Biology subjects

Xu, Y.

Publications and source records attributed to Xu, Y..

At least 199 records · Page 11Linked to original sources

bioRxiv2025

Development and characterisation of a promoter library for Sulfolobus acidocaldarius

The hyperthermoacidophilic archaeon Sulfolobus acidocaldarius is a promising production host for industrial biotechnology applications due to its ability to thrive in extreme conditions. However, the lack of well-characterised genetic parts and tools, particularly promoters, limits its potential for metabolic engineering. In this study, we developed the first promoter library for S. acidocaldarius by randomising specific regions of the core promoter sequence of PSaci 2137, a promoter known to function in both S. acidocaldarius and Escherichia coli. The library was initially screened in E. coli using mKate2, a red fluorescent reporter protein, and seven promoters were selected for characterisation in S. acidocaldarius using the thermostable {beta}-galactosidase reporter LacS. The resulting promoter collection exhibited a 5-fold range of expression levels in S. acidocaldarius, spanning from low to high constitutive expression when compared to S. acidocaldarius promoters Psac7d and PmalE. This study demonstrates a successful workflow for generating and characterising S. acidocaldarius promoters, providing a valuable toolkit for fine-tuning gene expression and optimising metabolic pathways in this extremophilic archaeon. The design principles established here can be extended to other archaeal systems with similar promoter architectures.

synthetic biology↗

bioRxiv2025

Incomplete functional divergence drives genetic synergy during floral development in tomato

Genetic synergy arises from interactions between functionally related genes that control complex traits in plants and animals. Synergy occurs when the combined effect of multiple genes exceeds the additive contribution from each individual gene. However, genetic mechanisms that drive and maintain synergy remain largely elusive. Here, we investigated synergistic interactions among SEPALLATA MADS-box genes during floral development in tomato. We discovered that synergy emerges from duplicated genes that partitioned functions to regulate inflorescence architecture and floral organ identity. Moreover, synergistic interactions are reflected in non-additive expression changes that coordinate successive developmental stages. Finally, we demonstrate that synergy occurs due to residual redundancy on a dose-sensitive module guiding floral identity. These results indicate that synergy emerges as a relic of redundancy when functional divergence remains incomplete due to gene dosage constraints. Our work provides insights into mechanisms through which gene families diverge to produce the substrate for biological innovations during evolution.

genetics↗

bioRxiv2025

Emergence of Individualized Functional Topography in the Neonatal Brain

The early postnatal period represents a critical phase for establishing the brains fundamental architecture. However, how individualized functional topography emerges and shapes long-term cognition remains unknown. Using multimodal neuroimaging data from 419 neonates, we map personalized functional topographies in the first weeks of life and reveal their association with 18-month neurocognitive outcomes. Unique and stable functional topographies are already present at birth, with interindividual variability organized along a conserved sensorimotor-to-association hierarchy. These individualized maps encode early brain maturity and robustly predict cognitive, language, and motor outcomes at 18-month of age, with predictive features concentrated at network boundaries. This functional refinement is structurally anchored by concurrent maturation in cortical myelination and sulcal depth. Preterm birth results in distinctive topographic alterations characterized by accelerated maturation of association networks. Our work establishes a foundation for precision models of early brain development and elucidates its significance for long-term neurocognitive outcomes.

neuroscience↗

bioRxiv2025

Convergent and divergent spatial topographies of individualized brain functional networks and their developmental origins

The human brain is intrinsically organized into canonical functional networks with distinct spatial topographies. While precision functional mapping delineates individualized topographies of single networks, the spatial coordination among networks and its developmental origin remains largely unknown. Here, we propose functional topography covariance analysis (FOCA), a novel framework that quantifies convergent and divergent spatial alignments across individualized functional networks and further delineates their internetwork relationships, neurobiological basis, ontogenetic layouts, and cognitive outcomes. Across two well-established task-free functional MRI (fMRI) datasets encompassing both conventional and densely sampled scans, FOCA consistently revealed self-clustered hierarchies in the coordination of functional topographies, closely aligned with existing functional gradients and characterized by convergent couplings within primary systems and divergent couplings in higher-order systems. Such pattern was well predicted by fundamental neurobiological attributes, especially aerobic glycolysis. In a large public neonatal cohort, FOCA matrix exhibited adult-inverted hierarchical couplings and marked changes in auditory and action-mode networks, primarily driven by prominent redistributions of negative couplings. Moreover, neonatal FOCA profiles in the primary visual system significantly predicted neurodevelopmental outcomes at 18 months. Finally, compared with conventional functional connectivity (FC), FOCA proved more robust to global signals and more sensitive to the maturation of negative couplings. These findings highlight the critical role of negative connectivity in brain functional reorganization and advance our understanding of the cooperative and competitive relationships among functional systems and their developmental origins.

