Biology subjects

Chu, L.

Publications and source records attributed to Chu, L..

At least 19 recordsLinked to original sources

bioRxiv2026

MaskTalk: cell-identity-gated spatial lag for target-aware cell-cell communication inference in high-resolution spatial transcriptomics

MotivationHigh-resolution spatial transcriptomics enables single-cell ligand-receptor analysis, but unmasked receptor spatial lags include receptor expression from non-target neighbors, complicating the attribution of local communication signals to specified source-target cell-type pairs. ResultsWe present MaskTalk, a Python package implementing the cell-identity-gated spatial lag model (CIG-SLM). CIG-SLM restricts receptor-side neighborhoods to target cells through W(C) = WD(C). In cell-level breast cancer Visium HD data, CIG-SLM produced target-cell-dependent communication profiles relative to the matched LIANA+ bivariate unmasked baseline, and masked-specific records showed larger between-condition effect sizes and shorter physical source-target distances. Public breast cancer Xenium data demonstrated that MaskTalk runs on external cell-level spatial data and exhibits target-aware masking behavior. Availability and ImplementationImplemented in Python with AnnData; code is available at https://github.com/JiaPP1994/MaskTalk. Software and data archive DOIs are 10.5281/zenodo.21735883 and 10.5281/zenodo.21735951, respectively. Contactshaobin79@aliyun.com; cuihw2001423@163.com Supplementary InformationSupplementary Methods S1-S4, Figures S1-S3, and Tables S1-S5.

bioinformatics↗

bioRxiv2026

Spatiotemporal Patterns and Structural Substrates of Individual Functional Variability in Youth

Youth is a period of emerging individuality and extensive neural remodeling, yet how functional brain individuality is organized across development remains unclear. Prior work has often conflated variability in functional topography with variability in functional connectivity, highlighting the need to examine them separately to better understand how functional individuality relates to brain structure and cognition. Here, using individualized functional parcellation in two large multimodal developmental cohorts (total N = 1211), we separately quantified variability in individualized functional parcellation (vIFP) and in functional connectivity (vFC). Both forms of variability were organized along the sensorimotor-association axis and were greatest in the association cortex. During development, vIFP increased significantly with age at both regional and whole-brain level, whereas vFC showed regionally specific age effects but no significant whole-brain increase. Both trajectories exhibited a common mid-adolescent inflection (14-16 years), marking a window of accelerated functional individualization. Despite shared spatial and temporal organization, vIFP and vFC showed dissociable associations with brain structure and cognition. vIFP was more strongly coupled to structural variability, whereas vFC was more strongly associated with cognitive variability. These findings reveal convergent and divergent developmental principles of topographic and connectional functional variability, highlighting their complementary roles in structural constraints and cognitive specialization.

neuroscience↗

bioRxiv2026

Piezo1 transduces mechanical signals to inhibit osteoclast fusion and coordinate bone homeostasis

Osteoclasts originate from bone marrow-derived macrophages, and their maturation relies on fusion of pre-osteoclasts into mature osteoclasts that maintain bone homeostasis. Previous studies established that mechanical signals regulate osteoblast activity in bone homeostasis, although whether such signals regulate bone homeostasis by acting on osteoclasts remains unclear. Herein, membrane tension decreased during pre-osteoclast fusion, accompanied by reduced Piezo1. This suggests that mechanical stimulation inhibits fusion of monocytes into osteoclasts through Piezo1. Piezo1-knockout monocytes (CTSKCre; Piezo1fl/fl) attenuated the anabolic effect of exercise on bone mass in vivo, whereas shear stress inhibited osteoclast fusion in vitro. Piezo1 activation elevated E-cadherin, which anchors Merlin. This led to hyperactivation of the Yes-associated protein (YAP) signaling pathway, subsequently activating TAX1BP1 and suppressing NF-{kappa}B signaling as well as osteoclast differentiation and maturation. Thus, physical exercise activates a Piezo1-E-cadherin-Merlin-YAP axis that prevents osteoclast fusion, presenting a druggable mechanotransduction pathway for osteoporosis.

