Nanomechanics of individual aerographite tetrapods

R.A., O.L. and K.S. would like to thank the German Research Foundation (DFG) for the financial support under schemes AD 183/17-1 and SFB 986-TP-B1, respectively, and the Graphene FET Flagship. R.M. and D.E. would like to thank for financial support from Latvian Council of Science, no. 549/2012. N.M.P. is supported by the European Research Council (ERC PoC 2015 SILKENE no. 693670) and by the European Commission H2020 under the Graphene Flagship (WP14 ‘Polymer Composites’, no. 696656) and under the FET Proactive (‘Neurofibres’ no. 732344). S.S. acknowledges support from SILKENE

The immunoproteasome in antigen processing and other immunological functions

Treatment of cells with interferon-g leads to the replacement of the constitutive catalytic proteasome subunits b1, b2, and b5 by the inducible subunits LMP2 (b1i), MECL-1 (b2i), and LMP7 (b5i), respectively, building the so-called immunoproteasome. The incorporation of these subunits is required for the production of numerous MHC class-I restricted T cell epitopes. Recently, new evidence for an involvement of the immunoproteasome in other facets of the immune response emerged. Investigations of autoimmune diseases in animal models and a genetic predisposition of b5i in human autoimmune disorders suggest a crucial function of the immunoproteasome in proinflammatory diseases. The recent elucidation of the high-resolution structure of the immunoproteasome will facilitate the design of immunoproteasome selective inhibitors for pharmacological intervention

Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells

Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) analogs in their potency to influence LPS-stimulated production of interleukin-1 beta (IL-1 beta) and TNF-alpha by human mononuclear cells (MNC). Our results show, that the stable analogs of PGI2, iloprost and cicaprost, markedly suppress TNF-alpha synthesis in LPS-stimulated MNC without effect on IL-1 beta production. Although there was no significant difference in maximal suppression of TNF-alpha, iloprost and cicaprost reached suppression to 50% of control at 20-fold lower concentrations than PGE2. The ID50 for iloprost and cicaprost were 8 nM and 5 nM, respectively, compared to 125 nM for PGE2. Moreover, the prostacyclin analogs as well as PGE2 suppressed LPS-induced production of TNF-alpha in Mono Mac 6 cells, a permanent human cell line with characteristics of mature monocytes. Suppression of TNF-alpha synthesis by cicaprost and PGE2 is probably mediated by an increased intracellular cAMP formation. We were able to show elevated cAMP levels with 1 microM and 10 microM of PGE2 and cicaprost in this system. The suppression of TNF-alpha synthesis may add to the beneficial effects of iloprost reported in animal models of acute respiratory distress syndrome (ARDS) and may offer a therapeutic approach in TNF-alpha mediated pathologic processes

Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a chronic demyelinating immune mediated disease of the central nervous system. The immunoproteasome is a distinct class of proteasomes found predominantly in monocytes and lymphocytes. Recently, we demonstrated a novel function of immunoproteasomes in cytokine production and T cell differentiation. In this study, we investigated the therapeutic efficacy of an inhibitor of the immunoproteasome (ONX 0914) in two different mouse models of MS. ONX 0914 attenuated disease progression after active and passive induction of experimental autoimmune encephalomyelitis (EAE), both in MOG35–55 and PLP139–151-induced EAE. Isolation of lymphocytes from the brain or spinal cord revealed a strong reduction of cytokine-producing CD4+ cells in ONX 0914 treated mice. Additionally, ONX 0914 treatment prevented disease exacerbation in a relapsing-remitting model. An analysis of draining lymph nodes after induction of EAE revealed that the differentiation to Th17 or Th1 cells was strongly impaired in ONX 0914 treated mice. These results implicate the immunoproteasome in the development of EAE and suggest that immunoproteasome inhibitors are promising drugs for the treatment of MS

Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity

Constitutive proteasomes and immunoproteasomes shape the peptide repertoire presented by major histocompatibility complex class I (MHC-I) molecules by harboring different sets of catalytically active subunits. Here, we present the crystal structures of constitutive proteasomes and immunoproteasomes from mouse in the presence and absence of the epoxyketone inhibitor PR-957 (ONX 0914) at 2.9 Å resolution. Based on our X-ray data, we propose a unique catalytic feature for the immunoproteasome subunit Beta5i/LMP7. Comparison of ligand-free and ligand-bound proteasomes reveals conformational changes in the S1 pocket of Beta5c/X but not Beta5i, thereby explaining the selectivity of PR-957 for Beta5i. Time-resolved structures of yeast proteasome: PR-957 complexes indicate that ligand docking to the active site occurs only via the reactive head group and the P1 side chain. Together, our results support structure-guided design of inhibitory lead structures selective for immunoproteasomes that are linked to cytokine production and diseases like cancer and autoimmune disorders

Hybridization of Zinc Oxide Tetrapods for Selective Gas Sensing Applications

In this work, the exceptionally improved sensing capability of highly porous three-dimensional (3-D) hybrid ceramic networks toward reducing gases is demonstrated for the first time. The 3-D hybrid ceramic networks are based on doped metal oxides (MexOy and ZnxMe1–xOy, Me = Fe, Cu, Al) and alloyed zinc oxide tetrapods (ZnO-T) forming numerous junctions and heterojunctions. A change in morphology of the samples and formation of different complex microstructures is achieved by mixing the metallic (Fe, Cu, Al) microparticles with ZnO-T grown by the flame transport synthesis (FTS) in different weight ratios (ZnO-T:Me, e.g., 20:1) followed by subsequent thermal annealing in air. The gas sensing studies reveal the possibility to control and change/tune the selectivity of the materials, depending on the elemental content ratio and the type of added metal oxide in the 3-D ZnO-T hybrid networks. While pristine ZnO-T networks showed a good response to H2 gas, a change/tune in selectivity to ethanol vapor with a decrease in optimal operating temperature was observed in the networks hybridized with Fe-oxide and Cu-oxide. In the case of hybridization with ZnAl2O4, an improvement of H2 gas response (to ∼7.5) was reached at lower doping concentrations (20:1), whereas the increase in concentration of ZnAl2O4 (ZnO-T:Al, 10:1), the selectivity changes to methane CH4 gas (response is about 28). Selectivity tuning to different gases is attributed to the catalytic properties of the metal oxides after hybridization, while the gas sensitivity improvement is mainly associated with additional modulation of the electrical resistance by the built-in potential barriers between n-n and n-p heterojunctions, during adsorption and desorption of gaseous species. Density functional theory based calculations provided the mechanistic insights into the interactions between different hybrid networks and gas molecules to support the experimentally observed results. The studied networked materials and sensor structures performances would provide particular advantages in the field of fundamental research, applied physics studies, and industrial and ecological applications