Biology subjects

Irmler, M.

Publications and source records attributed to Irmler, M..

3 recordsLinked to original sources

bioRxiv2020

Towards predictive nanotoxicology: from roundabout of molecular events to chronic inflammation prediction

Nanomaterial-induced diseases cannot be reliably predicted because of the lack of clearly identified causal relationships, in particular between acute exposures and chronic symptoms. By applying advanced microscopies and omics to in vitro and in vivo systems, together with in silico molecular modelling, we have here determined that the long-lasting response to a single exposure originates in the counteracting of a newly discovered nanomaterial quarantining and nanomaterial cycling among different lung cell types. This allows us to predict the nanomaterial-induced spectrum of lung inflammation using only in vitro measurements and in silico modelling. Besides its profound implications for cost-efficient animal-free predictive toxicology, our work also paves the way to a better mechanistic understanding of nanomaterial- induced cancer, fibrosis, and other chronic diseases.

molecular biology↗

bioRxiv2020

Correlation guided Network Integration (CoNI) reveals novel genetic regulators of hepatic metabolism

ABSTRACTThe steadily increasing amount of newly generated omics data of various types from genomics to metabolomics is a chance and a challenge to systems biology. To fully use its potential, one key is the meaningful integration of different types of omics. We here present a fully unsupervised and versatile correlation-based method, termed Correlation guided Network Integration (CoNI), to integrate multi-omics data into a hypergraph structure that allows for identification of effective regulators. Our approach further unravels single transcripts mapped to specific densely connected metabolic sub-graphs or pathways. By applying our method on transcriptomics and metabolomics data from murine livers under standard chow or high-fat-diet, we isolated eleven genes with a regulatory effect on hepatic metabolism. Subsequent in vitro and ex vivo experiments in human liver cells and human obtained liver biopsies validated seven candidates including INHBE and COBLL1, to alter lipid metabolism and to correlate with diabetes related traits such as overweight, hepatic fat content and insulin resistance (HOMA-IR). Last, we successfully applied our methods to an independent data-set to confirm its versatile and transferable character.Competing Interest StatementMatthias H. Tschoep is a scientific advisor to Novo Nordisk, and ERX. Jerzy Adamski is a scientific advisor to Biocrates Life Sciences AG. View Full Text

bioinformatics↗

bioRxiv2020

A mosaic renal myeloid subtype with T-cell inhibitory and protumoral features is linked to immune escape and survival in clear cell renal cell cancer

Mononuclear phagocytes moderate tissue repair, immune activation and tolerance. In the renal tubulo-interstitium specialized dendritic cells help maintain homeostasis and protect tubuli from immune injury. Human renal cell carcinoma (RCC) is immunogenic; yet immunotherapies that target T-cell dysfunction show limited clinical efficacy suggesting additional mechanisms of immunoinhibiton. We previously described "enriched-in-renal cell carcinoma" (erc)DCs that are often found in tight contact with T cells which are dysfunctional. Here we describe that ercDCs exhibit a distinct polarization state imparted by tissue-specific signals characteristic for RCC and renal tissue homeostasis. The resulting mosaic transcript signature includes features associated with host defense activity, angiogenesis/invasion and T-cell inhibition. An ercDC-specific profile was predictive for patient survival and suggests potential therapeutic targets for improved immunotherapy. SignificanceImmunotherapies, which re-invigorate T-cell activity, achieve clinical responses in subsets of patients only revealing additional layers of T-cell inhibition. Mononuclear phagocytes can be immunoinhibitory. But, they are highly plastic and repolarization may be possible if key programming molecules can be identified, potentially enabling antitumor responses in tumors refractory to checkpoint blockade. We describe a myeloid cell type with mosaic feature including tumor-promotion and immunoinhibition in human clear cell renal cell carcinoma. Observed tight contacts with T cells may translate into T-cell dysfunction. A high ercDC score in tumor tissue correlates with poor patient survival suggesting ercDCs as targets for therapeutic intervention. Targeting molecules that are identified in the ercDC profile may expand the range of patients effectively treated by immunotherapy. HighlightsBullet points: O_LIRenal cell carcinoma (ccRCC) harbors polarized mosaic myeloid cells (ercDCs) C_LIO_LIercDCs are found in contact with dysfunctional T cells in ccRCC C_LIO_LIercDCs express novel immunoinhibitory proteins C_LIO_LIHigh ercDC z-score in ccRCC tissue correlates with poor patient survival C_LI

immunology↗