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31.
Fischer H Lutay N Ragnarsdóttir B Yadav M Jönsson K Urbano A Al Hadad A Rämisch S Storm P Dobrindt U Salvador E Karpman D Jodal U Svanborg C 《PLoS pathogens》2010,6(9):e1001109
The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3(-/-) mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3(-/-) mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response. 相似文献
32.
Wober J Möller F Richter T Unger C Weigt C Jandausch A Zierau O Rettenberger R Kaszkin-Bettag M Vollmer G 《The Journal of steroid biochemistry and molecular biology》2007,107(3-5):191-201
The special extract ERr 731® from the roots of Rheum rhaponticum is the major constituent of Phytoestrol® N which is used for the treatment of climacteric symptoms in menopausal women. However, the molecular mode of action of ERr 731® was unknown. For the first time, ERr 731® and its aglycones trans-rhapontigenin and desoxyrhapontigenin were investigated with regard to the activation of the estrogen receptor- or estrogen receptor-β (ER, ERβ). The related hydroxystilbenes cis-rhapontigenin, resveratrol and piceatannol were studied as comparators. As controls, 17β-estradiol or the selective ER-(propylpyrazoltriol) or ERβ-agonists (diarylpropionitril) were used. Neither in ER-expressing yeast cells, in the ER-responsive Ishikawa cells, nor in human endometrial HEC-1B cells transiently transfected with the ER an activation of ER by ERr 731® or the other single compounds was detected. Furthermore, an antiestrogenic effect was not observed. In contrast in human endometrial HEC-1B cells transiently transfected with the ERβ, 100 ng/ml ERr 731® and the single compounds significantly induced the ERβ-coupled luciferase activity in a range comparable to 10−8 M 17β-estradiol. All effects were abolished with the pure ER antagonist ICI 182780, indicating an ER-specific effect. The ERβ agonistic activity by ERr 731® could be of importance for its clinical use, as central functions relevant to climacteric complaints are proposed to be mediated via ERβ activation. 相似文献
33.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin-1 gene FBN1. Mutation detection of this 65-exon gene presents a particular challenge for the diagnostic service in cost, time constraints, and the need to maintain a stringently optimized assay procedure. Using denaturing high-performance liquid chromatography (dHPLC), we have designed a procedure for rapid mutation scanning, redesigning 50% of published primer sets, screening by Ensembl to avoid inclusion of polymorphic variations and employing a limited set of PCR conditions to allow for a high-throughput 96-well format. We have screened 262 unrelated patients with MFS or Marfan-like phenotypes and detected 103 (39.3%) mutations including 93 different mutations, 72 of which are novel. The mutations include 55 missense (53.4%) 19 splice site (18.5%), 17 frameshift (16.5%), 11 nonsense (10.7%) and 1 in-frame deletion/insertion. 相似文献
34.
Boots AM Hubers H Kouwijzer M den Hoed-van Zandbrink L Westrek-Esselink BM van Doorn C Stenger R Bos ES van Lierop MJ Verheijden GF Timmers CM van Staveren CJ 《Arthritis research & therapy》2007,9(4):R71
We sought to identify an altered peptide ligand (APL) based on the endogenously expressed synovial auto-epitope of human cartilage glycoprotein-39 (HC gp-39) for modulation of cognate, HLA-DR4-restricted T cells. For this purpose we employed a panel of well-characterized T cell hybridomas generated from HC gp-39-immunized HLA-DR4 transgenic mice. The hybridomas all respond to the HC gp-39(263-275) epitope when bound to HLA-DR4(B1*0401) but differ in their fine specificities. First, the major histocompatibility complex (MHC) and T-cell receptor (TCR) contact residues were identified by analysis of single site substituted analogue peptides for HLA-DR4 binding and cognate T cell recognition using both T hybridomas and polyclonal T cells from peptide-immunized HLA-DR4 transgenic mice. Analysis of single site substituted APL by cognate T cells led to identification of Phe265 as the dominant MHC anchor. The amino acids Ala268, Ser269, Glu271 and Thr272 constituted the major TCR contact residues, as substitution at these positions did not affect HLA-DR4(B1*0401) binding but abrogated T cell responses. A structural model for visualisation of TCR recognition was derived. Second, a set of non-classical APLs, modified at the MHC key anchor position but with unaltered TCR contacts, was developed. When these APLs were analysed, a partial TCR agonist was identified and found to modulate the HC gp-39(263-275)-specific, pro-inflammatory response in HLA-DR4 transgenic mice. We identified a non-classical APL by modification of the p1 MHC anchor in a synovial auto-epitope. This APL may qualify for rheumatoid arthritis immunotherapy. 相似文献
35.
Zhang Yang Catharina Steentoft Camilla Hauge Lars Hansen Allan Lind Thomsen Francesco Niola Malene B. Vester-Christensen Morten Fr?din Henrik Clausen Hans H. Wandall Eric P. Bennett 《Nucleic acids research》2015,43(9):e59
The nuclease-based gene editing tools are rapidly transforming capabilities for altering the genome of cells and organisms with great precision and in high throughput studies. A major limitation in application of precise gene editing lies in lack of sensitive and fast methods to detect and characterize the induced DNA changes. Precise gene editing induces double-stranded DNA breaks that are repaired by error-prone non-homologous end joining leading to introduction of insertions and deletions (indels) at the target site. These indels are often small and difficult and laborious to detect by traditional methods. Here we present a method for fast, sensitive and simple indel detection that accurately defines indel sizes down to ±1 bp. The method coined IDAA for Indel Detection by Amplicon Analysis is based on tri-primer amplicon labelling and DNA capillary electrophoresis detection, and IDAA is amenable for high throughput analysis. 相似文献
36.
Disentangling the effects of land‐use change,climate and CO2 on projected future European habitat types
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Diffusion through the extracellular matrix (ECM) is a critical step for the delivery of nanoparticles and genes. Gene delivery requires a carrier that protects the nucleic acid from degradation and facilitates transport. Chitosan is a promising carrier. To increase the circulation time, PEGylation of the carrier is performed. However, the effect of PEGylation on the transport and stability of gene delivery systems in the ECM has only been studied in solutions containing ECM components. We used polymerized collagen and collagen-hyaluronic acid (HA) gels to study the effects of PEGylation on the diffusion and stability of chitosan-DNA polyplexes. We found that PEGylation of the polyplexes was required for diffusion to occur, and PEGylation increased the dissociation between DNA and chitosan to some extent. The presence of HA had a contradictory role: it decreased the penetration depth of PEGylated polyplexes into the gels and increased the diffusion of the polyplexes being mixed into the gels. 相似文献
40.
Molecular characterization of acquired tolerance of tumor cells to picropodophyllin (PPP) 总被引:1,自引:0,他引:1
Hashemi J Worrall C Vasilcanu D Fryknäs M Sulaiman L Karimi M Weng WH Lui WO Rudduck C Axelson M Jernberg-Wiklund H Girnita L Larsson O Larsson C 《PloS one》2011,6(3):e14757