Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

DancE: A DNA-Activated Bacterial cGAS-like Enzyme in Antiphage Immune Defense

Vertebrate cGAS senses DNA and synthesizes cyclic GMP-AMP to launch an immune response through the adaptor protein STING. Bacterial cyclic oligonucleotide-based signaling systems (CBASS) are evolutionarily related to the metazoan cGAS-STING pathway, but the molecular cues triggering bacterial cGAS activation remain poorly understood. Here, we identify a cGAS-like enzyme, termed DancE (DNA-activated di-nucleotide cyclase in Escherichia), that is activated by binding to double-stranded DNA. DancE is repressed by the bacterial chaperone DnaK, which prevents DNA binding by DancE. We further identified lambda phage prohead protease gpC that activates DancE through its protease activity. These results provide an example of a bacterial cGAS-like enzyme that is activated by DNA but through a guard-like mechanism that normally suppresses DNA sensing, suggesting that DNA sensing by cGAS family proteins is an ancient antiviral strategy conserved across kingdoms of life.

immunology↗

bioRxiv2026

Mesaconic acid delivery via biomaterials and engineered probiotics to the gut reduces inflammation in Crohn's Diseases mouse models

Mesaconate (MES, an immunosuppressive metabolite) but not itaconate is upregulated in stool of Crohns Disease (CD) patients, albeit below therapeutic levels.. However, colonic MES level is difficult to maintain because of its high absorption rate, limiting its therapeutic potential for CD. Herein, we developed two strategies that elevate MES level and suppress inflammation: EcN-CAD, an engineered probiotic Escherichia coli Nissle 1917 (EcN) that overexpresses cis-aconitate decarboxylase (CAD, produces itaconic acid that is converted to MES); and MES+Zn, a Zinc-MES ionically crosslinked formulation. Mechanistically, MES modulates T cell function by downregulating glycolytic and mitochondrial activity and decrease ROR{gamma}t expression. In preclinical SAMP1/YitFC dexamethasone-withdrawal model and TNFDARE model, MES+Zn decreased gut permeability significantly compared to controls and reduced myeloperoxidase (MPO, an inflammatory marker) 1000-fold compared to controls. EcN-CAD probiotics decreased ROR{gamma}t expression in CD4+ and CD8+ T cells, gut permeability and inflammation in preventive SAMP1/YitFC model, and SAMP1/YitFC dexamethasone-withdrawal model. Overall, MES rewires T cell responses and technologies that enhance MES levels can be effective in gut-related inflammatory diseases.

immunology↗

bioRxiv2026

A genome-scale ORF screen for resilience factors that protect the RPE and restore vision in aged mice

Aging is a complex phenomenon, yet therapeutic discovery has largely relied on testing individual hypothesis-driven targets. Here, we performed a genome-scale open reading frame (ORF) screen for oxidative-stress resistance in retinal pigment epithelium (RPE) cells, which are vulnerable to oxidative damage during aging. The screen identified nine protective ORFs including antioxidant factors and an epithelial-to-mesenchymal transition regulator. Notably, we also identified three factors that reduce transcriptomic age including the cardiac transcription factor NKX2-5. NKX2-5 conferred robust oxidative resilience in vitro and in vivo. Domain dissection revealed that its homeodomain is dispensable for resilience, enabling development of NKX2-5{Delta}HD, which retained protective activity without detectable toxicity over 14 months. In middle-aged mice, subretinal NKX2-5{Delta}HD restored visual and electrophysiological function, and its systemic delivery improved grip strength and reduced frailty in late-aged mice. These findings highlight the value of unbiased, genome-scale gain-of-function screening, as resilience factors normally expressed in other contexts can be reengineered as potential therapeutics for age-related decline in other tissues.

genetics↗

bioRxiv2026

Pectin is a critical contributor to the mechanical properties of Chara cell walls

