Bjergwillumsen4424

OBJECTIVE Ankylosing spondylitis (AS) is a common spondyloarthropathy primarily affecting the axial skeleton and strongly associated with HLA-B*27 carriage. Genetic evidence implicates both autoinflammatory processes and autoimmunity against a HLA-B*27-restricted autoantigen in immunopathology. Additional to articular symptoms, up to 70% of AS patients present with concurrent bowel inflammation, suggesting that adverse interactions between a genetically-primed host immune system and the gut microbiome contributes to disease. Accordingly, this study aimed to characterise adaptive immune responses to antigenic stimuli in AS. METHODS We profiled the peripheral CD4 and CD8 T-cell receptor (TCR) repertoire of AS patients (n=47) and HLA-B*27 matched controls (n=38). We estimated repertoire diversity and employed univariate and multivariate statistical techniques to characterise AS-associated clonal signatures. We further investigated T-cell proliferation and cytokine production in response to immunogenic antigen exposure in vitro using AS patient (n=19) and control (n=14) peripheral blood mononuclear cells. RESULTS AS patients showed increased TCR diversity (CD4 P=7.8x10-6 , CD8 P=9.3x10-4 ), attributed to a significant reduction in the magnitude of peripheral T-cell expansions globally, and fewer patient T-cells expressed IFNγ (CD8 P=0.03) and TNFα (CD4 P=0.01, CD8 P=0.002) upon in vitro stimulation. Additionally, the CD8 TCR signature was altered, with significantly expanded EBV (P=0.03) and CMV-specific (P=0.02) clonotypes and increased incidence of public CD8 TCRs in HLA-B*27+ AS relative to controls, including homologous clonotypes matching those previously isolated from individuals with bacterial-induced reactive arthritis (ReA). CONCLUSIONS The dynamics of peripheral T-cell responses in AS patients are altered, suggesting that differential antigen exposure and disrupted adaptive immunity are underlying features of disease pathology. This article is protected by copyright. All rights reserved.Photoimmunotherapy can not only effectively ablate the primary tumor but also trigger strong antitumor immune responses against metastatic tumors by inducing immunogenic cell death. Herein, Cu2 MoS4 (CMS)/Au heterostructures are constructed by depositing plasmonic Au nanoparticles onto CMS nanosheets, which exhibit enhanced absorption in near-infrared (NIR) region due to the newly formed mid-gap state across the Fermi level based on the hybridization between Au 5d orbitals and S 3p orbitals, thus resulting in more excellent photothermal therapy and photodynamic therapy (PDT) effect than single CMS upon NIR laser irradiation. The CMS and CMS/Au can also serve as catalase to effectively relieve tumor hypoxia, which can enhance the therapeutic effect of O2 -dependent PDT. Notably, the NIR laser-irradiated CMS/Au can elicit strong immune responses via promoting dendritic cells maturation, cytokine secretion, and activating antitumor effector T-cell responses for both primary and metastatic tumors eradication. Moreover, CMS/Au exhibits outstanding photoacoustic and computed tomography imaging performance owing to its excellent photothermal conversion and X-ray attenuation ability. Overall, the work provides an imaging-guided and phototherapy-induced immunotherapy based on constructing CMS/Au heterostructures for effectively tumor ablation and cancer metastasis inhibition. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.A series of chlorine-substituted benzotriazole derivatives, representing all possible substitution patterns of halogen atoms attached to the benzotriazole benzene ring, were synthetized as potential inhibitors of human protein kinase CK2. Basic ADME parameters for the free solutes (hydrophobicity, electronic properties) together with their binding affinity to the catalytic subunit of protein kinase CK2 were determined with reverse-phase HPLC, spectrophotometric titration, and Thermal Shift Assay Method, respectively. The analysis of position-dependent thermodynamic contribution of a chlorine atom attached to the benzotriazole ring confirmed the previous observation for brominated benzotriazoles, in which substitution at positions 5 and 6 with bromine was found crucial for ligand binding. In all tested halogenated benzotriazoles the replacement of Br with Cl decreases the hydrophobicity, while the electronic properties remain virtually unaffected. Supramolecular architecture identified in the just resolved crystal structures of three of the four possible dichloro-benzotriazoles shows how substitution distant from the triazole ring affects the pattern of intermolecular interactions. Summarizing, the benzotriazole benzene ring substitution pattern has been identified as the main driver of ligand binding, predominating the non-specific hydrophobic effect. © 2020 International Union of Biochemistry and Molecular Biology.Annelated purinedione derivatives have been shown to act as possible multiple target ligands, addressing adenosine receptors and monoaminooxidases. Within this study, based on our previous results, novel annelated pyrimido- and diazepino[2,1-f]purinedione derivatives were designed as dual-target-directed ligands combining A 2A adenosine receptor (AR) antagonistic activity with blockade of monoamine oxidase B. A library of 20 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. This allowed for identification of 9-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (13e; K i human A 2A AR 264 nM and IC 50 human MAO-B 243 nM) as most potent dual acting ligand from this series. ADMET parameters were estimated in vitro and analysis of structure-activity relationships was complemented by molecular docking studies based on previously published X-ray structures of the protein targets. Such dual acting ligands, by selectively blocking A 2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO-B might provide symptomatic and neuroprotective effects in e.g. Parkinson disease treatment. © 2020 WILEY-VCH Verlag GmbH & Co. Semaglutide cell line KGaA, Weinheim.