Project description:The molecular basis of TNF tolerance is poorly understood. In this experiment, primary human monocytes were used to examine TNF refractoriness. We detect absolute tolerance as selective, dose-dependently affecting a small group of powerful effector molecules; induction tolerance represented a more general phenomenon. Primary human monocytes were incubated for 48 h with Medium or different TNF-doses and subsequently short-term stimulated for two hours with TNF. Total RNA was prepared and analysed by use of Agilent microarrays. 6 different conditions were analyzed in total, corresponding to cells that were: 1) medium incubated (M+M), 2) medium incubated and short time TNF (400 U/ml) incubated (M+T), 3) low dose TNF (40 U/ml) preincubated (40+M), 4) low dose TNF preincubated and short time TNF incubated (40+T), 5) high dose TNF (400 U/ml) preincubated (400+M), 6) high dose TNF preincubated and short time TNF incubated (400+T). 3 biological replicates (corresponding to three different healthy donors) were analyzed regarding high-dose tolerance conditions (preincubation with 400 U TNF/ml), one of which was analyzed in duplicates (including cell culture, RNA preparation and a dye-swap microarray approach). 2 biological replicates (corresponding to two different healthy donors) were analyzed under low-dose tolerance conditions (preincubation with 40 U/ml). The different human donors were numbered and indicated in brackets (d1-d5).

2014-02-11 | E-GEOD-45371 | biostudies-arrayexpress

Multi-omic profiling of single nuclei uncovers regulatory diversity of brain cell types and diseases

Project description:Most existing single-cell techniques can only make one type of molecular measurements. Although computational approaches have been developed to integrate single-cell datasets, their efficacy still needs to be determined with reference to authentic single-cell multi-omic profiles. To address this challenge, we devised single-nucleus methylCytosine, Chromatin accessibility and Transcriptome sequencing (snmC2T-seq) and applied the approach to post-mortem human frontal cortex tissue. We developed a computational framework to evaluate the quality of finely defined cell types using multi-modal information and validated the efficacy of computational multi-omic integration methods. Correlation analysis in individual cells revealed gene groups showing distinct relations between methylation and expression. Integration of snmC2T-seq with other multi- and single- modal datasets enabled joint analyses of the methylome, chromatin accessibility, transcriptome, and chromatin architecture for 63 human cortical cell types. We reconstructed the regulatory lineage of these cortical cell types and found pronounced cell-type-specific enrichment of disease risks for neuropsychiatric traits, predicting causal cell types that can be targeted for treatment.

2019-12-12 | GSE140493 | GEO

Profiling of pancreatic adenocarcinoma using artificial intelligence-based integration of multi-omic and computational pathology features

Project description:Contemporary analyses focused on a limited number of clinical and molecular features have been unable to accurately predict clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). Here we describe a novel, conceptual approach and use it to analyze clinical, computational pathology, and molecular (DNA, RNA, protein, and lipid) analyte data from 74 patients with resectable PDAC. Multiple, independent, machine learning models were developed and tested on curated singleand multi-omic feature/analyte panels to determine their ability to predict clinical outcomes in patients. The multi-omic models predicted recurrence with an accuracy and positive predictive value (PPV) of 0.90, 0.91, and survival of 0.85, 0.87, respectively, outperforming every singleomic model. In predicting survival, we defined a parsimonious model with only 589 multi-omic analytes that had an accuracy and PPV of 0.85. Our approach enables discovery of parsimonious biomarker panels with similar predictive performance to that of larger and resource consuming panels and thereby has a significant potential to democratize precision cancer medicine worldwide.

2024-01-23 | PXD037038 | Pride

A single malaria episode induces mechanisms that minimise inflammation and promote tolerance in spleen inflammatory monocytes.

Project description:Disease tolerance is an important alternative strategy for rapidly acquired immunity to malaria. We show that tolerance is induced by a single malaria episode - in the absence of parasite clearance. Inflammatory spleen monocytes from C57Bl6/J mice respond with interferon-stimulated inflammation to acute first Plasmodium chabaudi infection and are destined to differentiate into inflammatory macrophages. This dramatic transcriptional response is tolerised during persisting chronic infection (with parasite densities up to 1000 parasites per µl), since the fitness costs of maintaining an emergency inflammatory response for several months would not be compatible with survival. However, spleen monocytes from chronically infected mice are not in a permanent refractory state, since their inflammatory response is identical to monocytes from uninfected mice when removed from the spleen and stimulated with LPS in vitro. Using a newly developed reinfection model to closely match parasitaemia between first and second P. chabaudi infection, we further uncover that memory of first malaria infection (30 days after drug treatment of chronic infection) dramatically changes the transcriptional response of inflammatory spleen monocytes to second infection. They now minimise inflammation and instead promote stress and tissue tolerance. This unique functional profile is not underpinned by alterations in the epigenetic landscape of inflammatory monocytes before their release from the bone marrow (link to GEO ChIPseq) - tolerance is therefore imprinted within the spleen. Hosts thus acquire long-lasting mechanisms that control inflammation (reducing collateral tissue damage) and learn to actively promote stress tolerance (protecting tissues against toxic products and processes) after one malaria episode.

2020-11-26 | GSE150047 | GEO

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