Biology subjects

Shao, E.

Publications and source records attributed to Shao, E..

4 recordsLinked to original sources

bioRxiv2026

Regulation of Mechanosensor PIEZO Channel Trafficking in C. elegans Germline

PIEZO proteins are essential mechanotransductive ion channels, yet mechanisms governing their subcellular localization and membrane trafficking remain elusive. Here, we leverage the C. elegans germline as an in vivo imaging platform to decipher the molecular networks directing PIEZO channel dynamics. High-resolution confocal imaging of endogenously tagged PEZO-1, the C. elegans ortholog, reveals that PEZO-1 compartmentalizes with caveolae protein CAV-1 and the recycling endosome regulator RAB-11. Depletion of rab-11 or the t-SNARE syx-4 severely impairs the translocation of PEZO-1-positive vesicles to the plasma membrane, establishing a reliance on conserved, RAB-11-dependent machinery. Furthermore, we demonstrated that PEZO-1 structural integration is essential for vesicle formation and transport; truncating either the N-terminal transmembrane domains or the C-terminal ion pore induces aberrant vesicle morphology and arrests trafficking. Crucially, PEZO-1 vesicle formation and transport are non-autonomously modulated by reproductive signals requiring male sperm or major sperm protein (MSP) signaling. Finally, introducing conserved disease-associated pathogenic PIEZO mutations markedly suppresses its cytosolic and plasma membrane expression. Collectively, our findings define a fundamental cytological framework regulating PIEZO channel dynamics, shedding light on the molecular etiology of PIEZO-associated channelopathies.

genetics↗

bioRxiv2021

Molecular Graph Contrastive Learning with Parameterized Explainable Augmentations

Learning generalizable, transferable, and robust representations for molecule data has always been a challenge. The recent success of contrastive learning (CL) for self-supervised graph representation learning provides a novel perspective to learn molecule representations. The most prevailing graph CL framework is to maximize the agreement of representations in different augmented graph views. However, existing graph CL frameworks usually adopt stochastic augmentations or schemes according to pre-defined rules on the input graph to obtain different graph views in various scales (e.g. node, edge, and subgraph), which may destroy topological semantemes and domain prior in molecule data, leading to suboptimal performance. Therefore, designing parameterized, learnable, and explainable augmentation is quite necessary for molecular graph contrastive learning. A well-designed parameterized augmentation scheme can preserve chemically meaningful structural information and intrinsically essential attributes for molecule graphs, which helps to learn representations that are insensitive to perturbation on unimportant atoms and bonds. In this paper, we propose a novel Molecular Graph Contrastive Learning with Parameterized Explainable Augmentations, MolCLE for brevity, that self-adaptively incorporates chemically significative information from both topological and semantic aspects of molecular graphs. Specifically, we apply deep neural networks to parameterize the augmentation process for both the molecular graph topology and atom attributes, to highlight contributive molecular substructures and recognize underlying chemical semantemes. Comprehensive experiments on a variety of real-world datasets demonstrate that our proposed method consistently outperforms compared baselines, which verifies the effectiveness of the proposed framework. Detailedly, our self-supervised MolCLE model surpasses many supervised counterparts, and meanwhile only uses hundreds of thousands of parameters to achieve comparative results against the state-of-the-art baseline, which has tens of millions of parameters. We also provide detailed case studies to validate the explainability of augmented graph views. CCS CONCEPTS* Mathematics of computing [->] Graph algorithms; * Applied computing [->] Bioinformatics; * Computing methodologies [->] Neural networks; Unsupervised learning.

bioinformatics↗

bioRxiv2021

Insertive vaginal sex has a profound impact on the penile immune correlates of HIV susceptibility

