Biology subjects

Haas, J. T.

Publications and source records attributed to Haas, J. T..

4 recordsLinked to original sources

bioRxiv2026

Rev-erbα inhibits vascular calcification by repressing osteogenic reprogramming in atherosclerosis

Background: Atherosclerotic plaque rupture is the most deleterious atherogenic event, responsible for the majority of fatal acute atherothrombotic and myocardial infarctions. Intimal microcalcification is a major cause of atherosclerotic plaque instability. Yet, a thorough characterization of the mechanisms controlling intimal calcification is needed to develop innovative therapeutic strategies to treat high risk patients. The nuclear receptor Rev-erb regulates lipoprotein metabolism and exerts anti-inflammatory activities. Here, we hypothesized that Rev-erb modulates atherogenesis by regulating arterial calcification processes. Methods: We used a multi-omics approach in the ANGIOSAFE and the ATHEROPORTAL human cohort to identify pathways and factors associated with vascular calcification in diabetic patients. We then compared REV-ERB expression between calcified and non-calcified areas of human endarterectomies using laser capture microdissection assays (n=11-22/group). We assessed the role of Rev-erb on calcium deposition and expression of osteoblast markers in aortic roots of 18-month-old Ldlr-/-Rev-erb-/- and Ldlr-/-Rev-erb+/+ mice (n=10/group). Rev-erb-dependent molecular pathways that drive calcification were identified using gene expression profiling in aortic plaques from Ldlr-/-Rev-erb-/- and Ldlr-/-Rev-erb+/+ mice (n=8-10/group). We then confirmed omics data using primary aortic smooth muscle cells (SMCs) (n=3-6) in vitro assessing inflammation-driven calcification process as well as Rev-erb-dependent transcriptional mechanisms. Results: REV-ERB expression is significantly lower in circulating anti-inflammatory classical CD14+CD16- monocytes from diabetic patients with low coronary artery calcium (CAC) compared to those exhibiting high CAC scores while its expression is lower in highly calcified plaques from patients with diabetes mellitus compared to those with no diabetes or no calcification. Consistently, REV-ERB is markedly downregulated in calcified areas of human endarterectomy samples, while remaining higher in non-calcified regions. Rev-erb deficient Ldlr-/- mice exhibit accelerated atherogenesis and vascular calcification, and aortic smooth muscle cells (SMCs) exhibit a reprogramming toward an osteochondroblastic phenotype. Functional in vitro studies show that Rev-erb maintains SMC identity by preventing their IL-1{beta}-driven transdifferentiation into osteochondroblast-like cells, notably through the repression of key osteogenic regulators. Finally, while hyaluronic acid degradation is known to promote intimal calcification, we demonstrate that Rev-erb represses the hyaluronidase Cemip expression during SMC transdifferentiation. Conclusions: Rev-erb is identified as an important brake on SMC-driven vascular calcification, suppressing both osteogenic reprogramming and matrix-remodeling pathways. Thus, this study opens new avenues for developing novel therapeutic tools targeting Rev-erb to reduce vascular calcification and associated cardiovascular risk in high-risk patients.

pathology↗

bioRxiv2026

A multimodal framework for immune cell annotation across blood and tissue single-cell data

