摘要: High myopia is the leading cause of blindness worldwide. It promotes the overgrowth of lens, which is an important component of ocular refractive system, and increases the risks of lens surgery. While postnatal growth of lens is based on the addition of lens fibre cells (LFCs) supplemented by proliferation and differentiation of lens epithelial cells (LECs), it remains unknown how these cellular processes change in highly myopic eyes and what signalling pathways may be involved. Single-cell RNA sequencing was performed and a total of 50,375 single cells isolated from the lens epithelium of mouse highly myopic and control eyes were analysed to uncover their underlying transcriptome atlas. The proportion of LFCs was significantly higher in highly myopic eyes. Meanwhile, Notch2 signalling was inhibited during lineage differentiation trajectory towards LFCs, while Notch2 predominant LEC cluster was significantly reduced in highly myopic eyes. In consistence, Notch2 was the top down-regulated gene identified in highly myopic lens epithelium. Further validation experiments confirmed NOTCH2 downregulation in the lens epithelium of human and mouse highly myopic eyes. In addition, NOTCH2 knockdown in primary human and mouse LECs resulted in enhanced differentiation towards LFCs accompanied by up-regulation of MAF and CDKN1C. These findings indicated an essential role of NOTCH2 inhibition in lens overgrowth of highly myopic eyes, suggesting a therapeutic target for future interventions.

摘要: Glioblastoma (GBM) is a malignant brain tumour, but its subtypes (mesenchymal, classical, and proneural) show different prognoses. Pyroptosis is a programmed cell death relating to tumour progression, but its association with GBM is poorly understood. In this work, we collected 73 GBM samples (the Xiangya GBM cohort) and reported that pyroptosis involves tumour-microglia interaction and tumour response to interferon-gamma. GBM samples were grouped into different subtypes, cluster 1 and cluster 2, based on pyroptosis-related genes. Cluster 1 samples manifested a worse prognosis and had a more complicated immune landscape than cluster 2 samples. Single-cell RNA-seq data analysis supported that cluster 1 samples respond to interferon-gamma more actively. Moreover, the machine learning algorithm screened several potential compounds, including nutlin-3, for cluster 1 samples as a novel treatment. In vitro experiments supported that cluster 1 cell line, T98G, is more sensitive to nutlin-3 than cluster 2 cell line, LN229. Nutlin-3 can trigger oxidative stress by increasing DHCR24 expression. Moreover, pyroptosis-resistant genes were upregulated in LN229, which may participate against nutlin-3. Therefore, we hypothesis that GBM may be able to upregulate pyroptosis resistant related genes to against nutlin-3-triggered cell death. In summary, we conclude that pyroptosis highly associates with GBM progression, tumour immune landscape, and tumour response to nutlin-3.

摘要: Sensorineural hearing loss a result from hair cell damage, which is irreversible in mammals owing to the lack of hair cell regeneration, but recent researches have shown that Lgr5(+) supporting cells are progenitors capable of regenerating hair cells. RPS14 (ribosomal protein S14) is a 40S ribosomal subunit component and is associated with erythrocyte differentiation, and in this study, we used a novel adeno-associated virus-inner ear system to upregulate Rps14 expression in cultured hair cell progenitors and observed an enhancement on their ability to proliferate and differentiate into hair cells. Similarly, Rps14 overexpression in the mice cochlea could promote supporting cells proliferation by activating the Wnt signalling pathway. In addition, over-expressing Rps14 induced hair cells regeneration in the organ of Corti, and lineage tracing showed that the new hair cells had transformed from Lgr5(+) progenitors. In conclusion, our analysis reveals the potential role of Rps14 in driving hair cell regeneration in mammalian.

摘要: Intervertebral disc degeneration (IDD), an important cause of chronic low back pain (LBP), is considered the pathological basis for various spinal degenerative diseases. A series of factors, including inflammatory response, oxidative stress, autophagy, abnormal mechanical stress, nutritional deficiency, and genetics, lead to reduced extracellular matrix (ECM) synthesis by intervertebral disc (IVD) cells and accelerate IDD progression. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a vital role in diverse degenerative diseases. Recent studies have shown that mTOR signalling is involved in the regulation of autophagy, oxidative stress, inflammatory responses, ECM homeostasis, cellular senescence, and apoptosis in IVD cells. Accordingly, we reviewed the mechanism of mTOR signalling in the pathogenesis of IDD to provide innovative ideas for future research and IDD treatment.

摘要: Zonula occludens-1 (ZO-1) is a scaffolding protein of tight junctions, which seal adjacent epithelial cells, that is also expressed in adherens junctions. The distribution pattern of ZO-1 differs among stratified squamous epithelia, including that between skin and oral buccal mucosa. However, the causes for this difference, and the mechanisms underlying ZO-1 spatial regulation, have yet to be elucidated. In this study, we showed that epithelial turnover and proliferation are associated with ZO-1 distribution in squamous epithelia. We tried to verify the regulation of ZO-1 by comparing normal skin and psoriasis, known as inflammatory skin disease with rapid turnover. We as well compared buccal mucosa and oral lichen planus, known as an inflammatory oral disease with a longer turnover interval. The imiquimod (IMQ) mouse model, often used as a psoriasis model, can promote cell proliferation. On the contrary, we peritoneally injected mice mitomycin C, which reduces cell proliferation. We examined whether IMQ and mitomycin C cause changes in the distribution and appearance of ZO-1. Human samples and mouse pharmacological models revealed that slower epithelial turnover/proliferation led to the confinement of ZO-1 to the uppermost part of squamous epithelia. In contrast, ZO-1 was widely distributed under conditions of faster cell turnover/proliferation. Cell culture experiments and mathematical modelling corroborated these ZO-1 distribution patterns. These findings demonstrate that ZO-1 distribution is affected by epithelial cell dynamics.