target for reducing chemotherapy-associated cardiac injury.

cell biology↗

bioRxiv2026

IL-21-producing peripheral helper T cells associate with autoimmune bile duct injury in biliary atresia

BackgroundBiliary atresia (BA) is a severe neonatal liver disease characterized by progressive fibrosis and bile duct obliteration. ObjectiveAlthough immune dysregulation is implicated in the pathogenesis of BA, the specific mechanisms driving bile duct injury remain incompletely understood. This study aimed to characterize tertiary lymphoid structures (TLSs) within extrahepatic biliary remnants (EBRs), identify their cellular mediators, and evaluate the therapeutic potential of targeting IL-21 receptor signaling. DesignWe performed integrated bulk RNA sequencing, single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and flow cytometry on clinical samples from BA patients and non-BA cholestatic controls. TLS maturation was assessed by CD23 immunohistochemistry in EBRs from 148 BA patients and correlated with clinical parameters. Anti-IL-21R antibody treatment was evaluated in a rhesus rotavirus-induced BA mouse model, with treatment initiated on day 4 post-infection. ResultsTLSs were identified in BA EBRs with significantly higher prevalence than in matched liver tissues. Mature TLSs containing CD23 germinal centers were associated with elevated serum matrix metalloproteinase-7, more advanced hepatic fibrosis, and localized autoantibody deposition on injured bile ducts. Single-cell profiling revealed expanded CD4+ T peripheral helper (Tph) cells expressing IL-21 and CXCL13 within TLS-containing EBRs. Tph cells were enriched in peripheral blood of BA patients compared to non-BA cholestatic controls (P = 0.0025), and serum IL-21 was significantly elevated (P < 0.0001). Post-infection IL-21R blockade in the mouse model reduced jaundice incidence, improved weight gain, prevented extrahepatic biliary obstruction, and significantly improved long-term survival. ConclusionTLSs in BA extrahepatic biliary remnants harbor expanded Tph cells associated with IL-21-mediated B cell activation and bile duct injury. IL-21R blockade ameliorated disease in a murine BA model, identifying the IL-21/IL-21R axis as a potential therapeutic target warranting further investigation. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSImmune dysregulation contributes to biliary atresia (BA), with documented lymphocyte infiltration and defective B cell tolerance. However, the cellular mechanisms linking local immune activation to bile duct injury are unclear, and the roles of organized lymphoid structures and specific CD4 T cell subsets in orchestrating local humoral responses have not been characterized. What this study addsThis study demonstrates that mature tertiary lymphoid structures in extrahepatic biliary remnants are associated with disease severity markers and localized bile duct injury in BA. We identify T peripheral helper cells as an expanded IL-21-producing CD4 T cell population within these structures, and show that post-infection IL-21 receptor blockade prevents biliary obstruction and improves survival in a murine BA model. How this study might affect research, practice or policyThese findings identify the IL-21/IL-21R signaling axis as a candidate therapeutic target in BA warranting further preclinical and translational investigation. TLS maturation status in biliary remnants and serum autoantibody levels may serve as potential biomarkers of disease severity, meriting prospective evaluation in clinical cohorts.

immunology↗

bioRxiv2026

CellPilot: an agentic framework that pilots small language models through autonomous single-cell annotation

Large language models can annotate cell types from marker gene lists, but they typically operate after preprocessing and clustering are complete, treating annotation as a terminal labeling step rather than controlling the analytical decisions that produce the evidence for cell identity. We present CellPilot, an agentic framework that guides a locally deployable small language model through the full single-cell analysis workflow, from raw count matrices to cluster-level annotation. CellPilot combines standard single-cell analysis tools with structured workflow control and observation-guided reasoning, allowing the model to plan analyses, execute tools, inspect intermediate results and revise decisions within a traceable session. On GTEx, structured workflow orchestration raised the same 8B model from 0.39 in a prompt-only setting to 0.89, closing most of the gap to GPT-4o (0.92) within the same framework; the framework gain was substantially larger for the smaller backbone across datasets (+0.35 versus +0.19). Across GTEx, Tabula Sapiens, and Mouse Cell Atlas, CellPilot achieves cluster-level annotation accuracies of 0.891, 0.750, and 0.773, outperforming representative reference-based, marker-based, and LLM-based methods. CellPilot confidence scores were associated with annotation correctness and supported post hoc filtering, while complete execution traces were retained for each analysis. These results suggest that structured workflow orchestration can be a critical determinant of performance in multi-step single-cell analysis, enabling locally deployable small language models to approach larger proprietary models while preserving transparency and practical usability.

