Biology subjects

Hua, Y.

Publications and source records attributed to Hua, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Gating of hair cell Ca2+ channels governs the activity of cochlear neurons

Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, postsynaptic spiral ganglion neurons (SGNs) tile this intensity range with their firing rate codes. Presynaptic inner hair cells (IHCs) vary Ca2+-influx among their active zones (AZs) diversifying glutamate release and likely contributing to SGN firing diversity. Here we show that low-voltage activation of IHC-Ca2+-influx of mice, modeling the human CaV1.3A749G mutation, increases spontaneous SGN-firing and lowers sound threshold. Altered synaptic morphology in CaV1.3A749G/A749G mice already at ambient sound levels of standard mouse husbandry indicates a risk for noise-induced alterations in CaV1.3A749G patients. We conclude that heterogeneous voltage-dependence of CaV1.3 activation among IHC-AZs contributes to the diversity of SGN firing for sound intensity coding and synaptic vulnerability.

neuroscience↗

bioRxiv2024

Infectivity of a pathogenicity-attenuated Chlamydia muridarum mutant in the genital tract

A C. muridarum mutant designated as intrOv was evaluated as an intracellular Oral vaccine vector because it can induce protection in the genital tract following oral inoculation but does not elicit genital pathology following intravaginal infection. However, the mechanism of intrOvs attenuation is unclear. Here we report that few live organisms were recovered from vaginal swabs during the early stage of intrOv intravaginal infection in mice. At a low inoculating dose, an isogenic wild-type control strain established a productive infection, while intrOv failed to do so. Although a higher inoculating dose allowed intrOv and its control to productively infect mice, fewer live intrOv than the control organisms were recovered from the lower genital tract tissues on day 3 post-infection. By day 7, animals infected with intrOv or the control shed similar numbers of live organisms, suggesting the intrOvs deficiency on day 3 was transient. Consistently, intrOv reduced invasion of epithelial cells but maintained as robust intracellular replication as its control. Our results correlate intrOvs delay in infecting the lower genital tissues and reduction in invading epithelial cells with its attenuation in genital pathogenicity, laying the foundation for further revealing the mechanisms of the intrOvs attenuation in pathogenicity during genital tract infection.

microbiology↗

bioRxiv2024

Targeting SLC7A11-mediated cysteine metabolism for the treatment of trastuzumab resistant HER2 positive breast cancer

Trastuzumab resistance remains a challenge for HER2 positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics and epigenomics data of trastuzumab sensitive and primary resistant HER2 positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.

cancer biology↗

bioRxiv2024

A regulator controls both DNA damage response and anti-phage defense networks in Moraxellaceae

DNA damage chemicals, including many antibiotics, often induce prophage induction and phage outbreaks in microbial communities, a major threat to bacterial survival. Moraxellaceae contains clinically highly relevant strains with outstanding antibiotic and radio resistance, yet their cellular-level regulation in DNA damage response and anti-phage defense is largely unknown. Here, we identified a WYL family protein that had replaced the ubiquitous SOS system in evolution and directly regulated a transcriptional network of both DNA repair genes and anti-phage defense genes under DNA damage stress. This study depicts a mechanism that how bacteria maintain immunity to phages without compromising on antibiotic resistance, and sheds light on controlling the resistance of Moraxellaceae strains in clinical practice.

