A5089810766- Computational Drug Discovery Methods
- Gene Regulatory Network Analysis
- NF-κB Signaling Pathways
- Protein Kinase Regulation and GTPase Signaling
- Monoclonal and Polyclonal Antibodies Research
- Immune Response and Inflammation
- Cytokine Signaling Pathways and Interactions
- Microfluidic and Capillary Electrophoresis Applications
- Astronomical Observations and Instrumentation
- Cell death mechanisms and regulation
- interferon and immune responses
- Cell Image Analysis Techniques
- Microfluidic and Bio-sensing Technologies
- Wnt/β-catenin signaling in development and cancer
- Click Chemistry and Applications
- Advanced Database Systems and Queries
- Hippo pathway signaling and YAP/TAZ
- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
- T-cell and B-cell Immunology
- 3D Printing in Biomedical Research
- Data Mining Algorithms and Applications
- PI3K/AKT/mTOR signaling in cancer
- COVID-19 Clinical Research Studies
- Plant biochemistry and biosynthesis
Novartis (United States)
2024
Herzberg Institute of Astrophysics
2022
Harvard University
2010-2021
Dana-Farber Cancer Institute
2010-2021
Boston VA Research Institute
2019
Center for Systems Biology
2006-2014
Massachusetts General Hospital
2014
Broad Institute
2014
Washington University in St. Louis
2014
Harvard University Press
2012
Signal transduction pathways control cellular responses to stimuli, but it is unclear how molecular information processed as a network. We constructed systems model of 7980 intracellular signaling events that directly links measurements 1440 response outputs associated with apoptosis. The accurately predicted multiple time-dependent apoptotic induced by combination the death-inducing cytokine tumor necrosis factor prosurvival factors epidermal growth and insulin. By capturing role...
We report the selective and real-time detection of label-free DNA using an electronic readout. Microfabricated silicon field-effect sensors were used to directly monitor increase in surface charge when hybridizes on sensor surface. The electrostatic immobilization probe a positively charged poly- l -lysine layer allows hybridization at low ionic strength where sensing is most sensitive. Nanomolar concentrations can be detected within minutes, single base mismatch 12-mer oligonucleotides...
hDlg, the human homologue of Drosophila D iscs- l ar g e (Dlg) tumor suppressor protein, is known to interact with protein APC and papillomavirus E6 transforming protein. In a two-hybrid screen, we identified 322-aa serine/threonine kinase that binds PDZ2 domain hDlg. The mRNA for this PDZ-binding kinase, or PBK, most abundant in placenta absent from adult brain tissue. sequence PBK has all characteristic subdomains C-terminal T/SXV motif. vitro , specifically hDlg through its are...
Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, inhibition which likely to be necessary effective KRAS-directed therapy. Here, we show that IκB (IKK)-related kinases Tank-binding kinase-1 (TBK1) IKKε promote by regulating autocrine CCL5 interleukin (IL)-6 identify CYT387 as a potent JAK/TBK1/IKKε inhibitor....
Significance Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for treatment various cancers. All approved kinase inhibitors eventually rendered useless by emergence drug-resistant tumors. We used structure-based drug design to develop first, our knowledge, selective, next-generation covalent FGFR that can overcome most common form inhibitor resistance, mutation so-called “gatekeeper” residue located in ATP-binding pocket. also describe a novel strategy uses...
Cell-signaling networks consist of proteins with a variety functions (receptors, adaptor proteins, GTPases, kinases, proteases, and transcription factors) working together to control cell fate. Although much is known about the identities biochemical activities these signaling ways in which they are combined into process transduce signals poorly understood. Network-level understanding requires data on wide processes such as posttranslational modification, assembly macromolecular complexes,...
We report a microfabricated field flow fractionation device for continuous separation of subcellular organelles by isoelectric focusing. The microdevice provides fast in very small samples while avoiding large voltages and heating effects typically associated with conventional electrophoresis-based devices. basis the is presence membrane proteins that give rise to effective points organelles. Simulations focusing mitochondria microchannels are used assess design parameters, such as...
BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions the possibility that more exist, we performed complementary systematic screens in search of new protein-interacting partners. New and/or better understanding existing ones were sought. Among interacting proteins identified, genetic interactions detected between four interactors: TONSL, SETX, TCEANC, TCEA2. Genetic also certain interactors including both members FACT complex. From these...
Stochastic fluctuations in gene expression give rise to cell-to-cell variability protein levels which can potentially cause cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) manifests itself as dramatic differences the time between ligand exposure and sudden activation of effector caspases that kill cells. However, contribution individual proteins phenotypic has not been explored detail. In this paper we use feature-based sensitivity analysis a means estimate impact...
We present WALLABY pilot data release 1, the first public of HI survey from Wide-field ASKAP L-band Legacy All-sky Blind Survey (WALLABY) on Australian Square Kilometre Array Pathfinder. Phase 1 targeted three $60~{\rm deg}^2$ regions sky in direction Hydra and Norma galaxy clusters NGC 4636 group, covering redshift range z < 0.08. The source catalogue, images spectra nearly 600 extragalactic detections kinematic models for 109 spatially resolved galaxies are available. As containing nearby...
Biological signaling networks process extracellular cues to control important cell decisions such as death–survival, growth–quiescence, and proliferation–differentiation. After receptor activation, intracellular proteins change in abundance, modification state, enzymatic activity. Many of the have been identified, but it is not known how molecules work together decisions. To begin address this issue, we report use partial least squares regression an analytical method glean signal–response...
We describe a microfluidic device with rapid stimulus and lysis of mammalian cells for resolving fast transient responses in cell signaling networks. The uses segmented gas−liquid flow to enhance mixing has integrated thermoelectric heaters coolers control the temperature during lysis. Potential negative effects on are investigated three different types, no morphological changes activation stress-sensitive mitogen activated protein kinases observed. Jurkat E6-1 stimulated using α-CD3,...
Article22 November 2011Open Access Source Data Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis Bree B Aldridge Department of Systems Biology, Center for Cell Decision Processes, Harvard Medical School, MA, USA Biological Engineering, Massachusetts Institute Technology, Cambridge, Present address: Immunology Infectious Diseases, School Public Health, Boston, MA 02115, Search more papers by this author Suzanne Gaudet Cancer Biology Dana-Farber...
Abstract In tissues and tumours, cell behaviours are regulated by multiple time-varying signals. While in the laboratory cells often exposed to a stimulus for duration of experiment, vivo exposures may be much shorter. this study, we monitored NF-κB caspase signalling human cancer treated with short pulse Tumour Necrosis Factor (TNF). TNF is an inflammatory cytokine that can induce both pro-survival NF-κB-driven gene transcription pathway pro-apoptotic pathway. We find few seconds exposure...
Noisy gene expression generates diverse phenotypes, but little is known about mechanisms that modulate noise. Combining experiments and modeling, we studied how tumor necrosis factor (TNF) initiates noisy of latent HIV via the transcription nuclear κB (NF-κB) genomic integration site modulates noise to generate divergent (low-versus-high) phenotypes viral activation. We show TNF-induced transcriptional varies more than mean transcript number amplification this explains low-versus-high For a...
hDlg is the human homolog of the<i>Drosophila</i> Discs-large tumor suppressor. As a member MAGUK (membrane-associatedguanylate kinase) family scaffolding proteins, composed three PDZ (PSD-95, Dlg, and ZO-1) repeats, an SH3 (Src homology 3) motif, GUK (guanylate kinase-like) domain. Additionally, contains two regions alternative splicing. Here we identify novel insertion, I1B, located N-terminal to repeats. We further analyze tissue-specific combinations insertions correlate those results...
Mathematical modeling is being applied to increasingly complex biological systems and datasets; however, the process of analyzing calibrating against experimental data often challenging a rate limiting step in model development. To address this problem, we developed systematic methodology for quantitative models dynamic processes illustrate its utility by validating TRAIL (Tumor necrosis factor Related Apoptosis-Inducing Ligand)-induced cell death.We propose serial framework integrating...