bioinformatics↗

bioRxiv2026

Chromosome-level genome assembly of Calotes wangi with dynamic colour variation

The Wangs garden lizard, Calotes wangi, is a widely distributed agamid species in Southern China and Northern Vietnam and exhibits pronounced colour variation and rapid body colour change. Despite increasing interest in the genomic basis of colour variation, chromosome-level genomic resources remain limited in agamid lizards. Here, we generated a chromosome-level reference genome of C. wangi using PacBio HiFi sequencing and Hi-C scaffolding. The final genome assembly was approximately 1.66 Gb in size and comprised 6 macrochromosomes and 11 microchromosomes, with a contig N50 of 110.09 Mb and 98.9% complete BUSCO genes. A total of 20,442 protein-coding genes were annotated. Comparative genomic analyses identified 297 significantly expanded gene families, with enriched functions associated with steroid metabolism, chromatin regulation, and epigenetic processes. This high-quality genome assembly provides an important genomic resource for future studies of colour variation, phenotypic plasticity, and evolutionary diversification in agamid lizards.

evolutionary biology↗

bioRxiv2026

Muscle March5 restrains an ATF4-GDF15 endocrine stress axis that modulates feeding and body composition

Skeletal muscle can release endocrine stress signals during aging and wasting, but the upstream mechanisms that restrain this response remain incompletely defined. Here we identify March5 as a muscle proteostatic checkpoint that limits ATF4-dependent GDF15 production. March5 expression declined in aged and atrophic muscle, whereas muscle-specific March5 deletion induced ATF4 accumulation, marked GDF15 elevation, reduced food intake and progressive loss of body, muscle and bone mass. Restoration of feeding, GDF15 neutralization or muscle Atf4 deletion substantially attenuated the wasting phenotype. Mechanistically, March5 interacted with ATF4 and promoted its ubiquitination at K92, thereby limiting ATF4 stability and Gdf15 expression. Conversely, muscle March5 gain-of-function or pharmacological attenuation of ATF4 signaling improved feeding, body composition and physical performance in aged mice. These findings define a March5-ATF4-GDF15 endocrine stress axis linking muscle proteostatic control to feeding suppression and systemic body-composition remodeling.

physiology↗

bioRxiv2026

TFAP2A links drug resistance to antitumor immunity

Combination targeted therapy with BRAF/MEK inhibitors and immune therapy show promising therapeutic outcomes in melanoma; however, the development of drug resistance still represents a formidable challenge. Remaining unexplored is the possibility that BRAF/MEK inhibitors themselves inadvertently compromise the tumor immune microenvironment, limiting the efficacy of immunotherapy when it is used in combination with targeted inhibitors. Herein, we profiled the landscape of the BRAF regulatome identifying a novel transcription factor, TFAP2A, newly linking BRAF/MEK drug resistance to antitumor immunity. Specifically, we found that BRAF/MEK inhibitors significantly upregulate TFAP2A. Further, genetic disruption of TFAP2A overcomes BRAF/MEK-inhibitor resistance, promotes stromal enrichment, and enhances intratumoral infiltration of macrophages in an immune-compromised mouse model. In a syngeneic mouse model, TFAP2a knockout not only suppresses tumor growth but also induces potent anti-tumor tertiary lymphoid structures (TLSs). Single cell transcriptomics revealed that the absence of TFAP2A shapes the antitumor microenvironment with an influx of M1-like macrophages, CD8+ T cells and mature dendritic cells. By identifying TFAP2A as a shared driver of both targeted therapy resistance and immunosuppression, our work offers a one-stone-two-bird strategy to overcome drug resistance and elicit antitumor immunity.