cell biology↗

bioRxiv2026

Engineering Endogenous T Cell Receptors to Recognize Cancer Neoantigens Using a Hybrid Physics-AI Approach

T cell receptors (TCRs) are critical for immune surveillance and successful adaptive immune response against foreign antigens. TCRs drive this key arm of the immune system through recognition of peptide epitopes presented on MHC complexes. However, they are limited due to their stochastic nature and generation via genetic recombination. In silico design of functional TCRs that target defined peptide epitopes would be of considerable utility but has up until now been unsuccessful. Here, we develop an artificial intelligence (AI)-powered approach using a hybrid physics-based simulation and generative AI that successfully engineers TCRs against defined epitopes presented by MHC-I. We use this approach to design TCRs against two cancer antigens, a HERC1 neoantigen and an immunogenic neoepitope in mutant EGFR. We engineer multiple TCRs against the HERC1 neoantigen which activate T cells in response to exposure to peptide-MHC I and kill cancer cells more effectively than a patient-derived TCR. In addition, we used generative AI to design functional TCRs that target the EGFR T790M neoantigen, engineering greater specificity against the mutant sequence. We present an AI-based approach to TCR design with broad utility for efforts to engineer TCRs and for the development of new cell therapies. One sentence summaryArtificial intelligence-based approach enables the directed engineering of functional TCRs with enhanced features that target cancer neoantigens.

immunology↗

bioRxiv2026

A brain dynamic model based on graph neural network reflect the inter-region interaction of cortical areas

A central objective in neuroscience is to elucidate how the brain generates complex dynamic activity through the interactions of brain areas. In this study, we utilized Interaction Network, a graph neural network model, to develop a computational framework for predicting whole-brain cortical blood oxygenation level dependent (BOLD) signals. We derived an Inter-Regional Interaction (IRI) metric to quantify information exchange among brain areas probing the underlying dynamical mechanisms. In addition, the total IRI emitted from each brain region was calculated and defined as the IRI sent by region (RS-IRI). Our model predicted the following 10 time points BOLD activity from initial BOLD signals, and achieved a mean absolute error of 0.04. The predicted functional connectivity (FC) achieves a correlation coefficient of 0.97 compared to the empirical FC. The fluctuation amplitude of the IRI increases with the length of the connection and the largest RS-IRI oscillation amplitude is observed in visual areas. The RS-IRI demonstrates a hierarchical organization, characterized by more concentrated distributions in association regions and larger fluctuation amplitudes in unimodal regions. Applying our approach to Alzheimers disease (AD), we demonstrate that the frequency-specific amplitudes of IRI oscillations discriminate AD patients from healthy controls and correlate with Mini-Mental State Examination scores. Together, this work presents a deep learning-based framework for modeling brain dynamics as well a quantitative index of inter-areal interactions, and offers a new perspective for disease characterization. Author SummaryThe human brain comprises distinct regions that interact through complex fiber tracts, forming the functional dynamics for diverse cognitive processes. We employed fMRI to assess functional activity and DTI to reconstruct fiber tract connectivity. To elucidate how brain function emerges from these inter-regional interactions, we developed a novel computational framework based on Graph Neural Network (GNN) to model the brains interactive dynamics for its capacity to uncover hidden and intricate patterns within data. From this model, we derived a quantitative metric termed Inter-Regional Interaction (IRI), which characterized the fine-grained, dynamic fluctuations in communication between brain areas. Our results suggest that this GNN-based model can accurately simulate brain functional activity and provide a quantitative description of neural interaction patterns. Applying this model to a cohort of Alzheimers disease patients, we demonstrated that the IRI metric not only effectively distinguished patients from healthy controls but also significantly correlated with clinical cognitive performance (MMSE scores). This approach advances our understanding of the fundamental principles of brain function and offers a promising tool for identifying the underlying mechanisms of neurological disorders.

