1,224 research outputs found

    Metalloproteinase-dependent TLR2 ectodomain shedding is involved in soluble toll-like receptor 2 (sTLR2) production

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    Toll-like receptor (TLR) 2, a type I membrane receptor that plays a key role in innate immunity, recognizes conserved molecules in pathogens, and triggering an inflammatory response. It has been associated with inflammatory and autoimmune diseases. Soluble TLR2 (sTLR2) variants have been identified in human body fluids, and the TLR2 ectodomain can negatively regulate TLR2 activation by behaving as a decoy receptor. sTLR2 generation does not involve alternative splicing mechanisms, indicating that this process might involve a post-translational modification of the full-length receptor; however, the specific mechanism has not been studied. Using CD14+ peripheral human monocytes and the THP-1 monocytic leukemia-derived cell line, we confirm that sTLR2 generation increases upon treatment with pro-inflammatory agents and requires a post-translational mechanism. We also find that the constitutive and ligand-induced release of sTLR2 is sensitive to pharmacological metalloproteinase activator and inhibitors leading us to conclude that metalloproteinase TLR2 shedding contributes to soluble receptor production. By expressing human TLR2 in ADAM10- or ADAM17-deficient MEF cells, we find both enzymes to be implicated in TLR2 ectodomain shedding. Moreover, using a deletion mutant of the TLR2 juxtamembrane region, we demonstrate that this domain is required for sTLR2 generation. Functional analysis suggests that sTLR2 generated by metalloproteinase activation inhibitsTLR2-induced cytokine production by this monocytic leukemia-derived cell line. The identification of the mechanisms involved in regulating the availability of soluble TLR2 ectodomain and cell surface receptors may contribute further research on TLR2-mediated processes in innate immunity and inflammatory disorders

    Accuracy in Copy Number Calling by qPCR and PRT: A Matter of DNA

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    The possible implication of copy number variation (CNV) in the genetic susceptibility to human disease needs to be assessed using robust methods that can be applied at a population scale. In this report, we analyze the performance of the two major techniques, quantitative PCR (qPCR) and paralog ratio test (PRT), and investigate the influence of input DNA amount and template integrity on the reliability of both methods. Analysis of three genes (PRELID1, SYNPO and DEFB4) in a large sample set showed that both methods are prone to false copy number assignments if sufficient attention is not paid to DNA concentration and quality. Accurate normalization of samples is essential for reproducible qPCR because it avoids the effect of differential amplification efficiencies between target and control assays, whereas PRT is generally more sensitive to template degradation due to the fact that longer amplicons are usually needed to optimize sensitivity and specificity of paralog sequence PCR. The use of normalized, high quality genomic DNA yields comparable results with both methods

    Oral direct anticoagulants in the treatment of nonvalvular atrial fibrillation. Results of the daily clinical practice.

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    Atrial fibrillation (AF) is the most common arrhythmia. It leads to significant morbidity and mortality. The new oral anticoagulants (NOAC) represent an improvement compared with standard treatment (vitamin K antagonists (AVK)) in the prevention of thromboembolic complications in patients with non-valvular AF.N

    The Influence of Molecular Adsorption on Elongating Gold Nanowires

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    Using molecular dynamics simulations, we study the impact of physisorbing adsorbates on the structural and mechanical evolution of gold nanowires (AuNWs) undergoing elongation. We used various adsorbate models in our simulations, with each model giving rise to a different surface coverage and mobility of the adsorbed phase. We find that the local structure and mobility of the adsorbed phase remains relatively uniform across all segments of an elongating AuNW, except for the thinning region of the wire where the high mobility of Au atoms disrupts the monolayer structure, giving rise to higher solvent mobility. We analyzed the AuNW trajectories by measuring the ductile elongation of the wires and detecting the presence of characteristic structural motifs that appeared during elongation. Our findings indicate that adsorbates facilitate the formation of high-energy structural motifs and lead to significantly higher ductile elongations. In particular, our simulations result in a large number of monatomic chains and helical structures possessing mechanical stability in excess of what we observe in vacuum. Conversely, we find that a molecular species that interacts weakly (i.e., does not adsorb) with AuNWs worsens the mechanical stability of monatomic chains.Comment: To appear in Journal of Physical Chemistry

    Eleven-month longitudinal study of antibodies in SARS-CoV-2 exposed and na√Įve primary health care workers upon COVID-19 vaccination