cancer biology↗

bioRxiv2026

A quantum interface with mitochondrial bioenergetics

Summary ParagraphRecent work has shown that genetically engineered proteins can serve as quantum bits in living systems. These quantum bits arise from the photochemistry of protein-bound flavins: blue-light excitation drives electron transfer to form a spin-correlated radical pair whose coherent singlet-triplet interconversion makes the proteins fluorescence sensitive to weak magnetic fields. Because this radical-pair reaction depends on the redox state of the flavin--itself a central electron carrier in cellular metabolism--the magneto-fluorescence of a biological qubit is intrinsically coupled to the biochemistry around it. This suggests a powerful application of fundamental significance in biology, until now an unsolved problem in the field of quantum sensing. Here we show a new class of quantum sensor, mtMagLOV2, that interfaces directly to a defining feature of life itself: the bioenergetic state of the cell. We genetically engineer flavin mononucleotide (FMN)-containing, magnetic-field-sensitive fluorescent proteins ("biological qubits") to be expressed and translocated into the key bioenergetic machinery of the cell: the mitochondrial matrix. Using confocal and super-resolution microscopy, mtMagLOV2 localizes to the mitochondrial cristae, home of the electron transport chain complexes I-V and ATP synthase--the site of oxidative phosphorylation (OXPHOS). By pharmacological manipulation of OXPHOS, we show that the sensors magneto-fluorescence tracks the redox (oxidation-reduction) state of the mitochondrial flavins, providing a quantum readout of redox status. The response differs between cancer cells (which rely heavily on glycolysis) and cardiomyocytes (which rely predominantly on OXPHOS), demonstrating "quantum bioenergetic profiling". Together, these results establish biological qubits as quantum sensors capable of probing mitochondrial bioenergetics, opening a quantum window into the energetic machinery of living cells. More broadly, we anticipate that coupling quantum redox sensitivity to specific biochemical targets will extend the reach of quantum technologies across the life sciences.

biophysics↗

bioRxiv2026

CSGDA: A Cell State-Guided Graph Domain Adaptation Network for Single-Cell Drug Response Prediction

Intratumoral heterogeneity drives cancer recurrence and metastasis, yet single-cell drug response prediction faces severe "cross-domain" challenges, such as applying in vitro models to in vivo tissues or inferring metastatic resistance from primary tumors. These scenarios trigger distribution shifts arising from heterogeneous sequencing platforms, distinct tissue microenvironments, and metastatic evolution--problems rarely addressed by existing methods. We introduce CSGDA, a cell state-guided graph domain adaptation framework designed to predict drug responses across these biological heterogeneities. CSGDA incorporates biological priors to map gene expression into functional cell states, guiding a structure learning module to construct robust cell topology. To conquer distribution shifts, the model employs graph domain adaptation combined with a novel overlap penalty mechanism. Extensive benchmarks on five scRNA-seq datasets demonstrate that CSGDA outperforms state-of-the-art methods, achieving an average gain of [~]6% in ACC and AUPR. Beyond prediction accuracy, we employed integrated gradients to effectively pinpoint key genes involved in drug resistance within a challenging cross-metastasis cisplatin dataset. These findings underscore CSGDAs superior performance in single-cell drug response prediction and its potential in resolving single-cell heterogeneity, paving the way for precision medicine.

bioinformatics↗

bioRxiv2026

Medin-Induced Pro-inflammatory and Prothrombotic Activation of Coronary Artery Endothelial Cells: A Potential Novel Mediator Linking Aging and Atherosclerosis

BackgroundAge is the most important risk factor for coronary artery disease (CAD) independent of traditional risk factors. Aging induces classic pro-inflammatory and prothrombotic vascular phenotypic changes whose molecular mediators remain poorly understood. Medin is a common cleavage product protein that accumulates in vasculature with aging and shown to cause endothelial dysfunction. Its role in CAD is unknown. The study aimed to evaluate the effects of medin on human coronary artery endothelial cell (HCAEC) pro-inflammatory and prothrombotic activation and establish the relationship between medin and coronary atherosclerosis in human decedents. MethodsHCAECs were exposed to physiologic dose of medin (5 {micro}M) for 20 hours and ribonucleic acid sequencing (RNAseq) with signaling pathway analyses and reverse transcription polymerase chain reaction of select pro-inflammatory and prothrombotic genes performed. Corresponding protein expression was measured by Western blot or enzyme linked immunosorbent assay in HCAECs exposed to medin (5 {micro}M) without or with nuclear factor-{kappa}B (NF{kappa}B) inhibitor RO106-9920 (10 {micro}M). Coronary arteries from 40 deceased individuals underwent immunohistochemistry and medin and plaque burden were quantified and their relationship evaluated. ResultsRNAseq showed predominant pro-inflammatory gene expression changes induced by medin. HCAECs treated with medin showed increased phosphorylated NF{kappa}B, elevated protein expression of interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and plasminogen activator inhibitor (PAI)-1 and reduced protein expression of thrombomodulin; these changes were reversed by RO106-9920 co-treatment. In human tissues, coronary artery medin strongly correlated with plaque burden (R=0.76, p<0.0001) and coronary macrophage content (R=0.72, p<0.0001). Coronary arteries from decedents with myocardial infarction had higher medin than those without (5.53{+/-}2.67% versus 0.02{+/-}0.02%, p=0.0005). ConclusionsMedin induced NF{kappa}B-mediated endothelial cell pro-inflammatory and prothrombotic activation and was strongly associated with coronary plaque burden and inflammation. Medin is a novel candidate mediator linking aging and coronary atherosclerosis.

