Several SNPs mapping to the TLR and NFkappaB signalling systems demonstrated association with anti-TNF response as a whole and, in particular, with response to etanercept. Validation of these findings in an independent cohort is now warranted.

We anesthetized, paralyzed, and ventilated 32 dogs. In 16 dogs we measured total pulmonary resistance (RL) during inhalation of acetylcholine (ACh), serotonin (5-HT), and histamine (Hist) aerosols. Cooling both cervical vagi reduced the bronchoconstriction caused by 5-HT 64% (P = 0.001), reduced Hist-induced bronchoconstriction 17% (P = 0.003), and did not significantly reduce bronchoconstriction due to ACh. In seven dogs, we ventilated both lungs separately through a double-lumen catheter. Application of 5-HT to one lung increased the transpulmonary pressure amplitude in the homolateral but not in the contralateral lung. Cooling the homolateral vagus reduced this response 32% (P = 0.02). In nine dogs, we stimulated the peripheral ends of both cut cervical vagi before and during aerosol application of ACh, 5-HT, and Hist. ACh and Hist increased baseline RL 97 and 134%, respectively, without increasing the effect of vagal stimulation. 5-HT increased baseline RL only 27% but greatly augmented the effect of vagal stimulation (mean increase, 271%, P = 0.001). We conclude that 5-HT acts to potentiate vagal effects on airway smooth muscle via the efferent vagal pathway.

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11Expression of the macrophage immunometabolism regulator gene (MACIR) is associated 12 with severity of autoimmune disease pathology and the regulation of macrophage biology 13 through unknown mechanisms. The 206 amino acid protein lacks homology to any 14 characterized protein sequence and is a disordered protein according to structure prediction 15algorithms. Here we identify specific interactions of MACIR using a fragment 16complementation-based affinity pull down of cellular proteins prepared with a membrane 17 solubilization buffer. Quantitative mass spectrometry showed enrichment of nuclear and 18 mitochondrial proteins and of 63 significant interacting proteins, binding to the nuclear 19 transport receptor TNPO1 and trafficking proteins UNC119 homolog A and B were validated 20 by immunoprecipitation. Analysis of mutations in two candidate recognition motifs in the 21 MACIR amino acid sequence confirmed TNPO1 binds via a PY-NLS motif (aa98-117). 22Characterizing nuclear MACIR activity in macrophage and fibroblasts is a priority with 23 respect to developing strategies for treatment of autoimmune disease. 24