Biology subjects

Kim, V.

Publications and source records attributed to Kim, V..

4 recordsLinked to original sources

bioRxiv2023

Self-supervision advances morphological profiling by unlocking powerful image representations

Cell Painting is an image-based assay that offers valuable insights into drug mechanisms of action and off-target effects. However, traditional feature extraction tools such as CellProfiler are computationally intensive and require frequent parameter adjustments. Inspired by recent advances in AI, we trained self-supervised learning (SSL) models DINO, MAE, and SimCLR on subsets of the JUMP-CP dataset to obtain powerful image representations for Cell Painting. We assessed the reproducibility and biological relevance of SSL features and uncovered the critical factors influencing model performance, such as training set composition and domain-specific normalization techniques. Our best model (DINO) surpassed CellProfiler in drug target and gene family classification, significantly reducing computational time and costs. All SSL models showed remarkable generalizability without fine-tuning, outperforming CellProfiler on an unseen dataset of genetic perturbations. Our study demonstrates the effectiveness of SSL methods for morphological profiling, suggesting promising research directions for improving the analysis of related image modalities.

bioinformatics↗

bioRxiv2022

High-throughput profiling of drug interactions in Gram-positive bacteria

Drug combinations present a powerful strategy to tackle antimicrobial resistance, but have not been systematically tested in many bacterial species. Here, we used an automated high-throughput setup to profile [~] 8000 combinations between 65 antibacterial drugs in three Gram-positive species: the model species, Bacillus subtilis and two prominent pathogens, Staphylococcus aureus and Streptococcus pneumoniae. Thereby, we recapitulate previously known drug interactions, but also identify ten times more interactions than previously reported in the pathogen S. aureus, including two synergies that were also effective in multi-drug resistant clinical S. aureus isolates in vitro and in vivo. Interactions were largely species-specific and mostly synergistic for drugs targeting the same cellular process, as observed also for Gram-negative species1. Yet, the dominating synergies are clearly distinct between Gram-negative and Gram-positive species, and are driven by different bottlenecks in drug uptake and vulnerabilities of their cell surface structures. To further explore interactions of commonly prescribed non-antibiotic drugs with antibiotics, we tested 2728 of such combinations in S. aureus, detecting a plethora of unexpected antagonisms that could compromise the efficacy of antimicrobial treatments in the age of polypharmacy. We uncovered even more synergies than antagonisms, some of which we could demonstrate as effective combinations in vivo against multi-drug resistant clinical isolates. Among them, we showed that the antiaggregant ticagrelor interferes with purine metabolism and changes the surface charge of S. aureus, leading to strong synergies with cationic antibiotics. Overall, this exemplifies the untapped potential of approved non-antibacterial drugs to be repurposed as antibiotic adjuvants. All data can be browsed through an interactive interface (https://apps.embl.de/combact/).

microbiology↗

bioRxiv2022

Imaging-based coculture model for high-throughput compound screening in hematological cancers

Large-scale compound screens are a powerful model system for understanding variability of treatment response and for discovering druggable tumor vulnerabilities of hematological malignancies. However, as mostly performed in a monoculture of tumor cells, these assays disregard modulatory effects of the in vivo microenvironment. It is an open question whether and to what extent coculture with bone marrow stromal cells could improve the biological relevance of drug testing assays over monoculture. Here, we measured ex vivo sensitivity of 108 primary blood cancer samples to 50 drugs in monoculture and in coculture with bone marrow stromal cells. Stromal coculture conferred resistance to 52 % of compounds in chronic lymphocytic leukemia (CLL) and to 36% of compounds in acute myeloid leukemia (AML), including chemotherapeutics, BCR inhibitors, proteasome inhibitors and BET inhibitors. While most of the remaining drugs were similarly effective in mono- and coculture, only the JAK inhibitors ruxolitinib and tofacitinib exhibited increased efficacy in AML and CLL stromal coculture. We further confirmed the importance of JAK-STAT signaling for stroma-mediated resistance by showing that stromal cells induce phosphorylation of STAT3 in CLL cells. We genetically characterized the 108 cancer samples and found that drug-gene associations agreed well between mono- and coculture. Overall, effect sizes were lower in coculture, thus more drug-gene associations were detected in monoculture than in coculture. Our results suggest a two-step strategy for drug perturbation testing, with large-scale screening performed in monoculture, followed by focused evaluation of potential stroma-mediated resistances in coculture.

cancer biology↗

bioRxiv2022

Relapse-like behavior and nAChR sensitization following intermittent access nicotine self-administration

ABSTRACTMany tobacco smokers consume nicotine intermittently, but the underlying mechanisms and neurobiological changes associated with intermittent nicotine intake are unclear. Understanding intermittent nicotine intake is a high priority, as it could promote therapeutic strategies to attenuate tobacco consumption. We examined nicotine intake behavior and neurobiological changes in male rats that were trained to self-administer nicotine during brief (5 min) trials interspersed with longer (15 min) drug-free periods. Rats readily adapted to intermittent access (IntA) SA following acquisition on a continuous access (ContA) schedule. Probabilistic analysis of IntA nicotine SA suggested reduced nicotine loading behavior compared to ContA, and nicotine pharmacokinetic modeling revealed that rats taking nicotine intermittently may have increased intake to maintain blood levels of nicotine that are comparable to ContA SA. After IntA nicotine SA, rats exhibited an increase in unreinforced responses for nicotine-associated cues (incubation of craving) and specific alterations in the striatal proteome after 7 days without nicotine. IntA nicotine SA also induced nAChR functional upregulation in the interpeduncular nucleus (IPN), and it enhanced nicotine binding in the brain as determined via [11C]nicotine positron emission tomography. Reducing the saliency of the cue conditions during the 5 min access periods attenuated nicotine intake, but incubation of craving was preserved. Together, these results indicate that IntA conditions promote nicotine SA and nicotine seeking after a nicotine-free period.

neuroscience↗