physiology↗

bioRxiv2026

A molecular integrator of sleep duration and interruption

Sleep is regulated across multiple timescales. Transitions between sleep and wake happen within seconds1,2; individual sleep bouts last minutes to hours3; and homeostatic sleep need has classically been tracked across multiple bouts4. Rapid sleep-to-wake transitions are driven by identified neurons, circuits, and neuromodulators1, while slow wave activity correlates with sleep need across hours5,6. However, no signal has been shown to encode sleep history within individual sleep bouts, the timescale at which the brain must continuously monitor how much sleep has occurred and how likely waking is at any given moment. Biochemical signals downstream of sleep/wake-associated neuromodulators display slower dynamics than the neuromodulators themselves7,8, making them candidate encoders of within-bout sleep history. Here, by measuring protein kinase A substrate phosphorylation (PKA-SP) in real time in freely behaving mice7-9, we show that membrane PKA-SP decreases exponentially within each sleep bout with consistent kinetics across bouts, integrates sleep duration and sleep interruption, and continuously forecasts moment-to-moment waking probability. Following sleep deprivation, PKA-SP reaches lower levels at the end of sleep bouts, correlating with increased sleep need dissipation. These findings identify a molecular signal encoding within-bout sleep history, revealing how biochemical dynamics bridge fast arousal circuits and the slow timescale of classical sleep homeostasis.

neuroscience↗

bioRxiv2026

Behavioral and Functional Profiling of Acomys cahirinus Fibroblasts Reveals Enhanced Matrix Remodeling Capacity

The African spiny mouse (Acomys cahirinus) exhibits a unique capacity among mammals for scarless tissue regeneration, making it a compelling model for investigating the cellular mechanisms underlying regenerative healing. To determine how cellular heterogeneity and specific phenotypes influence fibroblast behavior, we established an immortalized Acomys fibroblast line along with a CRISPR/Cas9-mediated Col3A1 knockout variant and a DNA damage-induced senescent population. Compared with Mus musculus, NIH 3T3 fibroblasts, Acomys cells displayed distinct morphology, similar migration speeds, reduced directional persistence, and greater biophysical heterogeneity. While previous studies have linked regenerative wound healing to the elevated expression of collagen type III (Col3A1), CRISPR-mediated knockout of Col3A1 in Acomys fibroblasts yielded comparable biophysical profiles to wild-type cells in 2D culture. To examine additional contributors to the enhanced wound-like matrix environment, we established a senescence model in which Acomys fibroblasts exhibited elevated resistance to DNA-damaging agents, complete loss of proliferation, and altered single-cell morphology. In 3D collagen gel contraction assays, Col3A1 knockout attenuated matrix remodeling capacity, whereas the introduction of a small fraction of senescent cells enhanced gel contraction and remodeling dynamics, suggesting that senescent fibroblasts can modulate collective matrix behaviors. Together, these findings demonstrate that both Col3A1 expression and senescence-associated cell states contribute to fibroblast-driven matrix remodeling, highlighting Acomys fibroblasts as a valuable model for investigating how cellular heterogeneity and senescence-associated cell phenotypes could influence regenerative wound healing.

bioengineering↗

bioRxiv2026

A vascular chip for disease-relevant flow shear stress topology

Vascular chips have advanced endothelial mechanobiology by enabling controlled responses to hemodynamic cues, yet disease-relevant wall shear stress (WSS) modeling remains limited. Simplified one-dimensional flow shear systems, designed mainly for physiological mechanobiology, miss the topological organization of pathological flow, whereas patient-specific vascular models capture complex hemodynamics but sacrifice generality and imaging compatibility. Here we develop a programmable vascular chip that converts disease-associated WSS topology into a physiologically parameterized experimental input. The device reconstructs a representative pathological shear-topology field on endothelial layer, supports stationary and physiologically paced oscillatory flow modes, and integrates matched unidirectional-shear references within the same chip. Using this system, we show that oscillatory WSS topology destabilizes endothelial monolayers, drives asymmetric collective emergent behaviors, impairs actin-nuclear mechanotransduction, accompanied by nuclear softening and enhanced perinuclear nanoparticle uptake. Integrated live-cell imaging, fluorescence analysis, Brillouin microscopy, and transport assays enable multimodal phenotyping across collective, subcellular mechanical and functional scales. By making disease-relevant WSS topology experimentally controllable, this vascular-chip framework bridges computational hemodynamics and experimental mechanomedicine, supporting standardized vascular disease modeling and functional screening.

