A5001819434- Bacillus and Francisella bacterial research
- Microbial Inactivation Methods
- Bacterial Genetics and Biotechnology
- Toxin Mechanisms and Immunotoxins
- Cancer Research and Treatments
- Poxvirus research and outbreaks
- Bacteriophages and microbial interactions
- Transgenic Plants and Applications
- Virus-based gene therapy research
- Thyroid Cancer Diagnosis and Treatment
- Neurological Disease Mechanisms and Treatments
- Bacterial biofilms and quorum sensing
- Vibrio bacteria research studies
- RNA modifications and cancer
- Trace Elements in Health
- Viral Infections and Outbreaks Research
- Cancer-related Molecular Pathways
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
- MicroRNA in disease regulation
- Endoplasmic Reticulum Stress and Disease
- Intracerebral and Subarachnoid Hemorrhage Research
- Fungal and yeast genetics research
- Cell death mechanisms and regulation
- Cancer-related molecular mechanisms research
University of Pittsburgh Medical Center
2020-2025
University of Pittsburgh
2017-2025
Guangzhou University of Chinese Medicine
2022-2025
Zhengzhou University
2024-2025
Guizhou University
2007-2025
Shanghai University of Traditional Chinese Medicine
2024
China-US (Henan) Hormel Cancer Institute
2024
Northwest University
2022-2024
China Medical University
2024
First Hospital of China Medical University
2024
The protective antigen (PA) of the anthrax toxin binds to a cell surface receptor and thereby allows lethal factor (LF) be taken up exert its toxic effect in cytoplasm. Here, we report that clustering (ATR) with heptameric PA or an antibody sandwich causes association specialized cholesterol glycosphingolipid-rich microdomains plasma membrane (lipid rafts). We find although endocytosis ATR is slow, it into rafts either via heptamerization using necessary sufficient trigger efficient...
NOD-like receptor (NLR) proteins (Nlrps) are cytosolic sensors responsible for detection of pathogen and danger-associated molecular patterns through unknown mechanisms. Their activation in response to a wide range intracellular danger signals leads formation the inflammasome, caspase-1 activation, rapid programmed cell death (pyroptosis) maturation IL-1β IL-18. Anthrax lethal toxin (LT) induces caspase-1-dependent pyroptosis mouse rat macrophages isolated from certain inbred rodent strains...
Commercial drug information systems follow a variety of naming conventions. A smooth electronic exchange the in these - not only between organizations but even within single organization is crucial assuring patient safety. This requires standardized nomenclature. To meet this need, National Library Medicine (NLM) created RxNorm, nomenclature for clinical drugs that one suite standards designated use US federal government health information.
Anthrax toxin, a major virulence factor of Bacillus anthracis, gains entry into target cells by binding to either 2 von Willebrand A domain-containing proteins, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). The wide tissue expression TEM8 CMG2 suggest that both receptors could play role in anthrax pathogenesis. To explore the roles normal physiology, as well pathogenesis, we generated TEM8- CMG2-null mice TEM8/CMG2 double-null deleting transmembrane domains....
Physiologic turnover of interstitial collagen is mediated by a sequential pathway in which fragmented pericellular collagenases, endocytosed receptors, and routed to lysosomes for degradation cathepsins. Here, we use intravital microscopy investigate if malignant tumors, are characterized high rates extracellular matrix turnover, utilize similar pathway. Tumors epithelial, mesenchymal, or neural crest origin all display vigorous endocytic degradation. The cells engaged this process...
Bacillus anthracis infects hosts as a spore, germinates, and disseminates in its vegetative form. Production of anthrax lethal edema toxins following bacterial outgrowth results host death. Macrophages inbred mouse strains are either sensitive or resistant to toxin depending on whether they express the responsive non-responsive alleles inflammasome sensor Nlrp1b (Nlrp1bS/S Nlrp1bR/R, respectively). In this study, was shown affect susceptibility infection. Inbred congenic mice harboring...
Anthrax lethal factor (LF) is the protease component of anthrax toxin (LT). LT induces pyroptosis in macrophages certain inbred mouse and rat strains, while from other strains are resistant to toxin. In rats, sensitivity toxin-induced cell death determined by presence an LF cleavage sequence inflammasome sensor Nlrp1. cleaves Nlrp1 toxin-sensitive macrophages, activating caspase-1 inducing death. Toxin-resistant however, express proteins which do not harbor site. We report here that Nlrp1b...