microbiology↗

bioRxiv2024

The Cryo-EM structure of TRPC1 and TRPC5 heterotetramer

Ion channel heteromers display distinct electrophysiological and ligand-binding properties, allowing precise modulation of cellular functions in specific tissues. Among the TRPC subtypes, the TRPC1/4/5 heteromers are the most abundant isoform in the human brain and represent a primary target for treating anxiety and depression. However, the structural organization of TRPC1/4/5 heteromers remain unclear, limiting the advancement of research on these channels. Here, we report the cryo-EM structure of TRPC1/5 heterotatramer at a resolution of 2.84 [A]. It consists of an asymmetric structure with three TRPC5 subunits and one TRPC1 subunit. Further structural and functional analysis revealed that the TRPC1 subunit contributes to an asymmetrical ion conduction pathway, a characteristic that differentiates it from TRPC5 homomers. The unique features of the TRPC1 pore loop and its interface interactions with TRPC5 were shown to play crucial roles in modulating the ion conduction properties and gating mechanisms of the heteromeric complex. In addition, we identified key residues within the gating regions that influence channel activation and ion permeability, elucidating the structural basis for the functional divergence between the TRPC1/C5 heterotetramer and TRPC5 homotetramer. Notably, TRPC5 residues were found to dominate gating mechanisms, underscoring the complex interplay between subunit composition and functional outcomes in TRPC channels. Our findings provide novel insights into the structural and functional dynamics of TRPC1/C5 heteromers, paving the way for targeted therapeutic strategies in TRPC5-related disorders.

biophysics↗

bioRxiv2024

Efficient cell-wide mapping of mitochondria in electron microscopic volumes using webKnossos

Recent technical advances in volume electron microscopy (vEM) and artificial intelligence-assisted image processing have facilitated high throughput quantifications of cellular structures, such as mitochondria that are ubiquitous and morphologically diversified. A still often overlooked computational challenge is to assign cell identity to numerous mitochondrial instances, for which both mitochondrial and cell membrane contouring used to be required. Here, we present a vEM reconstruction procedure (called mito-SegEM) that utilizes virtual path-based annotation to assign automatically segmented mitochondrial instances at the cellular scale, therefore bypassing the requirement of membrane contouring. The embedded toolset in webKnossos (an open-source online annotation platform) is optimized for fast annotation, visualization, and proofreading of cellular organelle networks. We demonstrate broad applications of mito-SegEM on volumetric datasets from various tissues, including the brain, intestine, and testis, to achieve an accurate and efficient reconstruction of mitochondria in a use-dependent fashion.

cell biology↗

bioRxiv2024

Capturing sclera anisotropy using direct collagen fiber models. Linking microstructure to macroscopic mechanical properties.

Because of the crucial role of collagen fibers on soft tissue mechanics, there is great interest in techniques to incorporate them in computational models. Recently we introduced a direct fiber modeling approach for sclera based on representing the long-interwoven fibers. Our method differs from the conventional continuum approach to modeling sclera that homogenizes the fibers and describes them as statistical distributions for each element. At large scale our method captured gross collagen fiber bundle architecture from histology and experimental intraocular pressure-induced deformations. At small scale, a direct fiber model of a sclera sample reproduced equi-biaxial experimental behavior from the literature. In this study our goal was a much more challenging task for the direct fiber modeling: to capture specimen-specific 3D fiber architecture and anisotropic mechanics of four sclera samples tested under equibiaxial and four non-equibiaxial loadings. Samples of sclera from three eyes were isolated and tested in five biaxial loadings following an approach previously reported. Using microstructural architecture from polarized light microscopy we then created specimen-specific direct fiber models. Model fiber orientations agreed well with the histological information (adjusted R2s>0.89). Through an inverse-fitting process we determined model characteristics, including specimen-specific fiber mechanical properties to match equibiaxial loading. Interestingly, the equibiaxial properties also reproduced all the non-equibiaxial behaviors. These results indicate that the direct fiber modeling method naturally accounted for tissue anisotropy within its fiber structure. Direct fiber modeling is therefore a promising approach to understand how macroscopic behavior arises from microstructure.

bioengineering↗

bioRxiv2024

Probing the role of Nogo receptor homolog NgR2 in setting up cochlear connectivity

Sound encoding depends on the precise and reliable neurotransmission at the afferent synapses between the sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs). The molecular mechanisms contributing to the formation, as well as interplay between the pre- and postsynaptic components remain largely unclear. Here, we tested the role of the synaptic adhesion molecule and Nogo/RTN4 receptor homolog RTN4RL2 (also referred to as NgR2) in the development and function of afferent IHC-SGN synapses. Upon deletion of RTN4RL2 in mice (RTN4RL2-/-), presynaptic IHC active zones showed enlarged synaptic ribbons and a depolarized shift in the activation of CaV1.3 Ca2+ channels. The postsynaptic densities (PSDs) of SGNs were smaller and deficient of GluA2-4 AMPA receptor subunits despite maintained Gria2 mRNA expression in SGNs. Next to synaptically engaged PSDs we observed "orphan" PSDs located away from IHCs. They likely belong to a subset of SGN peripheral neurites that do not contact the IHCs in RTN4RL2-/- cochleae as found by volume electron microscopy reconstruction of SGN neurites. Auditory brainstem responses of RTN4RL2-/- mice showed increased sound thresholds indicating impaired hearing. Together, these findings suggest that RTN4RL2 contributes to the proper formation and function of auditory afferent synapses and is critical for normal hearing.

