Modeling reverberation mapping data II: dynamical modeling of the Lick AGN Monitoring Project 2008 dataset

We present dynamical modeling of the broad line region (BLR) for a sample of five Seyfert 1 galaxies using reverberation mapping data taken by the Lick AGN Monitoring Project in 2008. By modeling the AGN continuum light curve and H$\beta$ line profiles directly we are able to constrain the geometry and kinematics of the BLR and make a measurement of the black hole mass that does not depend upon the virial factor, $f$, needed in traditional reverberation mapping analysis. We find that the geometry of the BLR is generally a thick disk viewed close to face-on. While the H$\beta$ emission is found to come preferentially from the far side of the BLR, the mean size of the BLR is consistent with the lags measured with cross-correlation analysis. The BLR kinematics are found to be consistent with either inflowing motions or elliptical orbits, often with some combination of the two. We measure black hole masses of $\log_{10}(M_{\rm\,BH}/M_\odot)=6.62^{+0.10}_{-0.13}$ for Arp 151, $7.42^{+0.26}_{-0.27}$ for Mrk 1310, $7.51^{+0.23}_{-0.14}$ for NGC 5548, $6.42^{+0.24}_{-0.18}$ for NGC 6814, and $6.99^{+0.32}_{-0.25}$ for SBS 1116+583A. The $f$ factors measured individually for each AGN are found to correlate with inclination angle, although not with $M_{\rm\,BH}$, $L_{5100}$, or FWHM/$\sigma$ of the emission line profile.Comment: 21 pages, 24 figures, 3 tables, Accepted for publication in MNRAS, corrected masses for NGC 5548 and NGC 6814 in the abstrac

Chemopreventive Effects of the p53-Modulating Agents CP-31398 and Prima-1 in Tobacco Carcinogen-Induced Lung Tumorigenesis in A/J Mice

AbstractLung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation

The Lick AGN Monitoring Project: Recalibrating Single-Epoch Virial Black Hole Mass Estimates

We investigate the calibration and uncertainties of black hole mass estimates based on the single-epoch (SE) method, using homogeneous and high-quality multi-epoch spectra obtained by the Lick Active Galactic Nucleus (AGN) Monitoring Project for 9 local Seyfert 1 galaxies with black hole masses < 10^8 M_sun. By decomposing the spectra into their AGN and stellar components, we study the variability of the single-epoch Hbeta line width (full width at half-maximum intensity, FWHM_Hbeta; or dispersion, sigma_Hbeta) and of the AGN continuum luminosity at 5100A (L_5100). From the distribution of the "virial products" (~ FWHM_Hbeta^2 L_5100^0.5 or sigma_Hbeta^2 L_5100^0.5) measured from SE spectra, we estimate the uncertainty due to the combined variability as ~ 0.05 dex (12%). This is subdominant with respect to the total uncertainty in SE mass estimates, which is dominated by uncertainties in the size-luminosity relation and virial coefficient, and is estimated to be ~ 0.46 dex (factor of ~ 3). By comparing the Hbeta line profile of the SE, mean, and root-mean-square (rms) spectra, we find that the Hbeta line is broader in the mean (and SE) spectra than in the rms spectra by ~ 0.1 dex (25%) for our sample with FWHM_Hbeta < 3000 km/s. This result is at variance with larger mass black holes where the difference is typically found to be much less than 0.1 dex. To correct for this systematic difference of the Hbeta line profile, we introduce a line-width dependent virial factor, resulting in a recalibration of SE black hole mass estimators for low-mass AGNs.Comment: Accepted for publication in ApJ. 18 pages, 17 figure

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155

MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic Δhly or ΔactA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-γ mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45intCD11bpos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155−/−) mice. Brain influxes of Ly-6Chigh monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155−/− mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45highCD11bpos brain cells from B6.miR-155−/− mice isolated at 7 d p.i. expressed 2-fold fewer IFN-γ transcripts than did cells from B6.WT mice suggesting reduced IFN-γ stimulation contributed to dampened gene expression in B6.miR-155−/− microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155−/− microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-γ-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2

Multitargeted Low-Dose GLAD Combination Chemoprevention: A Novel and Promising Approach to Combat Colon Carcinogenesis