neuroscience↗

bioRxiv2025

Hepatocyte FGFR2 Mediates the Antifibrotic Effects of FGF10 in Advanced Liver Fibrosis.

Fibroblast growth factor 10 (FGF10) supports epithelial repair, but its role in liver fibrogenesis remains uncertain. Here we found that hepatic FGF10 and its receptor FGFR2 decline with progression to advanced fibrosis in patient biopsies and in carbon tetrachloride (CCl4)- and diet-induced mouse models. Restoring hepatic FGF10 with recombinant human FGF10 or adeno-associated virus mediated liver-targeted expression attenuated and partially reversed established advanced bridging fibrosis, reduced inflammation, and decreased hepatocyte apoptosis, and these benefits required hepatocyte FGFR2 because hepatocyte-specific Fgfr2 deletion abolished protection. In primary hepatocytes, FGF10 activated FGFR2-FRS2, increased inhibitory GSK3{beta}(Ser9) phosphorylation, and suppressed NF-{kappa}B activation, reducing TGF-{beta}1 and other cytokines and thereby limiting paracrine hepatic stellate cells activation. The molecular and histologic benefits extended to metabolically primed steatohepatitis, supporting translatability beyond toxicant injury. Mechanistic signaling readouts confirm FGFR2 engagement, while the main text centers on the hepatocyte FGF10-FGFR2 axis as an intrinsic brake on fibrogenesis. Together, these data identify a hepatocyte-centric FGF10-FGFR2 axis as a negative regulator and potential regressor of fibrogenesis, highlighting it as a tractable therapeutic target in advanced liver fibrosis.

pharmacology and toxicology↗

bioRxiv2025

Wormtrails: a python package for viewing C. elegans movement

Wormtrails is a python package designed to create images and videos depicting the motion of C. elegans on solid media. Darkfield or brightfield images may be converted into stills or movies, with time encoded by color. This package was primarily designed to be used for visualizing locomotion during chemotaxis, but it may be used to visualize locomotory patterns in a wide array of behavioral assays.

neuroscience↗

bioRxiv2025

Revisiting Humidity Ramp Protocols for Assessing Human Heat Tolerance

BackgroundHumidity ramp protocols are widely used to estimate human heat tolerance limits, yet reported critical environmental limits (CELs) vary markedly across studies. Whether this variability reflects true physiological differences or systematic methodological artifacts related to ramp design remains unresolved. MethodsWe combined first-order thermal modeling with controlled physiological trials to examine how ramp temporal structure (step dwell time) influences apparent rectal temperature (Tcr) inflection points. Twenty-six healthy young adults completed randomized trials at 42 {degrees}C under two protocols: an aggressive-ramp (30-min equilibration followed by humidity increases every 5 min) and a slow-ramp (4-h equilibration followed by hourly humidity increments). CELs derived from ramp protocols were further evaluated using prolonged fixed-condition exposures in independent cohorts (n=14 per sex). ResultsShort-step dwell times ({Delta}t/{tau} <<1) prevented rectal temperature from approaching its step-specific equilibrium, resulting in kinetically constrained, non-equilibrium dynamics and earlier Tcr inflection points. Consequently, aggressive-ramp protocols yielded substantially lower CELs than slow-ramp protocols in both sexes ({approx}3.5 {degrees}C difference). CELs derived from the slow ramp closely matched those obtained from prolonged fixed-condition exposures, whereas aggressive ramps misclassified physiologically compensable conditions as uncompensable. ConclusionRapid humidity increments systematically underestimate heat tolerance because environmental forcing outpaces physiological response kinetics. Accurate CEL determination requires either prolonged fixed-condition exposures (benchmark approach) or sufficiently slow ramps that allow near-equilibrium responses ({Delta}t/{tau} {gtrsim}0.3-0.5).

