Biology subjects

Yang, J. Y.

Publications and source records attributed to Yang, J. Y..

13 recordsLinked to original sources

bioRxiv2026

Thalamocortical constraints on areal connectivity in the developing human brain

The thalamus plays a central role in cortical development, organisation and function. Thalamic nuclei acquire distinct molecular identities during gestation, with first-order relays maturing before higher-order nuclei. Thalamic afferents innervate the cortical plate with a precise order, disruptions to which alter cortical function. Recent models propose that thalamic input to primary sensory cortex constrains the development of wider cortical networks, promoting the formation of highly-connected hubs in association cortex. Here, we combine neuroimaging, post mortem gene expression data and network modelling to examine how the timing and spatial distribution of thalamocortical innervation influences the formation of cortical networks during gestation. We find that the maturation rates of thalamic nuclei align with predicted timing and distribution of afferent outgrowth. While higher order nuclei connect widely across the cortex, they do not preferentially target high-degree hubs. Instead, hubs emerge from interdependent spatiotemporal constraints imposed by both wiring distance and thalamocortical maturation.

neuroscience↗

bioRxiv2025

APOL1 G1 and G2 risk alleles modulate severity of diet-induced obesity in a transgenic mouse model

APOL1 G1 and G2 risk alleles are associated with an increased risk of chronic kidney disease. However, a causal relationship between these alleles and cardiometabolic traits has not been experimentally validated. To address this gap, we placed transgenic APOL1 G0, G1, and G2 FVB/NJ mice on a high-fat diet and analyzed them for weight gain as well as obesity-related cardiometabolic phenotypes. To test whether APOL1 risk alleles modulate the inflammatory basis of obesity, we also exposed bone marrow derived macrophages from these mice to pro-inflammatory, pro-hypertensive, and dyslipidemic conditions. APOL1 high-risk allele female mice gained fat mass more readily than their low-risk female counterparts, while APOL1 high-risk male mice gained fat mass less readily than low-risk males. A parallel sex difference was seen in expression of higher levels of Abca1, Hmox1, and Srebf1 in lipid-loaded female bone-marrow derived macrophages expressing G1 and G2 APOL1, along with minor differences in cardiac function. However, this finding occurred independently of hypertension and insulin resistance, and with only minor albuminuria. Thus, our results highlight the importance of sex as a biological variable in future APOL1 experiments.

genomics↗

bioRxiv2025

G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway

The G1 and G2 variants of the gene encoding Apolipoprotein L1 (APOL1) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 APOL1 cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 APOL1. We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor -difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 APOL1 in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.

cell biology↗

bioRxiv2024

Hepatic aldose reductase drives a Warburg effect-like metabolic reprogramming to promote insulin resistance, fatty liver and obesity

Background & AimsEmerging evidence suggest that abnormal activation of aldose reductase/the polyol pathway (Ar/PP) is associated with the pathogenesis or development of fatty liver, obesity and metabolic syndrome. However, the underlying mechanisms were unclear. In this study, we investigated the metabolic reprogramming following activation or inhibition of Ar, the first and the rate-limiting enzyme of PP. We also investigated the long-term effects of Ar/PP-mediated metabolic shift in vivo. MethodsMetabolomic analyses were performed with the AB-SCIE QTRAP-5500 LC-MS/MS System for control mouse hepatocytes and hepatocytes stably overexpressing Ar and exposed to 25 mM glucose. Glycolysis stress tests and mitochondrial stress tests were performed using the Seahorse Bioscience Extracellular Flux Analyzer. The in vivo long-term effects of Ar overexpression and inhibition were evaluated in either transgenic mice overexpressing AR or a line of double transgenic mice carrying an Ar-null mutation and an Agouti-yellow Ay mutation. ResultsAbnormal activation of Ar in hepatocytes was found to trigger and drive a drastic Warburg effect-like metabolic reprogramming, induce de novo lipogenesis, and alter insulin and AMP-activated protein kinase signaling. In glucose-fed AR-overexpressing transgenic mice, AR activation causes systemic alterations in physiological parameters and the development of overt phenotypes of insulin resistance, fatty liver, obesity. In the yellow obese syndrome mice, Ar deficiency greatly improves Agouti Ay mutation-induced abnormalities. ConclusionsCollectively, the results highlight the important contribution of Ar/PP or the putative pseudo-glycolysis in hepatic metabolic homeostasis and the development of metabolic diseases. These findings have profound implications for the development of therapeutic strategies or drugs against metabolic diseases and cancer. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/614395v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@de91ddorg.highwire.dtl.DTLVardef@3a801corg.highwire.dtl.DTLVardef@b0cf35org.highwire.dtl.DTLVardef@1f3c1c1_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIActivation of aldose reductase triggers and drives a Warburg effect-like metabolic eprogramming in hepatocytes. C_LIO_LILiver-specific activation of the polyol pathway leads to insulin resistance, fatty liver and obesity. C_LIO_LIInhibition of aldose reductase greatly ameliorates Agouti Ay-induced metabolic abnormalities. C_LI Impact and implicationsThis study reveals that abnormal activation of Ar/PP will trigger and drive a Warburg effect-like metabolic reprogramming in hepatocytes. In normal subjects, Ar/PP mediated metabolic reprogramming tends to promote lipogenesis, insulin resistance, fatty liver and obesity. In cancer cells, Ar/PP mediated metabolic reprogramming will be part of the Warburg effect to support the growth and proliferation of cancer cells. These findings imply that Ar and its down-stream metabolic enzymes are important therapeutic targets for cancers and metabolic diseases.

