A5001986668- SARS-CoV-2 and COVID-19 Research
- CRISPR and Genetic Engineering
- Animal Virus Infections Studies
- Hepatitis B Virus Studies
- RNA Interference and Gene Delivery
- Liver physiology and pathology
- Liver Disease Diagnosis and Treatment
- Endoplasmic Reticulum Stress and Disease
- Hippo pathway signaling and YAP/TAZ
- Viral gastroenteritis research and epidemiology
- RNA Research and Splicing
- Viral Infections and Outbreaks Research
- Ubiquitin and proteasome pathways
- DNA Repair Mechanisms
- Lipid metabolism and biosynthesis
- MicroRNA in disease regulation
- Organ Transplantation Techniques and Outcomes
- Mosquito-borne diseases and control
- interferon and immune responses
- PI3K/AKT/mTOR signaling in cancer
- COVID-19 Clinical Research Studies
- Cancer-related gene regulation
- Polyomavirus and related diseases
- Pluripotent Stem Cells Research
- Protein Degradation and Inhibitors
Rockefeller University
2017-2024
Weizmann Institute of Science
2013-2022
A tool to study SARS-CoV-2 Work with infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires high-level biocontainment facilities, making it important develop safer molecular tools that can potentially be used under less stringent conditions. Self-replicating RNAs known as replicons have long been pathogenic RNA viruses; however, developing SARS-SoV-2 has challenging because of its large genome. Ricardo-Lax et al . a yeast-based system construct cannot assemble virus...
Primary human hepatocytes (PHHs) are an essential tool for modeling drug metabolism and liver disease. However, variable plating efficiencies, short lifespan in culture, resistance to genetic manipulation have limited their use. Here, we show that the pyrrolizidine alkaloid retrorsine improves PHH repopulation of chimeric mice on average 10-fold rescues ability even poorly plateable donor provide cells subsequent ex vivo cultures. These mouse-passaged (mp) cultures overcome marked...
Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes PNPLA3 148I and 148M variants engrafted the livers of broadly immunodeficient chimeric mice respond hypercaloric diets. As early as four weeks, developed dyslipidemia, impaired...
Interferons (IFNs) play a crucial role in the regulation and evolution of host–virus interactions. Here, we conducted genome-wide arrayed CRISPR knockout screen presence absence IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis interacting with SARS-CoV-2, drawing from selection 67 large-scale studies, including our own. identified 28 high relevance both genetic studies Disease 2019...
Hepatitis C virus (HCV) requires the liver specific micro-RNA (miRNA), miR-122, to replicate. This was considered unique among RNA viruses until recent discoveries of HCV-related hepaciviruses prompting question a more general miR-122 dependence. Among hepaciviruses, closest known HCV relative is equine non-primate hepacivirus (NPHV). Here, we used Argonaute cross-linking immunoprecipitation (AGO-CLIP) confirm AGO binding single predicted site in NPHV 5'UTR vivo. To study requirements...
SUMMARY The COVID-19 pandemic has claimed the lives of more than one million people worldwide. causative agent, SARS-CoV-2, is a member Coronaviridae family, which are viruses that cause respiratory infections varying severity. cellular host factors and pathways co-opted by SARS-CoV-2 other coronaviruses in execution their life cycles remain ill-defined. To develop an extensive compendium required for infection three seasonal (HCoV-OC43, HCoV-NL63, HCoV-229E), we performed parallel...
SUMMARY The ongoing SARS-CoV-2 pandemic has devastated the global economy and claimed nearly one million lives, presenting an urgent health crisis. To identify host factors required for infection by seasonal coronaviruses, we designed a focused high-coverage CRISPR-Cas9 library targeting 332 members of recently published protein interactome. We leveraged compact nature this to systematically screen four related coronaviruses (HCoV-229E, HCoV-NL63, HCoV-OC43 SARS-CoV-2) at two physiologically...
Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent CoVs to investigate their cell entry mechanisms. Unexpectedly, successful recovery of rVSVs spike SHC014, a SARS-like CoV, was associated with acquisition novel substitution in S2 fusion peptide-proximal region (FPPR). This enhanced viral both VSV and coronavirus contexts increasing...