Urokinase plasminogen activator receptor (uPAR) binds pro-urokinase (pro-uPA) and thereby localizes it near plasminogen, causing the generation of active uPA plasmin on cell surface. uPAR are overexpressed in a variety human tumors tumor lines, expression is highly correlated to invasion metastasis. To exploit these characteristics design cell-selective cytotoxins, we constructed mutated anthrax toxin-protective antigen (PrAg) proteins which furin cleavage site replaced by sequences cleaved...
Diphthamide, a posttranslational modification of translation elongation factor 2 that is conserved in all eukaryotes and archaebacteria the target diphtheria toxin, formed yeast by actions five proteins, Dph1 to -5, still unidentified amidating enzyme.Dph2 Dph5 were previously identified.Here, we report identification remaining three proteins ( Dph1, -3, and-4) show Dph have either functional -2, and-5) or sequence (Dph4) homologs mammals.We propose unified nomenclature for these (e.g.,...
The interaction of anthrax toxin protective antigen (PA) and target cells was assessed, the importance cytosolic domain tumor endothelium marker 8 (TEM8) in its function as a cellular receptor for PA evaluated. binding proteolytic processing on Chinese hamster ovary cell surface occurred rapidly, with both processes nearly reaching steady state 5 min. Remarkably, resulting PA63 fragment present only an oligomer, furthermore, oligomer species internalized, suggesting that oligomerization...
Anthrax lethal toxin (LT) is a bipartite protease-containing and key virulence determinant of Bacillus anthracis. In mice, LT causes the rapid lysis macrophages isolated from certain inbred strains, but correlation between murine macrophage sensitivity mouse strain susceptibility to challenge poor. rats, induces death in as little 37 minutes through unknown mechanisms. We used recombinant (RI) rat panel 19 strains generated LT-sensitive LT-resistant progenitors map rats locus on chromosome...
To study the role of diphthamide modification on eukaryotic elongation factor 2 (eEF2), we generated an eEF2 Gly(717)Arg mutant mouse, in which first step biosynthesis is prevented. Interestingly, Gly(717)-to-Arg mutation partially compensates functional loss resulting from deficiency, possibly because added +1 charge for diphthamide. Therefore, contrast to mouse embryonic fibroblasts (MEFs) OVCA1(-/-) mice, eEF2(G717R/G717R) MEFs retain full activity polypeptide and have normal growth...
At present, it remains difficult to deconvolute serum in order identify the cell or tissue origin of a given circulating protein. Here, by exploiting properties proximity biotinylation, we describe mouse model that enables elucidation vivo tissue-specific secretome. As an example, demonstrate how can readily endothelial-specific secretion as well this allows for characterization muscle-derived proteins either increase decrease with exercise. This genetic platform should, therefore, be wide...
Aging is a primary risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). SIRT2, an NAD+(nicotinamide adenine dinucleotide)-dependent deacetylase, accumulates in the aging brain. Here, we report that, amyloid precursor protein (APP)/PS1 transgenic mouse model of AD, genetic deletion SIRT2 or pharmacological inhibition ameliorates cognitive impairment. We find that suppression enhances acetylation APP, which promotes non-amyloidogenic processing APP at cell surface,...
The acquisition of cell-surface urokinase plasminogen activator activity is a hallmark malignancy. We generated an engineered anthrax toxin that activated by in vivo and displays limited toxicity to normal tissue but broad potent tumoricidal activity. Native protective antigen, when administered with chimeric lethal factor, Pseudomonas exotoxin fusion protein, was extremely toxic mice, causing rapid fatal organ damage. Replacing the furin activation sequence antigen artificial peptide...
Anthrax lethal toxin (LT), a virulence factor secreted by Bacillus anthracis, is selectively toxic to human melanomas with the BRAF V600E activating mutation because of its proteolytic activities toward mitogen-activated protein kinase kinases (MEKs). To develop LT variants lower in vivo toxicity and high tumor specificity, therefore greater potential for clinical use, we generated mutated that requires activation matrix metalloproteinases (MMPs). This engineered was less than wild-type mice...
Diphthamide is a highly modified histidine residue in eukaryal translation elongation factor 2 (eEF2) that the target for irreversible ADP ribosylation by diphtheria toxin (DT). In Saccharomyces cerevisiae, initial steps of diphthamide biosynthesis are well characterized and require DPH1-DPH5 genes. However, last pathway step-amidation intermediate diphthine to diphthamide-is ill-defined. Here we mine genetic interaction landscapes identify candidate gene elusive amidase (YLR143w/DPH6)...