Undefined
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB60233 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10967143.fastq.gz | Fastqsanger.gz | |||
| ERR10967144.fastq.gz | Fastqsanger.gz | |||
| ERR10967145.fastq.gz | Fastqsanger.gz | |||
| ERR10967146.fastq.gz | Fastqsanger.gz | |||
| ERR10967147.fastq.gz | Fastqsanger.gz |
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Project description:Cytokines, such as interleukin-2, initiate signaling by dimerizing their receptors into orientations and proximities that induce intracellular signaling. We wished to explore a new pharmacological strategy for cytokine discovery based on variation of receptor dimer geometries using surrogate ligands, since natural cytokines are structurally limited as engineering scaffolds. Here, we report a structurally agonistic approach based on a modular, ‘plug and play’ class of ligands, that is amenable to high-throughout screening. We isolated nanobodies (Nb) and scFvs against human IL-2Rβ and γc, and generated a 40-member combinatorial matrix of tandem single-chain bispecific (IL-2Rβ:γc) molecules. We identified 28 surrogate IL-2 ligands exhibiting a wide range of agonist strengths and biased signaling properties, including cell-type bias for NK expansion and cytotoxity relative to T cells. Crystal structures of select Nb:receptor complexes validated that alternative receptor dimer geometries underly the functional diversification. This “cytokine med-chem” approach is generalizable to many dimeric cell surface receptor systems.
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Project description:We previously showed that pre-exposure of the cornea to TLR5 ligand flagellin induces profound mucosal innate protection against pathogenic microbes by reprogramming gene expression. To date, there was no genome-wide cDNA array to detect full scale of flagellin mediated reprogramming of gene expression in mucosal surface epithelial cells. Taking advantage of readily accessible, easily procurable epithelial cell population, this study is the first report to use genome-wide cDNA microarray approach to document genes associated with flagellin-induced protection against Pseudomonas aeruginosa infection in corneal epithelial cells (CECs). Total RNA obtained from isolated mouse corneal epithelial cells of the control (cells scrapped off from the corneas without infection), Pseudomonas aeruginosa infected (6 h post infection) and flagellin pretreated (24 h), followed by Pseudomonas aeruginosa infection (6 h).
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Project description:We previously showed that pre-exposure of the cornea to TLR5 ligand flagellin induces profound mucosal innate protection against pathogenic microbes by reprogramming gene expression. To date, there was no genome-wide cDNA array to detect full scale of flagellin mediated reprogramming of gene expression in mucosal surface epithelial cells. Taking advantage of readily accessible, easily procurable epithelial cell population, this study is the first report to use genome-wide cDNA microarray approach to document genes associated with flagellin-induced protection against Pseudomonas aeruginosa infection in corneal epithelial cells (CECs).
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Project description:Cognitive impairment in old age is associated with impaired toll-like receptor 2 and 4 signaling cascade in brain but higher TLR2 and TLR4 ligands in blood
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Project description:Class I cytokine receptors such as Thrombopoietin receptor (MPL) are dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Thrombopoietin (TPO) and its receptor (TpoR), to dimerize TpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism. Here we describe a single-cell transcriptome analysis of 659 human Hematopoietic Stem Cells cultured with different DA. We find several difference between differentiation and activation of signaling pathways compared to TPO.
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Project description:Plants initiate specific defense responses by recognizing conserved epitope peptides within the flagellin proteins derived from pathogenic bacteria. For perception of epitope by the plant receptor, proteolytic cleavage of epitope peptides from flagellin by plant apoplastic proteases is thought to be crucial. However, the identity of the plant proteases involved in this process remains unknown. Here, we established a one-step identification system for the target proteases in Arabidopsis apoplastic fluid by native two-dimensional electrophoresis followed by an in-gel proteolysis assay using a fluorescence-quenching peptide substrate. We designed a substrate to specifically detect proteolytic activity at the C-terminus of flg22 epitope in flagellin and identified two plant subtilases, SBT5.2, and SBT1.7, as specific proteases responsible for the C-terminal excision of flg22. In the apoplastic fluid of Arabidopsis mutant plants deficient in these two proteases, we observed a decrease in C-terminal excision activity of flg22 domain from flagellin, leading to increase in C-terminally longer flg22 epitope fragments. Consequently, defensive ROS production was delayed in sbt5.2 sbt1.7 double mutant leaf disks compared to WT upon flagellin treatment.
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Project description:Novel therapeutic approaches for addressing pneumonia caused by Streptococcus pneumoniae, which exhibit resistance to standard-of-care antibiotics are greatly needed. One viable approach involves precisely stimulating innate immune defenses within the lungs. Using murine models of pneumococcal pneumonia, prior studies demonstrated that intranasal administration of the Toll-like receptor 5 agonist, flagellin, results in a 100-fold decrease in lung infection compared to sole antibiotic therapy, when used as an adjunct treatment to the antibiotic. To promote the transfer of this immunotherapy to clinics and mitigate unwanted systemic inflammation, this project assessed whether the direct delivery of flagellin to the airways through nebulization stimulates respiratory defenses against bacterial infection. Similarly to intranasal administration, nebulized flagellin induced a transient activation of lung innate immunity. In contrast, inhalation by nebulization resulted in an attenuated activation of systemic immune responses. We conclude that flagellin aerosol therapy represents a secure and promising approach in addressing bacterial pneumonia within the context of antimicrobial resistance.
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