biochemistry↗

bioRxiv2024

MRI signatures of cortical microstructure in human development align with oligodendrocyte cell-type expression

Neuroanatomical changes to the cortex during adolescence have been well documented using MRI, revealing ongoing cortical thinning and volume loss with age. However, the underlying cellular mechanisms remain elusive with conventional neuroimaging. Recent advances in MRI hardware and new biophysical models of tissue informed by diffusion MRI data hold promise for identifying the cellular changes driving these morphological observations. This study used ultra-strong gradient MRI to obtain high-resolution, in vivo estimates of cortical neurite and soma microstructure in sample of typically developing children and adolescents. Cortical neurite signal fraction, attributed to neuronal and glial processes, increased with age (mean R2fneurite=.53, p<3.3e-11, 11.91% increase over age), while apparent soma radius decreased (mean R2Rsoma=.48, p<4.4e-10, 1% decrease over age) across domain-specific networks. To complement these findings, developmental patterns of cortical gene expression in two independent post-mortem databases were analysed. This revealed increased expression of genes expressed in oligodendrocytes, and excitatory neurons, alongside a relative decrease in expression of genes expressed in astrocyte, microglia and endothelial cell-types. Age-related genes were significantly enriched in cortical oligodendrocytes, oligodendrocyte progenitors and Layer 5-6 neurons (pFDR<.001) and prominently expressed in adolescence and young adulthood. The spatial and temporal alignment of oligodendrocyte cell-type gene expression with neurite and soma microstructural changes suggest that ongoing cortical myelination processes contribute to adolescent cortical development. These findings highlight the role of intra-cortical myelination in cortical maturation during adolescence and into adulthood.

neuroscience↗

bioRxiv2024

SpaNorm: spatially-aware normalisation for spatial transcriptomics data

Library size normalisation is necessary to enable comparisons between observations in transcriptomic datasets. Numerous methods have been developed to normalise these effects with sample and gene specific adjustments. However, in spatial transcriptomics data, normalisation is complicated by the fact that spatial region-specific library size confounds biology. The most popular approach of adapting methods developed for single-cell RNA-seq data has been shown to excessively remove biological signals associated with spatial domains and thus results in poorer downstream domain identification. To this end, we propose the first spatially-aware normalisation method, SpaNorm. SpaNorm concurrently models spatial library size effects and the underlying smooth biology, to tease apart these effects, and thereby remove library size effects without removing biology. This is achieved through optimal decomposition of spatially smooth variation into those related and unrelated to library size and the use of location-specific scaling factors. Using 27 tissue samples from 6 datasets spanning 4 spatial platforms, we show that SpaNorm outperforms current state of the art methods at retaining biological information in the form of spatial domains and spatially variable genes (SVGs) better than 4 commonly used single-cell normalisation approaches. SpaNorm is versatile and it can be used for both spot-based and subcellular spatial transcriptomics data. Notably, the benefit of using SpaNorm is more pronounced for the latter data such as those from Xenium, STOmics and CosMx platforms for which the proportion of genes exhibiting region-specific library size effect is higher. SpaNorm works equally well with segmented cell-level data and spot-based data where each spot contains multiple cells.

