Abstract
Engagement of the complement receptor CD46 on T cells drives Th1 responses and upregulates nutrient and amino acid channels, such as GLUT1 and LAT1. We found that CD46 stimulation ...upregulates both the arginine transporter SLC7A1 (CAT-1) on human CD4 T cells and, unexpectedly, Arginase 1 expression in these cells, indicating that CD46 may regulate arginine metabolism in T cells. While Arginase 1 has been well characterized in macrophages where it is associated with the IL-10 secreting M2 type, its function in T cells has not been described. During contraction human Th1 cells switch from IFN-γ to IL-10 production and to a self-regulatory phenotype, thus we assessed the role of Arginase 1 in Th1 induction and/or contraction. Surprisingly, CD4 T cells isolated from four patients with rare Arginase 1 deficiency initially mount Th1 responses but display significantly increased IL-10 switching with earlier cellular collapse when compared to healthy control cells. Importantly, although T cells from patients with Arginase 1 deficiency have increased arginine levels, as expected, they produce normal levels of polyamines and NO. Metabolic profiling of the patients’ cells demonstrates that they shunt into a compensatory ‘glutamine usage pathway’ for their critical ornithine and polyamine generation. Analysis of changes in glutamine metabolites and their corresponding downstream pathways, along with in vivo influenza infections of Arg1fl/fl CD4-cre+ mice validate and further define the in vivo role of this novel T cell modulating pathway. Overall, these data demonstrate an unexpected intrinsic role for Arginase 1 and unveil an important compensatory mechanism used to maintain protective Th1 function in the absence of normal arginine catabolism.
3'-Azido-3'-deoxythymidine (AZT), AZT 5'-monophosphate, and AZT 5'-triphosphate (AZTTP) were reduced by dithiothreitol with
second-order rate constants of 2.30 x 10(-3), 1.50 x 10(-3), and 7.46 x ...10(-4) M-1 s-1, respectively. Handlon and Oppenheimer
reported that AZT is quantitatively reduced by thiols to 3'-amino-3'-deoxythymidine (Handlon, A. L., and Oppenheimer, N. J.
(1988) Pharm. Res. (N.Y.) 5, 297-299). In the present report, multiple products of this reaction were identified by the techniques
of UV spectroscopy, phosphate analysis, coelution with authentic standards from reversed-phase high pressure liquid chromatography,
two-dimensional NMR spectroscopy, and mass spectrometry. The product mixture from reduction of AZT 5'-monophosphate at pH
7.1 and 25 degrees C was composed of 2,3'-anhydro-beta-D-threo-thymidine 5'-monophosphate (6.4%), 3'-amino-3'-deoxythymidine
5'-monophosphate (19.6%), beta-D-threo-thymidine 5'-monophosphate (6.8%), thymine and 3-amino-2,3-dideoxyribal 5-monophosphate
(8.9%), beta-D-threo-thymidine 3',5'-cyclic monophosphate (9.1%), 3'-deoxy-2',3'-didehydrothymidine 5'-monophosphate (31.5%),
and 3',5'-anhydro-beta-D-threo-thymidine (17.8%). Thymine and 3',5'-anhydro-beta-D-threo-thymidine were also products of reduction
of AZT and AZTTP. Furthermore, the nucleosides of the above monophosphates were products of reduction of AZT, and the corresponding
triphosphates were products of reduction of AZTTP. The product ratios were dependent on the level of phosphorylation of AZT
and on the pH of the reaction. Mechanisms for formation of these products are proposed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common ...genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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