Intestinal Microbiota Regulate Xenobiotic Metabolism in the Liver

BACKGROUND: The liver is the central organ for xenobiotic metabolism (XM) and is regulated by nuclear receptors such as CAR and PXR, which control the metabolism of drugs. Here we report that gut microbiota influences liver gene expression and alters xenobiotic metabolism in animals exposed to barbiturates. PRINCIPAL FINDINGS: By comparing hepatic gene expression on microarrays from germfree (GF) and conventionally-raised mice (SPF), we identified a cluster of 112 differentially expressed target genes predominantly connected to xenobiotic metabolism and pathways inhibiting RXR function. These findings were functionally validated by exposing GF and SPF mice to pentobarbital which confirmed that xenobiotic metabolism in GF mice is significantly more efficient (shorter time of anesthesia) when compared to the SPF group. CONCLUSION: Our data demonstrate that gut microbiota modulates hepatic gene expression and function by altering its xenobiotic response to drugs without direct contact with the liver

Effects of supplemented isoenergetic diets varying in cereal fiber and protein content on the bile acid metabolic signature and relation to insulin resistance

Bile acids (BA) are potent metabolic regulators influenced by diet. We studied effects of isoenergetic increases in the dietary protein and cereal-fiber contents on circulating BA and insulin resistance (IR) in overweight and obese adults. Randomized controlled nutritional intervention (18 weeks) in 72 non-diabetic participants (overweight/obese: 29/43) with at least one further metabolic risk factor. Participants were group-matched and allocated to four isoenergetic supplemented diets: control; high cereal fiber (HCF); high-protein (HP); or moderately increased cereal fiber and protein (MIX). Whole-body IR and insulin-mediated suppression of hepatic endogenous glucose production were measured using euglycaemic–hyperinsulinemic clamps with [6-62H2] glucose infusion. Circulating BA, metabolic biomarkers, and IR were measured at 0, 6, and 18 weeks. Under isoenergetic conditions, HP-intake worsened IR in obese participants after 6 weeks (M-value: 3.77 ± 0.58 vs. 3.07 ± 0.44 mg/kg/min, p = 0.038), with partial improvement back to baseline levels after 18 weeks (3.25 ± 0.45 mg/kg/min, p = 0.089). No deleterious effects of HP-intake on IR were observed in overweight participants. HCF-diet improved IR in overweight participants after 6 weeks (M-value 4.25 ± 0.35 vs. 4.81 ± 0.31 mg/kg/min, p = 0.016), but did not influence IR in obese participants. Control and MIX diets did not influence IR. HP-induced, but not HCF-induced changes in IR strongly correlated with changes of BA profiles. MIX-diet significantly increased most BA at 18 weeks in obese, but not in overweight participants. BA remained unchanged in controls. Pooled BA concentrations correlated with fasting fibroblast growth factor-19 (FGF-19) plasma levels (r = 0.37; p = 0.003). Higher milk protein intake was the only significant dietary predictor for raised total and primary BA in regression analyses (total BA, p = 0.017; primary BA, p = 0.011). Combined increased intake of dietary protein and cereal fibers markedly increased serum BA concentrations in obese, but not in overweight participants. Possible mechanisms explaining this effect may include compensatory increases of the BA pool in the insulin resistant, obese state; or defective BA transport

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave transient was identified in data recorded by the Advanced LIGO detectors on 2015 September 14. The event candidate, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the gravitational wave data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network Circulars, giving an overview of the participating facilities, the gravitational wave sky localization coverage, the timeline and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the electromagnetic data and results of the electromagnetic follow-up campaign will be disseminated in the papers of the individual teams

Evaluation of Serum Zinc Levels in Hyperbilirubinemic Neonates Before and After Phototherapy

Background The existing therapeutic methods for neonatal jaundice are costly, time-consuming and potentially risky. Zinc salts can reduce phototherapy duration by precipitating unconjugated bilirubin in the intestine (bilirubin and zinc can form a complex in physiologic pH); however, zinc toxicity is an issue that must be considered since theoretically bilirubin reduction by phototherapy may increase serum zinc levels, making additional zinc supplementation the potential cause of zinc toxicity. Objectives So, our purpose was evaluating the serum zinc level alterations before and after phototherapy, in hyperbilirubinemic newborns. Materials and Methods A prospective cohort study was performed at the children’s medical center of Tehran University of Medical Sciences from 2012 to 2014. Healthy, full-term exclusively breast fed newborns with non-hemolytic jaundice were enrolled in the study. Participants were divided into two groups based on serum bilirubin levels (TSB < 18 mg/dL and TSB ≥ 18 mg/dL) at admission. Pre- and post-phototherapy total serum zinc level was measured before and 12 - 24 hours after termination of phototherapy. Results Phototherapy was associated with a significant increase in the serum zinc level in neonates with severe hyperbilirubinemia (TSB ≥ 18 mg/dL) but not in those with mild-moderate hyperbilirubinemia (TSB < 18 mg/dL). In addition, phototherapy caused a significant increase in the rate of zinc with potentially toxic levels (zinc > 200) in only neonates with severe hyperbilirubinemia. Conclusions Phototherapy increases serum zinc level by reducing bilirubin level so that additional supplementation of this element can lead potentially to zinc toxicity

Computational thermodynamics in ferrite content prediction of austenitic stainless steel weldments

In this paper, four computational approaches using Thermo-Calc and DICTRA have been used to calculate the ferrite content of a set of austenitic stainless steel welds with different solidification modes and ferrite contents. To evaluate the computational approaches, the calculations were compared to the experimental results. It was found that for each solidification mode, there is one computational approach that predicts ferrite with better accuracy. For ferritic-austenitic alloys, the best accuracy is obtained when considering the peritectic model, with deviations of 1.2–1.4% ferrite. In the case of austenitic-ferritic alloys, the solidification analysed through the eutectic approach showed an accuracy of 0.6–1.6% ferrite, whilst in alloys with fully ferritic solidification, starting calculations, not from the liquid state but from fully ferritic below solidus, was the best approach, showing 2.3% ferrite deviation from the experimental measurements. Computational thermodynamics has proved to be a promising tool to explore simulation and calculation of ferrite content phase fractions in welding. However, further investigation is still needed to correlate the real microstructural features with the computational parameter “cell size”. The feasibility and accuracy of computational thermodynamics when predicting ferrite in low-heat-input welding processes such as laser welding is also another aspect for additional investigation.First Online: 05 December 2018Funders: Stiftelsen Axel Hultgrens fond; Swerim AB</p