physiology↗

bioRxiv2025

A human forebrain organoid model phenocopies dysregulated RNA and protein homeostasis in ALS/FTD-associated TDP-43 proteinopathies

TAR DNA-binding protein 43 (TDP-43) proteinopathy is a defining pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the downstream molecular events linking TDP-43 dysfunction to neurodegeneration remain incompletely understood. Here, we model TDP-43 proteinopathy by introducing the ALS/FTD-associated TARDBP K181E mutation into human induced pluripotent stem cells and differentiating them into three-dimensional forebrain organoids. Organoids carrying the K181E mutation exhibit spontaneous TDP-43 hyperphosphorylation, cytoplasmic p-TDP43 accumulation, RNA dysregulation, pro-inflammatory signaling, and activation of apoptotic pathways without TDP-43 overexpression or external stress. Single-cell transcriptomics and enhanced crosslinking immunoprecipitation reveal that the K181E mutation alters TDP-43 RNA-binding specificity, causing widespread RNA mis-splicing including cryptic exon inclusion. Among affected targets, we identify cryptic exon inclusion in the transcription factor PRDM2. PRDM2 cryptic exon-derived peptide immunoreactivity was detected in ALS spinal motor neurons and associated with p-TDP-43 pathology. These findings identify PRDM2 mis-splicing as a candidate downstream event linking TDP-43 dysfunction relevant to ALS and FTD. One sentence summaryHuman brain organoids reveal how mutant TDP-43 disrupts RNA processing and causes neuronal stress.

neuroscience↗

bioRxiv2025

Breaking the ''one nucleus, one whole genome'' rule: Neurospora crassa separates its haploid chromosomes into different nuclei

The nucleus is a defining feature of eukaryotic cells, compartmentalizing the genome to enable precise regulation of diverse cellular processes. The long-standing paradigm in textbooks states that each nucleus carries at least a complete haploid genome --the "one nucleus, one whole genome" rule. A striking exception was recently uncovered: in two sclerotia-forming plant pathogenic fungi in the Sclerotiniaceae family, Sclerotinia sclerotiorum and Botrytis cinerea, haploid chromosomes are irregularly distributed across multiple nuclei. However, whether such phenomenon occurs in other eukaryotes, particularly in non-pathogenic fungi, is unclear. Through a literature survey, we identified many fungi that can potentially also separate their haploid chromosomes across different nuclei. Interestingly, Neurospora crassa, a foundational fungal genetics model, came out as a candidate. Its conidia, typically containing two or three nuclei, were believed to harbor a complete haploid genome within each nucleus. However, using approaches including chromosome counting, flow cytometry, and fluorescence in situ hybridization, we found that haploid chromosomes in N. crassa can be unevenly distributed among multiple nuclei. These findings challenge longstanding assumptions in fungal genetics and provide new directions for investigating genome organization. Our results indicate that the organisms violating the "one nucleus, one whole genome" rule are beyond sclerotia-forming pathogenic fungi. Since over 90% of fungi have not even been described, we propose that many more of them may likewise partition their genomes non-uniformly across nuclei, a process that could facilitate their adaptation and evolution.

microbiology↗

bioRxiv2025

A multi-tissue atlas of genetic regulatory effects in sheep

Characterizing the impact of genomic variants on genome function and ultimately complex traits in livestock is essential for the development of sustainable precision agriculture and comparative genomics. Here, as part of the Farm animal Genotype-Tissue Expression (FarmGTEx) project, we present the pilot phase of the SheepGTEx resource through analyzing 6,761 RNA-sequencing samples of 51 primary tissues in a multi-breed population of sheep. We identify millions of regulatory variants associated with seven types of molecular phenotypes, and fine-map 322,468 primary and 114,017 non-primary effects, revealing a high degree of regulatory allelic heterogeneity. We systematically characterize the pleiotropic effects of these variants on molecular phenotypes, assess their context-specific regulatory patterns across tissues, breeds, sexes, and developmental stages, as well as explore their evolutionary constraints across mammals. Finally, we demonstrate the substantial potential of the SheepGTEx resource (https://sheepgtex.farmgtex.org), by providing examples of regulatory mechanisms underpinning 34 complex traits, population divergence between European and Asian breeds, and adaptive evolution in sheep over the past ten millennia.

