Immunoproteasomes largely replace constitutive proteasomes during an antiviral and antibacterial immune response in the liver

The proteasome is critically involved in the production of MHC class I-restricted T cell epitopes. Proteasome activity and epitope production are altered by IFN-gamma treatment, which leads to a gradual replacement of constitutive proteasomes by immunoproteasomes in vitro. However, a quantitative analysis of changes in the steady state subunit composition of proteasomes during an immune response against viruses or bacteria in vivo has not been reported. Here we show that the infection of mice with lymphocytic choriomeningitis virus or Listeria monocytogenes leads to an almost complete replacement of constitutive proteasomes by immunoproteasomes in the liver within 7 days. Proteasome replacements were markedly reduced in IFN-gamma(-/-) mice, but were only slightly affected in IFN-alphaR(-/-) and perforin(-/-) mice. The proteasome regulator PA28alpha/beta was up-regulated, whereas PA28gamma was reduced in the liver of lymphocytic choriomeningitis virus-infected mice. Proteasome replacements in the liver strongly altered proteasome activity and were unexpected to this extent, since an in vivo half-life of 12 days had been previously assigned to constitutive proteasomes in the liver. Our results suggest that during the peak phase of viral and bacterial elimination the antiviral cytotoxic T lymphocyte response is directed mainly to immunoproteasome-dependent T cell epitopes, which would be a novel parameter for the design of vaccines

Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells.

The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior

The evaluation of SCIAMACHY CO and CH_4 scientific data products, using ground-based FTIR measurements

In the framework of the European EVERGREEN project, three scientific algorithms, namely WFM-DOAS, IMAPDOAS and IMLM, have been developed to retrieve the total column amounts of key atmospheric trace gases including CO and CH_4 from SCIAMACHY nadir observations in its near-infrared channels. These channels offer the capability to detect trace gases in the planetary boundary layer, potentially making the associated retrieval products suited for regional source-sink studies. The retrieval products of these three algorithms, in their present status of development, have been compared to independent data from a ground-based quasi-global network of Fourier-transform infrared (FTIR) spectrometers, for the year 2003. Comparisons have been made for individual data, as well as for monthly averages. To maximize the number of coincidences that satisfy the temporal and spatial collocation criteria, the individual SCIAMACHY data points have been compared with a 3rd order polynomial interpolation of the ground-based data with time. Particular attention has been paid to the question whether the products reproduce correctly the seasonal and latitudinal variabilities of the target species. We present an overall assessment of the data quality of the currently available latest versions of the CO and CH4 total column products from the three scientific retrieval algorithms

Techno-thermodynamic multi-objective optimization of organic Ranckine cycles for waste heat recovery

Papers presented to the 11th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, South Africa, 20-23 July 2015.Organic Rankine cycles (ORC) are considered a mature technology in waste heat recovery applications. Yet, many of the commercially available implementations have comparable design characteristics. They operate under subcritical regime and only few working fluids are considered. In this work, three ORC configurations are analyzed on thermodynamic and technical grounds. The cycles under consideration are the subcritical cycle (SCORC), the transcritical cycle (TCORC) and the partial evaporation cycle (PEORC). Technical design constraints on the expander generally limit the cycles which can be considered feasible. Yet, their impact on the optimization process is not clear. Therefore, in this work, the technical performance criteria are optimized in conjunction with maximization of the net power output. Thus the investigation results in a multi-objective optimization strategy. The proposed strategy is performed on two representative but distinctive waste heat recovery cases. The results of the investigation are particularly useful for manufacturers of ORCs. The thermodynamic performance of the cycles is compared under equal boundary conditions, expander criteria are taken into account, actual cases are used and a ranking is created.am201

Thiopurine metabolite levels in patients with atopic dermatitis and/or chronic hand/foot eczema treated with azathioprine

Background: Azathioprine is frequently used in severe eczema. It is converted in the liver into active metabolites, including 6-thioguanine nucleotide (6-TGN) and methylated 6-methylmercaptopurine (6-MMP). In the past, the therapeutic potential of azathioprine may have not been fully utilized. Recent investigations on inflammatory bowel disease have led to a better understanding of azathioprine metabolism and optimizing treatment. Objective: To investigate whether measuring thiopurine metabolites in circulation can improve the effectiveness and safety of azathioprine treatment in patients with atopic dermatitis and/or chronic hand/foot eczema. Methods: Azathioprine metabolite levels were measured in eczema patients during maintenance treatment (Part I) and dose escalation (Part II). Clinical effectiveness, hepatotoxicity, and bone marrow suppression were analyzed and TPMT genotype was assessed. Results: A wide variation in metabolite levels in all dose groups was observed. In Part I (32 patients), there were no significant differences in 6-TGN levels between clinical responders and non-responders (p = .806). No hepatoxicity or myelotoxicity was observed. In Part II, all 6-TGN and 6-MMP levels increased during dose escalation. Hypermethylation was observed in 2/8 patients. Conclusion: For individual eczema patients treated with azathioprine, routinely measuring 6-TGN and 6-MMP can be helpful in optimizing azathioprine dose, improving clinical effectiveness, and preventing side effects

Multi-objective optimization of a low-temperature transcritical organic Rankine cycle for waste heat recovery

Paper presented to the 10th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Florida, 14-16 July 2014.The subcritical Organic Rankine Cycle (SCORC) is widely recognized as a viable technology for converting waste heat to electricity. However, a relative large exergy share is destroyed in the evaporator because of the subcritical heat exchange process. A transcritical cycle has the potential to reduce these irreversibilities in detriment of a financial cost. Therefore the inclusion of financial parameters is crucial for a sound comparison. First, a thermo-hydraulic sizing model for the supercritical ORC is developed. Second, from this model a thermo-economic analysis is provided based on a multi-objective optimization. The Pareto front of net power output versus investment costs are compared for the subcritical and transcritical ORC. Also a single objective criterion, the minimum specific investment cost, is calculated. The results can be used as a guideline to the design of new ORCs.dc201