Biology subjects

Ji, Z.

Publications and source records attributed to Ji, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Firing rate adaptation in grid cells produces macroscopic hexadirectional modulation

Hexadirectional modulation (HexMod) of macroscopic neural activity by movement direction is widely used to measure grid cell activity in human neuroimaging, but its neuronal origin is unclear. Two mechanisms have been proposed: conjunctive gridxdirection cells whose preferred directions align with the grid axes, and firing rate adaptation, which reduces firing when grid fields are visited in quick succession during movement along grid axes. Analysing almost 4,000 grid cells from foraging rats, we found that conjunctive cells' directional tuning was broad and unaligned with grid axes, whereas firing was reduced shortly after grid field visits, consistent with firing rate adaptation. Simulations of realistic grid cell populations demonstrate HexMod with the typical trajectories of human experiments, and show how it depends on grid scale, adaptation time constant, movement speed, and controlling for variation with location. We show firing rate adaptation provides a plausible mechanism for HexMod and a framework for relating human neuroimaging to neuronal activity.

neuroscience↗

bioRxiv2026

The limbic navigation system as a hierarchical RNN

Path-integration-trained recurrent neural networks (RNNs) can reproduce grid-like and head-direction-like representations, but most existing models rely on low-dimensional velocity inputs and do not capture the hierarchical organisation of the brain's self-localisation circuit. We introduce a hierarchical recurrent neural network (HRNN) that separately processes angular velocity and linear speed to perform simultaneous angular and positional path integration. Trained on these tasks, the HRNN generalises to longer timescales than seen during training and develops neural response properties resembling all the key cell types: angular velocity cells, head direction cells, speed cells, conjunctive and pure grid cells. The learned circuit also recovers key motifs of the navigation system, including attractor dynamics and asymmetric connectivity patterns. Perturbation analyses reveal functional information flow across the hierarchy, consistent with experimental observations. Finally, introducing theta-paced mutual inhibition between two learned angular-velocity subpopulations enables the HRNN to reproduce the bidirectional theta sweeps observed in empirical data. These results establish hierarchical task-driven RNNs as a biologically interpretable framework for linking neural representations, circuit motifs, and population dynamics in spatial navigation, while enabling targeted in silico perturbations and the generation of experimentally testable predictions.

neuroscience↗

bioRxiv2026

Monothiol glutaredoxin DaGrxB couples iron homeostasis with redox balance to orchestrate development and virulence in the peach shoot blight fungus Diaporthe amygdali

Peach shoot blight (PSB), caused by Diaporthe amygdali, is one of the most devastating fungal diseases affecting peach production worldwide. Glutaredoxins (Grxs) are ubiquitous redox-regulatory proteins involved in antioxidant defense and iron metabolism, yet their functions in phytopathogenic fungi remain largely unknown. Here, we identified four Grxs (DaGrxA-DaGrxD) in D. amygdali. Among them, DaGrxB, a monothiol glutaredoxin, is the sole member essential for vegetative growth, asexual reproduction and virulence. DaGrxB interacts with iron-regulatory transcription factors DaHapX and DaSreA and modulates their activities via iron-dependent nucleocytoplasmic shuttling, coordinating iron acquisition and storage gene expression. During infection, D. amygdali encounters a biphasic iron environment: an inherently iron-limited host environment at early stages (1-2 dpi) followed by host-mediated iron excess (3-4 dpi), and DaGrxB is essential for navigating this transition. Consistently, deletion of either DaHAPX or DaSREA significantly reduced virulence, confirming that iron homeostasis is a critical determinant of D. amygdali virulence. Notably, deletion of DaGRXB disrupts Fe-S cluster biosynthesis, causing mitochondrial Fe2+ accumulation, impaired aconitase activity, and reduced ATP production, which triggers constitutive activation of the GSH-dependent antioxidant system, with elevated GSH/GSSG ratios, increased GR and GST activities, and reduced H2O2 levels. Exogenous GSH and H2O2 depletion both reduced virulence, suggesting that disturbed redox balance directly contributes to attenuated virulence. Additionally, the Trx domain assists the Grx domain in nucleocytoplasmic translocation through intramolecular interactions. Finally, LDH-delivered dsRNA targeting DaGRXB effectively controls PSB. Collectively, these findings reveal how a monothiol glutaredoxin integrates iron homeostasis, redox balance and virulence in a plant pathogen, providing a foundation for RNAi-based disease management.