genomics↗

bioRxiv2025

Rapid-Response, High-Gain Inkjet-Printed Organic Electrochemical Transistors with Geometry-Optimized Design for Neural Recording and Biosensing

Organic Electrochemical Transistors (OECTs) are witnessing rapid growth in biomedical applications and are increasingly becoming an integral part of bio-electronic interfaces. High-performing OECTs are typically fabricated using multistep photolithography and conventional spin-coating and lift-off processes, and while printing techniques have emerged as promising alternatives, they still face challenges in achieving comparable resolutions, reproducibility and performance metrics. Several groups have demonstrated printed OECTs using PEDOT:PSS as the channel material, highlighting the promise of additive manufacturing for scalable bioelectronics. In this work, we build upon these advances and develop an optimized inkjet-printed OECT platform that achieves transconductance values up to 15 mS and sub-millisecond response times as low as 0.31 ms. Our approach systematically optimizes OECT geometrical parameters--channel width, length, and thickness--through precise patterning and oxygen plasma surface modification to overcome longstanding limitations in inkjet printing resolution and reproducibility. The resulting devices exhibit outstanding electrical stability, high amplification, and fast dynamic response. Using a configuration optimized for biosensing, we demonstrate the detection of the heart failure biomarker NT-proBNP within a clinically relevant range of 10-400 pg/mL, with a sensitivity of 0.038% {Delta}IDS/pg/mL. In a separate configuration on a flexible substrate tailored for in vivo biopotential recording, we showcase the devices capabilities by effectively capturing epileptic seizure progression in a rat model with high signal fidelity. This work demonstrates how careful process and geometry optimization can close the performance gap between printed and conventionally fabricated OECTs, enabling scalable, reproducible, and substrate-flexible bioelectronic platforms.

bioengineering↗

bioRxiv2025

Effects of carbon dioxide enrichment and environmental factors on photosynthesis, growth and yield and their interaction in cucumber: a meta-analysis

Despite the ongoing increase in atmospheric carbon dioxide concentrations, these levels remain well below the optimal threshold for cucumber growth and development. In addressing the challenges posed by climate change to agricultural production, the use of carbon dioxide enrichment (eCO2) has become increasingly widespread in order to meet global demand for cucumbers. Nevertheless, the impact of eCO2 and environmental factors on cucumber growth remains to be elucidated. In this study, we conducted a meta-analysis of 73 research papers on eCO2 in cucumbers was conducted, and their photosynthesis, growth, and yield were analysed. In summary, under conditions of elevated CO2 levels, the net photosynthetic rate, biomass, and yield of cucumbers exhibited a marked increase of 56.31%, 27.75%, and 21.98%, respectively. Concurrently, stomatal conductance and transpiration rate exhibited a decline of 36.07% and 30.42%, respectively. In the context of the implementation of eCO2 at varying levels within a production environment, the prevailing recommendation pertains to the range of 800-1200 ppm. It is advised that this be integrated with elevated light intensity, augmented temperature, suitable humidity levels, and a sufficient supply of fertiliser to achieve a synergistic effect. The findings of this study contribute to enhancement of environmental control in the context of greenhouse cultivation of cucumber in response to climate change, as well as promoting the green and sustainable development of the cucumber industry.

plant biology↗

bioRxiv2025

A gene program dictionary of human cells

Defining all human cell types and their roles in health and disease is a central goal of biology. Single-cell RNA sequencing has enabled the construction of organ-specific cell atlases, but building a comprehensive organism-wide atlas spanning multiple organs remains challenging due to batch effects, study biases, and inter-organ complexity. Here, we present Gene Program Dictionary (GPD), a framework that leverages robust gene co-expression programs--rather than direct cell integration--to overcome these barriers. Using SpacGPA, a partial correlation-based network method, we analyzed 466 scRNA-seq datasets, generating 1,975 independent networks and 90,701 gene co-expression modules, which were consolidated into 1,534 consensus gene programs representing a wide range of human tissues and cell types. Each program serves as a composite marker, capturing both cell-type-specific and shared biological processes. We demonstrate their utility by mapping endothelial cell subtypes across tissues to reveal their heterogeneity--including tumor-specific programs--annotating colorectal cancer spatial transcriptomes, and linking programs and their corresponding cell types to disease loci, revealing hotspots such as neuronal programs in psychiatric disorders and a proximal tubule program in kidney diseases. GPD provides an organism-wide reference for studying cellular diversity and disease mechanisms.

