Validation Through Simulations of a Cn2 Profiler for the ESO/VLT Adaptive Optics Facility

The Adaptive Optics Facility (AOF) project envisages transforming one of the VLT units into an adaptive telescope and providing its ESO (European Southern Observatory) second generation instruments with turbulence corrected wavefronts. For MUSE and HAWK-I this correction will be achieved through the GALACSI and GRAAL AO modules working in conjunction with a 1170 actuators Deformable Secondary Mirror (DSM) and the new Laser Guide Star Facility (4LGSF). Multiple wavefront sensors will enable GLAO and LTAO capabilities, whose performance can greatly benefit from a knowledge about the stratification of the turbulence in the atmosphere. This work, totally based on end-to-end simulations, describes the validation tests conducted on a Cn2 profiler adapted for the AOF specifications. Because an absolute profile calibration is strongly dependent on a reliable knowledge of turbulence parameters r0 and L0, the tests presented here refer only to normalized output profiles. Uncertainties in the input parameters inherent to the code are tested as well as the profiler response to different turbulence distributions. It adopts a correction for the unseen turbulence, critical for the GRAAL mode, and highlights the effects of masking out parts of the corrected wavefront on the results. Simulations of data with typical turbulence profiles from Paranal were input to the profiler, showing that it is possible to identify reliably the input features for all the AOF modes.Comment: 15 pages, 12 figures, accepted for publication in the MNRAS Accepted 2015 January 22. Received 2015 January 21; in original form 2014 December

An atlas of Calcium triplet spectra of active galaxies

We present a spectroscopic atlas of active galactic nuclei covering the region around the 8498, 8542, 8662 Calcium triplet (CaT) lines. The sample comprises 78 objects, divided into 43 Seyfert 2s, 26 Seyfert 1s, 3 Starburst and 6 normal galaxies. The spectra pertain to the inner ~300 pc in radius, and thus sample the central kinematics and stellar populations of active galaxies. The data are used to measure stellar velocity dispersions (sigma_star) both with cross-correlation and direct fitting methods. These measurements are found to be in good agreement with each-other and with those in previous studies for objects in common. The CaT equivalent width is also measured. We find average values and sample dispersions of W_CaT of 4.6+/-2.0, 7.0 and 7.7+/-1.0 angstrons for Seyfert 1s, Seyfert 2s and normal galaxies, respectively. We further present an atlas of [SIII]\lambda 9069 emission line profiles for a subset of 40 galaxies. These data are analyzed in a companion paper which addresses the connection between stellar and Narrow Line Region kinematics, the behaviour of the CaT equivalent width as a function of sigma_star, activity type and stellar population properties.Comment: 18 pages, 10 figures, accepted for publication in MNRA

Blueprint for mechanistic, data-rich early phase clinical pharmacology studies in dermatology

Drug Delivery Technolog

Chandra monitoring of UGC 4203: the structure of the X-ray absorber

We present a Chandra monitoring campaign of the highly variable Seyfert galaxy UGC 4203 (the "Phoenix Galaxy") which revealed variations in the X-ray absorbing column density on time scales of two weeks. This is the third, clear case, after NGC 1365 and NGC 7582, of dramatic N_H variability on short time scales observed in a "changing look" source, i.e. an AGN observed in the past in both a reflection-dominated and a Compton-thin state. The inferred limits on the distance of the X-ray absorber from the center suggest that the X-ray "torus" could be one and the same with the broad emission line region. This scenario, first proposed for an "ad-hoc" picture for NGC 1365, may be the common structure of the circumnuclear medium in AGN.Comment: 5 Pages, 4 figures. Accepted for publication in MNRAS. Missing references added and typos correcte

The impact of CYP2C19 genotype on phenoconversion by concomitant medication

Introduction: Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test results, whereupon dosage or drugs are adjusted. Drug-drug-interactions (DDIs) caused by concomitant medication can however cause mismatches between predicted and observed phenotypes (phenoconversion). Here we investigated the impact of CYP2C19 genotype on the outcome of CYP2C19-dependent DDIs in human liver microsomes.Methods: Liver samples from 40 patients were included, and genotyped for CYP2C19*2, *3 and *17 variants. S-mephenytoin metabolism in microsomal fractions was used as proxy for CYP2C19 activity, and concordance between genotype-predicted and observed CYP2C19 phenotype was examined. Individual microsomes were subsequently co-exposed to fluvoxamine, voriconazole, omeprazole or pantoprazole to simulate DDIs.Results: Maximal CYP2C19 activity (Vmax) in genotype-predicted intermediate metabolizers (IMs; *1/*2 or *2/*17), rapid metabolizers (RMs; *1/*17) and ultrarapid metabolizers (UMs; *17/*17) was not different from Vmax of predicted normal metabolizers (NMs; *1/*1). Conversely, CYP2C19*2/*2 genotyped-donors exhibited Vmax rates ∼9% of NMs, confirming the genotype-predicted poor metabolizer (PM) phenotype. Categorizing CYP2C19 activity, we found a 40% concordance between genetically-predicted CYP2C19 phenotypes and measured phenotypes, indicating substantial phenoconversion. Eight patients (20%) exhibited CYP2C19 IM/PM phenotypes that were not predicted by their CYP2C19 genotype, of which six could be linked to the presence of diabetes or liver disease. In subsequent DDI experiments, CYP2C19 activity was inhibited by omeprazole (−37% ± 8%), voriconazole (−59% ± 4%) and fluvoxamine (−85% ± 2%), but not by pantoprazole (−2 ± 4%). The strength of CYP2C19 inhibitors remained unaffected by CYP2C19 genotype, as similar percental declines in CYP2C19 activity and comparable metabolism-dependent inhibitory constants (Kinact/KI) of omeprazole were observed between CYP2C19 genotypes. However, the consequences of CYP2C19 inhibitor-mediated phenoconversion were different between CYP2C19 genotypes. In example, voriconazole converted 50% of *1/*1 donors to a IM/PM phenotype, but only 14% of *1/*17 donors. Fluvoxamine converted all donors to phenotypic IMs/PMs, but *1/*17 (14%) were less likely to become PMs than *1/*1 (50%) or *1/*2 and *2/*17 (57%).Conclusion: This study suggests that the differential outcome of CYP2C19-mediated DDIs between genotypes are primarily dictated by basal CYP2C19 activity, that may in part be predicted by CYP2C19 genotype but likely also depends on disease-related factors