bioinformatics↗

bioRxiv2023

Benchmarking the translational potential of spatial gene expression prediction from histology

Spatial transcriptomics has enabled the quantification of gene expression at spatial coordinates, offering crucial insights into molecular underpinnings of diseases. In light of this, several methods predicting spatial gene expression from paired histology images have offered the opportunity of enhancing the utility of readily obtainable and cost-effective haematoxylin-and-eosin-stained histology images. To this end, we conducted a comprehensive benchmarking study encompassing six developed methods. These methods were reproduced and evaluated using HER2-positive breast tumour and human cutaneous squamous cell carcinoma datasets, followed by external validation using The Cancer Genome Atlas data. Our evaluation incorporates diverse metrics which capture the performance of predicted gene expression, model generalisability, translational potential, usability and computational efficiency of each method. Our findings demonstrate the capacity of methods to spatial gene expression from histology and highlight key areas that can be addressed to support the advancement of this emerging field.

bioinformatics↗

bioRxiv2023

MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

immunology↗

bioRxiv2022

Chemical-induced degradation of PreS2 mutant surface antigen reverses HBV- mediated hepatocarcinogenesis

Naturally evolved immune-escape PreS2 mutant is an oncogenic caveat of liver cirrhosis and hepatocellular carcinoma (HCC) during chronic hepatitis B virus (HBV) infection. Notably, PreS2 mutants is prevalent in above 50% of patients with HCC. Intrahepatic expression of PreS2 mutant large surface antigen (PreS2-LHBS) induces endoplasmic reticulum stress, mitochondria dysfunction, cytokinesis failure and subsequent chromosome hyperploidy. In this study, we ask if long-term inhibition of PreS2-LHBS may act to reverse HBV-mediated hepatocarcinogenesis. We set up a stability reporter platform and identified ABT199 as an inhibitor of PreS2-LHBS from a library of 1068 FDA-approved drugs. Treatment of ABT199 induced PreS2-LHBS degradation without affecting the general cell viability, as shown in hepatoma and immortalized hepatocyte cell lines. We found that ABT199 induced the recruitment of PreS2-LHBS to ring-shaped structures in close proximity to lysosomal marker Lamp1 and multivesicular body marker Rab7. Simultaneously, inhibitions of lysosomal degradation or microautophagy restored the expression of PreS2-LHBS. Specifically, a 24-hr treatment of ABT199 reduced DNA damages and cytokinesis failure induced by PreS2-LHBS. Persistent treatment of ABT199 for 3 weeks reversed chromosome hyperploidy in PreS2-LHBS cells and suppressed anchorage-independent growth of HBV-positive hepatoma cell line. Together, we showed that ABT199 provoked selective degradation of PreS2-LHBS through the induction of microautophagy, and a long-term treatment of ABT199 reversed oncogenic mechanisms induced by HBV. Our results indicate that long-term degradation of PreS2-LHBS may serve as a novel therapeutic strategy to constrain HBV-mediated hepatocarcinogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/477454v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1720c85org.highwire.dtl.DTLVardef@943121org.highwire.dtl.DTLVardef@1257a22org.highwire.dtl.DTLVardef@1756348_HPS_FORMAT_FIGEXP M_FIG C_FIG Author summaryHBV PreS2 mutant large surface antigen (PreS2-LHBS) is an oncoprotein that induces liver cirrhosis and liver cancer. This study identified ABT199 as a potential inhibitor of PreS2-LHBS. We found that ABT199 could trigger the degradation of PreS2-LHBS through the induction of microautophagy. Moreover, a long-term treatment of ABT199 significantly reversed LHBS-induced oncogenic events including DNA damage, mitotic failure, chromosome hyperploidy, and anchorage-independent growth. This study not only identifies a specific inhibitor of PreS2-LHBS but also highlights a plausible strategy to constrain HBV-mediated hepatocarcinogenesis through targeting the degradation of PreS2-LHBS.

microbiology↗

bioRxiv2021

Resolving the structure of phage-bacteria interactions in the context of natural diversity

