Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors

Altres ajuts: This work has also been supported by a "Marató TV3" grant (20141210 to J.F. and 044412 to R.B.).Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS

Holocene and Late Pleistocene Bat Fossils (Mammalia: Chiroptera) from Hamilton County, TN, and their Ecological Implications

Chiropteran mandibles from late Pleistocene/Holocene fossil cave localities in Hamilton County were identified in order to examine changes in bat species diversity and population trends over extended periods of time, providing insight into how bats in Southeast Tennessee have responded to major environmental changes over the past 10,000–20,000 years. Generic and species identifications were based on an unpublished key developed by the authors. Measurements of alveolar length (c1–m3) and total length measurements from the symphysis to the condyle were taken for all specimens identified as members of the genus Myotis in an attempt to identify species in this genus. The results of this study failed to confirm those of previous univariate morphological studies, suggesting that multivariate morphometric analyses may be needed to establish a means to differentiate among the species in this genus. Diversity data indicated two patterns of species abundance, with Eptesicus fuscus (Big Brown Bat) dominating some sites and Myotis sp. dominating others. The data suggest, but do not conclusively demonstrate, that a temporal replacement of older Eptesicus faunas by younger, Myotis-dominated faunas has occurred, connected with post-Pleistocene global warming. In addition, a correspondence between human disturbance and bat populations levels was observed. It is very likely that human disturbance has caused bat populations to become extinct in the caves under study, reinforcing the claim of previous researchers that bat population decline is a recent phenomenon that is tightly linksed to human disturbance

Supplementary Material for: Association of Serum Amyloid A with Kidney Outcomes and All-Cause Mortality in American Indians with Type 2 Diabetes

<p><b><i>Background:</i></b> Serum amyloid A (SAA) induces inflammation and apoptosis in kidney cells and is found to be causing the pathologic changes that are associated with diabetic kidney disease (DKD). Higher serum SAA concentrations were previously associated with increased risk of end-stage renal disease (ESRD) and death in persons with type 2 diabetes and advanced DKD. We explored the prognostic value of SAA in American Indians with type 2 diabetes without DKD or with early DKD. <b><i>Methods:</i></b> SAA concentration was measured in serum samples obtained at the start of follow-up. Multivariate proportional hazards models were employed to examine the magnitude of the risk of ESRD or death across tertiles of SAA concentration after adjustment for traditional risk factors. The C statistic was used to assess the additional predictive value of SAA relative to traditional risk factors. <b><i>Results:</i></b> Of 256 participants (mean ± SD glomerular filtration rate [iothalamate] = 148 ± 45 mL/min, and median [interquartile range] urine albumin/creatinine = 39 [14-221] mg/g), 76 developed ESRD and 125 died during a median follow-up period of 15.2 and 15.7 years, respectively. After multivariable proportional hazards regression, participants in the 2 highest SAA tertiles together exhibited a 53% lower risk of ESRD (hazard ratio [HR] 0.47, 95% CI 0.29-0.78), and a 30% lower risk of death (HR 0.70, 95% CI 0.48-1.02), compared with participants in the lowest SAA tertile, although the lower risk of death was not statistically significant. Addition of SAA to the ESRD model increased the C statistic from 0.814 to 0.815 (<i>p </i>= 0.005). <b><i>Conclusions:</i></b> Higher circulating SAA concentration is associated with a reduced risk of ESRD in American Indians with type 2 diabetes.</p