bioinformatics↗

bioRxiv2025

Macrophage EHD1 promotes inflammation and stabilizes sortilin to accelerate atherosclerosis

BackgroundMacrophages are key players in the pathogenesis of atherosclerosis. They trigger immune responses through their cell-surface receptors. However, how macrophages regulate those receptors in response to pro-inflammatory stimuli is not completely understood. Endocytic membrane trafficking involving receptor internalization, followed by endosomal transport and recycling of the internalized receptors, plays essential roles in balancing cell-surface receptors to meet cellular needs. Here, we explored the role of the endocytic regulator EHD1 in immune responses in macrophages and determined its contribution to atherosclerosis progression. MethodsEHD1 expression profiles in mouse and human plaques were determined by single-cell RNA sequencing (scRNA-seq) and immunofluorescence staining. Bone marrow transplantation (BMT) by transplanting bone marrow cells from Ehd1-/- or littermate wild-type mice to irradiated Ldlr-/- mice was performed to determine the effect of EHD1 deletion on atherosclerosis progression. In vitro mechanistic studies including inflammation signaling and endocytosis assays were performed in bone marrow-derived macrophages. ResultsEHD1 expression in macrophages is enhanced as atherosclerosis progresses in both mice and humans. Histological analysis of aortic root sections from BMT mice showed that EHD1 deletion reduces lesion size. ScRNA-seq of aortic CD45+ cells demonstrated that EHD1 deletion attenuates pro-inflammatory responses and cell-cell interactions. Mechanistic studies revealed that EHD1 accelerates the endocytic recycling of TNFR2 and activates NF-kB, leading to increased expression of inflammatory cytokines. Moreover, EHD1 interacts with retromer and stabilizes sortilin, a retrograde cargo of retromer and a risk factor for atherosclerosis. ConclusionsEHD1 promotes inflammation by enhancing TNFR2-NF-kB signaling and stabilizing sortilin, leading to accelerated atherosclerosis. Our study reveals novel roles for EHD1-mediated membrane trafficking in macrophage function and paves the way to innovative therapeutic strategies that aim to address dysregulated membrane trafficking in atherosclerosis.

cell biology↗

bioRxiv2025

Levosimendan Ameliorates Adverse Pulmonary Vascular Remodeling in Group-2 Pulmonary Hypertension.

AimsPulmonary hypertension (PH) due to left heart disease (Group-2PH) is the most common form of PH and comprises two distinct subtypes: isolated post-capillary-PH (IpcPH) and combined post-and pre-capillary-PH (CpcPH). Despite its high prevalence and poor prognosis, no targeted therapies are currently approved, largely due to the absence of reliable preclinical models that recapitulate these human hemodynamic phenotypes. Levosimendan, a calcium sensitizer with inotropic and vasodilatory properties, has shown promise in early clinical trials for Group-2PH, but its mechanisms of action remain unclear. This study aimed to develop and validate experimental models of IpcPH and CpcPH and to assess the therapeutic effects of levosimendan on pulmonary vascular remodeling, inflammation, and cardiac function to support ongoing clinical translation. Methods and ResultsIn a multicentre preclinical study, we established two rodent models that faithfully replicate the human IpcPH and CpcPH hemodynamic profiles. CpcPH animals exhibited severe pulmonary vascular remodeling, inflammatory cell infiltration, and a distinct pro-proliferative transcriptomic signature, whereas IpcPH animals showed minimal pulmonary vascular involvement. Levosimendan (3 mg/kg/day, 3 weeks) improved biventricular function and pulmonary hemodynamics in both models. In CpcPH, levosimendan additionally reduced pulmonary vascular remodeling, attenuated inflammation, and partially reversed disease-associated transcriptomic reprogramming. Transcription factor enrichment analysis identified NF-{kappa}B as a key upstream regulator inhibited by treatment. In a translational extension, nine circulating inflammation-related-proteins differentiated CpcPH from IpcPH patients; among them, TNF, IL-12B, 4E-BP1, NT-3, NGF, FGF21, and FGF23 predicted poor survival. IL-18 and 4E-BP1 were elevated in CpcPH lungs and decreased following levosimendan treatment. ConclusionsInflammation is a major contributor to adverse pulmonary vascular remodeling in CpcPH. Levosimendan improves cardiac performance and mitigates pulmonary vascular inflammation and remodeling, supporting its potential as a dual-action therapeutic agent in Group-2PH. These findings validate novel preclinical models and provide mechanistic evidence reinforcing ongoing clinical evaluation of levosimendan in this condition. Translational perspectiveGroup-2 PH lacks targeted therapies, partly due to the absence of validated preclinical models. We validated models recapitulating human IpcPH and CpcPH and identified inflammation as a key driver of pulmonary vascular remodeling in CpcPH. Levosimendan improved biventricular function and reduced vascular remodeling and inflammation through NF-{kappa}B inhibition. Circulating IL-18 and 4E-BP1 reflected disease severity and treatment response. These findings establish robust translational models, reveal inflammatory mechanisms underlying CpcPH, and provide mechanistic evidence supporting ongoing clinical trials of levosimendan as a dual-action therapeutic strategy in Group-2 PH.

