Activation of interferon regulatory factor-3 via toll-like receptor 3 and immunomodulatory functions detected in A549 lung epithelial cells exposed to misplaced U1-snRNA

U1-snRNA is an integral part of the U1 ribonucleoprotein pivotal for pre-mRNA splicing. Toll-like receptor (TLR) signaling has recently been associated with immunoregulatory capacities of U1-snRNA. Using lung A549 epithelial/carcinoma cells, we report for the first time on interferon regulatory factor (IRF)-3 activation initiated by endosomally delivered U1-snRNA. This was associated with expression of the IRF3-inducible genes interferon-β (IFN-β), CXCL10/IP-10 and indoleamine 2,3-dioxygenase. Mutational analysis of the U1-snRNA-activated IFN-β promoter confirmed the crucial role of the PRDIII element, previously proven pivotal for promoter activation by IRF3. Notably, expression of these parameters was suppressed by bafilomycin A1, an inhibitor of endosomal acidification, implicating endosomal TLR activation. Since resiquimod, an agonist of TLR7/8, failed to stimulate A549 cells, data suggest TLR3 to be of prime relevance for cellular activation. To assess the overall regulatory potential of U1-snRNA-activated epithelial cells on cytokine production, co-cultivation with peripheral blood mononuclear cells (PBMC) was performed. Interestingly, A549 cells activated by U1-snRNA reinforced phytohemagglutinin-induced interleukin-10 release by PBMC but suppressed that of tumor necrosis factor-α, indicating an anti-inflammatory potential of U1-snRNA. Since U1-snRNA is enriched in apoptotic bodies and epithelial cells are capable of performing efferocytosis, the present data in particular connect to immunobiological aspects of apoptosis at host/environment interfaces

A Cyber-Physical Approach to Resilience and Robustness by Design

Modern critical infrastructures (e.g. Critical Energy Infrastructures) are increasingly evolving into complex and distributed networks of Cyber-Physical Systems. Although the cyber systems provide great flexibility in the operation of critical infrastructure, it also introduces additional security threats that need to be properly addressed during the design and development phase. In this landscape, resilience and robustness by design are becoming fundamental requirements. In order to achieve that, new approaches and technological solutions have to be developed that guarantee i) the fast incident/attack detection; and ii) the adoption of proper mitigation strategies that ensure the continuity of service from the infrastructure. The "Double Virtualization" emerged recently as a potential strategy/approach to ensure the robust and resilient design and management of critical energy infrastructures based on Cyber-Physical Systems. The presented approach exploits the separation of the virtual capabilities/functionalities of a device from the physical system and/or platform used to run/execute them while allowing to dynamically (re-) configure the system in the presence of predicted and unpredicted incidents/accidents. Internet-based technologies are used for developing and deploying the envisioned approach.publishersversionpublishe

Reconstitution of CD8 T cells is essential for the prevention of multiple-organ cytomegalovirus histopathology after bone marrow transplantation

Cytomegalovirus (CMV) infection in the period of temporary immunodeficiency after haematoablative treatment and bone marrow transplantation (BMT) is associated with a risk of graft failure and multiple-organ CMV disease. The efficacy of immune system reconstitution is decisive for the prevention of CMV pathogenesis after BMT. Previous data in murine model systems have documented a redundancy in the immune effector mechanisms controlling CMV. CD8 T cells proved to be relevant but not irreplaceable as antiviral effecters. Specifically, in a state of long-term in vivo depletion of the CD8 T-cell subset, CD4 T cells were educed to become deputy effecters controlling CMV by a mechanism involving antiviral cytokines. It is of medical importance to know whether one can trust in this 'flexible defence' in all clinical settings. It ii demonstrated here that reconstitution of CD8 T cells is crucial for the prevention of fatal multiple-organ CMV disease under the specific conditions of BMT

Securing CEI by-design

740898The effects on quality of supply and controllability of the power grid of applying these measures have beenstudiedand applied in atestbed infrastructure, containing the power grid, a physical communication network, a logical communication network and the control functionality network.publishersversionpublishe

A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation

Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p =.243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p =.053). No difference was observed in the BLT (n = 48) subpopulation (p =.973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Organic Dipole Layers for Ultralow Work Function Electrodes

The alignment of the electrode Fermi level with the valence or conduction bands of organic semiconductors is a key parameter controlling the efficiency of organic light-emitting diodes, solar cells, and printed circuits. Here, we introduce a class of organic molecules that form highly robust dipole layers, capable of shifting the work function of noble metals (Au and Ag) down to 3.1 eV, that is, ∼1 eV lower than previously reported self-assembled monolayers. The physics behind the considerable interface dipole is elucidated by means of photoemission spectroscopy and density functional theory calculations, and a polymer diode exclusively based on the surface modification of a single electrode in a symmetric, two-terminal Au/poly(3-hexylthiophene)/Au junction is presented. The diode exhibits the remarkable rectification ratio of ∼2·10³, showing high reproducibility, durability (>3 years), and excellent electrical stability. With this evidence, noble metal electrodes with work function values comparable to that of standard cathode materials used in optoelectronic applications are demonstrated