Cellulose has long been viewed as the major load-bearing component in plant primary cell walls. Recent studies, however, suggest that pectin plays a significant role in cell wall mechanics despite a kPa-scaled modulus. Here we quantify the mechanical properties of centimeter-sized internodal cell walls of Chara corallina following treatments to remove calcium crosslinks or digest pectin. We also characterize the flow of water and gas through the cell wall as a function of pressure. We found that removal of calcium crosslinks did not affect wall strength and stress-relaxation behavior, yet it decreased the elastic modulus and increased permeability to water. In contrast, pectin removal had a dramatic impact on all measurements. Samples from which pectin had been removed exhibited lower strength and stiffness and had greater stress relaxation under constant strain. Pectin removal increased the permeability of the cell wall to water above that observed when calcium was removed and reduced the pressure at which gas "tunnels" through the cell wall ~ 2-fold. Our findings support the idea that pectin locally restricts the movement of cellulose microfibrils, with implications for understanding functional properties of primary cell walls in vascular plants and developing high-performance double-network materials.

biophysics↗

bioRxiv2026

Coordinated Brain-Network Dynamics of Maternal Adaptation

The maternal brain exhibits impressive plasticity, undergoing many anatomical and functional alterations over the transition to parenting. Such alterations can reflect maternal adaptation to offspring needs, aligning with the onset and maintenance of maternal care behaviors. These brain-wide neural changes occur across stages, starting during pregnancy and continuing through the peripartal transition. We therefore wanted to understand brain changes with pregnancy, parenting, and care behaviors over time. Many brain regions have been implicated in the coordination of maternal adaptation and corresponding care behaviors. We used computational modeling of multi-region neural oscillation data to identify distinct electrical networks during naturally-occurring care behaviors and across multiple maternal stages in outbred, highly maternal mice. This work demonstrates that multi-region oscillatory electrical dynamics at high spatiotemporal resolution reflect these functions. Distinct, discriminative networks predict maternal behavior and stage, showcasing network adaptation with parental transition. Maternal behavior and stage also had substantial effects on other distinct, multi-region oscillatory electrical networks relevant to stress susceptibility, further linking maternal adaptation to the neurophysiology of stress. While these stress networks were perturbed by maternal experience of early life stress, networks trained on maternal behavior and stage remained robust against such perturbation. This suggests a uniquely persistent strength of maternal electrical dynamics. Together, this work supports the role of oscillatory electrical dynamics as networks underlying fundamentally conserved behaviors and transitions, demonstrating wide relevance and significance to brain-behavior discovery.

neuroscience↗

bioRxiv2026

The diversity, evolution, and conservation of African plants

Africa hosts remarkable biodiversity across diverse biomes, yet its evolutionary history at continental-scale remains poorly understood. We integrate a time-calibrated phylogeny covering 93% of African vascular plant genera with continental-scale distribution data to jointly evaluate phylogenetic diversity (PD), endemism, and diversification rates (DR). We reveal a pronounced decoupling between DR and accumulated evolutionary history across Africa. Mountain, arid, and semi-arid areas emerge as centers of neo-endemism and elevated diversification, whereas lowland and humid regions, particularly the Guineo-Congolian zone, are dominated by older lineages with low recent diversification. Several DR hotspots do not overlap with Global Biodiversity Hotspots, indicating a mismatch between rapid diversification and accumulated evolutionary history. High net diversification and speciation rates during the last 15 million years were likely driven by cooling, aridification, and mountain uplift that created new ecological gradients and isolation barriers. These abiotic changes, interacting with lineage-specific traits, shaped African modern flora and highlight conservation gaps, especially in arid regions

evolutionary biology↗

bioRxiv2026

Lysosomal proteome and lipidome analyses of intestinal cells reveal the crucial role of bis(monoacylglycero)phosphate for autophagosome-lysosome fusion

The transport of about 70 enzymes to lysosomes depends on mannose 6-phosphate signals formed by GNPTAB. Editing of Gnptab in an intestinal mouse cell line revealed the loss of multiple lysosomal enzymes associated with the accumulation of sphingomyelins, ceramides, and cholesterol, and reduced levels of bis(monoacylglycero)phosphate (BMP) in lysosomal proteomes and lipidomes. By cross-correlation we identified two subsets of lysosomal lipid-modifying enzymes linked with mixed unsaturated or di-monosaturated BMP. Autophagy-related proteins functioning in early stages of autophagosome formation associated with neutral ceramides, whereas proteins involved in autophagosome-lysosome fusion correlated with negatively charged BMPs. Therefore, the high cholesterol and low BMP level of lysosomes might be causal for impaired autophagic flux in GNPTAB deficient cells. We propose a functional axis of three lysosomal proteins as potential target to improve the autophagic flux in cells with dysfunctional lysosomes and in a newly established intestinal organoid model suitable as novel experimental tool.