molecular biology↗

bioRxiv2025

NyxBind: enhancing DNN representations via contrastive learning for TFBS prediction

While pretrained genomic language models effectively capture general DNA sequence patterns through masked language modeling, they often struggle to discriminate subtle yet biologically critical differences among transcription factor binding site (TFBS) motifs. Recent studies suggest that contrastive learning can enhance the discriminative power of embeddings by explicitly modeling inter-instance similarities and differences. Building on this insight, we introduce NyxBind, the first TFBS prediction model that applies contrastive learning across multiple TFBS types to enhance regulatory sequence representations. NyxBind better captures discriminative sequence features, enabling more accurate and biologically meaningful TFBS prediction. Extensive evaluations show that NyxBind consistently outperforms alternative models across multiple TFBS classification benchmarks, demonstrating strong robustness and generalizability. Moreover, NyxBind supports both full-parameter and parameter-efficient fine-tuning while maintaining high performance, and supports accurate motif visualization, aligning closely with experimentally validated transcription factor binding profiles. The code are available at https://github.com/ai4nucleome/NyxBind.

bioinformatics↗

bioRxiv2025

Multiple Allosteric Sites Allow for Synergistic Enhancement of GPCR Signaling

Allosteric modulation of G protein-coupled receptors (GPCRs) is an emerging therapeutic paradigm that has proven effective, yet the cooperative action of multiple modulators remains unexplored. Here, we reveal how positive allosteric modulators (PAMs) synergistically enable extraordinary signal amplification through the D1 dopamine receptor (D1R). We developed UNC9815 and UNC10062 as enhanced D1R PAMs from the parent compound MLS6585, and then employed cryo-electron microscopy to reveal concurrent occupancy of three distinct allosteric sites by PAMs of different scaffolds, including LY3154207, BMS-A1, and our UNC compounds. Remarkably, we discovered two adjacent allosteric pockets at the transmembrane helix (TM) 1-7 interface: BMS-A1 occupies an intracellular site promoting activation through TM7 conformational shifts, while the UNC compounds complementarily stabilize the extracellular side of the interface. When combined with LY3154207, this cooperative architecture enhances dopamine potency by more than 1,000-fold. These findings elucidate the first structural blueprint for multi-site GPCR cooperativity, unlocking transformative therapeutic strategies inaccessible to orthosteric and single- site allosteric drugs.

molecular biology↗

bioRxiv2025

A Single-cell Spatiotemporal Manifold of Tissue Morphology and Dynamics

Complex tissues are now characterizable at single-cell resolution, but the spatial logic underlying tissue organization remains challenging to access without effective single-cell spatial descriptors. We present a learned single-cell manifold of cell positions over time, with which one can measure tissue morphology and trace dynamics. Learning co-processes pairs of cell point clouds sampled along time using a Transformer encoder with inter-sample attention, a strategy that promotes efficient joint spatiotemporal learning. The manifold shows desirable properties of a general descriptor, e.g. interpretable cell type clusters, preserved local distances, and a pseudo-time axis, and enables common but challenging spatial reasoning tasks such as annotation of anatomical landmarks at cellular resolution and detection of subtle, transient phenotypes in large screens. Our study demonstrates a widely applicable cell-based learning strategy and representation for studying tissue biology.

developmental biology↗