pathology↗

bioRxiv2026

A breeder in the sky: scoring flowering with fewer flights

Flowering time is a trait of broad interest and importance to both plant breeders and plant biologists. Unlike many other traits, flowering time cannot be scored accurately from a single observation; its measurement requires repeated observations of the same experiments over time. Both classification- and object-detection-based approaches have demonstrated the potential to estimate flowering time from Unmanned aerial vehicle (UAV) imagery rather than by manual observation, but they still require data collection at many time points. Here, we train and deploy a regression-based framework for scoring flowering time. Using a dataset of more than 200,000 UAV images and associated flowering-time records collected across 27 environments, we demonstrate that this approach enables the prediction of flowering time from as few as one observation per field experiment and successfully generalizes to field experiments in environments not represented in the training dataset. These results indicate that regression-based approaches for predicting flowering time from sparse UAV observations have the potential to substantially reduce the data-collection burden in field experiments

plant biology↗

bioRxiv2026

Visual LLM-guided consensus spatial domain detection with L-STAR

Spatial domain detection is a central task in spatial transcriptomics, yet existing methods exhibit highly variable performance across datasets. We introduce L-STAR, a visual LLM-guided, consensus-based framework that leverages the visual reasoning capacity of large language models to adaptively rank and integrate spatial domain detection methods. L-STAR achieves robust and consistently improved performance, outperforming single spatial domain detection methods across diverse datasets.

bioinformatics↗

bioRxiv2026

Patient-Specific Vascularized Lung Tumor Organoids for Tumor-Immune Profiling

The use of cellular systems to advance cancer therapeutics has expanded rapidly, spanning cell therapies to patient-specific tumor models. Platforms that recapitulate key features of the tumor microenvironment, including vascular and immune components, hold significant potential to improve the predictive power and translational relevance of preclinical models. Here, we report a vascularized tumor organoid platform that combines self-organizing microvascular networks with patient-derived tumor organoids and tumor-infiltrating lymphocytes. To minimize non-specific endothelial immunogenicity and enable broader compatibility across patient samples, we engineered the vasculature using {beta}2-microglobulin-knockout endothelial cells. Leveraging this system, we established patient-specific, lymphocyte-incorporated tumor models that enabled quantitative assessment of T cell infiltration. In conjunction with immune checkpoint blockade, this platform distinguishes responder and non-responder patient samples, consistent with the clinical observations. Single-cell RNA-sequencing revealed tumor-intrinsic and immune-associated programs underlying this stratification, identifying tumor-driven hyperangiogenic signaling as a barrier to T cell extravasation. Pharmacological co-targeting of PD1 and VEGF restored T cell infiltration in non-responder organoids, shifting them from an immune-excluded to an immune-inflamed state. Together, this vascularized tumor organoid platform provides a predictive and mechanistic framework for modeling patient-specific immunotherapy responses and design of combination therapies.

bioengineering↗

bioRxiv2026

Human hindbrain organoids with segment-specific 5-HT neurons for motor modulation

The serotonergic system regulates human mood, reward, and motor control, and its impairment contributes to debilitating psychiatric disorders. Serotonergic neurons (SNs) arise predominantly in the hindbrain and acquire segment-specific identities and functions; however, the lack of human models remains a challenge to understanding the human serotonergic system. Here, we generate human serotonergic-enriched rostral and caudal hindbrain organoids (hsrHOs and hscHOs) that produce segment-specific SNs with regional identities corresponding to rhombomeres r2-r3 and r5-r8, respectively. hsrHOs and hscHOs produce SNs that recapitulate their in vivo counterparts in transcriptomic profiles, function, and ascending or descending projection preferences. Assembly with human neuromusculoskeletal organoids enables modeling of serotonergic modulation of motor control. This system further reveals that deficiency of the schizophrenia risk gene DISC1 disrupts human serotonergic development and impairs motor modulation. Together, our study establishes a human organoid platform for modeling development, circuit function and disease-associated dysfunction of the serotonergic modulatory system.