neuroscience↗

bioRxiv2024

Proposing a methodology for axon-centric analysis of IOP-induced mechanical insult

PurposeIOP-induced mechanical insult on retinal ganglion cell axons within the optic nerve head (ONH) is believed to be a key factor in axonal damage and glaucoma. However, most studies focus on tissue-level mechanical deformations, overlooking that axons are long and thin, and that their susceptibility to damage likely depends on the insults type (e.g. stretch/compression) and orientation (longitudinal/transverse). We propose an axon-centric approach to quantify IOP-induced mechanical insult from an axon perspective. MethodsWe used optical coherence tomography (OCT) scans from a healthy monkey eye along with histological images of cryosections to reconstruct the axon-occupied volume including detailed lamina cribrosa (LC) pores. Tissue-level strains were determined experimentally using digital volume correlation from OCT scans at baseline and elevated IOPs, then transformed into axonal strains using axon paths estimated by a fluid mechanics simulation. ResultsAxons in the LC and post-LC regions predominantly experienced longitudinal compression and transverse stretch, whereas those in the pre-LC and ONH rim mainly suffered longitudinal stretch and transverse compression. No clear patterns were observed for tissue-level strains. ConclusionsOur approach allowed discerning axonal longitudinal and transverse mechanical insults, which are likely associated with different mechanisms of axonal damage. The technique also enabled quantifying insult along individual axon paths, providing a novel link relating the retinal nerve fiber layer and the optic nerve through the LC via individual axons. This is a promising approach to establish a clearer connection between IOP-induced insult and glaucoma. Further studies should evaluate a larger cohort.

bioengineering↗

bioRxiv2024

Impact of anatomic variability and other vascular factors on lamina cribrosa hypoxia

Insufficient oxygenation in the lamina cribrosa (LC) may contribute to axonal damage and glaucomatous vision loss. To understand the range of susceptibilities to glaucoma, we aimed to identify key factors influencing LC oxygenation and examine if these factors vary with anatomical differences between eyes. We reconstructed 3D, eye-specific LC vessel networks from histological sections of four healthy monkey eyes. For each network, we generated 125 models varying vessel radius, oxygen consumption rate, and arteriole perfusion pressure. Using hemodynamic and oxygen supply modeling, we predicted blood flow distribution and tissue oxygenation in the LC. ANOVA assessed the significance of each parameter. Our results showed that vessel radius had the greatest influence on LC oxygenation, followed by anatomical variations. Arteriole perfusion pressure and oxygen consumption rate were the third and fourth most influential factors, respectively. The LC regions are well perfused under baseline conditions. These findings highlight the importance of vessel radius and anatomical variation in LC oxygenation, providing insights into LC physiology and pathology. Pathologies affecting vessel radius may increase the risk of LC hypoxia, and anatomical variations could influence susceptibility. Conversely, increased oxygen consumption rates had minimal effects, suggesting that higher metabolic demands, such as those needed to maintain intracellular transport despite elevated intraocular pressure, have limited impact on LC oxygenation.

bioengineering↗

bioRxiv2024

Impact of elevated IOP on lamina cribrosa oxygenation; A combined experimental-computational study on monkeys