neuroscience↗

bioRxiv2025

A simplified MiMe for producing clonal gametes to enable synthetic apomixis in allotetraploid Brassica napus

Synthetic apomixis has been established in Arabidopsis and rice by combining MiMe that produces clonal unreduced gametes with the factors inducing parthenogenesis or haploids. The MiMe requires the simultaneous inactivation of three genes, which imposes challenges for its application in polyploids harbouring multiple copies for each gene. Here, we demonstrate that mutating two genes in the allotetraploid oil crop Brassica napus effectively converts meiosis into mitosis-like division, producing over 95% viable clonal gametes and thus establishing a simplified MiMe system in polyploids.

plant biology↗

bioRxiv2025

Hepatocyte FAM210A deficiency disrupts mitochondrial function and triggers juvenile steatosis with compensatory repair in adulthood

Mitochondrial dynamics are central to maintaining liver metabolic homeostasis, yet the mechanisms that safeguarding mitochondrial integrity during development and metabolic dysfunction remain poorly defined. Here, we identify Family with sequence similarity 210 member A (FAM210A) as a hepatocyte-enriched mitochondrial regulator essential for postnatal liver maturation. Hepatocyte-specific deletion of Fam210a (Fam210aHKO) in mice caused early growth restriction, reduced body and liver mass, and pronounced hepatic steatosis with glycogen depletion. These defects were accompanied by lower postprandial glucose levels in the fasted-refeeding state, impaired oxidative phosphorylation, reduced mtDNA content, and abnormal cristae architecture. Transcriptomic and proteomic profiling revealed broad suppression of fatty acid, sterol, and bile acid metabolism, with concomitant glutathione stress responses. Mechanistically, FAM210A deficiency disrupted the YME1L-OPA1 axis, driving excessive OPA1 cleavage and cristae destabilization. Strikingly, these juvenile defects were transient and resolved by adulthood, underpinned by enhanced hepatocyte proliferation and mitochondrial biogenesis, consistent with a compensatory stress-adaptive response via the activation of ISR signaling. Together, these findings uncover FAM210A as a developmental safeguard of mitochondrial remodeling in hepatocytes and indicate compensatory programs with therapeutic relevance for chronic liver disease.

physiology↗

bioRxiv2025

The HORMA-domain protein ASY1 recruits the plant-specific cyclin SDS to promote DMC1-mediated meiotic recombination

The chromosome axis is a proteinaceous scaffold essential for crossover formation in meiosis. While the axis associated HORMA-domain protein ASY1 is known to be necessary for the localization of the recombinase DMC1 to the axis, the molecular mechanism linking ASY1 to DMC1 loading remains unclear. Here, we demonstrate that ASY1 directly recruits the plant-specific cyclin SDS to chromosomes, which ensures efficient DMC1 localization and interhomolog recombination. Live-cell imaging and immunodetection revealed that SDS localizes to chromosomes from leptotene to zygotene and dissociates from chromosomes after pachytene resembling DMC1 dynamics. Biochemical assays demonstrated a direct interaction between ASY1 and SDS. Further analyses revealed that ASY1s closure motif, a conformational regulatory element, is required for SDS recruitment despite being dispensable for ASY1s own chromosome association. Moreover, unlike in sds mutants, depletion of the DMC1 inhibitor FIGL1-FLIP complex failed to restore DMC1 foci in asy1 mutants, positioning ASY1 upstream of both positive (SDS) and negative (FIGL1-FLIP) regulators of DMC1. These findings establish ASY1 as a key coordinator of meiotic recombination, bridging chromosome axis architecture with recombinase dynamics to control crossover formation and genome stability.

plant biology↗

bioRxiv2024

Silicon-rhodamine-enabled Identification (SeeID) for Near-Infrared Light Controlled Proximity Labeling In Vitro and In Vivo

