Biology subjects

de Vos, J.

Publications and source records attributed to de Vos, J..

6 recordsLinked to original sources

bioRxiv2025

Human pluripotent stem cell-derived bronchial airway organoids provide insights into differential innate immune and long-term responses to SARS-CoV-2 infection in healthy and COPD.

Respiratory infections are a major global health concern, as underscored by the COVID-19 pandemic. To better understand bronchial tissue responses to viral infection, we have developed a preclinical in vitro model mimicking the multiciliated airway epithelium, from induced pluripotent stem cell (iPSC) and cultured in an air-liquid interface (iALI). By using iPSCs reprogrammed from patients with chronic obstructive pulmonary disease (COPD), we successfully generated a fully differentiated and functional bronchial epithelium exhibiting key COPD features with goblet and basal cell hyperplasia and tissue inflammation. SARS-CoV-2 could infected and replicated for several weeks in both healthy and COPD models, with a recurrent peak at 3 days after infection. Infected iALI exhibited cilia destruction and increased mucus secretion. Innate immune response of different infected iALI reveals a differential expression of interferon-stimulated genes (ISGs) and pro-inflammatory cytokine secretion. Notably, COPD iALI displayed an earlier innate immune response to SARS-CoV-2 infection as compared to healthy iALI, suggesting a genetic susceptibility of COPD iALI towards inflammation induced by SARS-CoV-2 infection, and a less efficient response to antivirals. In conclusion, our study demonstrates that the iALI bronchial organoid model is a powerful tool for investigating bronchial tissue responses to long term respiratory viral infections, antivirals, and patients with COPD or other airway pathology. Grapical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/662440v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@9e5ef7org.highwire.dtl.DTLVardef@16ccf60org.highwire.dtl.DTLVardef@a2b29dorg.highwire.dtl.DTLVardef@17c6f14_HPS_FORMAT_FIGEXP M_FIG C_FIG HighLightsO_LIhiPSC-derived COPD airway organoids C_LIO_LISARS-CoV-2 productively infects induced pluripotent stem-cell derived bronchial organoids iALI and persisted over the long term C_LIO_LISARS-CoV-2 iALI infection results in cilia destruction, increased mucus secretion and a strong innate immune response C_LIO_LISARS-CoV-2 infection elicited a higher and earlier innate immune response in iCOPD C_LIO_LISARS-CoV-2 infection in iCOPD respond less to antivirals C_LI Short AbstractSARS-CoV-2 causes severe lower respiratory tract infection in COVID-19 patients, which can persist over time. Here, we used an in-house developed in vitro airway organoid derived from induced human pluripotent stem cells (iALI) to study SARS-CoV-2 infection over long term in healthy or COPD patients whom respiratory failure is at risk during infection. Our results show that SARS-CoV-2 infection results in high and lethal infection of bronchial epithelial cells, that persist over time, inducing mucus secretion, destruction of ciliated cells and specific cytokine release. A late innate immune response is observed in the healthy iALI, while in iCOPD, it appears earlier and stronger, suggesting a different sensing of SARS-CoV-2 in COPD patients, accompanied by a reduce sensitivity to antivirals. In conclusion, our study demonstrates that the iALI organoid model is a powerful tool for investigating bronchial tissue responses to long term respiratory viral infections, from healthy to pathologic patients.

cell biology↗

bioRxiv2025

DNA methylation networks during pig fetal development: a joint fused ridge estimation approach