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    We evaluated the kinetics of antibody responses to Two years into the COVID-19 pandemic and 1 year after the start of vaccination rollout, the world faced a peak of cases associated with the highly contagious Omicron variant of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) and nucleocapsid (N) antigens over five cross-sectional visits (January-November 2021), and the determinants of pre-booster immunoglobulin levels, in a prospective cohort of vaccinated primary health care workers in Catalonia, Spain. Antibodies against S antigens after a full primary vaccination course, mostly with BNT162b2, decreased steadily over time and were higher in pre-exposed (n = 247) than naive (n = 200) individuals, but seropositivity was maintained at 100% (100% IgG, 95.5% IgA, 30.6% IgM) up to 319 days after the first dose. Antibody binding to variants of concern was highly maintained for IgG compared to wild type but significantly reduced for IgA and IgM, particularly for Beta and Gamma. Factors significantly associated with longer-term antibodies included age, sex, occupation, smoking, adverse reaction to vaccination, levels of pre-vaccination SARS-CoV-2 antibodies, interval between disease onset and vaccination, hospitalization, oxygen supply, post COVID and symptomatology. Earlier morning vaccination hours were associated with higher IgG responses in pre-exposed participants. Symptomatic breakthroughs occurred in 9/447 (2.01%) individuals, all among naive (9/200, 4.5%) and generally boosted antibody responses. Additionally, an increase in IgA and/or IgM seropositivity to variants, and N seroconversion at later time points (6.54%), indicated asymptomatic breakthrough infections, even among pre-exposed. Seropositivity remained highly stable over almost a year after vaccination. However, gradually waning of anti-S IgGs that correlate with neutralizing activity, coupled to evidence of an increase in breakthrough infections during the Delta and Omicron predominance, provides a rationale for booster immunization

    Ion-exchanged geopolymer for photocatalytic degradation of a volatile organic compound

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    In thepresentworkitisshownhowgeopolymerscanbeusedtocontrolindoorandoutdoorair pollution byphotolysisof2-ButanoneasaVolatileOrganicCompound(VOC).Anionexchange procedurewasfollowedtoincorporateTiO2 into ageopolymer(IEG),anddifferent2-Butanone concentrations wereusedinabatchreactorunderdryandhumidconditions.Variationon 2-Butanone concentrationwasfollowedbygaschromatography.ALangmuir Hinshelwood modelwas used todeterminethedisappearancerateofreactantattheinitialstageofthereaction.Gasca-Tirado, J.; Manzano-Ramirez, A.; Vazquez-Landaverde, PA.; Herrera-Diaz, EI.; Rodriguez-Ugarte, ME.; Rubio-Avalos, JC.; Amigó Borrás, V.... (2014). Ion-exchanged geopolymer for photocatalytic degradation of a volatile organic compound. Materials Letters. 134:222-224. doi:10.1016/j.matlet.2014.07.090S22222413

    BCR-ABL1-induced expression of HSPA8 promotes cell survival in chronic myeloid leukaemia

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    In order to determine new signal transduction pathways implicated in chronic myeloid leukaemia (CML), we performed a gene expression profile comparison between CD34+ cells from CML patients and healthy donors. Functional studies were performed using the Mo7e and Mo7e-p210 cell lines. Expression of CCND1 (Cyclin D1), as well as the chaperone HSPA8, which is important for regulation of CCND1, were significantly upregulated in CD34+ CML cells. Upregulation of HSPA8 was dependent, at least in part, on STAT5 (signal transducer and activator of transcrition 5)-dependent transcriptional activation, as demonstrated by chromatin immunoprecipitation. The presence of HSPA8 in the nuclear protein fraction as well as its binding to CCND1 suggests that it may contribute to stabilization of the CCND1/CDK4 complex, which, in turn, may participate in proliferation of CML cells. Treatment of CML cells with the specific HSPA8 inhibitor 15-deoxyspergualin induced inhibition of CML cell viability but did not induce apoptosis. In conclusion, our studies suggest that STAT5-mediated activation of HSPA8 induces nuclear translocation and activation of the CCND1/CDK4 complex leading to increased proliferation of CML cells, deciphering a new pathway implicated in CML and supporting a potential role of chaperone inhibitors in the treatment of CML

    Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

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    Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range ‚ą£ő∑‚ą£<0.8|\eta| < 0.8 are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286
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