PurposeOur goal is to evaluate how lamina cribrosa (LC) oxygenation is affected by the tissue distortions resulting from elevated IOP. DesignExperimental study on monkeys SubjectsFour healthy monkey eyes with OCT scans with IOP of 10 to 50 mmHg, and then with histological sections of LC. MethodsSince in-vivo LC oxygenation measurement is not yet possible, we used 3D eye-specific numerical models of the LC vasculature which we subjected to experimentally-derived tissue deformations. We reconstructed 3D models of the LC vessel networks of 4 healthy monkey eyes from histological sections. We also obtained in-vivo IOP-induced tissue deformations from a healthy monkey using OCT images and digital volume correlation analysis techniques. The extent that LC vessels distort under a given OCT-derived tissue strain remains unknown. We therefore evaluated two biomechanics-based mapping techniques: cross-sectional and isotropic. The hemodynamics and oxygenations of the four vessel networks were simulated for deformations at several IOPs up to 60mmHg. The results were used to determine the effects of IOP on LC oxygen supply, assorting the extent of tissue mild and severe hypoxia. Main Outcome MeasuresIOP-induced deformation, vasculature structure, blood supply, and oxygen supply for LC region ResultIOP-induced deformations reduced LC oxygenation significantly. More than 20% of LC tissue suffered from mild hypoxia when IOP reached 30 mmHg. Extreme IOP(>50mmHg) led to large severe hypoxia regions (>30%) in the isotropic mapping cases. ConclusionOur models predicted that moderately elevated IOP can lead to mild hypoxia in a substantial part of the LC, which, if sustained chronically, may contribute to neural tissue damage. For extreme IOP elevations, severe hypoxia was predicted, which would potentially cause more immediate damage. Our findings suggest that despite the remarkable LC vascular robustness, IOP-induced distortions can potentially contribute to glaucomatous neuropathy.

bioengineering↗

bioRxiv2024

A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy

Osteosarcoma (OS) exhibit intra- and inter-heterogeneity, complicating the exploration of effective therapeutic strategies. Traditional in vitro and in vivo models are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliability in vitro or transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTA inhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.

cancer biology↗

bioRxiv2024

SeuratExtend: Streamlining Single-Cell RNA-Seq Analysis Through an Integrated and Intuitive Framework

Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of cellular heterogeneity, but the rapid expansion of analytical tools has proven to be both a blessing and a curse, presenting researchers with significant challenges. Here, we present SeuratExtend, a comprehensive R package built upon the widely adopted Seurat framework, which streamlines scRNA-seq data analysis by integrating essential tools and databases. SeuratExtend offers a user-friendly and intuitive interface for performing a wide range of analyses, including functional enrichment, trajectory inference, gene regulatory network reconstruction, and denoising. The package seamlessly integrates multiple databases, such as Gene Ontology and Reactome, and incorporates popular Python tools like scVelo, Palantir, and SCENIC through a unified R interface. SeuratExtend enhances data visualization with optimized plotting functions and carefully curated color schemes, ensuring both aesthetic appeal and scientific rigor. We demonstrate SeuratExtends performance through case studies investigating tumor-associated high-endothelial venules and autoinflammatory diseases, and showcase its novel applications in pathway-Level analysis and cluster annotation. SeuratExtend empowers researchers to harness the full potential of scRNA-seq data, making complex analyses accessible to a wider audience. The package, along with comprehensive documentation and tutorials, is freely available at GitHub, providing a valuable resource for the single-cell genomics community. Practitioner PointsO_LISeuratExtend streamlines scRNA-seq workflows by integrating R and Python tools, multiple databases (e.g., GO, Reactome), and comprehensive functional analysis capabilities within the Seurat framework, enabling efficient, multi-faceted analysis in a single environment. C_LIO_LIAdvanced visualization features, including optimized plotting functions and professional color schemes, enhance the clarity and impact of scRNA-seq data presentation. C_LIO_LIA novel clustering approach using pathway enrichment score-cell matrices offers new insights into cellular heterogeneity and functional characteristics, complementing traditional gene expression-based analyses. C_LI