The polyomavirus middle T antigen (PyMT) oncogene activates the cellular nonreceptor tyrosine kinase c-Src and recruits Hippo pathway effectors, Yap (yes-associated protein) Taz (transcriptional coactivator with PDZ-binding motif), as key steps in oncogenesis. are transcription coactivators shuttling from cytoplasm to nucleus. Lats1/2 (large tumor suppressor homolog) reduces Yap/Taz nuclear localization minimizes their cytoplasmic levels by facilitating ubiquitination E3 ligase SCF(β-TrCP)....
Subcellular fractionation in combination with mass spectrometry–based proteomics is a powerful tool to study localization of key proteins health and disease. Here we offered reliable rapid method for mammalian cell fractionation, tuned such proteomic analyses. This proves readily applicable different lines which all the cellular contents are accounted for, while maintaining nuclear envelope integrity. We demonstrated method’s utility by quantifying effects export inhibitor on nucleoplasmic...
Abstract Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted genome-wide arrayed CRISPR knockout screen presence absence IFN to identify human genes that influence SARS-CoV-2 infection. We then performed an integrated analysis interacting with SARS-CoV-2, drawing from selection 67 large-scale studies, including our own. identified 28 high relevance both genetic studies COVID-19 patients functional screens cell culture, many...
Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent CoVs to investigate their cell entry mechanisms. Unexpectedly, successful recovery of rVSVs spike SHC014-CoV, a SARS-like CoV, was associated with acquisition novel substitution in S2 fusion peptide-proximal region (FPPR). This enhanced viral both VSV and coronavirus contexts increasing...
TAF 4b is a cell type‐specific subunit of the general transcription factor TFIID . Here, we show that highly expressed in embryonic stem cells ( ESC ) and down‐regulated upon differentiation. To examine role , applied knockdown KD approach. depletion associated with morphological changes reduced expression self‐renewal marker alkaline phosphatase. In contrast, 4, ubiquitously paralog, retained even stabilized stemness. Retinoic acid‐induced differentiation was facilitated absence but...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), has emerged as a global pandemic pathogen with high mortality. While treatments have been developed to reduce morbidity and mortality of COVID-19, more antivirals broad-spectrum activities are still needed. Here we identified lonafarnib (LNF), Food Drug Administration (FDA)-approved drug inhibitor cellular farnesyltransferase (FTase), an effective anti-SARS-CoV-2 agent. LNF...
The hepatitis B virus (HBV) is one of the smallest but most highly infectious human pathogens. With a DNA genome only 3.2 kb and four genes, HBV successfully completes its life cycle by using intricate processes to hijack host machinery. infects non-dividing liver cells in which dNTPs are limited. As virus, requires for replication. induces ATR-mediated cellular damage response pathway overcome this constraint. This upregulates R2 (RRM2) expression generating an active RNR holoenzyme...
ABSTRACT Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes PNPLA3 148I and 148M variants engrafted the livers of chimeric mice respond hypercaloric Western-style diet. As early as 4 weeks, developed dyslipidemia, impaired glucose...
DNA viruses require dNTPs for replication and have developed different strategies to increase intracellular dNTP pools. Hepatitis B virus (HBV) infects non-dividing cells in which are scarce the question is how viral takes place. Previously we reported that induces damage response (DDR) pathway culminating RNR-R2 expression generation of an active RNR holoenzyme, key regulator levels, leading dNTPs. How DDR upregulation not completely known. The HBx open reading frame (ORF) was believed...
Abstract Hepatitis B virus infects non-dividing cells in which dNTPs are scarce. HBV replication requires dNTPs. To cope with this constraint the induces DNA damage response (DDR) pathway culminating RNR-R2 expression and generation of an active RNR holoenzyme, key regulator dNTP levels. Previously we reported that HBx open reading frame (ORF) triggers pathway. Unexpectedly however, report here production protein is not essential. We found a small region 125 bases within transcript...