cell biology↗

bioRxiv2026

Tracing high transductive cohort AUC to same-site supervision in a site-aware population GNN for multisite fMRI

Population-graph models can use cohort-level context, complicating interpretation of strong multisite neuroimaging performance. We investigated which information pathways accounted for high transductive cohort discrimination in a site-aware heterogeneous population graph neural network for autism classification. Using a frozen ABIDE-I cohort (871 participants, 20 sites) and evaluation protocol, we applied controlled graph, feature, supervision, and architecture interventions to a clean-room re-implementation across C-PAC and NIAK preprocessing pipelines. Cohort out-of-fold AUC was approximately 0.94. A site-only graph retained similarly high discrimination (0.948 versus 0.941 for the full model), with no statistically significant difference detected. Removing same-site supervision under a site-wise intervention reduced AUC to 0.480, whereas a supervision-budget control retaining same-site supervision achieved 0.921. Among the alternative heads evaluated, the high cohort AUC was observed only with the sex-heterogeneous dual-channel head; a canonical topology-only Parisot-GCN did not reproduce it. A demographic classifier using site, sex, and their interaction achieved a best pooled AUC of 0.51. Under leave-one-site-out evaluation, AUC was 0.522 for C-PAC and 0.532 for NIAK, with confidence intervals including 0.5 and no clear evidence of unseen-site discrimination; an imaging-only reference achieved 0.653 and 0.588. Because leave-one-site-out evaluation jointly changes supervision availability, target-site topology, and training-domain composition, the decrease cannot be attributed to a single factor. These findings distinguish cohort-visible transductive performance from unseen-site generalization and motivate explicit site-only, no-graph, and site-held-out controls.

neuroscience↗

bioRxiv2026

Hierarchical chromatin polyvalency governs robust gene regulation and organogenesis

Precise temporal control of gene expression is fundamental for embryonic development, yet the epigenetic and chromatin basis governing transcriptional timing remain poorly understood. The bivalency model, characterized by coexistence of H3K4me3 and H3K27me3, has been proposed to mark a poised state ready for activation. However, this model has been challenged by lacking of rapid gene activation in response to H3K27me3 depletion, suggesting that the H3K27me3 mark is not responsible for the silencing. Here, through temporal epigenomic profiling of post-implantation mouse embryos and use of the protein degradation tag (dTAG) system, we demonstrate that H2Aub, but not H3K27me3, functions as the major repressor. We further reveal a hierarchical repression architecture in which H2Aub is responsible for transcriptional silencing, while H3K27me3 and H3K9me3 serve to reinforce the silencing state in post-implantation embryos. Functionally, disruption of this H2Aub-centered hierarchy perturbs temporal control of polyvalent gene activation, leading to severe organogenesis defects. Mechanistically, acute loss of H2Aub disrupts retinoic acid-FGF signaling pathway, causing somitogenesis arrest. Together, our findings establish chromatin polyvalency model as a multi-layered, hierarchical repression mechanism that governs temporal control of gene expression during embryogenesis.

genetics↗

bioRxiv2026

Melanoma evolution in the lymph node shapes systemic outcomes

Lymph node (LN) metastasis predicts poor patient outcomes, but the mechanistic drivers that shape metastatic fitness, immune evasion, and clinical impact remain elusive. While preclinical models indicate that active tumor adaptation is necessary for LN metastasis, observations of clonal heterogeneity in human tumors has supported a stochastic model of passive and continuous seeding. Reconciling LN metastasis as a passive or active process is essential to understanding if LN metastasis is simply a marker of disease progression or a clinically informative therapeutic target. Here, we report evidence that LNs are active niches that facilitate ongoing melanoma evolution to progressively subvert immune surveillance and enable progression. To construct a spatial trajectory of LN metastasis, we examined paired primary melanomas and metastatic sentinel LNs through integrated genomic, phenotypic, and immunologic analyses. In contrast to a model of continuous seeding, we observe that early dissemination from the primary tumor is followed by extensive intra-nodal diversification, indicating that metastatic outgrowth requires ongoing adaptation within the LN. As clones evolve in the LN, they re-differentiate towards a melanocytic state and reprogram the microenvironment for immune exclusion. In further evolved clones, loss of inflammatory interferon signaling and induction of p53 and mitochondrial stress are associated with decreased overall survival. Collectively, these results implicate the LN as a critical battleground for melanoma progression, where tumor evolution drives adaptation and immune escape to biologically link regional metastasis to patient survival.

