A5101665641- Cell Adhesion Molecules Research
- Protease and Inhibitor Mechanisms
- Peptidase Inhibition and Analysis
- Platelet Disorders and Treatments
- Cancer, Lipids, and Metabolism
- Cancer, Hypoxia, and Metabolism
- Drug Transport and Resistance Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Peroxisome Proliferator-Activated Receptors
- Metabolomics and Mass Spectrometry Studies
- Biochemical and Structural Characterization
- Advanced Proteomics Techniques and Applications
- Surgical site infection prevention
- Immune Response and Inflammation
- S100 Proteins and Annexins
- Mosquito-borne diseases and control
- Blood Coagulation and Thrombosis Mechanisms
- Bacterial Identification and Susceptibility Testing
- Glycosylation and Glycoproteins Research
- Diet and metabolism studies
- Antibiotics Pharmacokinetics and Efficacy
- Antimicrobial Resistance in Staphylococcus
- Insect symbiosis and bacterial influences
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Machine Learning in Bioinformatics
Scripps Research Institute
1993-2025
Clatterbridge Cancer Centre NHS Foundation Trust
2021-2024
University of Oxford
2023
Sanford Burnham Prebys Medical Discovery Institute
2012-2022
Discovery Institute
2000-2022
University of Arizona
2011-2022
National Bureau of Economic Research
2016-2022
Scripps Memorial Hospital
2022
Thermo Fisher Scientific (United States)
2020-2022
University of Wisconsin–Madison
2022
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of neurodegenerative diseases and stroke. However, mechanism MMP activation remains unclear. We report that involves S-nitrosylation. During cerebral ischemia vivo, MMP-9 colocalized with neuronal nitric oxide synthase. S-Nitrosylation activated vitro induced apoptosis. Mass spectrometry identified active derivative MMP-9, both as a stable sulfinic or sulfonic acid, whose formation was triggered by These findings suggest...
Abstract One of the fundamental principles pharmacology is that most drugs have side effects. Although considerable attention paid to detrimental effects, can also beneficial Given time and expense drug development, it would be particularly exciting if a systematic method could applied reveal all activities, including unappreciated actions, potential drug. The present study takes first step along this path. An activity-based proteomics strategy was used simultaneously identify targets screen...
Metastasis is the primary cause of death in human breast cancer. to bone, lungs, liver, and brain involves dissemination cancer cells via bloodstream requires adhesion within vasculature. Blood cell vasculature depends on integrins, a family transmembrane receptors, regulated by integrin activation. Here we show that αvβ3 supports attachment under blood flow conditions an activation-dependent manner. Integrin was found two distinct functional states cells. The activated, but not...
To identify the risk factors for development of postoperative septic complications in patients with intestinal perforation after abdominal trauma, and to compare efficacies single-drug dual-drug prophylactic antibiotic therapy, we studied 145 who presented trauma at two hospitals between July 1979 June 1982. Logistic-regression analysis showed that a higher infection (P<0.05) was associated increased age, injury left colon necessitating colostomy, larger number units blood or products...
p32/gC1qR/C1QBP/HABP1 is a mitochondrial/cell surface protein overexpressed in certain cancer cells. Here we show that knocking down p32 expression human cells strongly shifts their metabolism from oxidative phosphorylation (OXPHOS) to glycolysis. The knockdown exhibited reduced synthesis of the mitochondrial-DNA-encoded OXPHOS polypeptides and were less tumorigenic vivo. Expression exogenous restored wild-type cellular phenotype tumorigenicity. Increased glucose consumption lactate...
Metabolic rewiring is an established hallmark of cancer, but the details this at a systems level are not well characterized. Here we acquire insight in melanoma cell line panel by tracking metabolic flux using isotopically labeled nutrients. profiling and balance analysis were used to compare normal melanocytes lines both normoxic hypoxic conditions. All cells exhibited Warburg phenomenon; they more glucose produced lactate than melanocytes. Other changes observed that described phenomenon....
The emergence and prevalence of antibiotic-resistant bacteria are an increasing cause death worldwide, resulting in a global 'call to action' avoid receding into era lacking effective antibiotics. Despite the urgency, healthcare industry still relies on single vitro bioassay determine antibiotic efficacy. This assay fails incorporate environmental factors normally present during host-pathogen interactions vivo that significantly impact Here we report standard antimicrobial susceptibility...
The vitronectin receptor (alpha v beta 3) is a member of the integrin superfamily adhesive protein receptors that mediate wide spectrum cellular interactions, including attachment to vitronectin, von Willebrand factor, fibrinogen, and thrombospondin. We have studied binding fibronectin purified receptor, role this in cells fibronectin. A solid-phase microtiter assay was developed investigate properties receptor. Purified alpha 3 bound with high affinity saturable, divalent cation-dependent...