Advancement in fluorescence imaging techniques enables the study of protein dynamics and localization with unprecedented spatiotemporal resolution. However, current imaging tools are unable to elucidate dynamic protein interactomes underlying imaging observations. In contrast, proteomics tools such as proximity labeling enable the analysis of protein interactomes at a single time point but lack information about protein dynamics. We herein developed Silicon-rhodamine-enabled Identification (SeeID) for near-infrared light controlled proximity labeling that could bridge the gap between imaging and proximity labeling. SeeID was benchmarked through characterization of various organelle-specific proteomes and the KRAS protein interactome. The fluorogenic nature of SiR allows for intracellular proximity labeling with high subcellular specificity. Leveraging SiR as both a fluorophore and a photocatalyst, we developed a protocol that allows the study of dynamic protein interactomes of Parkin during mitophagy. We discovered the association of the proteasome complex with Parkin at early time points, indicating the involvement of the ubiquitin-proteasome system for protein degradation in the early phase of mitophagy. In addition, by virtue of the deep tissue penetration of near-infrared light, we achieved spatiotemporally controlled proximity labeling in vivo across the mouse brain cortex with a labeling depth of [~]2 mm using an off-the-shelf 660 nm LED light set-up.

molecular biology↗

bioRxiv2024

Association of the benzoxazinoid pathway with boron homeostasis in maize

Both deficiency and toxicity of the micronutrient boron lead to severe reductions in crop yield. Despite this agricultural importance, the molecular basis underlying boron homeostasis in plants is not resolved. To identify molecular players involved in boron homeostasis in maize (Zea mays), we measured boron levels in the Goodman-Buckler association panel and performed genome-wide association studies. These analyses detected the benzoxazinless (bx) gene, bx3, involved in the biosynthesis of benzoxazinoids, like DIMBOA, major defense compounds in maize. Genes involved in DIMBOA biosynthesis are all located in close proximity in the genome and the biosynthesis mutants, including bx3 are all DIMBOA deficient. We show that the bx3 mutant has enhanced boron concentration in leaves compared to the B73 control plants, which correlates with enhanced leaf tip necrosis, a phenotype associated with boron toxicity. In contrast, other DIMBOA-deficient maize mutants did not show altered boron levels nor the leaf tip necrosis phenotype, suggesting that boron is not associated with DIMBOA. Instead, our analyses suggest that the accumulation of boron is linked to the benzoxazinoid intermediates indolin-2-one (ION) and 3-hydroxy-ION. Therefore, our results connect boron homeostasis to the benzoxazinoid plant defense pathway through bx3 and specific intermediates, rendering the benzoxazinoid biosynthesis pathway a potential target for crop improvement in inadequate boron conditions. One sentence summaryGWAS identified benzoxazinless3 in the benzoxazinoid biosynthesis pathway to play a role in boron homeostasis in maize.

plant biology↗

bioRxiv2024

Single-nucleus RNA sequencing of striatal microglia reveals distinct transcriptomic signatures of acute stress and chronic exercise

Acute stress has enduring effects on the brain and motivated behavior across species. For example, acute stress produces persisting decreases in voluntary physical activity as well as molecular changes in the striatum, a brain region that regulates voluntary physical activity and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, are positioned at the interface between neural responses to stress and neural coordination of voluntary activity in that they respond to stress, sense molecular changes in the striatum, and modulate neuronal activity. However, the role of striatal microglia in stress-induced long-term suppression of voluntary activity is unknown. Here we employ single nucleus RNA-sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that striatal microglia display altered activation profiles six weeks after an acute stressor. Furthermore, we show that access to a running wheel is associated with an additional and distinct microglial activation profile characterized by upregulation of genes related to complement components and phagocytosis pathways. Lastly, we find that distinct gene sets show expression changes associated with general access to a running wheel versus variation in running levels. Taken together, our results deepen our understanding of the diverse molecular states that striatal microglia assume in response to stress and exercise and suggest that microglia exhibit a broader range of functional states than previously thought.