bioengineering↗

bioRxiv2026

Connectome-scale self-supervised representation learning reveals neuronal organization beyond canonical labels

Dense electron-microscopy connectomes provide synaptic-resolution maps of neuronal structure and wiring, but learning scalable representations that integrate structure and connectivity for connectome discovery with minimal human intervention remains difficult. Here we present a self-supervised framework for structure-connectivity representation learning in dense connectomes. A hierarchical graph neural network with skeleton decomposition enables contrastive learning from finely sampled FlyWire neuronal skeletons, showing that fine skeletons preserve substantially richer identity information than coarse representations. Coordinate-free topology reduces developmental and geometric confounds, improving clustering and label-efficient inference. We then use learned structural embeddings as continuous descriptors of synaptic partners to construct structure-driven connectivity representations, improving subtype discrimination without predefined partner-type labels. Iterative multi-hop learning further reveals higher-order organization, including hemispheric connectivity lateralization and connectivity-defined subgroups. Attention analysis links these differences to specific synaptic partners. Together, these results establish a self-supervised and scalable framework for discovering neuronal identity and connectome organization in a large-scale dense connectome.

neuroscience↗

bioRxiv2026

GIGYF2/4EHP-Mediated Translational Attenuation Maintains Cellular Homeostasis Following Ionizing Radiation

Translational regulation is a critical component of the cellular response to environmental stress. Ionizing radiation (IR) exists naturally at low doses (e.g., cosmic rays and radioactive materials) but is applied at much higher doses in clinical settings, where accelerated photons (X-rays) and particle beams (protons, ions etc) are utilized for the treatment of cancer. While the effects of IR on DNA damage and cell cycle are well established, its impacts on cellular RNA metabolism remains less understood. In particular, the role of the mRNA translation machinery in shaping the early cellular response to IR is largely unexplored. Here, we demonstrate that IR induces an acute and persistent translational repression. This acute repression is independent of the mTOR and Integrated Stress Response pathways, which are known regulators of mRNA translation in response to environmental cues. Instead, we discovered that the translational repression is, at least partially, mediated by the GIGYF2/4EHP translational repressor complex. We show that GIGYF2/4EHP recruitment to the mRNAs upon IR exposure is driven by rapidly enhanced interactions with RNA-binding proteins such as ZFP36 and components of the miRNA-Induced Silencing Complex (miRISC) that are poised on their target mRNAs. Importantly, the presence of the GIGYF2/4EHP complex is required for the maintenance of proteostasis and cell viability following irradiation. Together, our results establish mRNA translational control as a key determinant of cellular response to IR and identify GIGYF2/4EHP as a critical component of this adaptive mechanism.

cell biology↗

bioRxiv2026

Revising the genetic and epigenetic architecture of in vitro regeneration capacity in natural Arabidopsis thaliana populations

Plant regeneration is a dynamic developmental process that spans from cell dedifferentiation to organ reconstruction in response to inductive cues, such as wounding stress and hormonal signals. Although this capacity varies widely both between and within species, a comprehensive understanding of the genetic and epigenetic bases of this variation remains incomplete. To address this issue, we revisited published datasets on natural variation in in vitro regeneration capacity in Arabidopsis thaliana. Using quantitative genetic approaches, including meta-analyses of genome-wide association studies (GWAS) and multi-locus models, we dissected the genetic architecture underlying regeneration traits. Our results showed that shoot regeneration capacity is primarily explained by allelic variation in the cis-regulatory region of WUSCHEL (WUS), a key regulator of shoot meristem formation. Notably, these polymorphisms are also associated with epigenetic variants of the DNA transposon ATDNA2T9C, which is located within the regulatory region. Furthermore, allelic variation in ARABIDOPSIS RESPONSE REGULATOR 2 (ARR2), a positive regulator of cytokinin signaling, is associated with callus formation and greening traits and may promote shoot formation through genetic interactions with WUS alleles. Although in vitro regeneration is controlled by complex, multilayered gene regulatory networks, our results suggest that, in A. thaliana, natural variation in regeneration capacity is largely shaped by a small number of major-effect modifiers together with epigenetic variation and genetic interactions, despite the substantial heterogeneity observed among natural populations.

genetics↗