Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture

In human endometrium, cell proliferation is regulated by ovarian steroids through heterotypic interactions between stromal and epithelial cells populating this tissue. We tested the proliferative effects of tibolone and its metabolites using endometrial co-cultures that mimic the normal proliferative response to hormones. We found that both the Δ4-tibolone metabolite and the pure progestin ORG2058 counteract estradiol-driven epithelial cell proliferation. Surprisingly, the estrogen receptor binding 3-hydroxyl-metabolites of tibolone also counteracted estradiol-driven proliferation. Inhibition of proliferation by 3β-OH-tibolone was abrogated by low doses of the progesterone receptor antagonist mifepristone, This suggests that 3β-OH-tibolone is converted to a progestagenic metabolite. We found that the stromal cells used in the co-cultures express high levels of the ketosteroid dehydrogenase, AKR1C2, which is able to oxidize 3β-OH-tibolone back to tibolone. Thus the unexpected progestagenic effect of 3β-OH-tibolone in these co-cultures may be due to metabolic activity present in the stromal cells of the co-cultures

Physics Behind Precision

This document provides a writeup of contributions to the FCC-ee mini-workshop on "Physics behind precision" held at CERN, on 2-3 February 2016.Comment: https://indico.cern.ch/event/469561

Predictions for p+p+Pb Collisions at sNN=5\sqrt{s_{NN}} = 5 TeV: Comparison with Data

Predictions made in Albacete {\it et al} prior to the LHC $p+$Pb run at $\sqrt{s_{NN}} = 5$ TeV are compared to currently available data. Some predictions shown here have been updated by including the same experimental cuts as the data. Some additional predictions are also presented, especially for quarkonia, that were provided to the experiments before the data were made public but were too late for the original publication are also shown here.Comment: 55 pages 35 figure

Response to : The GPRC5A frameshift variant c.183del is not associated with increased breast cancer risk in BRCA1 mutation carriers

Non peer reviewe

Impact-parameter dependent nuclear parton distribution functions: EPS09s and EKS98s and their applications in nuclear hard processes

We determine the spatial (impact parameter) dependence of nuclear parton distribution functions (nPDFs) using the $A$-dependence of the spatially independent (averaged) global fits EPS09 and EKS98. We work under the assumption that the spatial dependence can be formulated as a power series of the nuclear thickness functions $T_A$. To reproduce the $A$-dependence over the entire $x$ range we need terms up to $[T_A]^4$. As an outcome, we release two sets, EPS09s (LO, NLO, error sets) and EKS98s, of spatially dependent nPDFs for public use. We also discuss the implementation of these into the existing calculations. With our results, the centrality dependence of nuclear hard-process observables can be studied consistently with the globally fitted nPDFs for the first time. As an application, we first calculate the LO nuclear modification factor $R^{1jet}_{AA}$ for primary partonic-jet production in different centrality classes in Au+Au collisions at RHIC and Pb+Pb collisions at LHC. Also the corresponding central-to-peripheral ratios $R_{CP}^{1jet}$ are studied. We also calculate the LO and NLO nuclear modification factors for single inclusive neutral pion production, $R_{dAu}^{\pi^0}$, at mid- and forward rapidities in different centrality classes in d+Au collisions at RHIC. In particular, we show that our results are compatible with the PHENIX mid-rapidity data within the overall normalization uncertainties given by the experiment. Finally, we show our predictions for the corresponding modifications $R_{pPb}^{\pi^0}$ in the forthcoming p+Pb collisions at LHC.Comment: 36 page

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice

The amount of keratins matters for stress protection of the colonic epithelium

Keratins (K) are important for epithelial stress protection as evidenced by keratin mutations predisposing to human liver diseases and possibly inflammatory bowel diseases. A role for K8 in the colon is supported by the ulcerative colitis-phenotype with epithelial hyperproliferation and abnormal ion transport in K8-knockout (K8-/-) mice. The heterozygote knockout (K8+/-) colon appears normal but displays a partial ion transport-defect. Characterizing the colonic phenotype we show that K8+/- colon expresses ~50% less keratins compared to K8 wild type (K8+/+) but de novo K7 expression is observed in the top-most cells of the K8+/- and K8-/- crypts. The K8+/- colonic crypts are significantly longer due to increased epithelial hyperproliferation, but display no defects in apoptosis or inflammation in contrast to K8-/-. When exposed to colitis using the dextran sulphate sodium-model, K8+/- mice showed higher disease sensitivity and delayed recovery compared to K8+/+ littermates. Therefore, the K8+/- mild colonic phenotype correlates with decreased keratin levels and increased sensitivity to experimental colitis, suggesting that a sufficient amount of keratin is needed for efficient stress protection in the colonic epithelia