neuroscience↗

bioRxiv2024

The continuous differentiation of multiscale structural gradients from childhood to adolescence correlates with the maturation of cortical morphology and functional specialization

From childhood to adolescence, the structural organization of the human brain undergoes dynamic and regionally heterogeneous changes across multiple scales, from synaptic pruning to the reorganization of large-scale anatomical wiring. However, during this period, the developmental process of multiscale structural architecture, its association with cortical morphological changes, and its role in the maturation of functional organization remain largely unknown. Here, we utilized a longitudinal multimodal imaging dataset including 276 children aged 6 to 14 years to investigate the developmental process of multiscale cortical wiring. We used an in vivo model of cortical wiring that combines features of white matter tractography, cortico-cortical proximity, and microstructural similarity to construct a multiscale brain structural connectome. By employing the gradient mapping method, the gradient space derived from the multiscale structural connectome effectively recapitulated the sensory-association axis and anterior-posterior axis. Our findings revealed a continuous expansion of the multiscale structural gradient space during development, with the principal gradient increasingly distinguishing between primary and transmodal regions. This age-related differentiation coincided with regionally heterogeneous changes in cortical morphology. Furthermore, our study revealed that developmental changes in coupling between multiscale structural and functional connectivity were correlated with functional specialization refinement, as evidenced by changes in the participation coefficient. We also found that the differentiation of the principal multiscale structural gradient was associated with improved cognitive abilities, such as enhanced working memory and attention performance, and potentially supported by molecular processes related to synaptic functions. These findings advance our understanding of the intricate maturation process of brain structural organization and its implications for cognitive performance.

neuroscience↗

bioRxiv2024

Characterization of liver-pancreas crosstalk following beta-cell loss reveals a role for the molybdenum cofactor in beta-cell regeneration

Regeneration of insulin-producing {beta}-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of {beta}-cells. Here, we aimed to characterize how hepatocytes can contribute to {beta}-cell regeneration in a zebrafish model of {beta}-cell ablation. Using lineage-tracing, we show that hepatocytes do not directly convert into {beta}-cells even under extreme {beta}-cell ablation conditions. A transcriptomics analysis of isolated hepatocytes following {beta}-cell ablation displayed altered lipid- and glucose-related processes. Based on the transcriptomics, we performed a genetic screen that uncovers a potential role for the molybdenum cofactor (Moco) biosynthetic pathway in {beta}-cell regeneration and glucose metabolism in zebrafish. Consistently, Mocs2 haploinsufficiency in mice indicated dysregulated glucose metabolism and liver function. Together, our study sheds light on the liver-pancreas crosstalk and suggests that the molybdenum cofactor biosynthesis pathway should be further studied in relation to glucose metabolism and diabetes.

developmental biology↗

bioRxiv2024

Crossover Interference Mediates Multiscale Patterning Along Meiotic Chromosomes

The classical phenomenon of crossover interference is a one-dimensional spatial patterning process that produces evenly spaced crossovers during meiosis. Quantitative analysis of diagnostic molecules along budding yeast chromosomes reveals that this process also sets up a second, interdigitated pattern of related but longer periodicity, in a "two-tiered" patterning process. The second tier corresponds to a previously mysterious minority set of crossovers. Thus, in toto, the two tiers account for all detected crossover events. Both tiers of patterning set up spatially clustered assemblies of three types of molecules ("triads") representing the three major components of meiotic chromosomes (crossover recombination complexes and chromosome axis and synaptonemal complex components), and give focal and domainal signals, respectively. Roles are suggested. All observed effects are economically and synthetically explained if crossover patterning is mediated by mechanical forces along prophase chromosomes. Intensity levels of domainal triad components are further modulated, dynamically, by the conserved protein remodeler Pch2/TRIP13.

