A5051487266- Cytokine Signaling Pathways and Interactions
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- DNA Repair Mechanisms
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Cell Adhesion Molecules Research
- T-cell and B-cell Immunology
- Glycosylation and Glycoproteins Research
- Amino Acid Enzymes and Metabolism
- Toxin Mechanisms and Immunotoxins
- Cancer Immunotherapy and Biomarkers
- interferon and immune responses
- Clostridium difficile and Clostridium perfringens research
- Receptor Mechanisms and Signaling
- NF-κB Signaling Pathways
- IL-33, ST2, and ILC Pathways
- Protein Kinase Regulation and GTPase Signaling
- Neuroscience and Neuropharmacology Research
- Cell death mechanisms and regulation
- Viral Infectious Diseases and Gene Expression in Insects
- Virus-based gene therapy research
- Ion channel regulation and function
- HER2/EGFR in Cancer Research
Synthego (United States)
2020-2024
Ansys (United States)
2022-2024
Menlo School
2020-2024
Stanford University
2004-2022
GTx (United States)
2022
Genentech
2012-2013
Stanford Medicine
2009-2011
Stratford University
2011
Howard Hughes Medical Institute
2007-2010
University of Wisconsin–Madison
1999-2000
Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation their activity has been implicated a broad range diseases, including cancer, cardiovascular, neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids benzamides have shown promising results cancer therapy. Although it also suggested that HDACi with increased isozyme selectivity potency may broaden clinical utility minimize side...
Significance Cytokine signaling is essential for cell growth, hematopoiesis, and immune system function. Cytokine-mediated receptor dimerization induces intracellular activation of receptor-bound Janus kinases (JAKs), which then induce downstream transcriptional responses. We have determined a two-domain crystal structure containing the pseudokinase kinase domains from JAK family member TYK2, identifies an inhibitory interaction interface between two domains. Cancer-associated mutations...
Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure full-length JAK1 complexed with a cytokine domain Box1 and Box2 regions captured as an activated homodimer bearing valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains form extended structural unit, dimerization which is mediated by close-packing pseudokinase (PK)...
The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis necroptosis. Its activity has been implicated a range of inflammatory, neurodegenerative, oncogenic diseases. Here, we explore the effect inhibiting genetically, using knock-in mice that express catalytically inactive D138N, or pharmacologically, murine-potent inhibitor GNE684. Inhibition reduced collagen antibody-induced arthritis, prevented skin inflammation caused by...
The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate that activated by the coagonists glycine glutamate. NMDARs are critical to synaptic signaling plasticity, their dysfunction has been implicated in number of neurological disorders, including schizophrenia, depression, Alzheimer's disease. Herein we describe discovery potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from high-throughput screening hit. Using...
Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions embryonic development; however, the postnatal pathological roles activation mechanisms TGFβ2 TGFβ3 not been well characterized. Here, we show that latent forms can be activated by integrin-independent lower thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 TGFB3 expression increased human lung liver fibrotic tissues healthy control tissues....
Tumor-specific mutations can generate neoantigens that drive CD8 T cell responses against cancer. Next-generation sequencing and computational methods have been successfully applied to identify predict neoantigens. However, only a small fraction of predicted are immunogenic. Currently, peptide binding affinity for MHC-I is often the major criterion prioritizing neoantigens, although little progress has made toward understanding precise functional relationship between immunogenicity. We...
Using the Xenopus egg extract system, we investigated involvement of DNA replication in activation damage checkpoint. We show here that slows a checkpoint-independent manner and is accompanied by replication-dependent recruitment ATR Rad1 to chromatin. also find proteins RPA Polalpha accumulate on chromatin following damage. Finally, damage-induced Chk1 phosphorylation checkpoint arrest are abrogated when inhibited. These data indicate required for suggest unifying model diverse lesions...
Vibrio cholerae RTX (repeats in toxin) is an actin-disrupting toxin that autoprocessed by internal cysteine protease domain (CPD). The CPD efficiently activated the eukaryote-specific small molecule inositol hexakisphosphate (InsP 6 ), and we present 2.1 angstrom structure of complex with InsP . binds to a conserved basic cleft distant from active site. Biochemical kinetic analyses mutants indicate binding induces allosteric switch leads autoprocessing intracellular release toxin-effector domains.
Broadly neutralizing antibodies targeting the stalk region of influenza A virus (IAV) hemagglutinin (HA) are effective in blocking infection both vitro and vivo. The highly conserved epitopes recognized by these critical for membrane fusion function HA therefore less likely to be permissive mutational escape. Here we report three resistant viruses A/Perth/16/2009 strain that were selected presence a broadly stalk-binding antibody. harbor different mutations stalk: (1) Gln387Lys; (2)...