Bile Acid Signaling in Liver Metabolism and Diseases

Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that bile acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of bile acid metabolism or bile acid signaling pathways such as using bile acid receptor agonists or bile acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, bile acid signaling is complex, and the molecular mechanisms mediating the bile acid effects are still not completely understood. This paper will summarize recent advances in our understanding of bile acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target bile acid metabolism for the treatment of metabolic disorders

Regulation of Bile Acid and Cholesterol Metabolism by PPARs

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARα alters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome

HST and Spitzer Observations of the HD 207129 Debris Ring

A debris ring around the star HD 207129 (G0V; d = 16.0 pc) has been imaged in scattered visible light with the ACS coronagraph on the Hubble Space Telescope and in thermal emission using MIPS on the Spitzer Space Telescope at 70 microns (resolved) and 160 microns (unresolved). Spitzer IRS (7-35 microns) and MIPS (55-90 microns) spectrographs measured disk emission at >28 microns. In the HST image the disk appears as a ~30 AU wide ring with a mean radius of ~163 AU and is inclined by 60 degrees from pole-on. At 70 microns it appears partially resolved and is elongated in the same direction and with nearly the same size as seen with HST in scattered light. At 0.6 microns the ring shows no significant brightness asymmetry, implying little or no forward scattering by its constituent dust. With a mean surface brightness of V=23.7 mag per square arcsec, it is the faintest disk imaged to date in scattered light.Comment: 28 pages, 8 figure

The expression of hyperpolarization activated cyclic nucleotide gated (HCN) channels in the rat ovary are dependent on the type of cell and the reproductive age of the animal: a laboratory investigation

<p>Abstract</p> <p>Background</p> <p>Aim of this study was to test the hypothesis that levels of hyperpolarization activated cyclic nucleotide gated channels 1 to 4 (HCN1-4) are linked to the reproductive age of the ovary.</p> <p>Methods</p> <p>Young, adult, and reproductively aged ovaries were collected from Sprague-Dawley rats. RT-PCR and western blot analysis of ovaries was performed to investigate the presence of mRNA and total protein for HCN1-4. Immunohistochemistry with semiquantitative H score analysis was performed using whole ovarian histologic sections.</p> <p>Results</p> <p>RT-PCR analysis showed the presence of mRNA for HCN1-4. Western blot analysis revealed HCN1-3 proteins in all ages of ovarian tissues. Immunohistochemistry with H score analysis demonstrated distinct age-related changes in patterns of HCN1-3 in the oocytes, granulosa cells, theca cells, and corpora lutea. HCN4 was present only in the oocytes, with declining levels during the reproduction lifespan.</p> <p>Conclusion</p> <p>The evidence presented here demonstrates cell-type and developmental age patterns of HCN1-4 channel expression in rat ovaries. Based on this, we hypothesize that HCN channels have functional significance in rat ovaries and may have changing roles in reproductive aging.</p

The Universal One-Loop Effective Action

We present the universal one-loop effective action for all operators of dimension up to six obtained by integrating out massive, non-degenerate multiplets. Our general expression may be applied to loops of heavy fermions or bosons, and has been checked against partial results available in the literature. The broad applicability of this approach simplifies one-loop matching from an ultraviolet model to a lower-energy effective field theory (EFT), a procedure which is now reduced to the evaluation of a combination of matrices in our universal expression, without any loop integrals to evaluate. We illustrate the relationship of our results to the Standard Model (SM) EFT, using as an example the supersymmetric stop and sbottom squark Lagrangian and extracting from our universal expression the Wilson coefficients of dimension-six operators composed of SM fields.Comment: 30 pages, v2 contains additional comments and corrects typos, version accepted for publication in JHE

Scientific Verification Of Faraday Rotation Modulators: Detection Of Diffuse Polarized Galactic Emission