neuroscience↗

bioRxiv2026

Amphiphilic Peptide Fusion Promotes Endocytic Uptake of Nanodiscs

A major limitation across nanoparticle delivery platforms is sequestration within endosomal compartments, which restricts access to intracellular targets despite efficient cellular uptake. Here, we show that peptide architecture can be used to control intracellular trafficking and reduce endosomal accumulation in lipid-protein nanocarriers. Specifically, we fuse R6W3 (RRWWRRWRR), an amphipathic cell penetrating peptide, to the N- or C- terminus of the nanodisc scaffold proteins and systematically evaluate its impact on membrane interactions and cellular behavior. Structural and biophysical characterization confirms that R6W3 incorporation preserves nanodisc assembly and protein-lipid interactions, enabling direct attribution of functional differences to peptide-driven interfacial effects. R6W3-functionalized nanodiscs exhibit enhanced binding and cellular uptake, with N-terminal fusion producing the strongest interfacial interactions. In live cells, R6W3-functionalization increases endocytic activity, evidenced by increased formation of clathrin-coated pits and intracellular colocalization with clathrin-coated vesicles. Notably, R6W3-funtionalized nanodiscs display reduced accumulation in early endosomes relative to unmodified nanodiscs, indicating decreased endosomal sequestration following endosomal uptake. These trafficking differences translate to functional outcomes, as doxorubicin-loaded, R6W3-functionalized nanodiscs achieve greater cytotoxicity than unmodified controls at equivalent concentrations. Together, these results establish peptide architecture as a design parameter for controlling intracellular trafficking and overcoming endosomal bottlenecks, providing a broadly applicable strategy for improving nanocarrier- based delivery systems.

bioengineering↗

bioRxiv2026

Lense: Optimizing data preprocessing in single-cell omics using LLMs

Data preprocessing is critical for single-cell omics analyses, but default pipelines often underperform on diverse datasets, especially from emerging platforms like spatial transcriptomics. We introduce Lense, a language-model-guided method that automatically selects optimal preprocessing by comparing plots that visualize low-dimensional representations across pipeline variants. Integrated with Seurat, Lense streamlines analysis and improves preprocessing robustness without requiring manual tuning. Biographical NoteJingyun Liu is a Masters student in the Department of Biostatistics and Bioinformatics at Duke University. Dr. Zhicheng Ji is a tenure-track Assistant Professor in the Department of Biostatistics and Bioinformatics at Duke University. His research focuses on artificial intelligence and statistical modeling for single-cell genomics, spatial genomics, and biomedical imaging.

bioinformatics↗

bioRxiv2026

Halo: a pretrained model for whole-cell segmentation from nuclei images in spatial transcriptomics

Spatial transcriptomics enables measurement of gene expression while preserving spatial organization within tissues. Accurate reconstruction of single-cell transcriptomes requires precise whole-cell segmentation, yet many spatial transcriptomics experiments provide only nuclear staining images, making reliable inference of cell boundaries difficult. Here we introduce Halo, a pretrained segmentation model that reconstructs whole-cell boundaries by integrating nuclear morphology with the spatial distribution of RNA transcripts. Halo converts transcript coordinates into molecular density maps that are processed jointly with DAPI images using a Cellpose-SAM segmentation architecture. Unlike existing approaches that require dataset-specific training, Halo is pretrained on multimodal Xenium data from 12 tissue types and can be directly applied to new datasets without additional training. Across diverse tissues, Halo substantially outperforms the widely used nuclear expansion strategy, achieving higher agreement with ground-truth cell boundaries and more accurate RNA-to-cell assignment. Improved segmentation leads to more reliable cell type identification and more accurate estimation of cell morphological features. By providing a pretrained, generalizable model for whole-cell reconstruction, Halo enables scalable and reproducible cell segmentation for image-based spatial transcriptomics.

bioinformatics↗

bioRxiv2026

An upstream open reading frame represses translation of the neuronal potassium channel KCNQ2

Upstream open reading frames (uORFs) within the 5-untranslated region (5-UTR) of mRNA transcripts can regulate protein translation. Despite widespread prevalence within the human genome, they remain unidentified for many clinically relevant genes. A gene frequently associated with neonatal-onset epilepsy is KCNQ2, which encodes a neuronal voltage-gated potassium channel subunit that functions to dampen neuronal excitability. Heterozygous loss-of-function pathogenic KCNQ2 variants are known to cause a range of neurodevelopmental disorders and epileptic encephalopathies, but there remains an unmet clinical need for patients harboring these variants. We identified a single uORF in KCNQ2 that is highly repressive of protein translation and demonstrated that mutations disabling the uORF start codon enhance translation of encoded potassium channels. Additionally, we show that adenine base editing of the uORF start codon can weaken ribosome engagement at the uORF and enhance translation of the protein in a neuron-like cell line. This study establishes a previously underexplored regulatory feature for KCNQ2 and highlights the importance of understanding uORFs for clinically relevant genes, both for assessing disease risk and therapeutic potential.

