A5077209777- Bioinformatics and Genomic Networks
- Computational Drug Discovery Methods
- Carcinogens and Genotoxicity Assessment
- DNA Repair Mechanisms
- Cancer Genomics and Diagnostics
- SARS-CoV-2 and COVID-19 Research
- Legionella and Acanthamoeba research
- Protein Degradation and Inhibitors
- Bacterial biofilms and quorum sensing
- Molecular Biology Techniques and Applications
- Mathematical Biology Tumor Growth
- Vibrio bacteria research studies
- CRISPR and Genetic Engineering
- Radiation Effects and Dosimetry
- PARP inhibition in cancer therapy
- Cancer-related molecular mechanisms research
- interferon and immune responses
- Cytomegalovirus and herpesvirus research
- Pharmacogenetics and Drug Metabolism
- Health Systems, Economic Evaluations, Quality of Life
- Epigenetics and DNA Methylation
- Statistical Methods in Clinical Trials
- Effects of Radiation Exposure
- Radiation Therapy and Dosimetry
- Glycogen Storage Diseases and Myoclonus
Columbia University Irving Medical Center
2005-2025
Columbia University
2012-2024
High Throughput Biology (United States)
2017-2024
National Center on Addiction and Substance Abuse at Columbia University
2018
Cancer Research Center
2018
New York Genome Center
2014-2017
Tel Aviv University
2004
Institut Pasteur
2004
Roswell Park Comprehensive Cancer Center
2004
Institute of Experimental Cardiology
2001
We present the genomic sequence of Legionella pneumophila, bacterial agent Legionnaires' disease, a potentially fatal pneumonia acquired from aerosolized contaminated fresh water. The genome includes 45-kilobase pair element that can exist in chromosomal and episomal forms, selective expansions important gene families, genes for unexpected metabolic pathways, previously unknown candidate virulence determinants. highlight may account Legionella's ability to survive protozoa, mammalian...
ABSTRACT Intracellular pathogens exploit host cell functions to create a replication niche inside eukaryotic cells. The causative agent of Legionnaires' disease, the γ-proteobacterium Legionella pneumophila , resides and replicates within modified vacuole protozoan mammalian L. translocates effector proteins into cells through Icm-Dot complex, specialized type IVB secretion system that is required for intracellular growth. To find out if some may have been acquired interdomain horizontal...
Legionella pneumophila is the causative agent of severe and potentially fatal pneumonia Legionnaires' disease. L. able to replicate within macrophages protozoa by establishing a replicative compartment in process that requires Icm/Dot type IVB secretion system. The signals regulatory pathways required for infection intracellular replication are poorly understood. Mutation rpoS gene, which encodes sigma(S), does not affect growth rich medium but severely decreases multiplication protozoan...
The cytokinesis-block micronucleus (CBMN) assay has become a fully-validated and standardized method for radiation biodosimetry. is typically performed using microscopy, which labor intensive, time consuming impractical after large-scale radiological/nuclear event. Imaging flow cytometry (IFC), combines the statistical power of traditional with sensitivity specificity been recently used to perform CBMN assay. Since this technology capable automated sample acquisition multi-file analysis, we...
Abstract Prioritizing treatments for individual patients with cancer remains challenging, and performing coclinical studies using patient-derived models in real time is often unfeasible. To circumvent these challenges, we introduce OncoLoop, a precision medicine framework that predicts drug sensitivity human tumors their preexisting high-fidelity (cognate) model(s) by leveraging perturbation profiles. As proof of concept, applied OncoLoop to prostate genetically engineered mouse (GEMM)...
Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific network rewiring, continue to challenge therapeutic efficacy. Leveraging progress in proteomic technologies network-based methodologies, we introduce Virtual Enrichment-based Signaling Protein-activity Analysis (VESPA)-an algorithm designed elucidate mechanisms cell response...
We demonstrate the use of high-throughput biodosimetry platforms based on commercial high-throughput/high-content screening robotic systems. The cytokinesis-block micronucleus (CBMN) assay, using only 20 μl whole blood from a fingerstick, was implemented PerkinElmer cell::explorer and General Electric IN Cell Analyzer 2000. On average 500 binucleated cells per sample were detected by our FluorQuantMN software. A calibration curve generated in radiation dose range up to 5.0 Gy data 8 donors...
Adult polyglucosan body disease (APBD) is a late-onset caused by intracellular accumulation of bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid-Schiff reagent, which interacts with polyglucosans the cell, this screen discovered that flavoring agent guaiacol can lower polyglucosans, result also confirmed...
We developed a fully-automated dicentric chromosome assay (DCA) in multiwell plates. All operations, from sample loading to scoring, are performed, without human intervention, by the second-generation Rapid Automated Biodosimetry Tool II (RABiT-II) robotic system, plate imager and custom software, FluorQuantDic. The system requires small volumes of blood (30 µl per individual) determine radiation dose received as result accident or terrorist attack. To visualize dicentrics plates, we...
Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) cooperate in migration survival of cells by activation phosphatidylinositol-3 (PI-3) kinase mitogen activating protein (MAP) pathways. However, Ang1 opposes the effect VEGF on permeability. We found that also blocks VEGF-mediated diffusion fluoresin isothiocyanate (FITC)-labeled albumin across an cell monolayer. permeability has been attributed, part, to phospholipase A(2) subsequent formation platelet factor. had no...
A large fraction of the proteins that are being identified as key tumor dependencies represent poor pharmacological targets or lack clinically-relevant small-molecule inhibitors. Availability fully generalizable approaches for systematic and efficient prioritization tumor-context specific protein activity inhibitors would thus have significant translational value. Unfortunately, inhibitor effects on cannot be directly measured in proteome-wide fashion by conventional biochemical assays. We...
In this work, we describe a fully automated cytokinesis-block micronucleus (CBMN) assay with significantly shortened time to result, motivated by the need for rapid high-throughput biodosimetric estimation of radiation doses from small-volume human blood samples. The Rapid Automated Biodosimetry Tool (RABiT-II) currently consists two commercial systems: PerkinElmer cell: :explorer Workstation and GE Healthcare IN Cell Analyzer 2000 Imager. Blood samples (30 ll) eight healthy volunteers were...
Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell that critically dysregulated following virus-mediated reprogramming of transcriptional state. To overcome these limitations, we propose elucidation pharmacologic targeting Master Regulator proteins—whose aberrant activities govern reprogramed state infected-coronavirus cells—presents unique opportunities develop novel mechanism-based therapeutic approaches therapy, either as...
ABSTRACT The cytokinesis-block micronucleus (CBMN) assay is considered to be the most suitable biodosimetry method for automation. Previously, we automated this on a commercial robotic biotech high-throughput system (RABiT-II) adopting both traditional and an accelerated protocol, using centrifugation steps lymphocyte harvesting washing, after whole blood culturing. Here describe further development of our CBMN protocol use high-throughput/high content screening (HTS/HCS) systems without...
Validation of biodosimetry assays is routinely performed using primarily orthovoltage irradiators at a conventional dose rate approximately 1 Gy/min. However, incidental/ accidental exposures caused by nuclear weapons can be more complex. The aim this work was to simulate the DNA damage effects mimicking those detonation several kilotons improvised device (IND). For this, we modeled complex to: 1. mixed (photons + IND-neutrons) field and 2. different rates that may come from blast, fallout,...
An automated platform for cytogenetic biodosimetry, the “Rapid Automated Biodosimetry Tool II (RABiT-II),” adapts dicentric chromosome assay (DCA) high-throughput mass-screening of population after a large-scale radiological event. To validate this test, U.S. Federal Drug Administration (FDA) recommends demonstrating that biodosimetric in question correctly reports dose an vivo model. Here we describe use rhesus macaques (Macaca mulatta) to augment human studies and accuracy version DCA....
SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable its replication. Here we show that analysis of Master Regulator proteins representing mechanistic determinants gene expression signature induced by in infected cells revealed coordinated inactivation Regulators enriched physical interactions with proteins, suggesting their role maintaining refractory virus To test functional relevance, measured replication epithelial treated drugs predicted...
Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific network rewiring, continue to challenge therapeutic efficacy. By leveraging progress in proteomic technologies network-based methodologies, the past decade, we developed VESPA-an algorithm designed elucidate mechanisms cell response adaptation drug perturbations-and used it...
Few tools are available for noninvasive imaging of synapses in the living mammalian brain. Current paradigms require use genetically modified mice or viral delivery genetic material to To develop an alternative chemical approach, utilizing recognition synaptic components by organic small molecules, we designed imaging-based, high-content screen cultured cortical neurons identify molecules based on their colocalization with fluorescently tagged proteins. We used this approach a library ∼7000...
In major radiological events, rapid assays to detect ionizing radiation exposure are crucial for effective medical interventions. The purpose of these is twofold: categorize affected individuals into groups initial treatments, and provide definitive dose estimates continued care epidemiology. However, existing high-throughput cytogenetic biodosimetry take about 3 days yield results, which delays critical We have developed a multiwell-based variant the chemical-induced G0-phase Premature...
In cytogenetic biodosimetry, assessing radiation exposure typically requires over 48 hours for cells to reach mitosis, significantly delaying the administration of crucial countermeasures needed within first 24 post-exposure. To improve medical response times, we incorporated G0-Premature Chromosome Condensation (G0-PCC) technique with Rapid Automated Biodosimetry Tool-II (RABiT-II), creating a faster alternative large-scale emergencies. Our findings revealed that using lower concentration...
Abstract The Mechanism of Action (MoA) a drug is generally represented as small, non-tissue-specific repertoire high-affinity binding targets. Yet, activity and polypharmacology are increasingly associated with broad range off-target tissue-specific effector proteins. To address this challenge, we have leveraged microfluidics-based Plate-Seq technology to survey perturbational profiles representing >700 FDA-approved experimental oncology drugs, in cell lines selected high-fidelity models...