Microbial communities are shaped by viral predators1. Yet, resolving which viruses (phages) and bacteria are interacting is a major challenge in the context of natural levels of microbial diversity2. Thus, fundamental features of how phage-bacteria interactions are structured and evolve in "the wild" remain poorly resolved3, 4. Here we use large-scale isolation of environmental marine Vibrio bacteria and their phages to obtain quantitative estimates of strain-level phage predator loads, and use all-by-all host range assays to discover how phage and host genomic diversity shape interactions. We show that killing in environmental interaction networks is sparse - with phage predator loads low for most bacterial strains and phages host-strain-specific in their killing. Paradoxically, we also find that although overlap in killing is generally rare between phages, recombination is common. Together, these results indicate that the number of hosts that phages infect is often larger than the number that they kill and suggest that recombination during cryptic co-infections is an important mode of phage evolution in microbial communities. In the development of phages for bioengineering and therapeutics it will be important to consider that nucleic acids of introduced phages may spread into local phage populations through recombination, and that the likelihood of transfer is not predictable based on killing host range.

microbiology↗

bioRxiv2020

Cross-Platform Omics Prediction procedure enables precision medicine in patients with stage-III melanoma

There is no consensus methodology that can account for the variation in omics signatures when they are acquired across different platforms and times. This poses a significant barrier to the implementation of valuable biomarkers into clinical practice. We present a novel procedure (Cross-Platform Omics Prediction) that accounts for these variations and demonstrate its utility in three risk models for different diseases that is suitable for prospective and multi-centre clinical implementation.

bioinformatics↗

bioRxiv2020

Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction

Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeler gene Ino80 results in defective coronary vessel development that leads to ventricular noncompaction in embryonic mouse hearts. Here, we used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts, and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behavior. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) upregulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation. These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.

developmental biology↗

bioRxiv2019

Inhibitory effects of β-caryophyllene on Helicobacter pylori infection in vitro and in vivo

The human specific bacterial pathogen Helicobacter pylori (H. pylori) is a Gram-negative microaerophilic bacterium and associated with severe gastric diseases such as peptic ulceration and gastric cancer. Recently, the increasing resistance and the emergence of adverse effects make the usage of antibiotics less effectively. Therefore, development of new antimicrobial agent is required to control H. pylori infection. In the current study, it has been demonstrated the inhibitory effect of {beta}-caryophyllene on H. pylori growth and the protective effect against H. pylori infection as well as antibacterial therapeutic effect. {beta}-caryophyllene inhibited H. pylori growth via down-regulation of dnaE, dnaN, holB and gyrA and also down-regulated virulence factors such as CagA, VacA and SecA proteins. {beta}-caryophyllene inhibited expression of several type IV secretion system (T4SS) components including virB2, virB4 and virB8, so that CagA translocation into H. pylori-infected AGS cells was decreased by {beta}-caryophyllene treatment. {beta}-caryophyllene also inhibited VacA toxin entry through down-regulation of type IV secretion system (T5SS). In vivo experiments using Mongolian gerbils demonstrated antibacterial therapeutic effects of {beta}-caryophyllene. After {beta}-caryophyllene administration, immunohistochemistry (IHC) stain using anti-H. pylori antibody showed the antibacterial effect and H&E stain showed the therapeutic effect in treated groups. Hematological data which conformed with histological data support the therapeutic effect of {beta}-caryophyllene administration. Such a positive effect of {beta}-caryophyllene on H. pylori infection potently substantiate that this natural compound could be used as a new antimicrobial agent or functional health food to help the patients whom suffering from gastroduodenal diseases due to H. pylori infection. Author summaryThe inhibitory effect on {beta}-caryophyllene on H. pylori growth and the protective effect against H. pylori infection as well as antibacterial therapeutic effect have been elucidated in this study. {beta}-caryophyllene inhibited H. pylori growth via downregulation of replication machinery of H. pylori. {beta}-caryophyllene also downregulated virulence factors such as CagA, VacA and SecA proteins which are necessary for successful colonization and pathogenesis of H. pylori. Besides, {beta}-caryophyllene significantly reduced H. pylori-induced actin-cytoskeletal rearrangement, vacuolation and apoptosis in AGS cells. In in vivo infection model, {beta}-caryophyllene showed splendid therapeutic effect against H. pylori infection. In particular, this is the first report that evaluates the toxicological effects of {beta}-caryophyllene administration on Mongolian gerbils. Such a positive effect of {beta}-caryophyllene on H. pylori infection potently substantiate that this natural compound could be used as a new antimicrobial agent or functional health food to help the patients whom suffering from gastroduodenal diseases due to H. pylori infection.

microbiology↗