cell biology↗

bioRxiv2024

ASY3 has dosage-dependent diverse effects on meiotic crossover formation

Crossovers create genetic diversity and are required for equal chromosome segregation during meiosis. Their number and distribution are highly regulated by different, yet not fully understood mechanisms including crossover interference. Crucial for crossover formation is the chromosome axis. Here, we explore the function of the axis protein ASY3. To this end, we use the allotetraploid species Brassica napus and due to its polyploid nature, this system allows a fine-grained dissection of the dosage of meiotic regulators. The simultaneous mutation of all four ASY3 alleles results in defective synapsis and drastic reduction of crossovers, which is largely rescued by the presence of only one functional ASY3 allele. Crucially, while the number of class I crossovers in mutants with two functional ASY3 alleles is comparable to that in wildtype, this number is significantly increased in mutants with only one functional ASY3 allele, indicating that reducing the dosage of ASY3 increases crossover formation. Moreover, the class I crossovers on each bivalent in mutants with one functional ASY3 allele follow a random distribution, indicating compromised crossover interference. These results reveal the dosage-dependent distinct effects of ASY3 on crossover formation, and provide insights into the role of chromosome axis in patterning recombination.

plant biology↗

bioRxiv2023

HERC5-catalyzed ISGylation potentiates cGAS-mediated innate immunity

The key cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) is essential to elicit anti-infection innate immunity whereas aberrant activation of cGAS by endogenous DNA promotes severe autoimmune diseases, thus the activity of cGAS must be strictly regulated to maintain immune homeostasis. Here we report that the E3 ISG15-protein ligase HERC5 interacts with and catalyzes the cGAS ISGylation robustly, whereas the deconjugating enzyme USP18 removes the ISG15 conjugation of cGAS. The interaction of cGAS and HERC5 depends on the cGAS N-terminal domain and the RRC1-4 and HECT domain of HERC5. Mass spectrometry reveals that the Lys21,187,219,458 are the potential ISGylation sites in human cGAS. Deficiency of ISG15 or the E1 ubiquitin-activating enzyme UBA7 greatly attenuate the downstream gene expression induced by cGAS-STING axis and the antiviral ability in mouse and human cells. Collectively, our study uncovered an important role of the HERC5-facilitated cGAS ISGylaion in promoting antiviral defense.

immunology↗

bioRxiv2022

Overexpression of PSR1 in Chlamydomonas reinhardtii induces luxury phosphorus uptake

Remediation using micro-algae offers an attractive solution to environmental phosphate (Pi) pollution. However, for maximum efficiency, pre-conditioning of algae to induce luxury phosphorus (P) uptake is needed. Here we show that natural pre-conditioning can be mimicked through over-expression of a single gene, the global regulator PSR1 (Myb transcription factor: Phosphate Starvation Response 1), raising P levels to 8% dry cell weight from 2% in control. Complete removal of Pi occurred in log phase, unlike the control. This was associated with increases in PolyP granule size and uptake of Mg2+, the principal counterion. Hyper-accumulation of P depended on a feed-forward mechanism, where a small set of Class I genes were activated despite abundant external Pi levels. This drove a reduction in external Pi levels, permitting more genes to be expressed (Class II), leading to more Pi-uptake. These discoveries enable a bio-circular approach of recycling nutrients from wastewater back to agriculture. TeaserManipulating a single gene drove uptake of P and a Mg2+ counter-ion for increased PolyP accumulation.

bioengineering↗

bioRxiv2022

An image cryptography method in highly error-prone DNA storage channel

Rapid development in synthetic technologies has boosted DNA as a potential medium for large-scale data storage. Meanwhile, how to implement data security in DNA storage system is still an unsolved problem. In this paper, we propose an image encryption method based on the modulation-based storage architecture. The key idea is to take advantage of the unpredictable modulation signals to encrypt image in highly error-prone DNA storage channel. Numerical results demonstrate that our image encryption method is feasible and effective with excellent security against various attacks (statistical, differential, noise and data loss, etc.). Compared with other methods by DNA molecules hybridization reaction, the proposed method is more reliable and feasible for large-scale applications.

synthetic biology↗