Nikolajsen Cortez (juicebobcat27)

Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe-/- mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe-/-mice compared to controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe-/-mice, the enzymatic activity was higher in Hfe-/-mice. We then examined various transporters involved in UA absorption/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe-/-mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe-/-mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis. Copyright 2020 The Author(s).BACKGROUND For malaria elimination efforts it is important to better understand parasite transmission to mosquitoes and develop models for early-clinical evaluation of transmission-blocking interventions. METHODS In a randomized open-label trial, 24 participants were infected by bites from Plasmodium falciparum 3D7-infected mosquitoes (MB, n=12) or by induced blood stage malaria with the same parasite line (IBSM, n=12). Following subcurative piperaquine treatment, asexual parasite and gametocytes kinetics were assessed and mosquito feeding experiments were performed. RESULTS Study procedures were well tolerated. Median peak gametocyte density was 1304 gametocytes/mL (interquartile range (IQR) 308-1607) following IBSM compared to 14 gametocytes/mL (IQR 10-64) following MB (P less then 0.001), despite similar peak asexual parasite densities (P = 0.478). Peak gametocyte density correlated with preceding pfap2-g transcripts, indicative of gametocyte commitment (ρ = 0.62; P = 0.002). Direct feeding assays resulted in mosquito infections from 9/12 participants following IBSM versus 0/12 following MB (P less then 0.001). CONCLUSIONS We observed a striking effect of inoculation method on gametocyte production, suggesting higher gametocyte commitment following IBSM. Our direct comparison of MB and IBSM establishes the CHMI-transmission model using intravenous administration of Pf-infected erythrocytes as a model for early-clinical evaluation of interventions that aim to interrupt malaria transmission. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.Vertical transmission of maternal microbes is a major route for establishing the gut microbiome in newborns. The impact of perinatal antibiotics on vertical transmission of microbes and antimicrobial resistance is not well understood. D-2-Amino-5-phosphonovaleric acid Using a metagenomic approach, we analyzed the fecal samples from mothers and vaginally delivered infants from a control group (10 pairs) and a treatment group (10 pairs) receiving perinatal antibiotics. Antibiotic-usage had a significant impact on the main source of inoculum in the gut microbiome of newborns. The control group had significantly more species transmitted f