Biology subjects

Levi, H.

Publications and source records attributed to Levi, H..

6 recordsLinked to original sources

bioRxiv2026

Mapping Genetic Risk Associations to Cellular Contexts via Deep Learning and Biological Ontologies

Translating genome-wide association studies (GWAS) signals into trait-relevant cellular contexts remains challenging due to the complexity of the genomic regulatory code and linkage disequilibrium among associated variants. We present a novel computational framework that aggregates deep learning-based predictions of the functional effects of noncoding variants on transcriptional regulatory elements across GWAS loci and empirically evaluates their statistical significance. By organizing these aggregated signals within biological ontologies, our approach enables statistically calibrated interpretation of GWAS associations, highlighting relevant cell-type and tissue contexts across human traits.

bioinformatics↗

bioRxiv2025

CAR T-cells dysfunction in the central nervous system is mediated by BBB-induced activation-induced cell death

Chimeric Antigen Receptor (CAR) T-cells can eliminate leukemia and lymphoma within the central nervous system (CNS). Following a case with CD19+ relapse in the CNS in the presence of persisting Tisagenlecleucel, we generated several models to study CAR T-cells in the CNS. In both immunocompetent and humanized leukemia-bearing mice, CNS-residing CAR T-cells were shown to have inferior ex-vivo killing capacities compared to CAR T-cells harvested from the spleen or bone marrow of receptive mice. In a mechanistic work-up, we identified two contributing factors: First, CAR T-cells cultured in cerebrospinal fluid showed impaired cytotoxic and proliferative function compared to those in serum or other media. Second, using a unique in vitro human blood-brain barrier (BBB) model composed of endothelial cells and brain pericytes, we demonstrated that CAR T-cells that crossed the BBB exhibited antigen-independent activation and diminished cytolytic capacity. This led to increased activation-induced cell death of the BBB-migrating CAR T-cells and was confirmed to be independent of the CAR target and the costimulatory domain. Our findings add possible mechanisms of CAR T-cell resistance in the CNS, relevant for CNS hematologic and non-hematologic tumors.

cancer biology↗

bioRxiv2021

The DOMINO web-server for active module identification analysis

Active module identification (AMI) is an essential step in many omics analyses. Such algorithms receive a gene network and a gene activity profile as input and report subnetworks that show significant over-representation of accrued activity signal ("active modules"). Such modules can point out key molecular processes in the analyzed biological conditions. ResultsWe recently introduced a novel AMI algorithm called DOMINO, and demonstrated that it detects active modules that capture biological signals with markedly improved rate of empirical validation. Here, we provide an online server that executes DOMINO, making it more accessible and user-friendly. To help the interpretation of solutions, the server provides GO enrichment analysis, module visualizations, and accessible output formats for customized downstream analysis. It also enables running DOMINO with various gene identifiers of different organisms. Availability and implementationThe server is available at http://domino.cs.tau.ac.il. Its codebase is available at https://github.com/Shamir-Lab.

bioinformatics↗

bioRxiv2021

Whole-genome duplication shapes the aneuploidy landscape of human cancers

Aneuploidy - a hallmark of cancer - has tissue-specific recurrence patterns suggesting it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on the cellular and genomic context in which it arises. Whole-genome duplication (WGD) is a common macro-evolutionary event that occurs in >25% of human tumors during the early stages of tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy than tumors that have not, it remains unknown whether WGD affects aneuploidy recurrence patterns in human cancers. Here we analyzed clinical tumor samples from 449 WGD- tumors and 157 WGD+ tumors across 22 tumor types. We found distinct recurrence patterns of aneuploidy in WGD- and WGD+ tumors. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct co-occurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy vs. arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation in WGD- and WGD+ tumors. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Lastly, we induced WGD in human colon cancer cell lines, and followed aneuploidy formation in the isogenic WGD+/WGD-cells under standard or selective conditions. These experiments validated key findings from the clinical tumor analysis, and revealed a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors, and propose that the interaction between WGD and aneuploidy is a major contributor to tumor evolution.

cancer biology↗

bioRxiv2020

Synapse-specific direction selectivity in retinal bipolar cell axon terminals

The ability to encode the direction of image motion is fundamental to our sense of vision. Direction selectivity along the four cardinal directions is thought to originate in direction-selective ganglion cells (DSGCs), due to directionally-tuned GABAergic suppression by starburst cells. Here, by utilizing two-photon glutamate imaging to measure synaptic release, we reveal that direction selectivity along all four directions arises earlier than expected, at bipolar cell outputs. Thus, DSGCs receive directionally-aligned glutamatergic inputs from bipolar cell boutons. We further show that this bouton-specific tuning relies on cholinergic excitation and GABAergic inhibition from starburst cells. In this way, starburst cells are able to refine directional tuning in the excitatory visual pathway by modulating the activity of DSGC dendrites and their axonal inputs using two different neurotransmitters.

neuroscience↗

bioRxiv2020

DOMINO: a novel network-based module detection algorithm with reduced rate offalse calls

Algorithms for active module identification (AMI) are central to analysis of omics data. Such algorithms receive a gene network and nodes activity scores as input and report sub-networks that show significant over-representation of accrued activity signal ( active modules), thus representing biological processes that presumably play key roles in the analyzed biological conditions. Although such methods exist for almost two decades, only a handful of studies attempted to compare the biological signals captured by different methods. Here, we systematically evaluated six popular AMI methods on gene expression (GE) and GWAS data. Notably, we observed that GO terms enriched in modules detected by these methods on the real data were often also enriched on modules found on randomly permuted input data. This indicated that AMI methods frequently report modules that are not specific to the biological context measured by the analyzed omics dataset. To tackle this bias, we designed a permutation-based method that evaluates the empirical significance of GO terms reported as enriched in modules. We used the method to fashion five novel performance criteria for evaluating AMI methods. Last, we developed DOMINO, a novel AMI algorithm, that outperformed the other six algorithms in extensive testing on GE and GWAS data. Software is available at https://github.com/Shamir-Lab.

bioinformatics↗