cancer biology↗

bioRxiv2026

Automatic Quality Control and Error Correction in MRI linear registration via a Residual Parameter Prediction Network for T1w MRI

Errors in linear registration can propagate to downstream nonlinear registration and bias volumetric estimations, deformation-based morphometry (DBM) and voxel-based morphometry (VBM) analyses. Subtle linear registration errors are particularly challenging as they are difficult to detect and may not result in obvious failures in nonlinear registration but still affect downstream results. Therefore, accurate identification and correction of these errors are critical. In this study, we present the Residual Affine COefficient Optimization Network (RACOON), a framework designed to identify and correct linear registration errors in T1w MRI scans registered to the MNI-ICBM152 space. RACOON's correction module achieved a residual misalignment RMSE of 0.778 mm on synthetic dataset, comparable to the variability observed among repeated QC-passed registrations using the same pipeline. For the classification module, RACOON achieved a balanced accuracy of 76.8% and a precision of 74.4%, outperforming existing state-of-the-art methods. RACOON is open source and publicly available at https://github.com/ZhaojinChen/RACOON.

neuroscience↗

bioRxiv2026

J-domain proteins stimulate PKL-mediated chromatin compaction at H3K4-hypomethylated genomic loci

Chromatin accessibility varies widely across distinct genomic regions in eukaryotes, yet the mechanisms governing these differential patterns remain poorly understood. Here, we identify a subfamily of functionally redundant J-domain proteins (JDPs) that assemble into a protein complex with PICKLE (PKL), an evolutionarily conserved CHD3-type chromatin remodeler, in Arabidopsis thaliana. JDPs are required not only for maintaining PKL protein stability but also for stimulating its nucleosome remodeling and ATPase activities. A previously uncharacterized histone-binding domain (HBD) within JDPs specifically recognizes the N-terminal tail of histone H3 when the H3K4me3 modification is absent. This interaction enhances PKL-mediated nucleosome sliding and ATPase activities in vitro, and promotes PKL-dependent chromatin compaction at H3K4me3-depleted genomic loci in vivo. The PKL-JDP complex drives chromatin compaction to repress developmentally regulated genes, thereby governing key developmental phase transitions, including the embryo-to-seedling transition and flowering. Collectively, these findings uncover a distinct mechanism by which the absence of H3K4me3 is sensed to initiate regional chromatin compaction, repress developmentally regulated genes, and facilitate key developmental transitions.

plant biology↗

bioRxiv2026

Ileal Gpbar1 gates depressive phenotypes via gut to brain "vagal-NTS-PVN"GABAergic axis

Depression represents a typical mental condition, yet whether intestinal metabolic signals drive central neural circuits remains unclear. Here we identify ileal enteric neuronal Gpbar1 as a previously unrecognized peripheral node that coordinates gut-to-brain communication to prevent depression-like behavior through a vagus-dependent, nucleus tractus solitaries (NTS)-paraventricular nucleus (PVN) signaling axis. The enteric plexus Gpbar1 is predominantly expressed on a subpopulation of GAD1-positive GABAergic neurons. Chronic restraint stress suppresses Gpbar1 expression, triggers glycolytic reprogramming and mitochondrial distress in both ileum and hypothalamus. Oral Gpbar1 agonism with INT-777 reverses hypothalamic HK2/TOM20 alterations and behavioral abnormalities by enhanced ileal mTOR/HIF-1 alpah signaling and glycolysis-related metabolite shifts, an effect specifically abolished by subdiaphragmatic vagotomy or chemogenetic silencing of PVN GABAergic neurons. Our findings establish ileal Gpbar1 as a gut-derived metabolic sensor that engages a defined vagal-brainstem-hypothalamic inhibitory circuit to regulate depressive phenotypes, shifting the roadmap from brain-centered to gut-initiated antidepressant mechanisms and unveiling a compelling peripheral therapeutic strategy that bypasses intractable central brain-directed intervention.