The design and performance of a wide bandwidth linear polarization modulator based on the Faraday effect is described. Faraday Rotation Modulators (FRMs) are solid-state polarization switches that are capable of modulation up to 10 kHz. Six FRMs were utilized during the 2006 observing season in the Background Imaging of Cosmic Extragalactic Polarization (BICEP) experiment; three FRMs were used at each of BICEP's 100 and 150 GHz frequency bands. The technology was verified through high signal-to-noise detection of Galactic polarization using two of the six FRMs during four observing runs in 2006. The features exhibit strong agreement with BICEP's measurements of the Galaxy using non-FRM pixels and with the Galactic polarization models. This marks the first detection of high signal-to-noise mm-wave celestial polarization using fast, active optical modulation. The performance of the FRMs during periods when they were not modulated was also analyzed and compared to results from BICEP's 43 pixels without FRMs.Astronom

Self-calibration of BICEP1 three-year data and constraints on astrophysical polarization rotation

Cosmic microwave background (CMB) polarimeters aspire to measure the faint $B$-mode signature predicted to arise from inflationary gravitational waves. They also have the potential to constrain cosmic birefringence, rotation of the polarization of the CMB arising from parity-violating physics, which would produce nonzero expectation values for the CMB’s temperature to $B$-mode correlation $(TB)$ and $E$-mode to $B$-mode correlation $(EB)$ spectra. However, instrumental systematic effects can also cause these $TB$ and $EB$ correlations to be nonzero. In particular, an overall miscalibration of the polarization orientation of the detectors produces $TB$ and $EB$ spectra which are degenerate with isotropic cosmological birefringence, while also introducing a small but predictable bias on the $BB$ spectrum. We find that Bicep1 three-year spectra, which use our standard calibration of detector polarization angles from a dielectric sheet, are consistent with a polarization rotation of $\alpha = −2.77^{\circ}\pm0.86^{\circ}$(statistical) $\pm1.3^{\circ}$(systematic). We have revised the estimate of systematic error on the polarization rotation angle from the two-year analysis by comparing multiple calibration methods. We also account for the (negligible) impact of measured beam systematic effects. We investigate the polarization rotation for the Bicep1 100GHz and 150GHz bands separately to investigate theoretical models that produce frequency-dependent cosmic birefringence. We find no evidence in the data supporting either of these models or Faraday rotation of the CMB polarization by the Milky Way galaxy’s magnetic field. If we assume that there is no cosmic birefringence, we can use the $TB$ and $EB$ spectra to calibrate detector polarization orientations, thus reducing bias of the cosmological $B$-mode spectrum from leaked E-modes due to possible polarization orientation miscalibration. After applying this “self-calibration” process, we find that the upper limit on the tensor-to-scalar ratio decreases slightly, from $r<0.70$ to $r<0.65$ at 95% confidence.Astronom

Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation

, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival., a direct Notch target that has an important role in Notch-associated T-ALL.We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis

Modulation of the peripheral blood transcriptome by the ingestion of probiotic yoghurt and acidified milk in healthy, young men

The metabolic health benefits of fermented milks have already been investigated using clinical biomarkers but the development of transcriptomic analytics in blood offers an alternative approach that may help to sensitively characterise such effects. We aimed to assess the effects of probiotic yoghurt intake, compared to non-fermented, acidified milk intake, on clinical biomarkers and gene expression in peripheral blood. To this end, a randomised, crossover study was conducted in fourteen healthy, young men to test the two dairy products. For a subset of seven subjects, RNA sequencing was used to measure gene expression in blood collected during postprandial tests and after two weeks daily intake. We found that the postprandial response in insulin was different for probiotic yoghurt as compared to that of acidified milk. Moreover changes in several clinical biomarkers were associated with changes in the expression of genes representing six metabolic genesets. Assessment of the postprandial effects of each dairy product on gene expression by geneset enrichment analysis revealed significant, similar modulation of inflammatory and glycolytic genes after both probiotic yoghurt and acidified milk intake, although distinct kinetic characteristics of the modulation differentiated the dairy products. The aryl hydrocarbon receptor was a major contributor to the down-regulation of the inflammatory genesets and was also positively associated with changes in circulating insulin at 2h after yoghurt intake (p = 0.05). Daily intake of the dairy products showed little effect on the fasting blood transcriptome. Probiotic yoghurt and acidified milk appear to affect similar gene pathways during the postprandial phase but differences in the timing and the extent of this modulation may lead to different physiological consequences. The functional relevance of these differences in gene expression is supported by their associations with circulating biomarkers