A5070109614- Cell Image Analysis Techniques
- Image Processing Techniques and Applications
- Computational Drug Discovery Methods
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
- Microtubule and mitosis dynamics
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Head and Neck Cancer Studies
- Cell death mechanisms and regulation
- Lung Cancer Treatments and Mutations
- Endoplasmic Reticulum Stress and Disease
- Advanced Fluorescence Microscopy Techniques
- Polyomavirus and related diseases
- Biological Research and Disease Studies
- BRCA gene mutations in cancer
- AI in cancer detection
- Genetics, Bioinformatics, and Biomedical Research
- RNA Interference and Gene Delivery
- Cellular transport and secretion
- Cancer Research and Treatment
- Ubiquitin and proteasome pathways
- Bioinformatics and Genomic Networks
- Neuroblastoma Research and Treatments
Uppsala University
2021-2025
Science for Life Laboratory
2016-2025
Karolinska Institutet
2014-2024
University of Rome Tor Vergata
2022
Universitat Autònoma de Barcelona
2020
Centre for Human Drug Research
2009-2015
Leiden University
2009-2015
Leiden University Medical Center
2015
Netherlands Metabolomics Centre
2010
The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well mRNA processing. Although highly conserved throughout all organisms, their biological roles biochemical redundancies remain largely unclear. To address this, we globally resolve individual properties inter-relationships. We purify 18 of the human proteins screen 52 substrates, providing a substrate redundancy map. Using crystal structures, generate sequence alignment analyses revealing four major structural...
ADP-ribosylation is a post-translational modification (PTM) of proteins found in organisms from all kingdoms life which regulates many important biological functions including DNA repair, chromatin structure, unfolded protein response and apoptosis. Several cellular enzymes, such as macrodomain containing PARG [poly(ADP-ribose) glycohydrolase] TARG1 [terminal ADP-ribose (ADPr) glycohydrolase], reverse ADP-ribosylation. In the present study, we show that human Nudix (nucleoside...
Mitochondrial toxicity is an important safety endpoint in drug discovery. Models based solely on chemical structure for predicting mitochondrial are currently limited accuracy and applicability domain to the space of training compounds. In this work, we aimed utilize both -omics data push beyond state-of-the-art. We combined Cell Painting Gene Expression with structural information from Morgan fingerprints 382 perturbants tested Tox21 membrane depolarization assay. observed that toxicants...
The applicability domain of machine learning models trained on structural fingerprints for the prediction biological endpoints is often limited by lack diversity chemical space training data. In this work, we developed similarity-based merger which combined outputs individual cell morphology (based Cell Painting) and structure fingerprints) morphological similarities compounds in test dataset to dataset. We applied these using logistic regression predictions as features predicted assay hit...
Cell Painting assays generate morphological profiles that are versatile descriptors of biological systems and have been used to predict in vitro vivo drug effects. However, features extracted from classical software such as CellProfiler based on statistical calculations often not readily biologically interpretable. In this study, we propose a new feature space, which call BioMorph, maps these with readouts comprehensive Health assays. We validated the resulting BioMorph space effectively...
ABSTRACT High-content image-based assays have fueled significant discoveries in the life sciences past decade (2013-2023), including novel insights into disease etiology, mechanism of action, new therapeutics, and toxicology predictions. Here, we systematically review substantial methodological advancements applications Cell Painting. Advancements include improvements Painting protocol, assay adaptations for different types perturbations applications, improved methodologies feature...
Drug-induced liver injury (DILI) is an important clinical problem. It involves crosstalk between drug toxicity and the immune system, but exact mechanism at cellular hepatocyte level not well understood. Here we studied of in apoptosis caused by diclofenac proinflammatory cytokine tumor necrosis factor α (TNF-α). HepG2 cells were treated with followed TNF-α challenge subsequent evaluation apoptosis. Diclofenac a mild cells, which was strongly potentiated TNF-α. A focused machinery short...
The mechanism of action (MoA) a compound describes the biological interaction through which it produces pharmacological effect. Multiple data sources can be used for purpose predicting MoA, including structural information, and various assays, such as those based on cell morphology, transcriptomics metabolomics. In present study we explored benefits potential additive/synergistic effects combining in form Morgan fingerprints, morphological five-channel Cell Painting image data. For set 10...
