Biology subjects

Thiesen, A.

Publications and source records attributed to Thiesen, A..

3 recordsLinked to original sources

bioRxiv2026

Endoplasmic Reticulum Associated Lipolysis Regulates Hepatic Fat Synthesis and Turnover

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is characterized and initiated by the excessive accumulation of triacylglycerols (TG) and cholesteryl esters (CE) in the liver. Hepatic TG and CE synthesis, lipolysis and transport are tightly regulated by nutritional status, and disruption of this homeostasis contributes to MASLD pathogenesis. We have found that an endoplasmic reticulum-localized arylacetamide deacetylase (AADAC) catalyzes hepatic TG/CE turnover, and suppresses SREBP- and LXR-regulated lipogenesis and fatty acid esterification. Consequently, AADAC deficiency in mice leads to increased hepatic lipid synthesis, exacerbated steatosis, and impaired whole-body metabolism during Western-type diet feeding. These findings implicate AADAC as an important regulator of hepatic neutral lipid metabolism, linking endoplasmic reticulum cholesteryl ester hydrolysis as a modulator of lipid synthesis, and suggest its potential role in limiting MASLD pathogenesis under conditions of chronic overnutrition.

physiology↗

bioRxiv2026

DIANNE: Segmentation-Free Localization of Histology Differential Attributes

Pathologist-guided distinctions within histology and spatial omic images provide insights into health and disease, with digital pathology leveraging artificial intelligence to automate such assessments. To train computational models, current digital pathology methods rely on upfront manual annotations, which are time-consuming to generate. Pre-annotation is poorly suited to investigating novel spatial behaviors--a major need driven by advances in spatial profiling--for which annotation criteria and data needs will be uncertain. To address these challenges, we present DIANNE, a digital pathology annotation support and discovery approach for rapid training and inference of spatial differential attributes, enabled by train-time Positive Class Mixup Augmentation. DIANNE can compute foundation model-derived segmentation-free localization of differential classifiers across whole slide H&E images within seconds on a workstation, enabling interactive investigation of spatial niches. Predictive models can be re-trained in real-time in response to patch or regional annotation changes, clarifying determinative biological attributes across slides from only a few dozen annotated patches. We demonstrate the effectiveness of DIANNE for tumor detection, artifact identification, and exploration of pancreatic, fetal membranes and kidney tissue structures. DIANNE also provides analogous capabilities for IHC, multiplex immunofluorescence, and registered spatial transcriptomic+H&E images. DIANNE is implemented in a Jupyter toolkit, enabling rapid development of high-resolution classifiers from weakly-supervised training. DIANNE provides a practical system to quantitatively understand known and novel spatial phenotypes.

pathology↗

bioRxiv2023

Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10-/- mouse model of inflammatory bowel disease

BackgroundFollowing viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-I0-/-) model derived from the SvEv mouse, had evidence of increased mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wildtype. MMTV is endemic in several mouse strains as an endogenously encoded betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10-/- model. ResultsViral preparations extracted from IL-10-/- weanling stomachs revealed augmented MMTV load compared to the SvEv wildtype. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4% - 97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10-/- spleen encoded the MTV-9 superantigen that preferentially activates T cell receptor V{beta}-12 subsets, which were expanded in the IL-10-/- versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10-/- splenocytes with amplified interferon-{gamma} production versus the SvEv wildtype. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12 weeks treatment versus placebo. The combination anti-retroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL10-/- mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis. ConclusionsThis study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis.

microbiology↗