The penis is the primary site of HIV acquisition in heterosexual men. Elevated penile inflammatory cytokines increase sexual acquisition risk, and topically applied cytokines enhance foreskin HIV susceptibility in an explant model. However, the impact of penile-vaginal sex on these immune parameters is undefined. Heterosexual couples were recruited to the Sex, Couples and Science (SECS) Study, with the collection of penile swabs, semen, cervico-vaginal secretions, and blood after a period of abstinence, and repeated sampling up to 72 hours after either condomless (n=30) or condom-protected (n=8) penile-vaginal sex. Soluble immune parameters were quantified by multiplex immunoassay. Co-primary immune endpoints were penile levels of IL-8 and MIG, cytokines previously linked to penile HIV acquisition. One hour after sex there were dramatic increases in penile IL-8 and MIG levels, regardless of condom use, with a gradual return to baseline by 72 hours; similar patterns were observed for other chemoattractant chemokines. Penile cytokine changes were similar in circumcised and uncircumcised men, and repeated measures ANOVA and ANCOVA models demonstrated that the degree of change after condomless sex was explained by cytokine levels in their partners cervico-vaginal secretions. This may have important implications for the biology of penile HIV acquisition. Author summaryIn heterosexual men, the penis is the primary site of Human Immunodeficiency Virus (HIV) acquisition. Levels of inflammatory cytokines in the coronal sulcus are associated with an increased HIV risk, and we hypothesized that these may be altered after insertive penile sex. Therefore, we designed the Sex, Couples and Science Study (SECS study) to define the impact of penile-vaginal sex on the penile immune correlates of HIV susceptibility. We found that multiple coronal sulcus cytokines increased dramatically and rapidly after sex, regardless of condom use, with a return to baseline levels by 72 hours. The changes observed after condomless sex were strongly predicted by cytokine concentrations in the vaginal secretions of the female partner, and were similar in circumcised and uncircumcised men. We believe that these findings have important implications for understanding the immunopathogenesis of penile HIV acquisition; in addition, they have important implications for the design of clinical studies of penile HIV acquisition and prevention.

immunology↗

bioRxiv2018

Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation

The retinal pigment epithelium (RPE) is a specialized monolayer of pigmented cells within the eye that is critical for maintaining visual system function. Diseases affecting the RPE have dire consequences for vision, and the most prevalent of these is atrophic (dry) age-related macular degeneration (AMD), which is thought to result from RPE dysfunction and degeneration. An intriguing possibility for treating RPE degenerative diseases like atrophic AMD is the stimulation of endogenous RPE regeneration; however, very little is known about the mechanisms driving successful RPE regeneration in vivo. Here, we developed a zebrafish transgenic model (rpe65a:nfsB-GFP) that enabled ablation of large swathes of mature RPE. RPE ablation resulted in rapid RPE degeneration, as well as degeneration of Bruchs membrane and underlying photoreceptors. Using this model, we demonstrate for the first time that larval and adult zebrafish are capable of regenerating a functional RPE monolayer after RPE ablation. Regenerated RPE cells first appear at the periphery of the RPE, and regeneration proceeds in a peripheral-to-central fashion. RPE ablation elicits a robust proliferative response in the remaining RPE. Subsequently, proliferative cells move into the injury site and differentiate into RPE. BrdU pulse-chase analyses demonstrate that the regenerated RPE is likely derived from remaining peripheral RPE cells. Pharmacological inhibition of Wnt signaling significantly reduces cell proliferation in the RPE and delays overall RPE recovery. These data demonstrate that the zebrafish RPE possesses a robust capacity for regeneration and highlight a potential mechanism through which endogenous RPE regenerate in vivo.\n\nSIGNIFICANCE STATEMENTDiseases resulting in RPE degeneration are among the leading causes of blindness worldwide, and no therapy exists that can replace RPE or restore lost vision. One intriguing possibility is the development of therapies focused on stimulating endogenous RPE regeneration. For this to be possible, we must first gain a deeper understanding of the mechanisms underlying RPE regeneration. Here, we ablate mature RPE in zebrafish and demonstrate that zebrafish regenerate RPE after widespread injury. Injury-adjacent RPE proliferate and regenerate RPE, suggesting that they are the source of regenerated tissue. Finally, we demonstrate that Wnt signaling is required for RPE regeneration. These findings establish an in vivo model through which the molecular and cellular underpinnings of RPE regeneration can be further characterized.

developmental biology↗