AbstractPreclinical studies have shown that gefitinib, licofelone, atorvastatin, and α-difluoromethylornithine (GLAD) are promising colon cancer chemopreventive agents. Because low-dose combination regimens can offer potential additive or synergistic effects without toxicity, GLAD combination was tested for toxicity and chemopreventive efficacy for suppression of intestinal tumorigenesis in adenomatous polyposis coli (APC)Min/+ mice. Six-week-old wild-type and APCMin/+ mice were fed modified American Institute of Nutrition 76A diets with or without GLAD (25 + 50 + 50 + 500 ppm) for 14 weeks. Dietary GLAD caused no signs of toxicity based on organ pathology and liver enzyme profiles. GLAD feeding strongly inhibited (80–83%, P < .0001) total intestinal tumor multiplicity and size in APCMin/+ mice (means ± SEM tumors for control vs GLAD were 67.1 ± 5.4 vs 11.3 ± 1.1 in males and 72.3 ± 8.9 vs 14.5 ± 2.8 in females). Mice fed GLAD had >95% fewer polyps with sizes of >2 mm compared with control mice and showed 75% and 85% inhibition of colonic tumors in males and females, respectively. Molecular analyses of polyps suggested that GLAD exerts efficacy by inhibiting cell proliferation, inducing apoptosis, decreasing β-catenin and caveolin-1 levels, increasing caspase-3 cleavage and p21, and modulating expression profile of inflammatory cytokines. These observations demonstrate that GLAD, a novel cocktail of chemopreventive agents at very low doses, suppresses intestinal tumorigenesis in APCMin/+ mice with no toxicity. This novel strategy to prevent colorectal cancer is an important step in developing agents with high efficacy without unwanted side effects

What Does the Geometry of the HβBLR Depend On?

We combine our dynamical modeling black-hole mass measurements from the Lick AGN Monitoring Project 2016 sample with measured cross-correlation time lags and line widths to recover individual scale factors, f, used in traditional reverberation-mapping analyses. We extend our sample by including prior results from Code for AGN Reverberation and Modeling of Emission Lines (CARAMEL) studies that have utilized our methods. Aiming to improve the precision of black-hole mass estimates, as well as uncover any regularities in the behavior of the broad-line region (BLR), we search for correlations between f and other AGN/BLR parameters. We find (i) evidence for a correlation between the virial coefficient log10(fmean,σ) and black-hole mass, (ii) marginal evidence for a similar correlation between log10( frms,σ) and black-hole mass, (iii) marginal evidence for an anticorrelation of BLR disk thickness with log10( fmean,FWHM) and log10( frms,FWHM), and (iv) marginal evidence for an anticorrelation of inclination angle with log10( fmean,FWHM), log10( frms,σ), and log10( fmean,σ). Last, we find marginal evidence for a correlation between line-profile shape, when using the root-mean-square spectrum, log10(FWHM/σ)rms, and the virial coefficient, log10( frms,σ), and investigate how BLR properties might be related to line-profile shape using CARAMEL models

The Lick AGN Monitoring Project 2016: Dynamical Modeling of Velocity-Resolved H\b{eta} Lags in Luminous Seyfert Galaxies

We have modeled the velocity-resolved reverberation response of the H\b{eta} broad emission line in nine Seyfert 1 galaxies from the Lick Active Galactic Nucleus (AGN) Monitioring Project 2016 sample, drawing inferences on the geometry and structure of the low-ionization broad-line region (BLR) and the mass of the central supermassive black hole. Overall, we find that the H\b{eta} BLR is generally a thick disk viewed at low to moderate inclination angles. We combine our sample with prior studies and investigate line-profile shape dependence, such as log10(FWHM/{\sigma}), on BLR structure and kinematics and search for any BLR luminosity-dependent trends. We find marginal evidence for an anticorrelation between the profile shape of the broad H\b{eta} emission line and the Eddington ratio, when using the root-mean-square spectrum. However, we do not find any luminosity-dependent trends, and conclude that AGNs have diverse BLR structure and kinematics, consistent with the hypothesis of transient AGN/BLR conditions rather than systematic trends

The Lick AGN Monitoring Project 2016 : dynamical modeling of velocity-resolved Hβ lags in luminous Seyfert galaxies

