Biology subjects

Roskams, T.

Publications and source records attributed to Roskams, T..

4 recordsLinked to original sources

bioRxiv2025

Oral 4-fluorouridine completely suppresses epidemic Oropouche virus replication in mice and confers protection against virus-induced disease.

Oropouche virus (OROV) is an orthobunyavirus that causes increasingly frequent and severe outbreaks in Central and South America. We report that 4'-fluorouridine (4'-FlU) inhibits the in vitro replication of epidemic and pre-epidemic OROV strains in multiple cell lines. In vitro polymerase assays demonstrate that 4'-FlU (as its triphosphate) targets the Peribunyaviridae L protein, is incorporated during RNA synthesis and causes premature chain termination. Following 69 consecutive days of in vitro passages of OROV in the presence of suboptimal concentrations of 4'-FlU, no drug-resistant variants were identified in the viral polymerase. In stringent mouse (AG129) or Syrian hamster OROV-infection models, oral administration of 4'-FlU completely blocked viral replication and virus-induced disease, even when administration was delayed until 72 hours after infection. Our findings support exploring the potential of 4'-FlU for the management of OROV infections in humans.

microbiology↗

bioRxiv2025

The molecular landscape of polycystic kidneys is marked by common alterations in purine metabolism

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Cysts develop through dedifferentiation of tubular epithelial cells, but the sequence of molecular events and their relative importance remain unclear. To address this gap in knowledge, 40 cysts from 4 ADPKD kidneys and 4 microcystic tissues were mapped on transcriptomic and histological level. Cyst were heterogenous and we identified 6 cystic subclusters with 2 deviations from the main trajectory, dependent on the rate of interstitial remodeling, inflammation and dedifferentiation. Loss of proximal tubular marker gene expression was more pronounced compared to those of other tubular segments. Altered expression of metabolic pathways was consistent among the cysts, which was further analyzed in human and mouse cell lines. Purine metabolism was similarly altered in all ADPKD cell lines, and its modulation with azathioprine suppressed cyst formation in vitro. In conclusion, by focusing on common altered pathways in cysts and cell models, we have identified purine metabolism as a novel potential target in ADPKD.

molecular biology↗

bioRxiv2020

Revealing the Key Regulators of Cell Identity in the Human Adult Pancreas

Cellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA-sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies regulators of cell identity in the human adult pancreas. We predict that HEYL, BHLHE41 and JUND are active in acinar, beta and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell (hiPSC)-derived islet cells. Using single-cell transcriptomics, we found that JUND represses beta cell genes in hiPSC-alpha cells. Both BHLHE41 and JUND depletion seemed to increase the number of sc-enterochromaffin cells in hiPSC-derived islets. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease. HIGHLIGHTSO_LIReconstruction of gene regulatory networks for human adult pancreatic cell types C_LIO_LIAn interactive resource to explore and visualize gene expression and regulatory states C_LIO_LIPrediction of putative transcription factors that drive pancreatic cell identity C_LIO_LIBHLHE41 depletion in primary islets induces apoptosis C_LI

bioinformatics↗

bioRxiv2020

A fully defined pluripotent stem cell derived multi-liver-cell model for steatohepatitis and fibrosis

Chronic liver injury, as observed in non-alcoholic steatohepatitis (NASH), progressive fibrosis, and cirrhosis, remains poorly treatable. Steatohepatitis causes hepatocyte loss in part by a direct lipotoxic insult, which is amplified by derangements in the non-parenchymal cellular (NPC) interactive network wherein hepatocytes reside, including, hepatic stellate cells, liver sinusoidal endothelial cells and liver macrophages. To create an in vitro culture model encompassing all these cells that allows studying liver steatosis, inflammation and fibrosis caused by NASH, we here developed a fully defined hydrogel microenvironment, termed hepatocyte maturation (HepMat) gel, that supports maturation and maintenance of pluripotent stem cell (PSC)-derived hepatocyte- and NPC-like cells for at least one month. The HepMat-based co-culture system modeled key molecular and functional features of TGF{beta}-induced liver fibrosis and fatty-acid induced inflammation and fibrosis better than monocultures its constituent cell populations. The novel co-culture system should open new avenues for studying mechanisms underlying liver steatosis, inflammation and fibrosis as well as for assessing drugs counteracting these effects.

bioengineering↗