Background —The platelet glycoprotein (GP) IIb/IIIa receptor is important in mediating thrombus formation, and the GP antagonist abciximab (c7E3 Fab; ReoPro) effective preventing thrombotic ischemic cardiovascular complications of unstable angina percutaneous coronary interventions. Small-molecule antagonists based on Arg-Gly-Asp (RGD) sequence show similar benefit, some these agents are orally active. However, there may be significant interindividual variation response to such antagonists,...
Osteopontin (OPN) is an extracellular matrix protein that binds to integrin αvβ3. Here we demonstrate two other integrins, αvβ1 and αvβ5, are also receptors for OPN. Human embryonic kidney 293 cells adhere human recombinant osteopontin (glutathione S-transferase-osteopontin; GST-OPN) using αvβ1. When the transfected with β5 subunit, they can GST-OPN αvβ5. Divalent cations regulate binding of both Mg2+ Mn2+ support these integrins but Ca2+ does not. The highest affinity observed in Mn2+. In...
We have purified a novel member of the integrin gene family from placenta that serves as vitronectin receptor. This is composed alpha v subunit and beta we designate 5. Purification was accomplished by immunodepleting placental extract 3, allowing us to purify 5 remaining monoclonal antibody affinity chromatography on LM 142-Sepharose, which binds subunit. homogeneity subsequently achieved wheat germ lectin-Sepharose. Western blot analysis with antibodies raised against 3 demonstrated were...
Abstract We have employed photoaffinity cross-linking to examine RGD recognition by the human placental vitronectin receptor. The peptide GRGDSPK was coupled a thiol-cleavable radioiodinatable aryl azide (sulfosuccinimidyl 2-(p-azido-salicylamido)-1,3'-dithiopropionate. When 125I-sulfosuccinimidyl 2-(p-azido-salicylamido)-1,3'-dithiopropionate-GRGDSPK cross-linked receptor in solution, 80% of label associated with beta subunit. Cross-linking both subunits highly specific and dependent upon...
Fibronectin (Fn) binding to the integrins aIIbP3 and w p 3 involves Arg-Gly-Asp sequence.The identification of other regions Fn that interact with aIIbp3 suggests a potential mechanism for differential ligand recognition by integrins.W e report here an 11-residue peptide sequence from 9th type I11 repeat (3Fn9), which inhibits interacting directly this receptor.Mutational analysis demonstrated same region was involved in formation epitopes two anti-Fn mAbs inhibit aIIbp3, thus emphasizing...
Integrins alpha IIb beta 3 and V mediate numerous cell-matrix cell-cell contacts. Both integrins contain multiple divalent cation-binding motifs that regulate ligand binding. Here, we elucidate a major difference in the regulation of by ions. Fibrinogen binding to Ca(2+)-containing buffer is rapid, with an apparent association rate constant (k1app) 8.2 x 10(5) M-1 s-1, but Ca2+ does not support between fibrinogen 3. Interestingly, Mn2+ supports both integrins, albeit relatively slow (k1app =...
The vitronectin receptor mediates cell adhesion to the extracellular matrix proteins vitronectin, fibrinogen, von Willebrand factor, and thrombospondin in an RGD-dependent manner. We previously demonstrated direct interaction between RGD-containing peptide by photoaffinity labeling with 125I-sulfosuccinimidyl-2-(p-azido-salicylamido)-1,3'-dithioprop ion ate (SASD)-GRGDSPK (Smith, J. W., Cheresh, D. A. (1988) Biol. Chem. 263, 18726-18731). In that report, we identified amino acid residues...
The tricarboxylic acid (TCA) cycle is the central hub of oxidative metabolism, running in classic forward direction to provide carbon for biosynthesis and reducing agents generation ATP. Our metabolic tracer studies melanoma cells showed that hypoxic conditions TCA largely disconnected from glycolysis. By studying branch point metabolites, acetyl CoA citrate, as well endpoint glutamine fatty acids, we developed a comprehensive picture rewiring occurs hypoxia. Hypoxic tumor maintain...
With its unique structure of two compartments, Janus particles can be used for many applications which monomorphic are inadequate, including to as a drug delivery system deliver multiple payloads with widely different solubility. Here we report on fluidic nanoprecipitation (FNPS), capable fabricating biocompatible polymeric nanoparticles comprised the FDA-approved polymer poly(lactic-co-glycolic acid) (PLGA). The FNPS contains dual inlets, one each half particle, that insert into...