Biology subjects

Yung, C.

Publications and source records attributed to Yung, C..

7 recordsLinked to original sources

bioRxiv2026

Longitudinal single-cell and spatial transcriptomics reveals intratumor heterogeneity, therapeutic response, and comparative value of canine marginal zone lymphoma

Diffuse B-cell lymphomas are the most prevalent canine hematologic malignancies, and their clinical presentation resembles that of human B-cell non-Hodgkin lymphomas (NHLs). However, a lack of a clear subtyping framework perpetuates imprecise treatment approaches that fail to address mechanisms of therapy resistance. Here, we employed deep phenotyping via serial sampling and longitudinal transcriptomics to evaluate intratumoral composition and therapy response in a 6-year-old neutered male goldendoodle with stage 5A marginal zone lymphoma (MZL). Following sequential treatment consisting of a single IV dose of oncolytic vesicular stomatitis virotherapy (VSV) and standard CHOP chemotherapy 30 days later, we performed scRNAseq on seven serial lymph node biopsies and spatial sequencing on a resection taken 10 days post-VSV treatment. B cells (>90%) comprised three transcriptionally distinct and temporally stable subpopulations, with specific copy number profiles and robust spatial organization despite disrupted lymph node architecture. Analysis across subpopulations revealed downregulation of the quiescence program including KLF2, suggesting similarity to KLF2-deficient human MZL. While VSV successfully reached target B cells, downstream transcriptional responses were predominantly localized to the T-cell compartment. T cells ([≤]6%) showed increased proliferation and upregulation of cytotoxicity markers post-VSV administration, enriching for leukocyte-mediated cytotoxicity pathways consistent with an anti-viral immune response. Ultimately, these results provide an in vivo proof-of-concept for the treatment paradigm in canine lymphoma, while emphasizing the need for improved subtyping frameworks and multidimensional treatment strategies targeting intratumoral heterogeneity.

cancer biology↗

bioRxiv2026

The RNA-binding protein Imp1 promotes a Spdef transcriptional program and mucus fucosylation during necrotizing enterocolitis

BackgroundIn the United States over 10% of all neonates are born premature (less than 37 weeks gestational age), and many face complications related to prematurity, including necrotizing enterocolitis (NEC). NEC is the most deadly gastrointestinal disease and the leading cause of death in preterm neonates, with up to 50% mortality. Since there is no cure for NEC, prevention is the best strategy. Enhancing our understanding of intestinal epithelial cell (IEC) responses to NEC damage will provide novel therapeutic targets to prevent NEC. Published evidence suggests that the RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) plays roles in intestinal development, barrier function, and intestinal repair. Notably, however, roles for IMP1 in NEC are not defined. Goblet cells produce protective mucus in the intestine, and their mature function is dependent on the transcription factor Spdef. Emerging evidence suggests that goblet cell mucus complexity impacts barrier function and inflammation susceptibility. This study aimed to define the role of IMP1 in NEC pathogenesis using neonatal human enteroids and a model of NEC-like intestinal injury in mice with IEC-specific Imp1 overexpression and loss. HypothesisIMP1 expression is protective in NEC. MethodsThis study used mice with intestinal epithelial Imp1 overexpression or loss and corresponding wild-type controls. At post-natal day 3, mice of both sexes were randomly assigned to control or NEC groups. NEC was induced with the well-established experimental NEC-like intestinal injury model that includes stress, formula feeding, and hypoxia. Imp1 effects on experimental NEC were assessed using RNA sequencing, western blotting, and immunostaining. ResultsInflammatory bacteria induced IMP1 expression in neonatal human enteroids. Mice with Imp1 overexpression incur worse intestinal damage during NEC. Pathway analysis of RNA sequencing data revealed a significant enrichment of the Spdef transcriptional network in Imp1IEC-OE during NEC. This included significant upregulation of Spdef target genes such as Agr2 (in NEC WT: 617.8 {+/-} 33.56 vs Imp1IEC-OE: 812.9 {+/-} 111.3, p=0.02) and Fut2 (in NEC WT: 219.4 {+/-} 34 vs Imp1IEC-OE: 396.6 {+/-} 62.9, p=0.05). In silico analysis predicted Imp1 binding to Spdef and mucus glycosylation mediator mRNAs. Although genotype did not affect goblet cell number, Imp1IEC-OE mice with NEC exhibited significant increases (p0.05) in Spdef protein, genes responsible for goblet cell function (Spink4, Klk1, Tspg1) and mucus glycosylation (Gcnt3, B3gnt7, Qsox1). Ultimately, Imp1 overexpression led to increased mucus fucosylation during NEC. ConclusionOur data indicate that during NEC, upregulation of Imp1 promotes goblet cell function via Spdef, including enhanced goblet cell maturation and mucus fucosylation. NEW AND NOTEWORTHYExpression of the RNA-binding protein Imp1 is enhanced in neonatal human enteroids in response to inflammatory bacteria. Imp1 regulates goblet cell function in response to early intestinal inflammation in a mouse model of necrotizing enterocolitis. Specifically, Imp1 promotes a Spdef transcriptional program by upregulating Spdef, resulting in elevated gene expression of Spdef target genes. Additionally, Imp1 increases the gene expression of (1,2)fucosyltransferase, Fut2, and subsequently, production of fucosylated mucus marked by UEA1. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/702645v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@189f615org.highwire.dtl.DTLVardef@7aeeedorg.highwire.dtl.DTLVardef@dc258corg.highwire.dtl.DTLVardef@1252b98_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Spatial Transcriptomic Analysis Identifies a SERPINA3-Expressing Astrocytic State Associated with the Human Neuritic Plaque Microenvironment

