Biology subjects

Hu, N.

Publications and source records attributed to Hu, N..

24 records · Page 2Linked to original sources

bioRxiv2022

RET enhancer haplotype-dependent remodeling of the human fetal gut development program

Hirschsprung disease (HSCR) is associated with deficiency of the receptor tyrosine kinase RET, resulting in loss of cells of the enteric nervous system (ENS) during fetal gut development. The major contribution to HSCR risk is from common sequence variants in RET enhancers with additional risk from rare coding variants in many genes. Here, we demonstrate that these RET enhancer variants specifically alter the human fetal gut development program through significant decreases in gene expression of RET, members of the RET-EDNRB gene regulatory network (GRN), other HSCR genes, and an altered transcriptome with 2,382 differentially expressed genes with diverse neuronal and mesenchymal functions. A parsimonious hypothesis for these results is that beyond RETs direct effect on its GRN, it also has a major role in enteric neural crest derived cell (ENCDC) precursor proliferation, its deficiency reducing ENCDCs with relative expansion of non-ENCDC cells. Thus, genes reducing RET proliferative activity can potentially cause HSCR. One such class is the 23 RET-dependent transcription factors enriched in early gut development. We show that their knockdown in human neuroblastoma SK-N-SH cells reduces RET and/or EDNRB gene expression, expanding the RET-EDNRB GRN. The human embryos we studied had major remodeling of the gut transcriptional but were unlikely to have had HSCR: thus, genetic changes in addition to those in RET are required for a significant enough reduction in ENCDCs to cause aganglionosis.

genetics↗

bioRxiv2022

Metformin Alleviates Arthrofibrosis in Rat via Fibroblast Metabolic Reprogramming and Lactate-Mediated Macrophage Polarization

BackgroundEmerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has the beneficial effect on arthrofibrosis and its underlying mechanism. MethodsArticular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation. ResultsWe found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin. ConclusionMetformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis. The translational potential of this articleThe finding of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.

cell biology↗

bioRxiv2021

Single cell RNA-seq identifies developing corneal cell fates in the human cornea organoid

The cornea is a protective and refractive barrier in the eye crucial for vision. Understanding the human cornea in health, disease and cell-based treatments can be greatly advanced with cornea organoids developed in culture from induced pluripotent stem cells. While a limited number of studies have investigated the single-cell transcriptomic composition of the human cornea, its organoids have not been examined similarly. Here we elucidated the transcriptomic cell fate map of 4 month-old human cornea organoids and the central cornea from three donors. The organoids harbor cell clusters representing corneal epithelium, stroma and endothelium with sub populations that capture signatures of early developmental states. Unlike the adult cornea where the largest cell population is stromal, the organoids develop almost equal proportion of the three major cell types. These corneal organoids offer a three-dimensional platform to model corneal diseases and integrated responses of the different cell types to treatments. TeaserTranscriptomic Map of Cornea Organoid and Human Cornea

developmental biology↗

bioRxiv2021

An international report on bacterial communities in esophageal squamous cell carcinoma

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One proposed biological pathway linking poor oral health and ESCC involves the alteration of the microbiome. Thus, we performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors and WGS of synchronous collections of saliva specimens from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella, and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed a similar tumor enrichment of the ESCC-associated bacterial community in these cancers. Because these genera are traditionally considered members of the oral microbiota, we explored if there is a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes are significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of ESCC patients. Longitudinal studies of the pre-diagnostic oral microbiome are needed to investigate whether these cross-sectional similarities reflect temporal associations.

microbiology↗

bioRxiv2021

Adaptation of Drosophila larva foraging in response to changes in food distribution

When foraging, animals combine internal cues and sensory input from their environment to guide sequences of behavioral actions. Drosophila larva executes crawls, turns, and pauses to explore the substrate and find food sources. This exploration has to be flexible in the face of changes in the quality of food so that larvae feed in patches with favorable food and look for another source when the current location does not fulfill their nutritional needs. But which behavioral elements adapt, and what triggers those changes remain elusive. Using experiments and modeling, we investigate the foraging behavior of larvae in homogeneous environments with different food types and in environments where the food sources are patchy. Our work indicates that the speed of larval crawling and frequency of pauses is modulated by the food quality. Interestingly, we found that the genetic dimorphism in the foraging gene influences the exploratory behavior only when larvae crawl on yeast patches. While in a homogeneous substrate larvae maintain a turning bias in a specific orientation, in a patchy substrate larvae orient themselves towards the food when the patch border is reached. Therefore, by adapting different elements in their foraging behavior, larvae either increase the time inside nutritious food patches or continue exploring the substrate in less nutritious environments.

animal behavior and cognition↗

bioRxiv2020

Sex determination through X-Y heterogamety in Salix nigra

The development of non-recombining sex chromosomes has radical effects on the evolution of discrete sexes and sexual dimorphism. Although dioecy is rare in plants, sex chromosomes have evolved repeatedly throughout the diversification of angiosperms, and many of these sex chromosomes are relatively young compared to those found in vertebrates. In this study, we designed and used a sequence capture array to identify a novel sex-linked region (SLR) in Salix nigra, a basal species in the willow clade, and demonstrated that this species has XY heterogamety. We did not detect any genetic overlap with the previously characterized ZW SLRs in willows, which map to a different chromosome. The S. nigra SLR is characterized by strong recombination suppression across a 2 MB region and an excess of low frequency alleles, resulting in a low Tajimas D compared to the remainder of the genome. We speculate that either a recent bottleneck in population size or factors related to positive or background selection generated this differential pattern of Tajimas D on the X and autosomes. This discovery provides insights into factors that may influence the evolution of sex chromosomes in plants and contributes to a large number of recent observations that underscore their dynamic nature.

genomics↗