neuroscience↗

bioRxiv2026

Dual-Mode Bio-CM2: Multimodal Computational Miniature Mesoscope for Fluorescence and Label-Free Imaging

Understanding biological function often requires complementary information on molecular identity, morphology, behavior, and physiology acquired simultaneously from the same specimen. Achieving this capability in miniature microscopes remains challenging because integrating multiple imaging contrasts typically increases optical complexity while compromising field of view (FOV), spatial resolution, or form factor. Here we present dual-mode Bio-CM2, a multimodal computational miniature mesoscope that simultaneously captures fluorescence and label-free reflectance through a shared optical architecture based on distributed computational optics. The system enables frame-interleaved, co-registered dual-mode imaging over a [~]7.5 x 10 mm2 FOV with [~]6 m lateral resolution. We demonstrate the versatility of dual-mode Bio-CM2 across diverse biological systems. In freely moving Caenorhabditis elegans, reflectance captures body posture and locomotor behavior that contextualize fluorescently labeled protein aggregates. In freely swimming larval zebrafish, reflectance captures whole-body morphology and swimming behavior, while fluorescence visualizes cardiac activity. In head-fixed mice, simultaneous fluorescence and reflectance imaging across the bilateral dorsal cortex provides complementary measurements of neuronal calcium activity and intrinsic hemodynamic signals. By integrating molecularly specific fluorescence with complementary reflectance contrast, dual-mode Bio-CM2 extends distributed computational optics into a scalable platform for multimodal miniature imaging.

bioengineering↗

bioRxiv2026

Genetic regulation of circulating metabolome in cattle

The circulating metabolome is a vital intermediate layer linking genetics to complex phenotypes, yet existing genome-wide studies-even in humans-rarely capture dynamic physiological contexts or cellular regulatory mechanisms. Here, we present the Cattle Metabolome Atlas (https://cattlema.farmgtex.org/), a comprehensive resource of 3,436 plasma metabolites and 4,851 serum metabolites from 4,651 animals with matched sequence-level genotypes across highly dynamic parity and lactation stages. We mapped 728 plasma and 622 serum metabolite quantitative trait loci (mQTL), revealing widespread context-dependent regulatory architectures. Integrating these mQTL with the multi-tissue expression quantitative trait loci (eQTL) and single-cell atlas of 59 tissues demonstrates that 74-79% of mQTL colocalize with eQTL across 29 tissues, prioritizing the liver as the primary systemic hub and resolving metabolic programs at single-cell resolution. Furthermore, we charted 538 causal gene-tissue-metabolite-trait cascades across 11 complex traits in cattle. Finally, cross-species analyses demonstrate partial evolutionary conservation of genetic metabolism between cattle and humans, establishing this atlas as a powerful asset for cattle genetics and genomics, selective breeding, and comparative biology.

genetics↗

bioRxiv2026

Concurrent model evidence computation and posterior sampling in continuous attractor network subspaces

Extensive studies suggest the brain performs Bayesian inference to infer the latent world states. It is a fundamental neuroscience question that how canonical recurrent neural circuits in the brain implement Bayesian inference. Many existing theoretical studies focused on how the recurrent circuits compute the posterior, while largely overlooking how the circuits compute the model evidence (normalization constant in Bayes' theorem), a key quantity that measures how well a model explains the observed data.Thus, it remains largely unknown about how the recurrent circuits compute the model evidence. The present study performs rigorous theoretical analyses of the continuous attractor networks, a canonical recurrent circuit model, and reveals that the nonlinear circuit dynamics can simultaneously compute the posterior and model evidence in first two dominant subspaces within the circuit dynamics. Specifically, the circuit dynamics in the stimulus feature subspace implements the Langevin posterior sampling, and the circuit dynamics in the subspace of total neuronal activity computes the model evidence in a way analogous to the evidence lower bound in stochastic variational inference. We further extend the circuit model to compute the model evidence of multiple inputs, and simulations validate the computation in the network. Our work for the first time reveals the concurrent model evidence and posterior sampling in subspaces in continuous attractor networks, significantly deepen our understanding of the computational algorithms adopted by the neural circuits.