bioinformatics↗

bioRxiv2024

Protein Editing using a Concerted Transposition Reaction

Protein engineering through the chemical or enzymatic ligation of polypeptide fragments has proven enormously powerful for studying countless biochemical processes in vitro. In general, this strategy necessitates a protein folding step following ligation of the unstructured fragments, a requirement that constrains the types of systems amenable to the approach. Here, we report an in vitro strategy that allows internal regions of target proteins to be replaced in a single operation. Conceptually, our system is analogous to a DNA transposition reaction, but employs orthogonal pairs of split inteins to swap out a designated region of a host protein with an exogenous molecular cassette. We show using isotopic labeling experiments that this protein transposition reaction is concerted when the kinetics for the embedded intein pairs are suitably matched. Critically, this feature allows for efficient manipulation of protein primary structure in the context of a native fold. The utility of this method is illustrated using several protein systems including the multi-subunit chromatin remodeling complex, ACF, where we also show protein transposition can occur in situ within the cell nucleus. By carrying out a molecular cut and paste on a protein or protein complex under native folding conditions, our approach dramatically expands the scope of protein semisynthesis.

biochemistry↗

bioRxiv2024

Evolutionary modes of wtf meiotic driver genes in Schizosaccharomyces pombe

Killer meiotic drivers (KMDs) are a class of selfish genetic elements that defy Mendels law and bias transmission in their favor by destroying meiotic progeny that do not carry them. How KMDs evolve is not well understood. In the fission yeast Schizosaccharomyces pombe, the largest gene family, known as the wtf genes, is a KMD family that causes intraspecific hybrid sterility. Here, we investigate how wtf genes evolve using long-read-based genome assemblies of 31 distinct S. pombe natural isolates, which encompass the known genetic diversity of S. pombe. Our analysis, involving nearly 1,000 wtf genes in these isolates, yields a comprehensive portrayal of the intraspecific diversity of wtf genes. Leveraging single-nucleotide polymorphisms in adjacent unique sequences, we pinpoint wtf-gene-containing loci that have recently undergone gene conversion events and infer their pre-gene-conversion state. These events include the revival of wtf pseudogenes, lending support to the notion that gene conversion plays a role in preserving this gene family from extinction. Moreover, our investigation reveals that solo long terminal repeats (LTRs) of retrotransposons, frequently found near wtf genes, can act as recombination arms, influencing the upstream regulatory sequences of wtf genes. Additionally, our exploration of the outer boundaries of wtf genes uncovers a previously unrecognized type of directly oriented repeats flanking wtf genes. These repeats may have facilitated the early expansion of the wtf gene family in S. pombe. Our findings enhance the understanding of the mechanisms influencing the evolution of this KMD gene family.

evolutionary biology↗

bioRxiv2024

An optimized somatic embryo transformation system assisted homozygous edited rubber tree generation method mediated by CRISPR/Cas9

Previously, we have realized the CRISPR/Cas9-RNP and plasmid mediated protoplast transient transformation genome editing in the rubber tree (Hevea brasiliensis), but no gene editing plants were acquired due to the bottleneck of genetic transformation. In present study, antibiotic sensitivity tests against kanamycin, hygromycin and basta were analyzed for embryo screening, the results demonstrated that 10 mg/L hygromycin is the best for transformation. Then Agrobacterium mediated transformation of H. brasiliensis embryos was carried out using a pCAMBIA1300-based CRISPR/Cas9 vector targeting Phytoene desaturase gene (HbPDS). High-throughput sequencing of T0 generation positive embryos which were used as regeneration materials in typical transformation procedure showed that more than 90% T0 edited embryos are chimeric with a 3.2% editing efficiency. A T0 embryo with 9.8% edited cells was sliced into small pieces for one more cycle embryogenesis to produce T1 generation embryos in order to improve the ratio of homozygous embryos. Subsequently, next-generation sequencing (NGS) demonstrated that 29 out of 33 T1 embryos were edited, nearly 50% of which were found homozygous. At last, besides four chimeric plantlets with partial albino leaves, four plantlets with complete albino phenotype were regenerated from the 29 T1 generation edited embryos, among which one is a homozygous mono-allelic mutant and the other three are homozygous bi-allelic mutants. NGS demonstrated that the threshold for the proportion of edited cells with expected albino phenotype is between 70-85%. Additionally, Tail-PCR indicate that the T-DNA was inserted into different genome positions in the four homozygous edited plantlets, combined with the different genotypes are considered, the four homozygous plantlets can be confirmed as independently derived from single transformed cells. Overall, this is the first edited rubber trees with expected phenotype reported publicly, which shows the potential in genetic improvement of H. brasiliensis by CRISPR/Cas9 gene editing, and subculture of T0 positive transformed somatic embryos into T1 generation is proved to be an effective and necessary procedure to produce homozygous transgenic plantlets. This study presents a significant advancement in transgenic and gene editing for rubber tree.