AbstractAccurate cell annotation remains a central challenge in single-cell analysis, particularly when datasets contain rare populations, transitional states, and tissue-adapted phenotypes. We previously developed scODIN as an expert-guided framework for immune cell annotation in single-cell RNA-sequencing data. Here, we present pyODIN, a major extension of this framework for Python. pyODIN supports multimodal annotation using RNA, antibody-derived tag (ADT), or combined RNA-ADT information. It also substantially expands the annotation database from a CD4 T-cell-centred framework to a broader cell-type reference resource spanning major and minor peripheral blood cell populations as well as tissue-associated subsets. We benchmarked pyODIN against CellTypist, MMoCHi and HiCAT using independently curated immune reference datasets. pyODIN demonstrated the highest overall classification accuracy, and at the top-lineage level, pyODIN reduced cross-lineage errors relative to the benchmark methods. At finer resolution, pyODIN preserved substantially greater CD4 T-cell subtype structure than CellTypist and HiCAT, resolving regulatory, follicular, helper, memory, and cytotoxic states that were collapsed into broader categories by the comparator methods. In a controlled marker-ablation experiment, pyODIN outperformed MMoCHi when key lineage-defining RNA markers were removed from the expression feature set, and the addition of ADT information restored NK and CD8 T-cell annotation, demonstrating the value of multimodal annotation when transcript-level evidence is incomplete. Finally, application to liver fine-needle aspirate data showed that the expanded framework supports annotation beyond PBMC datasets. Together, pyODIN provides an expert-guided, adaptable cell annotation framework for Python, designed for multimodal cell phenotyping across blood and tissue single-cell datasets. pyODIN is freely available at https://github.com/SondergaardLab/pyODIN.

immunology↗

bioRxiv2024

Integrative metagenomics and metabolomics reveal age-associated gut microbiota and metabolite alterations in experimental COVID-19

Aging is a key contributor of morbidity and mortality during acute viral pneumonia. The potential role of age-associated dysbiosis on disease outcomes is still elusive. In the current study, we used high-resolution shotgun metagenomics and targeted metabolomics to characterize SARS-CoV-2-associated changes in the gut microbiota from young (2-month-old) and aged (22-month-old) hamsters, a valuable model of COVID-19. We show that age-related dysfunctions in the gut microbiota are linked to disease severity and long-term sequelae in older hamsters. Our data also reveal age-specific changes in the composition and metabolic activity of the gut microbiota during both the acute phase (day 7 post-infection, D7) and the recovery phase (D22) of infection. Aged hamsters exhibited the most notable shifts in gut microbiota composition and plasma metabolic profiles. Through an integrative analysis of metagenomics, metabolomics, and clinical data, we identified significant associations between bacterial taxa, metabolites and disease markers in the aged group. On D7 (high viral load and lung epithelial damage) and D22 (body weight loss and fibrosis), numerous amino acids, amino acid-related molecules, and indole derivatives were found to correlate with disease markers. In particular, a persistent decrease in phenylalanine, tryptophan, glutamic acid, and indoleacetic acid in aged animals positively correlated with poor recovery of body weight and/or lung fibrosis by D22. In younger hamsters, several bacterial taxa (Eubacterium, Oscillospiraceae, Lawsonibacter) and plasma metabolites (carnosine and cis-aconitic acid) were associated with mild disease outcomes. These findings support the need for age-specific microbiome-targeting strategies to more effectively manage acute viral pneumonia and long-term disease outcomes.

immunology↗

bioRxiv2021

The hepatocyte insulin receptor is required to program rhythmic gene expression and the liver clock

In mammalian cells, gene expression is rhythmic and sensitive to various environmental and physiological stimuli. A circadian clock system helps to anticipate and synchronize gene expression with daily stimuli including cyclic light and food intake, which control the central and peripheral clock programs, respectively. Food intake also regulates insulin secretion. How much insulin contributes to the effect of feeding on the entrainment of the clock and rhythmic gene expression remains to be investigated. An important component of insulin action is mediated by changes in insulin receptor (IR)-dependent gene expression. In the liver, insulin at high levels controls the transcription of hundreds of genes involved in glucose homeostasis to promote energy storage while repressing the expression of gluconeogenic genes. In type 2 diabetes mellitus (T2DM), selective hepatic insulin resistance impairs the inhibition of hepatic glucose production while promoting lipid synthesis. This pathogenic process promoting hyperlipidemia as well as non-alcoholic fatty liver diseases. While several lines of evidence link such metabolic diseases to defective control of circadian homeostasis, the hypothesis that IR directly synchronizes the clock has not been studied in vivo. Here, we used conditional hepatocyte-restricted gene deletion to evaluate the role of IR in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in adult mouse liver.

physiology↗