Single-nucleus transcriptomic studies have revealed glial cell states associated with Alzheimers disease; however, these nuclei are dissociated from the complex architecture of the human neocortex. Here, we successfully performed an unbiased distance-based analytic strategy on spatially-registered transcriptomic data. Leveraging immunohistochemistry in the same tissue section, our analyses prioritized SERPINA3 and other genes, such as metallothioneins, as altered in the vicinity of neuritic amyloid plaques. Results were validated at the protein level by immunofluorescence, highlighting that a reactive SERPINA3+ astrocyte subtype, Ast.5, plays a role in the plaque microenvironment.

neuroscience↗

bioRxiv2023

Human milk extracellular vesicles survive neonatal digestion in vivo to be absorbed by neonatal enteroids

Human milk contains extracellular vesicles (HMEVs). Pre-clinical models suggest that HMEVs may enhance intestinal function and limit inflammation; however, it is unknown if HMEVs or their cargo survive neonatal human digestion. This limits the ability to leverage HMEV cargo as additives to infant nutrition or as therapeutics. This study aimed to develop an EV isolation pipeline from small volumes of human milk and neonatal intestinal contents after milk feeding (digesta) to address the hypothesis that HMEVs survive in vivo neonatal digestion to be taken up intestinal epithelial cells (IECs). Digesta was collected from nasoduodenal sampling tubes or ostomies. EVs were isolated from raw and pasteurized human milk and digesta by density-gradient ultracentrifugation following two-step skimming, acid precipitation of caseins, and multi-step filtration. EVs were validated by electron microscopy, western blotting, nanoparticle tracking analysis, resistive pulse sensing, and super-resolution microscopy. EV uptake was tested in human neonatal enteroids. HMEVs and digesta EVs (dEVs) show typical EV morphology and are enriched in CD81 and CD9, but depleted of {beta}-casein and lactalbumin. HMEV and some dEV fractions contain mammary gland-derived protein BTN1A1. Neonatal human enteroids rapidly take up dEVs in part via clathrin-mediated endocytosis. Our data suggest that EVs can be isolated from digestive fluid and that these dEVs can be absorbed by IECs.

molecular biology↗

bioRxiv2022

The evolution of novel biotic interactions at ecological margins in response to climate change involves alleles from across the geographical range of the UK Brown Argus butterfly

Understanding the rate and extent to which populations can adapt to novel environments at their ecological margins is fundamental to predicting the persistence of biological communities during ongoing and rapid global change. Recent range expansion in response to climate change in the UK butterfly Aricia agestis is associated with the evolution of novel interactions with a larval food plant, and the loss of its ability to use its ancestral larval host species. Using ddRAD analysis of 61210 variable SNPs from 261 females from throughout the UK range of this species, we identify genomic regions at multiple chromosomes that are associated with these evolutionary responses, and their association with demographic history and ecological variation. Gene flow appears widespread throughout the range, despite the apparently fragmented nature of the habitats used by this species. Patterns of haplotype variation between selected and neutral genomic regions suggest that evolution associated with climate adaptation is polygenic, resulting from the independent spread of existing alleles throughout the established range of this species, rather than the colonisation of pre-adapted genotypes from coastal populations. These data suggest that rapid responses to climate change do not depend on the availability of pre-adapted genotypes. Instead, the evolution of novel forms of biotic interaction in Aricia agestis has occurred during range expansion, through the assembly of novel genotypes from alleles from multiple localities.

evolutionary biology↗

bioRxiv2019

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression

Complexity of cell-type composition has created much skepticism surrounding the interpretation of brain bulk-tissue transcriptomic studies. We generated paired tissue genome-wide gene expression data and immunohistochemistry data, enabling us to assess statistical methods for modeling and estimating cellular heterogeneity in the brain. We demonstrate that several algorithms that rely on single-cell and cell-sorted data to define cell marker gene sets yield accurate relative and absolute estimates of constituent cell-type proportions.

neuroscience↗

bioRxiv2018

A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimers disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

neuroscience↗