Although an organisms genetic information is predominantly identical among most of its cell types, the epigenome regulates the expression of the genome in a cell type- and context-dependent manner. In mammals, DNA methylation in regulatory regions, such as promoters, primarily regulates gene expression by inducing transcriptional inactivation. With genome-wide approaches came the realization that DNA methylation patterns underlying mammalian development are considerably more dynamic than previously recognized. This realization highlights the need for methodological approaches capable of capturing this phenomenon. In this study, we investigated the feasibility of modeling DNA methylation networks by jointly estimating regularized precision matrices from time- and tissue-specific omics data derived from the pig genome. For that, we utilized RNA-Seq and RRBS data that span seven pig tissues at three developmental stages: early organogenesis, late organogenesis, and newborn. Our analysis focused on 61, 48, and 74 genes -- differentially expressed across developmental stages and CpG-methylated in promoter regions, from endoderm-, mesoderm-, and ectoderm-derived tissues, respectively. Using a joint fused ridge approach, we were able to borrow information across tissues and time points, enabling more robust network inference. This analytical framework advances exploratory methods for studying organism development using pig as a model species. Our results highlight the importance of fetal-maternal immunity and the circulatory system in early development, and shed light on dynamic interactions across tissues, organ systems, and germ layers. We anticipate that this flexible framework can be extended to other omics data and species, facilitating future research. Author summaryThis study explores how gene activity is controlled during pig fetal development using networks. The epigenome can turn genes on and off, depending on, e.g. the cells function and the organisms growth stage. This process includes chemical changes to DNA, such as methylation. We focused on DNA methylation patterns during pig fetal development by analyzing samples from several organs at three stages of fetal growth. We combined gene activity data with DNA methylation data by using a network-based method that allows us to visualize and study how genes interact across different tissues and developmental stages. We discovered that the immune and circulatory systems are critical during early development. We have also observed complex interactions across tissues and organ systems. Our study provides a flexible toolbox with clear, step-by-step explanations. This analytical framework can be used to explore developmental patterns at the genomic scale in other species and can be adapted to different types of biological data.

bioinformatics↗

bioRxiv2025

Guiding eQTL mapping and genomic prediction of gene expression in three pig breeds with tissue-specific epigenetic annotations from early development

Gene expression is a dynamic phenotype influenced by tissue-specific regulatory mechanisms, which can modulate expression directly or indirectly through cis or trans factors. Identifying genetic variants in these regulatory regions can improve both expression quantitative trait locus (eQTL) mapping and gene expression prediction. Whole genome sequences offer the possibility for enhanced eQTL mapping accuracy, but detecting causal variants remains challenging. Here, we evaluate the potential added-value of integrating tissue-specific epigenetic annotations, such as chromatin accessibility and methylation status, into within-breed genomic predictions of expression for three pig breeds. Functional annotations from early developmental stages improved eQTL mapping interpretability as shown by the enrichment of trait-relevant QTLs. However, despite the use of functional annotations, predictions across breeds remain challenging due to differences in genetic architectures. Our work contributes to the understanding of gene expression regulation in livestock and highlights the value of functional annotations, despite continued challenges for predictions across breeds. HighlightsO_LIMatched whole-genome sequences and expressions reveal transcriptional regulatory variants. C_LIO_LIEarly epigenetic marks can guide transcriptome prediction and eQTL mapping. C_LIO_LIAnnotation-guided models can enhance the interpretability of eQTL mapping. C_LIO_LIPorting predictions across pig breeds remains challenging even with annotations. C_LIO_LIA case study linked IGF2 liver eQTLs with annotations and cholesterol QTLs. C_LI

genomics↗

bioRxiv2024

Unravelling the neurocognitive mechanisms underlying counterconditioning in humans

Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS+ images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS+ and CS-category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+-specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS+ exemplars presented during CC, and retroactively also for CS+ exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.

neuroscience↗

bioRxiv2023

A macroevolutionary role for chromosomal fusion and fission in Erebia butterflies

