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The Effect involving Autophagy upon Inflammation Cytokines throughout Renal Ischemia/Reperfusion Damage.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.RNAs play major roles in the regulation of gene expression. Hence, designer RNA molecules are increasingly explored as regulatory switches in synthetic biology. Among these, the TetR-binding RNA aptamer was selected by its ability to compete with operator DNA for binding to the bacterial repressor TetR. A fortuitous finding was that induction of TetR by tetracycline abolishes both RNA aptamer and operator DNA binding in TetR. This enabled numerous applications exploiting both the specificity of the RNA aptamer and the efficient gene repressor properties of TetR. Here, we present the crystal structure of the TetR-RNA aptamer complex at 2.7 Å resolution together with a comprehensive characterization of the TetR-RNA aptamer versus TetR-operator DNA interaction using site-directed mutagenesis, size exclusion chromatography, electrophoretic mobility shift assays and isothermal titration calorimetry. The fold of the RNA aptamer bears no resemblance to regular B-DNA, and neither does the thermodynamic characterization of the complex formation reaction. Nevertheless, the functional aptamer-binding epitope of TetR is fully contained within its DNA-binding epitope. In the RNA aptamer complex, TetR adopts the well-characterized DNA-binding-competent conformation of TetR, thus revealing how the synthetic TetR-binding aptamer strikes the chords of the bimodal allosteric behaviour of TetR to function as a synthetic regulator. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.BACKGROUND African Americans (AAs) are at a higher risk for developing type 2 diabetes compared with non-Hispanic whites (NHWs). The causal role of β-cell glucose sensitivity (β-GS) and insulin clearance in hyperinsulinemia in AA adults is unclear. OBJECTIVE Using a cross-sectional study design, we compared β-cell function and insulin clearance in nondiabetic AAs (n = 36) and NHWs (n = 47) after a mixed meal test (MMT). METHODS Insulin secretion rate, glucose sensitivity, rate sensitivity, and insulin sensitivity during MMT were derived from a mathematical model. Levels of insulin-degrading enzyme (IDE) and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), key players in insulin clearance, were measured (by enzyme-linked immunosorbent assay) in hepatic cytosolic fractions from age-, sex-, and body mass index-matched AA and NHW cadaveric donors (n = 10). RESULTS Fasting and mean postprandial plasma glucose levels were similar in both ethnic groups. AAs had significantly higher fasting and mean postprandial plasma insulin levels. However, fasting ISR, total insulin output, and insulin sensitivity during MMT were not different between the groups. β-GS and rate sensitivity were higher in AAs. Fasting and meal plasma insulin clearance were lower in AAs. Hepatic levels of IDE and CEACAM-1 were similar in AAs and NHWs. Hepatic IDE activity was significantly lower in AAs. CONCLUSIONS In this study, lower insulin clearance contributes to higher plasma insulin levels in AAs. Reduced insulin clearance may be explained by lower IDE activity levels in AAs. Further confirmatory studies are needed to investigate diminished insulin clearance in AAs as a result of lower IDE activity levels. 4Phenylbutyricacid Published by Oxford University Press on behalf of the Endocrine Society 2020.BACKGROUND Obesity prevalence has been rising worldwide and currently is one of the most serious public health problems. Nutrition literacy is important to the development of healthier habits that could help prevent and stem obesity and overweight. The aim of this study was to evaluate the impact of using a multimedia web platform to provide nutrition education to Portuguese adolescents. METHODS The intervention consisted in a two-week period in which students (n = 1291) had access to an interactive multimedia web platform with nutritional content, and designed for a self-paced learning experience. Students completed a knowledge questionnaire at baseline and immediately after the end of the intervention. RESULTS The results obtained revealed that 85.8% of the students increased their nutrition knowledge. No gender differences were observed post-intervention. There were significant differences in the knowledge acquisition regarding age (P  less then  0.001). The baseline knowledge seemed to influence the learning process. CONCLUSIONS Overall, the intervention had a positive impact. The preliminary results observed will be important for the improvement of the intervention, though they need to be confirmed by further research. Nevertheless, it is safe to say that technology-based assets can be important tools to incorporate and complement health-related interventions in schools. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.BACKGROUND The causal link of sustained virological response (SVR) with outcome has been challenged. With markedly improved SVR rates with direct-acting antivirals (DAAs), the benefit of SVR would be expected to diminish if the association with outcome is not causal. METHODS Data were collected for patients starting treatment with interferon (IFN) or DAAs between June 2006 and December 2016. To control for disease severity, patients were IFN-eligible (IDEAL) based on criteria for the IDEAL peginterferon trial. Clinical events were decompensation, hepatocellular carcinoma, liver transplantation and all-cause mortality. RESULTS In 1078 IDEAL-eligible patients, 1306 treatments occurred; 52% IFN, 49% DAAs. Cirrhosis was present in 30% DAAs vs. 21% IFN (P less then 0.001). SVR was 97% with DAAs vs 52% with IFN (P less then 0.0001). The 24-month cumulative event-free survival was 99% for IFN and 97% for DAAs (P=0.08) with SVR and 96% and 75% for non-SVR, respectively (p=0.01). SVR was associated with improved event-free survival with an adjusted hazard ratio of 0.21 (95% CI 0.06-0.71, P=0.01) adjusted for treatment and other confounders. Using inverse probability of treatment weighting to match IFN non-responders with DAAs, event rate at 24-months was 1.1% in DAAs compared to 3.4% in IFN non-responders (P=0.005) highlighting the clinical benefit of higher SVR rates. CONCLUSIONS In IFN-eligible patients, SVR is more commonly achieved with DAAs and confers a similar clinical benefit as in those treated with IFN. The higher SVR rate and reduced event rate with DAAs compared to IFN, despite similar disease severity, confirms that SVR alters prognosis and is thus a surrogate endpoint leading to improved clinical outcomes. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.
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