Biology subjects

Gat-Viks, I.

Publications and source records attributed to Gat-Viks, I..

5 recordsLinked to original sources

bioRxiv2026

GGE: General-purpose deep meta-learning for classification of human transcriptomes with limited data

Transcriptomic classification is often hindered by the small number of samples relative to the high dimensionality of gene expression data. We introduce General Gene Expression (GGE), a deep meta-learning framework designed to support robust classification in this limited-sample setting. By training across 5,220 distinct biomedical prediction objectives drawn from 1,779 different human datasets, GGE learns a model initialization that captures biological patterns shared across heterogeneous classification tasks. This learned initialization has two key advantages. First, it enables improved performance to new datasets using only a small number of labeled samples. Second, because it is learned across diverse prediction objectives, it can be applied to a broad range of biomedical problems. We show that GGE outperforms established classifiers in data-limited settings across a wide range of applications, including datasets generated using different RNA-seq platforms and preprocessing pipelines. In addition, attention-based analysis identifies recurrent genes that contribute to performance across multiple biological objectives, providing insight into shared determinants of human biological states. Together, these results establish GGE is a general-purpose framework for human transcriptome-based classification in biomedical settings where labeled data are scarce.

bioinformatics↗

bioRxiv2025

Human biliary atresia extrahepatic cholangiocyte organoids express increased ER and oxidative stress, altered drug metabolism and cell polarity changes

Background & AimsBiliary atresia (BA), the leading cause of liver transplantation in children, presents in neonates with jaundice and progressive extrahepatic bile duct obstruction, yet its etiology and pathogenesis remain unknown. Here, we aimed to investigate the molecular mechanisms underlying BA and the susceptibility of cholangiocytes in the extrahepatic biliary tree using patient-derived extrahepatic cholangiocyte organoids (EHCOs). MethodsEHCOs were derived from common bile ducts remnants of BA patients undergoing Kasai portoenterostomy and from non-BA controls at the time of liver transplantation. Transcriptomic profiling was performed via bulk RNA sequencing, and analyzed in two ways: differentially expressed pathways and perturbation analysis to predict aberrant functions. Key findings were validated through mechanistic assays, immunofluorescence staining, qPCR and transmission electron microscopy (TEM). ResultsTranscriptomic analysis predicted significant alteration in endoplasmic reticulum (ER) stress, dysregulations of drug metabolism, alongside pronounced alterations in cellular adhesion and polarity-related genes in BA-derived EHCOs. Cell-to-cell alterations were observed with various proteins including E-cadherin, RhoU, Sox17 and CFTR. BA EHCOs had an increased endoplasmic reticulum (ER) stress response, exemplified by elevated PERK, BiP, and ATF4 along with abnormal ER on TEM. Furthermore CHOP, ERO1A, WFS1, and SOD3 were decreased suggestive of abnormal ER stress response. BA EHCOs displayed increased toxicity to biliatresone-induced injury and inhibition of cytochrome P450 resulted in attenuation of the ER stress markers PERK, BiP and ATF4. Finally, liver hilum biopsies from BA patients undergoing Kasai portoenterostomy confirmed elevated PERK and PGR78(BiP) consistent with the EHCOs analysis. ConclusionsBA EHCOs exhibit disrupted polarity, ER stress, and increased susceptibility to drug toxicity. These findings highlight key pathogenic mechanisms in BA and suggest that targeting these pathways may help mitigate cholangiocyte injury in BA. Impact and implicationsThis study provides the first transcriptomic and functional analysis of human extrahepatic cholangiocyte organoids (EHCOs) derived from biliary atresia (BA) patients. By focusing on the extra-hepatic biliary tree, we identified key mechanisms of cholangiocyte injury, including persistent ER stress, impaired stress response pathways, altered drug metabolism and disrupted epithelial polarity. These findings highlight ER stress and metabolic vulnerability as potential therapeutic targets and establish EHCOs as a tractable model for investigating BA pathogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/649927v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@150ab7org.highwire.dtl.DTLVardef@172953forg.highwire.dtl.DTLVardef@1a46e4eorg.highwire.dtl.DTLVardef@45c5c6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIFirst transcriptomic profiling of extrahepatic cholangiocyte organoids (EHCOs) from BA patients, C_LIO_LIrevealing distinct molecular alterations compared to controls. C_LIO_LIBA EHCOs exhibit disrupted epithelial polarity, with downregulation of E-cadherin and Sox17 and upregulation of CFTR. C_LIO_LIER stress is a hallmark of BA cholangiocytes, with elevated PERK, BiP, and ATF4, and C_LIO_LIdysregulation of downstream effectors including CHOP, ERO1A, and SOD3. C_LIO_LIBA EHCOs are more susceptible to biliatresone-induced injury, with enhanced ER stress and structural damage. C_LIO_LIInhibition of cytochrome P450 activity (CYP4A) reduces ER stress markers. C_LI

molecular biology↗

bioRxiv2022

The host transcriptional response to superinfection by influenza virus and streptococcus pneumonia

Secondary bacterial challenges during influenza virus infection ( superinfection) cause excessive mortality and hospitalization. Here we present a longitudinal study of gene-expression changes in murine lungs during superinfection, with an initial influenza A virus (IAV) infection and a subsequent Streptococcus pneumonia (SP) infection. In addition to the well-characterized impairment of the innate immune response, we identified superinfection-specific alterations in endothelial-related genes, including a previously uncharacterized rapid downregulation of particular angiogenic and vascular markers. Superinfection-specific alterations were also evident in the analysis of cellular states related to the hosts immune resistance against pathogens. We found that superinfected mice manifested an excessive rapid induction of immune resistance starting only a few hours after the secondary bacterial challenge. In addition, there was a substantial rewiring of the resistance program: interferon-regulated genes were switched from positive to negative correlations with resistance, whereas genes of fatty-acid metabolism were switched from negative to positive correlations with resistance. Thus, the transcriptional resistance state in superinfection is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into the remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions.

systems biology↗

bioRxiv2022

Pleural macrophages promote recovery from influenza virus infection

Seasonal influenza results in 3 to 5 million cases of severe disease and 250,000 to 500,000 deaths annually. Macrophages have been implicated in both the resolution and progression of the disease, but the drivers of these outcomes are poorly understood. We probed mouse lung transcriptomic datasets using the Digital Cell Quantifier algorithm to predict immune cell subsets that correlated with mild or severe influenza A virus (IAV) infection outcomes. We identified a novel lung macrophage population that transcriptionally resembled small serosal cavity macrophages and correlated with mild disease. Until now, the study of serosal macrophage translocation in the context of infections has been neglected. Here, we show that pleural macrophages (PMs) migrate from the pleural cavity to the lung after infection with pH1N1 A/California/04/2009 IAV. We found that the depletion of PMs increased morbidity and pulmonary inflammation. There were increased proinflammatory cytokines in the pleural cavity and an influx of neutrophils within the lung. Our results show PMs are recruited to the lung during IAV infection and contribute to recovery from influenza. This study expands our knowledge of PM plasticity and provides a new source of lung macrophages independent of monocyte recruitment and local proliferation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/493482v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e8880borg.highwire.dtl.DTLVardef@13b987dorg.highwire.dtl.DTLVardef@19856f9org.highwire.dtl.DTLVardef@76277d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Distinct gene programs underpinning 'disease tolerance' and 'resistance' in influenza virus infection

When challenged with an invading pathogen, the host defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs - one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.

systems biology↗