K.H. acknowledges support from STFC grant ST/R000824/1.We have modeled the velocity-resolved reverberation response of the Hβ broad emission line in nine Seyfert 1 galaxies from the Lick Active Galactic Nucleus (AGN) Monitoring Project 2016 sample, drawing inferences on the geometry and structure of the low-ionization broad-line region (BLR) and the mass of the central supermassive black hole. Overall, we find that the Hβ BLR is generally a thick disk viewed at low to moderate inclination angles. We combine our sample with prior studies and investigate line-profile shape dependence, such as log10(FWHM/σ), on BLR structure and kinematics and search for any BLR luminosity-dependent trends. We find marginal evidence for an anticorrelation between the profile shape of the broad Hβ emission line and the Eddington ratio, when using the rms spectrum. However, we do not find any luminosity-dependent trends, and conclude that AGNs have diverse BLR structure and kinematics, consistent with the hypothesis of transient AGN/BLR conditions rather than systematic trends.Publisher PDFPeer reviewe

Multitargeted Low-Dose GLAD Combination Chemoprevention: A Novel and Promising Approach to Combat Colon Carcinogenesis

Preclinical studies have shown that gefitinib, licofelone, atorvastatin, and α-difluoromethylornithine (GLAD) are promising colon cancer chemopreventive agents. Because low-dose combination regimens can offer potential additive or synergistic effects without toxicity, GLAD combination was tested for toxicity and chemopreventive efficacy for suppression of intestinal tumorigenesis in adenomatous polyposis coli (APC)Min/+ mice. Six-week-old wild-type and APCMin/+ mice were fed modified American Institute of Nutrition 76A diets with or without GLAD (25 + 50 + 50 + 500 ppm) for 14 weeks. Dietary GLAD caused no signs of toxicity based on organ pathology and liver enzyme profiles. GLAD feeding strongly inhibited (80–83%, P < .0001) total intestinal tumor multiplicity and size in APCMin/+ mice (means ± SEM tumors for control vs GLAD were 67.1 ± 5.4 vs 11.3 ± 1.1 in males and 72.3 ± 8.9 vs 14.5 ± 2.8 in females). Mice fed GLAD had >95% fewer polyps with sizes of >2 mm compared with control mice and showed 75% and 85% inhibition of colonic tumors in males and females, respectively. Molecular analyses of polyps suggested that GLAD exerts efficacy by inhibiting cell proliferation, inducing apoptosis, decreasing β-catenin and caveolin-1 levels, increasing caspase-3 cleavage and p21, and modulating expression profile of inflammatory cytokines. These observations demonstrate that GLAD, a novel cocktail of chemopreventive agents at very low doses, suppresses intestinal tumorigenesis in APCMin/+ mice with no toxicity. This novel strategy to prevent colorectal cancer is an important step in developing agents with high efficacy without unwanted side effects

Endogenous n-3 Polyunsaturated Fatty Acids Delay Progression of Pancreatic Ductal Adenocarcinoma in Fat-1-p48Cre/+-LSL-KrasG12D/+ Mice

Preclinical studies suggest that diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be beneficial for prevention of pancreatic cancer. Nutritional intervention studies are often complex, and there is no clear evidence, without potential confounding factors, on whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection. Experiments were designed using n-3 fatty acid desaturase (Fat-1) transgenic mice, which can convert n-6 PUFA to n-3 FAs endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC). Six-weekold female p48Cre/+-LSL-KrasG12D/+ andcompoundFat-1-p48Cre/+-LSL-KrasG12D/+ mice were fed (AIN-76A) diets containing 10% safflower oil for 35 weeks. Pancreata were evaluated histopathologically for PanINs and PDAC. Results showed a dramatic reduction in incidence of PDAC (84%; P < .02) in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. Importantly, significant reductions of pancreatic ducts with carcinoma (90%; P < .0001) and PanIN 3 (∼50%; P < .001) lesions were observed in the compound transgenic mice. The levels of n-3 PUFA were much higher (>85%; P < .05–0.01) in pancreas of compound transgenic mice than in those of p48Cre/+-LSL-KrasG12D/+ mice. Molecular analysis of the pancreas showed a significant down-regulation of proliferating cell nuclear antigen, cyclooxygenase-2, 5-lipoxygenase (5-LOX), 5-LOX-activating protein, Bcl-2, and cyclin D1 expression levels in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. These data highlight the promise of dietary n-3 FAs for chemoprevention of pancreatic cancer in high-risk individuals