Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

UV and (V)UV irradiation of sitagliptin in ultrapure water and WWTP effluent: Kinetics, transformation products and degradation pathway.

Sitagliptin (SITA) is an antidiabetic drug consumed worldwide in high quantities. Because of the low removal rate of this compound in conventional wastewater treatment plants (WWTPs), it enters receiving surface waters with the discharged WWTP effluents. SITA can be detected up to µg/L concentration in rivers. In this study, UV (254 nm) and (V)UV (185 nm + 254 nm) irradiation was applied in laboratory scale to degrade SITA. The effect of three parameters was evaluated on the degradation rate, namely i) the efficiency in UV and (V)UV irradiation, ii) the presence or absence of dissolved oxygen, iii) the matrix effect of WWTP effluent. Degradation rate of SITA was largely increased by (V)UV irradiation, and decreased in WWTP effluent as expected. The presence of dissolved oxygen increased the degradation rate only in UV experiments and did not have a considerable effect in (V)UV experiments. In total, 14 transformation products (TPs) were identified (twelve new); their structures were proposed based on high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy analyses. The most characteristic reaction steps of the degradation of SITA involved nucleophilic aromatic photosubstitution whereas hydroxide ions acted as attacking nucleophiles and replaced F atoms of the phenyl moiety by hydroxide groups, in agreement with the increase in photolysis rate with increasing pH. The photochemical degradation pathway of SITA was also interpreted. Kinetic profiles revealed TP 421, TP 208 and TP 192 to be the most recalcitrant TPs.

Application of (V)UV/O3 technology for post-treatment of biologically treated wastewater: A pilot-scale study.

For the first time, high energy VUV photons and generation of O3 by (V)UV lamps were applied together for removal of active pharmaceutical ingredients (APIs) from biologically treated wastewater (BTWW) in pilot-scale. The core of the pilot container unit was a photoreactor assembly consisting of six photoreactors, each containing a low-pressure Hg lamp (UV dose of 1.2 J/cm2 and 6.6 J/cm2 at 185 nm and 254 nm, respectively). BTWW was irradiated (4.75 min residence time) by (V)UV light in presence of in situ photochemically generated O3 from coolant air of the lamps. Experiments were conducted at the site of two wastewater treatment plants. Out of seven target APIs (namely carbamazepine, ciprofloxacin, clarithromycin, diclofenac, metoprolol, sitagliptin, and sulfamethoxazole), 80-100% removal was accomplished for five and 40-80% for two compounds. Two degradation products of carbamazepine were detected. Degradation products of other target compounds were not found. The applied O3 dose was 30-45 µg O3/mg dissolved organic carbon. Inactivation of up to log-4.8, log-4.5 and log-3.8 could be achieved for total coliform, Escherichia coli and Enterococcus faecalis, respectively. SOS Chromotest indicated no genotoxicity nor acute toxicity. Generation of neither NH4+, NO2- nor NO3- was observed during post-treatment. Electric energy per order values were calculated for the first time for (V)UV/O3 treatment in BTWW with a median value of 1.5 kWh/m3. This technology can be proposed for post-treatment of BTWWs of small settlements or livestock farms to degrade micropollutants before water discharge or for production of irrigation water. Further studies are essential in pilot-scale for other applications.