molecular biology↗

bioRxiv2026

Dorsoventral gradient of theta sweeps in medial entorhinal cortex

During random foraging, the positional signal decoded from entorhinal grid cells exhibits left-right theta sweeps, alternating from one side of the heading direction to the other across successive theta cycles. Here, we report that theta sweeps are topographically organised along the dorsoventral axis of the medial entorhinal cortex, with the angular deviation from heading direction increasing gradually from dorsal (smaller scale) to ventral (larger scale) modules. This gradient coexists with a corresponding dorsoventral increase in angular deviation decoded from theta-modulated directional cells, which drive grid-cell theta sweeps. These phenomena parallel a broadening of head direction tuning and increasing occurrence of theta cycle skipping in single cell firing along the dorsoventral axis. Computational modelling demonstrates that these patterns are consistent with continuous attractor dynamics and a dorsoventral gradient in firing rate adaptation. These results highlight how theta sweeps can simultaneously represent multiple potential future locations and reveal a clear neural mechanism underlying this process.

neuroscience↗

bioRxiv2026

ATP-independent unfolding of ubiquitin by Ufd1 initiates Cdc48/p97-mediated substrate processing

The Cdc48 ATPase (p97 or VCP in mammals) cooperates with its cofactors Ufd1 and Npl4 to extract polyubiquitinated proteins from membranes or multi-subunit complexes, promoting their proteasomal degradation. A ubiquitin molecule in the chain is unfolded in an ATP-independent manner and initiates substrate translocation through the central pore of the ATPase. How ubiquitin is unfolded remains unclear. Here, we demonstrate that the UT3 domain of Ufd1 interacts simultaneously with two Lys48-linked ubiquitins and unfolds one of the ubiquitins by binding its C-termianl {beta}-strand into a cleft. This unfolded ubiquitin is subsequently captured by Npl4 and Cdc48/p97. Experiments in vitro and in cells show that unfolding-defective mutants of Ufd1 indeed compromise Cdc48/p97 function. Our results explain how simple protein-protein interactions cause the unfolding of the remarkably stable ubiquitin. We also establish a linkage-specific recognition that involves ubiquitin unfolding.

biophysics↗

bioRxiv2026

No evidence for sleep-dependent memory generalization in a large online sample

Memory generalization allows individuals to extract and apply information from prior experiences to novel situations, supporting flexible learning and efficient decision-making. Theoretical models suggest that sleep should facilitate generalization, yet the literature examining its role in promoting generalization is mixed. We recruited 137 participants via Prolific to complete an image-location memory task over two sessions spaced 12 hours apart. Participants were randomly assigned to the Wake group (learning in the morning) or the Sleep group (learning in the evening). In Session 1, participants learned the location of stimuli on the screen and were tested on their memory five minutes later. Twelve hours later, in Session 2, they were tested on their memory again. Stimuli consisted of 160 images from eight semantic categories and were strategically positioned on-screen to test the effects of generalization on retrieval (i.e., category-based memory distortions and biases). After the delay, retrieval was less accurate and demonstrated more generalization. However, these effects were mostly independent of Group, with some evidence for enhanced generalization following a period of wakefulness over sleep. Generalization was also driven by time of day, with more generalization in the evening relative to the morning. Taken together, our results, based on a large online sample, do not support a role for sleep in promoting memory generalization. Significance StatementBehavior is often guided by memories of previous experiences. However, for behavior to be adaptive and flexible (e.g., when encountering never-before-seen stimuli), regularities about the world must be extracted from these memories. This process, termed memory generalization, has been hypothesized to rely on sleep. We used a large online sample to test sleeps role in generalization and found no support for this hypothesis. Our results suggest that sleep and wakefulness contribute to generalization equally, with the latter potentially having a larger contribution.

neuroscience↗

bioRxiv2026

Induction and regulation of a reversible form of suspended animation in C. elegans

Suspended animation, a state of extreme quiescence with microscopically invisible movement and development, is a remarkable yet poorly understood stress resilience strategy in animals. Here, we describe a newly discovered form of suspended animation inducible by high-population density in isosmotic liquids in C. elegans throughout larval development and adulthood. Transcriptomic, metabolomic and live-cell activity reporter imaging analyses reveal striking molecular and cellular landscape changes by such liquid-induced suspended animation (LISA), including remodeling of gene expression programs, energy metabolites, lysosomal and mitochondrial morphology. Genetic screens identify mutants with altered stress responses and survival against LISA. While key endo-lysosomal regulators promote survival during LISA, organelle remodeling and a neuronal axis via downstream neuropeptide and cAMP/PKA signaling orchestrate behavioral awakening from LISA. Our findings define a facile paradigm for reversible SA, providing a powerful model system to uncover key molecular and cellular mechanisms governing an extreme case of reversible life arrest and dormancy.

developmental biology↗

bioRxiv2026

A genetically encoded ionic-stress sensor reveals protons as a sleep driver

Dynamic ionic changes are hallmarks of physiological and behavioral state transitions, including sleep in animals. Although biosensors for specific cellular ions are widely available, real-time monitoring of overall ionic strength in living organisms remains challenging. Here, we present a genetically encoded nuclear translocation ionic sensor (GENTIS) that enables direct visualization of ionic stress in vivo. Using GENTIS in C. elegans, we uncover rhythmic elevations in ionic strength during larval molting transitions that coincide with the lethargus sleep. Cytosolic proton ionic increase through inhibition of v-ATPase is sufficient to induce GENTIS nuclear translocation and evoke behavioral quiescence, characterized by reduced feeding and activation of sleep-active neurons. Apical membrane v-ATPases undergo disassembly during lethargus and under sleep-inducing stress conditions, leading to proton accumulation. Notably, this proton-mediated sleep is suppressed by proton buffering with ammonium. Together, these findings establish GENTIS as a powerful tool for tracking ionic strength dynamics in living organisms and support protons as a physiological driver of sleep.

animal behavior and cognition↗

bioRxiv2026

MOV10 inhibits SADS-CoV replication by enhancing TRIM24-mediated K63-linked TRAF3 ubiquitination and this inhibition is antagonized by viral N protein

The global outbreak of SARS-CoV-2 has resulted in a renewed focus on coronaviruses with the potential for cross-species transmission and mutation risks. In particular, swine acute diarrhea syndrome coronavirus (SADS-CoV), potentially originating from intermediate horseshoe bat (Rhinolophus affinis), is a novel coronavirus that causes acute diarrhea, vomiting, and high mortality in suckling piglets. Innate immunity plays a crucial role in defending the host against invading pathogens. Previous studies have identified several host factors that inhibit SADS-CoV replication through innate immunity; however, research on SADS-CoV remains insufficient compared to that on other coronaviruses. In this study, the host factor Moloney leukemia virus 10 protein (MOV10) inhibited SADS-CoV replication by promoting interferon (IFN) production. Mechanistically, MOV10 exerted its antiviral effect primarily through its N-terminal domain, which regulated the TNF receptor-associated factor 3 (TRAF3)-mediated innate immune pathway. Specifically, we reveal that MOV10 enhanced tripartite motif-containing 24 (TRIM24)-mediated K63-linked ubiquitination of TRAF3, thereby promoting IFN production and inhibiting SADS-CoV replication. Furthermore, we identified the strategies by which SADS-CoV evaded innate immunity. The viral N protein inhibited the antiviral effect of MOV10 by disrupting interaction between MOV10 and TRAF3, and by promoting K48-linked polyubiquitination of TRAF3, leading to TRAF3 degradation via the ubiquitin-proteasome pathway. Collectively, our findings reveal the role of MOV10 in antiviral immunity and how SADS-CoV evades host immune defense.

molecular biology↗

bioRxiv2025

3'to 5'translation of linear mRNAs?

3[->]5 translation (termed "backward translation") mediated by eukaryotic circular RNAs has been reported recently. Whether linear mRNA can produce proteins through backward translation remained elusive. Here, we demonstrate that linear mRNAs can mediate backward translation in vitro. Backward translation was detected in human cells transfected with expression vectors used to produce linear mRNAs. Importantly, synthetic linear mRNAs could produce backward translation signal in multiple in vitro translation systems, with a level comparable to that of conventional 5 to 3 forward translation. Furthermore, we demonstrated that a single translation initiating sequence (TIS) was able to drive backward and forward translation in an in vitro experimental setup, with the efficiency of backward translation found to be significant lower than that of forward translation. In summary, this study further reinforces the notion of translation flexibility, demonstrates a broader applicability of backward translation and heralds a new strategy in synthetic biology.

cell biology↗