Abstract Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report novel activity the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, rate-limiting step biogenesis, in dose-dependent manner. Amodiaquine triggers degradation catalytic subunit RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization p53. Pol shutdown occurs absence DNA damage and without subsequent ATM-dependent transcription....
Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass characterised by small cellular subpopulation – stem cells (GSCs) that has been held responsible for initiation, cell invasion, proliferation, relapse resistance to chemo‐ radiotherapy. Targeted therapies against GSCs crucial, as understanding...
Fluorescence staining techniques, such as Cell Painting, together with fluorescence microscopy have proven invaluable for visualizing and quantifying the effects that drugs other perturbations on cultured cells. However, is expensive, time-consuming, labor-intensive, stains applied can be cytotoxic, interfering activity under study. The simplest form of microscopy, brightfield lacks these downsides, but images produced low contrast cellular compartments are difficult to discern....
Cellular responses to DNA-damaging agents involve the activation of various DNA damage signaling and transduction pathways.Using quantitative high-resolution tandem mass spectrometry, we determined global changes in protein level phosphorylation site profiles following treatment SILAC (stable isotope labeling by amino acids cell culture)-labeled murine embryonic stem cells with anticancer drug cisplatin.Network pathway analyses indicated that processes related response cytoskeleton...
Abstract Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor environment, cancer upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show increasing nonmalignant sensitization to effects inhibition, whereas decreasing pressure protected against inhibition. Furthermore, purified zebrafish solved crystal structure bound its...
Abstract Background The emergence and continued global spread of the current COVID-19 pandemic has highlighted need for methods to identify novel or repurposed therapeutic drugs in a fast effective way. Despite availability discovery antiviral drugs, majority tend focus on effects such given virus, its constituent proteins, enzymatic activity, often neglecting consequences host cells. This may lead partial assessment efficacy tested anti-viral compounds, as potential toxicity impacting...
In past times, the analysis of endocrine disrupting properties chemicals has mainly been focused on (anti-)estrogenic or (anti-)androgenic properties, as well aspects steroidogenesis and modulation thyroid signaling. More recently, disruption energy metabolism related signaling pathways by exogenous substances, so-called metabolism-disrupting (MDCs) have come into focus. While general effects such body organ weight changes are routinely monitored in animal studies, there is a clear lack...
DNA damage response signaling is crucial for genome maintenance in all organisms and corrupted cancer. In an RNA interference (RNAi) screen (de)ubiquitinases sumoylases modulating the apoptotic of embryonic stem (ES) cells to damage, we identified E3 ubiquitin ligase/ISGylase, ariadne homologue 1 (ARIH1). Silencing ARIH1 sensitized ES cancer genotoxic compounds ionizing radiation, irrespective their p53 or caspase-3 status. Expression wild-type but not ubiquitinase-defective constructs...
Abstract Purpose: Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head neck squamous cell carcinoma (HNSCC). Patients with HNSCC are not eligible for conventional therapies due toxicity in healthy cells, predominantly hematotoxicity, the only treatment currently available surgical resection. In this work, we searched validated two already approved drugs as new potential patients anemia. Experimental Design: We...
Environmental chemicals are commonly studied one at a time, and there is need to advance our understanding of the effect exposure their combinations. Here we apply high-content microscopy imaging cells stained with multiplexed dyes (Cell Painting) profile effects Cetyltrimethylammonium bromide (CTAB), Bisphenol A (BPA), Dibutyltin dilaurate (DBTDL) on four human cell lines; both individually in all We show that morphological features can be used multivariate data analysis discern between...
Analysis of single-cell data has emerged as a powerful tool for studying biological processes and response to perturbations. However, its application in morphological profiling is less explored. In this study we profile six cell death subtypes induced by 50 small molecule drugs across concentrations using the Cell Painting assay. We evaluate performance three feature extraction methods at aggregated level apply supervised unsupervised analyses uncover factors contributing mechanisms. Our...
Cell Painting is a popular assay for morphological profiling of multi-labeled 2D monolayer cell cultures used in wide range applications. Culturing cells 3D has potential higher physiological relevance, such as when studying effects perturbations. Robust and scalable models can be challenging to characterize through imaging - particularly because light difficulty penetrating multilayers. We introduce method where the combined with tissue-clearing applied spheroids generated ULA microplate...