The aryl hydrocarbon receptor (AhR) is best known as a mediator of toxicity of a diverse family of xenobiotic chemicals such as dioxins and PCBs. However, many naturally occurring compounds also ...activate AhR. One such compound, 2-(1′
H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), was isolated from tissue and found to be potent in preliminary tests J. Song, M. Clagett-Dame, R.E. Peterson, M.E. Hahn, W.M. Westler, R.R. Sicinski, H.F. DeLuca, Proc. Natl. Acad. Sci. USA 99 (2002) 14694–14699. We have synthesized ITE and
3HITE and further evaluated its AhR activity in several in vitro and in vivo assays in comparison with the toxic ligand, TCDD. AhR in Hepa1c1c7 cell cytosol bound
3HITE with high affinity and the AhR
·
ITE complex formed in vitro bound dioxin response element (DRE) oligonucleotide as potently as TCDD
·
AhR. In cells treated with ITE, nuclear translocation of AhR, and induction of CYP1A1 protein and of a DRE-dependent luciferase reporter gene were observed. ITE administered to pregnant DRE-
LacZ transgenic mice activated fetal AhR, observed as X-gal staining in the same sites as in TCDD-treated mice. However, unlike TCDD, ITE did not induce cleft palate or hydronephrosis. TCDD but not ITE induced thymic atrophy in young adult mice, but both ITE and TCDD caused similar loss of cells and alterations of cell profiles in cultured fetal thymi. These data demonstrate that ITE is a potent AhR agonist in cell extracts, cultured cells, and intact animals, but does not cause the toxicity associated with the more stable xenobiotic ligand, TCDD.
Insides and essences are both critical concepts for appreciating the importance of non-obvious entities: neither are observable, both contrast with external appearances, and both can be more ...important than external appearances. The present research examined understandings of insides and essences in 3- to 5- year-old children. In Study 1, children were asked questions requiring them to think about both the insides and the outer appearances of a series of objects. In Study 2, children were tested on their understanding that insides are typically more important than outer surfaces for an object's identity and functioning. In Studies 3, 4, and 5, children were tested on their understanding of innate potential, a concept that reflects understanding of an inborn essence. Contrary to the traditional view of children as externalists (cf. Piaget, 1951), these studies demonstrate that by age 4 children have a firm grasp of the importance of both insides and essences. Even by age 3 children reason clearly about the inside- outside distinction. These results suggest that preschool children attend to non- obvious features and realize their privileged status. They may also indicate a more basic predisposition toward psychological essentialism in young children.
New sets of parameters (“tunes”) for the underlying-event (UE) modelling of the
pythia
8,
pythia6
and
herwig++
Monte Carlo event generators are constructed using different parton distribution ...functions. Combined fits to CMS UE proton–proton (
p
p
) data at
s
=
7
TeV
and to UE proton–antiproton (
p
p
¯
) data from the CDF experiment at lower
s
, are used to study the UE models and constrain their parameters, providing thereby improved predictions for proton–proton collisions at 13
TeV
. In addition, it is investigated whether the values of the parameters obtained from fits to UE observables are consistent with the values determined from fitting observables sensitive to double-parton scattering processes. Finally, comparisons are presented of the UE tunes to “minimum bias” (MB) events, multijet, and Drell–Yan (
q
q
¯
→
Z
/
γ
∗
→
lepton-antilepton+jets) observables at 7 and 8
TeV
, as well as predictions for MB and UE observables at 13
TeV
.
ABSTRACT
Studies of the ages, abundances, and motions of individual stars in the Milky Way provide one of the best ways to study the evolution of disc galaxies over cosmic time. The formation of the ...Milky Way’s barred inner region in particular is a crucial piece of the puzzle of disc galaxy evolution. Using data from APOGEE and Gaia, we present maps of the kinematics, elemental abundances, and age of the Milky Way bulge and disc that show the barred structure of the inner Milky Way in unprecedented detail. The kinematic maps allow a direct, purely kinematic determination of the bar’s pattern speed of $41\pm 3\, \mathrm{km\, s}^{-1}\, \mathrm{kpc}^{-1}$ and of its shape and radial profile. We find the bar’s age, metallicity, and abundance ratios to be the same as those of the oldest stars in the disc that are formed in its turbulent beginnings, while stars in the bulge outside of the bar are younger and more metal-rich. This implies that the bar likely formed ${\approx}8\, \mathrm{Gyr}$ ago, when the decrease in turbulence in the gas disc allowed a thin disc to form that quickly became bar-unstable. The bar’s formation therefore stands as a crucial epoch in the evolution of the Milky Way, a picture that is in line with the evolutionary path that emerges from observations of the gas kinematics in external disc galaxies over the last ${\approx}10\, \mathrm{Gyr}$.
A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need.
We conducted a phase 3, ...double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
Of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group.
Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.).
Cells regulate the biophysical properties of their membranes by coordinated synthesis of different classes of lipids. Here, we identified a highly dynamic feedback mechanism by which the budding ...yeast Saccharomyces cerevisiae can regulate phospholipid biosynthesis. Phosphatidic acid on the endoplasmic reticulum directly bound to the soluble transcriptional repressor Opi1p to maintain it as inactive outside the nucleus. After the addition of the lipid precursor inositol, this phosphatidic acid was rapidly consumed, releasing Opi1p from the endoplasmic reticulum and allowing its nuclear translocation and repression of target genes. Thus, phosphatidic acid appears to be both an essential ubiquitous metabolic intermediate and a signaling lipid.
Renal Denervation in Moderate to Severe CKD HERING, Dagmara; MAHFOUD, Felix; SCHLAICH, Markus P ...
Journal of the American Society of Nephrology,
07/2012, Volume:
23, Issue:
7
Journal Article
PDF
