Inflammation plays a critical role in 2,8-dihydroxyadenine nephropathy

International audienceAdenine phosphoribosyltransferase (APRT) deficiency is a genetic disease characterized by an increased production of 2,8 dihydroxyadenine (2,8-DHA) precipitating in urine, leading to a crystalline nephropathy and end-stage renal disease. Here, we describe the high prevalence of granuloma (88%) in biopsies from patients with APRT deficiency. A murine model of 2,8-DHA nephropathy was generated, showing that anakinra or dexamethasone, combined with allopurinol, improved renal function to a larger extent than allopurinol alone, the standard therapy. Inflammation plays a critical role in the development of 2,8-DHA nephropathy, and therapy based upon drugs targeting innate immunity could improve renal function recovery

Inflammation plays a critical role in 2,8-dihydroxyadenine nephropathy

Adenine phosphoribosyltransferase (APRT) deficiency is a genetic disease characterized by an increased production of 2,8 dihydroxyadenine (2,8-DHA) precipitating in urine, leading to a crystalline nephropathy and end-stage renal disease. Here, we describe the high prevalence of granuloma (88%) in biopsies from patients with APRT deficiency. A murine model of 2,8-DHA nephropathy was generated, showing that anakinra or dexamethasone, combined with allopurinol, improved renal function to a larger extent than allopurinol alone, the standard therapy. Inflammation plays a critical role in the development of 2,8-DHA nephropathy, and therapy based upon drugs targeting innate immunity could improve renal function recovery

Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages

Objective Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response. Methods Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using 18F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition. Results We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo. Conclusion In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation

Characteristics of Copper-based Oxygen Carriers Supported on Calcium Aluminates for Chemical-Looping Combustion with Oxygen Uncoupling (CLOU)

Eight different oxygen carriers (OC) containing CuO (60 wt %) and different mass ratios of CaO to Al2O3 as the support were synthesized by wet-mixing followed by calcination at 1000 °C. The method of synthesis used involved the formation of calcium aluminum hydrate phases and ensured homogeneous mixing of the Ca2+ and Al3+ ions in the support at the molecular level. The performance of the OCs for up to 100 cycles of reduction and oxidation was evaluated in both a thermogravimetric analyzer (TGA) and a fluidized bed reactor, covering a temperature range of 800 to 950 °C. In these cycling experiments, complete conversion of the OC, from CuO to Cu and vice versa, was always achieved for all OCs. The reactivity of the materials was so high that no deactivation could be observed in the TGA, owing to mass transfer limitations. It was found that OCs prepared with a mass ratio of CaO to Al2O3 in the support >0.55 agglomerated in the fluidized bed, resulting in an apparent deactivation over 25 cycles for all temperatures investigated. High ratios of mass of CaO to Al2O3 in the support resulted in CuO interacting with CaO, forming mixed oxides that have low melting temperatures, and this explains the tendency of these materials to agglomerate. This behavior was not observed when the mass ratio of CaO to Al2O3 in the support was ≤0.55 and such materials showed excellent cyclic stability operating under redox conditions at temperatures as high as 950 °C.The authors thank Mohammad Ismail and Matthew Dunstan for helping with the XRD analysis and Alex Casabuena-Rodriguez and for helping with the SEM. This work was supported by the Engineering and Physical Sciences Research Council (EPSRC grant EP/I010912/1).This is the final version of the article. It first appeared from ACS via http://dx.doi.org/10.1021/acs.iecr.5b0117

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements