A5017895472- Melanoma and MAPK Pathways
- Synthesis of Tetrazole Derivatives
- Beetle Biology and Toxicology Studies
- Computational Drug Discovery Methods
- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Protein Degradation and Inhibitors
- Gene Regulatory Network Analysis
- Tuberculosis Research and Epidemiology
- Quinazolinone synthesis and applications
- Advanced Biosensing Techniques and Applications
- Cytokine Signaling Pathways and Interactions
- Advanced Fluorescence Microscopy Techniques
- Receptor Mechanisms and Signaling
- Mycobacterium research and diagnosis
- Bioinformatics and Genomic Networks
- Cancer Genomics and Diagnostics
- Cancer, Hypoxia, and Metabolism
- Histone Deacetylase Inhibitors Research
- Microbial Metabolic Engineering and Bioproduction
- Mitochondrial Function and Pathology
- Mathematical Biology Tumor Growth
- Nanoplatforms for cancer theranostics
- Metabolomics and Mass Spectrometry Studies
- Cutaneous Melanoma Detection and Management
University of Virginia
2020-2024
University of Michigan
2009-2020
Michigan United
2020
Scripps Research Institute
2006-2019
Harvard University
2012-2017
Center for Systems Biology
2012-2017
Stem Cell Technology Research Center
2006-2007
University of Tehran
2006-2007
University of Miami
2004
To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, endothelial cells. Malignant within same tumor displayed transcriptional heterogeneity associated with cell cycle, spatial context, a drug-resistance program. In particular, all tumors harbored malignant two states, such that characterized by high levels MITF transcription factor also...
Abstract Single-cell analysis reveals aspects of cellular physiology not evident from population-based studies, particularly in the case highly multiplexed methods such as mass cytometry (CyTOF) able to correlate levels multiple signalling, differentiation and cell fate markers. Immunofluorescence (IF) microscopy adds information on morphology microenvironment that are obtained using flow-based techniques, but multiplicity conventional IF is limited. This has motivated development imaging...
Abstract Treatment of BRAF ‐mutant melanomas with MAP kinase pathway inhibitors is paradigmatic the promise precision cancer therapy but also highlights problems drug resistance that limit patient benefit. We use live‐cell imaging, single‐cell analysis, and molecular profiling to show exposure tumor cells RAF / MEK elicits a heterogeneous response in which some die, arrest, remainder adapt drug. Drug‐adapted up‐regulate markers neural crest (e.g., NGFR ), melanocyte precursor, grow slowly....
Cyclic Immunofluorescence (CycIF) is a public-domain method for performing highly multiplexed immunofluorescence imaging using conventional epifluorescence microscope. It uses simple reagents and existing antibodies to construct images with up 30 channels by sequential 4- 6-channel followed fluorophore inactivation. Three variant methods are described, the most generally useful of which involves staining fixed cells directly conjugated Alexa Fluor dyes in four colors, inactivating...
Multiple immune factors control host responses to Mycobacterium tuberculosis infection, including the formation of granulomas, which are aggregates cells whose function may reflect success or failure contain infection. One such factor is TNF-α. TNF-α has been experimentally characterized have following activities in M. infection: macrophage activation, apoptosis, and chemokine cytokine production. Availability within a granuloma proposed play critical role immunity tuberculosis. However,...
Abstract Drugs that inhibit RAF / MEK signaling, such as vemurafenib, elicit profound but often temporary anti‐tumor responses in patients with BRAF V 600E melanoma. Adaptive to inhibition occur on a timescale of hours days, involve homeostatic reactivate MAP kinase signaling and compensatory mitogenic pathways, attenuate the effects inhibitors. We profile adaptive across panel melanoma cell lines using multiplex biochemical measurement, single‐cell assays, statistical modeling show...
In maturing T lineage cells, the helix–loop–helix protein E47 has been shown to enforce a critical proliferation and developmental checkpoint commonly referred as β selection. To examine how regulates cellular expansion progression, we have used an E2A-deficient lymphoma cell line DNA microarray analysis identify immediate target genes. Hierarchical cluster of gene expression patterns revealed that coordinately genes involved in survival, cycle lipid metabolism, stress response, lymphoid...
The NF-κB signaling pathway is central to the body's response many pathogens. Mathematical models based on cell culture experiments have identified important molecular mechanisms controlling dynamics of signaling, but this never been studied in context an infection a host. Here, we incorporate these into virtual setting. We build multi-scale model immune pathogen Mycobacterium tuberculosis (Mtb) explore impact occurring across molecular, cellular, and tissue scales lung. triggered via tumor...
Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher are observed anti-TNF Abs (e.g., infliximab) as compared TNF receptor fusion protein (etanercept). Mechanisms driving differential differences drug action not known. We use a computational model TB granuloma formation that includes TNF/TNF dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, binding membrane-bound...
During aging, there is a progressive loss of volume and function in skeletal muscle that impacts mobility quality life. The repair regulated by tissue-resident stem cells called satellite (or [MuSCs]), but MuSCs decrease numbers regenerative capacity. transcriptional networks epigenetic changes confer diminished as result natural aging are only partially understood. Herein, we use an integrative genomics approach to profile from young aged animals before after injury. Integration these...
Cellular plasticity associated with fluctuations in transcriptional programs allows individual cells a tumor to adopt heterogeneous differentiation states and switch phenotype during their adaptive responses therapies. Despite increasing knowledge of such programs, the molecular basis cellular remains poorly understood. Here, we combine multiplexed protein measurements at population single-cell levels multivariate statistical modeling show that state AP-1 transcription factor network plays...
G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors; they activate heterotrimeric G-proteins in response to ligand stimulation. Although many GPCRs have been shown form homo- and/or heterodimers on membrane, purpose this dimerization is not known. Recent research has that receptor may a role organization surface. In addition, microdomains membrane termed lipid rafts play GPCR localization. Using combination stochastic (Monte Carlo) and deterministic modeling,...
In the present study, based on a biomimetic approach, novel 3D nanofibrous hybrid scaffolds consisting of poly(ε-caprolactone), polyvinyl alcohol), and chitosan were developed via multi-jet electrospinning method. The influence chemical, physical, structural properties differentiation mesenchymal stem cells into osteoblasts, proliferation differentiated investigated. Osteogenically induced cultures revealed that well-attached, penetrated construct uniformly distributed. expression early late...
Tuberculosis (TB) granulomas are organized collections of immune cells comprised macrophages, lymphocytes and other that form in the lung as a result response to Mycobacterium tuberculosis (Mtb) infection. Formation maintenance essential for control Mtb infection regulated part by pro-inflammatory cytokine, tumor necrosis factor-α (TNF). To characterize mechanisms TNF availability within TB granuloma, we developed multi-scale two compartment partial differential equation model describes...
Abstract Postnatal T lymphocyte differentiation in the thymus is a multistage process involving serial waves of lineage specification, proliferative expansion, and survival/cell death decisions. Although these are believed to originate from signals derived various thymic stromal cells, ultimate consequence induce transcriptional changes that definitive each step. To help characterize this process, high density microarrays were used analyze transcription factor gene expression RNA progenitors...
An intensive study is underway to evaluate different potential candidates for cell therapy of neurodegenerative disorders such as Parkinson's disease (PD). Availability and lower immunogenicity compared other sources stem bone marrow have made human umbilical cord blood cells a considerable source therapy. The present aimed investigate differentiation recently introduced pluripotent cells, known unrestricted somatic (USSCs), into with neural features in serum-withdrawal medium. Using reverse...
Bipolar disorder is a highly heritable neuropsychiatric affecting nearly 2.5% of the population. Prior genetic studies identified panel common and rare single-nucleotide polymorphisms associated with disease that map to first intron PDE10A gene. RNA sequencing striatal brain tissue from bipolar healthy control subjects novel transcript PDE10A, named PDE10A19, codes for isoform unique N terminus. Genomic sequences can encode terminus were conserved in other primates but not rodents. The was...
Hyperactivation of the MAPK signaling pathway motivates clinical use inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results cell-to-cell variability dependency, diminishing efficacy inhibitors. To identify key regulators such variability, we screen 276 epigenetic-modifying compounds, individually or combined with inhibitors, across genetically diverse and isogenic populations melanoma cells. Following single-cell analysis...
Cell-to-cell variability generates subpopulations of drug-tolerant cells that diminish the efficacy cancer drugs. Efficacious combination therapies are thus needed to block via minimizing impact heterogeneity. Probabilistic models such as Bliss independence have been developed evaluate drug interactions and their based on probabilities specific actions mediated by drugs individually in combination. In practice, however, these often applied conventional dose-response curves which a normalized...
Abstract Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS tumor growth. NF1LoF cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly blocking growth vitro vivo. Single-cell analysis indicated that drug-induced cytotoxicity...