The impact of large-scale chromosomal rearrangements, such as fusions and fissions, on speciation is a long-standing conundrum. We assessed whether bursts of change in chromosome numbers resulting from chromosomal fusion and fission are related to increased speciation rates in Erebia, one of the most species-rich and karyotypically variable butterfly groups. We established a genome-based phylogeny and employed state-dependent birth-death models to infer trajectories of karyotype evolution across this genus. We demonstrated that rates of anagenetic chromosomal changes (i.e. along phylogenetic branches) exceed cladogenetic changes (i. e. at speciation events), but when cladogenetic changes occur, they are mostly associated with chromosomal fissions rather than fusions. Moreover, we found that the relative importance of fusion and fission differs among Erebia clades of different ages, where especially in younger, more karyotypically diverse clades, speciation is more frequently associated with chromosomal changes. Overall, our results imply that chromosomal fusions and fissions have contrasting macroevolutionary roles and that large-scale chromosomal rearrangements are associated with bursts of species diversification.

evolutionary biology↗

bioRxiv2022

Geology and discovery record of the Trinil Pithecanthropus erectus site, Java

The scientific utility of Eugene Dubois Pithecanthropus erectus (P.e.) Skullcap (Trinil 1), Femur I (Trinil 3) and associated paleontological specimens has been impaired for over a century by questions about their provenience. Firsthand accounts and contemporaneous field photographs, presented here, extensively document the site geology and discovery history. The P.e. specimens and numerous-other fossils were unearthed in 1891-1893 from small excavations dug into a flat-lying bonebed exposed near the seasonal low-water level of the Solo River along its incised left embankment. Dubois on-site supervisors specified that the two P.e. fossils came from a [~]0.2-m-thick bonebed subunit traced at a single elevation for [~]12m from the 1891 Skullcap pit ([~]30m2) to the 1892 Femur-discovery excavation and across an enlarged 1892-1893 trench ([~]170m2). The depositional co-occurrence of the finds is supported by key documentation: the supervisors letters to Dubois about Femur I; his initial reporting to the Indies government; 1892-1893 accounts about expanding excavation of the Femur I stratum; Dubois 1891-1893 government submissions and 1894-1896 publications; confirmation by the Selenka Expedition in 1907-1908; Dubois annotations on unpublished site photographs; and a letter he wrote the year he died. Field studies in the 1930s to 1970s confirmed the essential aspects of the site geology. The bonebed of 1891-1893 contained fossils referable to the extinct Trinil fauna species Axis lydekkeri, Duboisia santeng and Stegodon trigonocephalus. The Selenka Expedition excavations had a similar assemblage in the same stratigraphic position which they named the Hauptknochenschicht. The bonebed was thin bioclast-rich gravelly volcaniclastic sandstone with taphonomic and sedimentary features indicating an unusual origin. Bioclasts range from proboscidean craniums and logs to rat teeth, freshwater mollusc shells and leaves. The terrestrial-vertebrate skeletal elements are overwhelmingly disarticulated and frequently broken. Their surfaces are little-abraded by fluvial transport. The bone fossilization is quite uniform. More than one-hundred ungulate individuals perished. No evidence has been found of hominin- or terrestrial-carnivore involvement. The bioclasts varied in density from place-to-place and vertically, and were matrix supported in the bonebed. No substantial internal depositional hiatus was reported. In combination with Trinils paleogeographic context, these features implicate a catastrophic mortality of ungulates in a population aggregation along the floodplain of a perennial paleo-river, followed by lahar-flood transport and deposition of gravel-size lithic- and biotic-materials. Trinil provides evidence favoring a broad archaic-hominin presence in southern Sundaland. The Trinil fauna is a lynch-pin in a long-lasting paleobiogeographic association between H. erectus and certain lineages of large bovids, cervids, proboscideans, rhinoceros, suids and tiger. The bonebeds paleogeographic setting exemplifies the stratovolcanic drainages that H. erectus occupied for >0.8 million years in Java, including the watershed of a marine delta [~]150km east of Trinil, a volcanic island [~]100km north of Trinil, and areas to its west for 500km (where species associated with Trinil H. erectus occur). In the Java Sea (Sunda Shelf), seismic data image immense Pleistocene river- and coastal-terranes which archaic hominins and other large-mammals, like those at Trinil, might have inhabited.

paleontology↗