neuroscience↗

bioRxiv2026

Functional Ultrasound Characterization of Spatiotemporal Cerebral Hemodynamic Responses Evoked by Whisker Stimulation

Functional ultrasound imaging (fUS) measures task-associated changes in cerebral blood volume (CBV) with fine spatial sampling and rapid acquisition, supporting functional mapping and brain-signal decoding. As an indirect measure of neural activity, fUS-CBV signals are shaped by neurovascular coupling and vascular dynamics, which influence the spatial and temporal stimulus information available for decoding. Consequently, the functional distinctions accessible in fUS-CBV signals require characterization under controlled experimental conditions. Here, controlled whisker stimulation in awake, head-fixed mice was used to characterize these decoding-relevant response properties. Whisker identity and number, stimulation duration, and inter-stimulus interval were systematically varied. All-whisker stimulation produced contralaterally dominant responses in the primary somatosensory barrel field and ventral posteromedial thalamic nucleus. Different whisker inputs were associated with distinguishable cortical response distributions, while stimulation involving more whiskers produced broader representative activation patterns. Across durations of 0.5 s to10 s, brief stimulation generated measurable stimulus-associated signals, and response magnitude, persistence, and spatial distribution varied with stimulus duration. For paired 2-s stimuli, trial-level separability was already high at the shortest tested 1-s gap, corresponding to a 3-s onset-to-onset spacing, and reached 100% at gaps of 3 s or longer. Building on the experimentally characterized spatiotemporal response properties of fUS-CBV signals, a proof-of-concept modeling and decoding framework was developed, comprising cross-animal spatial prediction, classification of short versus long stimulation from S1BF {Delta}CBV time courses with known stimulus onset, and modeling of paired-event separability. Together, the results show that fUS-CBV signals retain structured spatial and temporal information about controlled sensory input after neurovascular transformation. These measured response properties characterize the spatiotemporal boundaries within which neural activity can be reliably distinguished using fUS-CBV signals, providing constraints for the development of fUS-based decoding models and the design of stimulation paradigms suitable for reliable fUS decoding.

neuroscience↗

bioRxiv2026

Beyond Imbalance: An Elasticity Framework for the Distance-averaged Force-Velocity Relationship in Vertical Jump

This study aimed to (1) establish the distance-averaged F-V relationship framework and (2) develop elasticity metrics that quantify how F-V relationship variables govern jump height and inform training prescription. Theoretical derivation and experimental validation across 108 F-V relationship models derived from 1578 jumps (countermovement jump and squat jump at three knee angles; 20 well-trained subjects) yielded a standard error of 2.1% and a nearly perfect correlation (r = 0.96, p < 0.001) between measured and predicted jump height. Four elasticity metrics were formulated: force elasticity (F_{e}), the elasticity of jump height to maximal force (F_{0}); velocity elasticity (v_{e}), the elasticity of jump height to maximal velocity (v_{0}); the force-velocity elasticity norm {(\mathrm{F}-\mathrm{V}}_{\mathrm{EN}}=\sqrt{F_{e}^{2}+v_{e}^{2}}), reflecting the overall sensitivity of jump height to changes in F-V relationship variables; and the force-velocity elasticity ratio {(\mathrm{F}-\mathrm{V}}_{\mathrm{ER}}=F_{e}{\div v}_{e}), indicating which variable dominates the jump height response. Simulations and experiments revealed that F_{e} bore an inverse relationship to F_{0}, and v_{e} was inversely related to v_{0}, reflecting diminishing marginal returns. At a fixed jump height, simulations showed {\mathrm{F}-\mathrm{V}}_{\mathrm{EN}} and {\mathrm{F}-\mathrm{V}}_{\mathrm{ER}} displayed a U-shaped relationship; a balanced profile ({\mathrm{F}-\mathrm{V}}_{\mathrm{ER}}=1) did not always correspond to the lowest {\mathrm{F}-\mathrm{V}}_{\mathrm{EN}}. The distance-averaged F-V elasticity framework offers a physically grounded and quantitative tool for linking F-V relationship variables directly to jump performance, providing a basis for informing individualized training decisions.

biophysics↗