plant biology↗

bioRxiv2023

Large-scale population genomics of Malayan pangolins reveals deep diversification and a new species

BackgroundArchipelagos and oceanic islands often present high percentage of endemism due to rapid speciation. The Malayan pangolin is a species distributing at both mainland (southern Yunnan, China) and oceanic islands via Malayan peninsula, which may result in deep differentiation among populations. In-depth investigation of population structure and genetic consequences for such species is of vital importance for their protection and conservation, practically for the critically endangered Malayan pangolin that is suffering from poaching, illegal trade, and habitat loss. ResultsHere we carried out a large-scale population genomic analysis for Malayan pangolins, and revealed three highly distinct genetic populations in this species, two of which are now being reported for the first time. Based on multiple lines of genomic and morphological evidence, we postulate the existence of a new pangolin species (Manis_1). Genetic diversity and recent inbreeding were both at a moderate level for both Malayan pangolins and Manis_1, but mainland Malayan pangolins presented relatively lower genetic diversity, higher inbreeding and fitness cost than island populations. ConclusionsWe found extremely deep and graded differentiation in Malayan pangolins, with two newly discovered genetic populations and a new pangolin species that is closely related to the Philippine pangolin than the typical Malayan pangolin, but a distant relative of the Indian pangolin. Anthropogenic factors did not significantly weaken the basis of genetic sustainability for Malayan pangolins, but mainland Malayan pangolins should be paid more attention for conservation due to higher genetic risks than island populations.

genomics↗

bioRxiv2023

Fibrous Finite Element Modeling of the Optic Nerve Head Region

The optic nerve head (ONH) region at the posterior pole of the eye is supported by a fibrous structure of collagen fiber bundles. Discerning how the fibrous structure determines the region biomechanics is crucial to understand normal physiology, and the roles of biomechanics on vision loss. The fiber bundles within the ONH structure exhibit complex three-dimensional (3D) organization and continuity across the various tissue components. Computational models of the ONH, however, usually represent collagen fibers in a homogenized fashion without accounting for their continuity across tissues, fibers interacting with each other and other synergistic effects in a fibrous structure. We present a novel fibrous finite element (FFE) model of the ONH that incorporates discrete collagen fiber bundles and their histology-based 3D organization to study ONH biomechanics as a fibrous structure. The FFE model was constructed using polarized light microscopy data of porcine ONH cryosections, representing individual fiber bundles in the sclera, dura and pia maters with beam elements and canal tissues as continuum structures. The FFE model mimics the histological in-plane orientation and width distributions of collagen bundles as well as their continuity across different tissues. Modeling the fiber bundles as linear materials, the FFE model predicts the nonlinear ONH response observed in an inflation experiment from the literature. The model also captures important microstructural mechanisms including fiber interactions and long-range strain transmission among bundles that have not been considered before. The FFE model presented here advances our understanding of the role of fibrous collagen structure in the ONH biomechanics. Statement of SignificanceThe microstructure and mechanics of the optic nerve head (ONH) are central to ocular physiology. Histologically, the ONH region exhibits a complex continuous fibrous structure of collagen bundles. Understanding the role of the fibrous collagen structure on ONH biomechanics requires high-fidelity computational models previously unavailable. We present a novel computational model of the ONH that incorporates histology-based fibrous collagen structure derived from polarized light microscopy images. The model predictions agree with experiments in the literature, and provide insight into important microstructural mechanisms of fibrous tissue biomechanics, such as long-range strain transmission along fiber bundles. Our model can be used to study the microstructural basis of biomechanical damage and the effects of collagen remodeling in glaucoma.

bioengineering↗