The CaT strength in Seyfert nuclei revisited: analyzing young stars and non-stellar light contributions to the spectra

In a former paper (Garcia-Rissmann et al. 2005; hereafter Paper I), we have presented spectra of 64 active, 9 normal and 5 Starburst galaxies in the region around the near-IR Calcium triplet absorption lines and the [SIII]9069 line. In the present paper we analyze the CaT strength (WCaT), and kinematical products derived in that study, namely stellar and ionized gas velocity dispersions. Our main results may be summarized as follows: (1) Seyfert 2s show no sign of dilution in WCaT with respect to the values spanned by normal galaxies, even when optical absorption lines such as the CaII K band at 3933 A are much weaker than in old, bulge-like stellar populations. (2) The location of Seyfert 2s in the WCaT-WCaK plane is consistent with evolutionary synthesis models. The implication is that the source responsible for the dilution of optical lines in these AGN is a young stellar population, rather than an AGN featureless continuum, confirming the conclusion of the pioneer study of Terlevich, Diaz & Terlevich. (3) In Seyfert 1s, both W[SIII] and WCaT tend to be diluted due to the presence of a non-stellar component, in agreement with the unification paradigm. (4) A comparison of stellar and gas velocity dispersions confirms the existence of a correlation between the typical velocities of stars and clouds of the Narrow Line Region. The strength and scatter around this correlation are similar to those previously obtained from the [OIII]5007 line width.Comment: 14 pages, 15 figures. Paper accepted for publication in MNRA

Antimicrobial peptide omiganan enhances interferon responses to endosomal toll-like receptor ligands in human peripheral blood mononuclear cells

LL-37 is a cationic antimicrobial peptide and the sole human member of cathelicidins. Besides its bactericidal properties, LL-37 is known to have direct immunomodulatory effects, among which enhancement of antiviral responses via endosomal toll-like receptors (TLRs). Omiganan pentahydrochloride is a synthetic cationic peptide in clinical development. Previously, omiganan was primarily known for its direct bactericidal and antifungal properties. We investigated whether omiganan enhances endosomal TLR responses, similar to LL-37. Human peripheral blood mononuclear cells were treated with endosomal TLR3, -7, -8, and -9 ligands in the presence of omiganan. Omiganan enhanced TLR-mediated interferon-alpha release. Subsequent experiments with TLR9 ligands showed that plasmacytoid dendritic cells were main contributors to omiganan-enhanced IFN production. Based on this type I interferon-enhancing effect, omiganan may qualify as potential treatment modality for virus-driven diseases. The molecular mechanism by which omiganan enhances endosomal TLR responses remains to be elucidated.Drug Delivery Technolog

Anti-IL-17A blockade did not significantly reduce inflammatory lesions in a placebo-controlled pilot study in adult patients with moderate to severe acne

BACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nCJM112 is a potent anti-IL-17A monoclonal antibody, whose clinical efficacy in psoriasis was recently documented. This study aimed to assess the effect of IL-17A blockade, using CJM112, in patients with moderate to severe acne.\nA randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study was conducted on patients with moderate to severe acne. Patients received CJM112 300 mg, 75 mg, or placebo subcutaneously during Treatment Period1 (0-12 weeks). Patients receiving placebo were re-randomized to receive CJM112 300 mg or 75 mg during Treatment Period 2 (12-24 weeks). The primary endpoint was the number of inflammatory facial lesions at Week 12.\nAs the futility criterion was met during the interim analysis, only 52/75 (69.3%) patients were recruited. In total, 48/52 (92.3%) and 26/41 (63.4%) completed Treatment Periods 1 and 2, respectively. All groups exhibited a reduction in facial inflammatory lesions, with no difference observed between CJM112 and placebo (CJM112 300 mg 27.6 ± 20.7; CJM112 75 mg 30.4 ± 34.8; placebo 23.6 ± 13.6; primary endpoint). Additionally, no differences were observed between groups in other secondary and exploratory endpoints at Week 12.\nAnti-IL-17A therapy was not significantly different compared to the placebo in reducing inflammatory lesions in patients with moderate to severe acne.Pharmacolog