Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of ...mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.
Abstract
We present mid-infrared (MIR; 7.5–13.5 μm) imaging and spectroscopy observations obtained with the CanariCam (CC) instrument on the 10.4-m Gran Telescopio CANARIAS for a sample of 20 nearby, ...MIR bright and X-ray luminous quasi-stellar objects (QSOs). We find that for the majority of QSOs the MIR emission is unresolved at angular scales ∼0.3 arcsec, corresponding to physical scales ≲600 pc. We find that the higher-spatial resolution CC spectra have similar shapes to those obtained with Spitzer/IRS, and hence we can assume that the spectra are not heavily contaminated by extended emission in the host galaxy. We thus take advantage of the higher signal-to-noise ratio Spitzer/IRS spectra, as a fair representation of the nuclear emission, to decompose it into a combination of active galactic nuclei (AGN), polycyclic aromatic hydrocarbon (PAH) and stellar components. In most cases, the AGN is the dominant component, with a median contribution of 85 per cent of the continuum light at MIR (5–15 μm) within the IRS slit. This IR AGN emission is well reproduced by clumpy torus models. We find evidence for significant differences in the parameters that describe the dusty tori of QSOs when compared with the same parameters of Seyfert 1 and 2 nuclei. In particular, we find a lower number of clouds (N
0 ≲ 12), steeper radial distribution of clouds (q ∼ 1.5–3.0) and clouds that are less optically thick (τ
V
≲ 100) than in Seyfert 1, which could be attributed to dusty structures that have been partially evaporated and piled up by the higher radiation field in QSOs. We find that the combination of the angular width σtorus, viewing angle i, and number of clouds along the equatorial line, N
0, produces large escape probabilities (P
esc > 2 per cent) and low geometrical covering factors (f
2 ≲ 0.6), as expected for AGN with broad lines in their optical spectra.
Background & Aims We assessed the accuracy of magnetic resonance enterography (MRE) in monitoring response to therapy in patients with Crohn’s disease (CD) using ileocolonoscopy as a reference ...standard. Methods We performed a prospective multicenter study of 48 patients with active CD and ulcers in at least one ileocolonic segment. All patients underwent ileocolonoscopy and MRE at baseline and 12 weeks after completing treatment with corticosteroids (CS) or anti−tumor necrosis factor agents. Disease activity was quantified using Crohn's Disease Endoscopic Index of Severity (CDEIS) and Magnetic Resonance Index of Activity (MaRIA). The primary analysis was to determine the accuracy of MRE in identification of healing, defined as the disappearance of ulcers in endoscopy examination. Additional analyses established the accuracy of MRE in determining endoscopic remission (a CDEIS score <3.5) and change in severity based on consideration of all segments. Results MRE determined ulcer healing with 90% accuracy and endoscopic remission with 83% accuracy. The mean CDEIS and MaRIA scores significantly changed at week 12 in segments with ulcer healing, based on endoscopic examination (CDEIS: 21.28 ± 9.10 at baseline vs 2.73 ± 4.12 at 12 weeks; P < .001 and MaRIA: 18.86 ± 9.50 at baseline vs 8.73 ± 5.88 at 12 weeks; P < .001). The MaRIA score accurately detected changes in lesion severity (Guyatt score: 1.2 and standardized effect size: 1.07). MRE was as reliable as endoscopy in assessing healing; no significant changes in CDEIS or MaRIA scores were observed in segments with persistent ulcers, based on endoscopic examination (CDEIS: 26.43 ± 9.06 at baseline vs 20.77 ± 9.13 at 12 weeks; P = .18 and MaRIA: 22.13 ± 8.42 at baseline vs 20.77 ± 9.17 at 12 weeks; P = .42). The magnitude of change in CDEIS scores correlated with those in MaRIA scores ( r = 0.51; P < .001). Conclusions MRE evaluates ulcer healing with a high level of accuracy when ileocolonoscopy is used as the reference standard. The MaRIA is a valid, responsive, and reliable index assessing response to therapy in patients with CD.
We investigate the evolutionary connection between local infrared (IR)-bright galaxies (...) and quasars. We use high-angular resolution (~0.3-0.4 arcsec ~ few hundred parsecs) 8-13 mu m ground-based ...spectroscopy to disentangle the active galactic nuclei (AGN) mid-IR properties from those of star formation. The comparison between the nuclear 11.3 mu m polycyclic aromatic hydrocarbon feature emission and that measured with Spitzer/Spitzer Infrared Spectrograph indicates that the star formation is extended over a few kpc in the IR-bright galaxies. The AGN contribution to the total IR luminosity of IR-bright galaxies is lower than in quasars. Although the dust distribution is predicted to change as IR-bright galaxies evolve to IR-bright quasars and then to optical quasars, we show that the AGN mid-IR emission of all the quasars in our sample is not significantly different. In contrast, the nuclear emission of IR-bright galaxies with low AGN contributions appears more heavily embedded in dust although there is no clear trend with the interaction stage or projected nuclear separation. This suggests that the changes in the distribution of the nuclear obscuring material may be taking place rapidly and at different interaction stages washing out the evidence of an evolutionary path. When compared to normal AGN, the nuclear star formation activity of quasars appears to be dimming, whereas it is enhanced in some IR-bright nuclei, suggesting that the latter are in an earlier star formation-dominated phase. (ProQuest: ... denotes formulae/symbols omitted.)
We present a statistical analysis of the properties of the obscuring material around active galactic nuclei (AGN). This study represents the first of its kind for an ultra-hard X-ray (14–195 keV;
...Swift
/BAT), volume-limited (
D
L
< 40 Mpc) sample of 24 Seyfert (Sy) galaxies (BCS
40
sample) using high angular resolution infrared data and various torus models: smooth, clumpy, and two-phase torus models and clumpy disc+wind models. We find that torus models (i.e. without including the polar dusty wind component) and disc+wind models provide the best fits for a comparable number of galaxies, 8 out of 24 (33.3%) and 9 out of 24 (37.5%), respectively. We find that the best-fit models depend on the hydrogen column density (
N
H
X−ray
), which is related to the X-ray (unobscured or obscured) and optical (Sy1/Sy2) classification. In particular, smooth, clumpy, and two-phase torus models are best at reproducing the infrared (IR) emission of AGN with relatively high hydrogen column density (median value of log (
N
H
X−ray
cm
−2
) = 23.5 ± 0.8; i.e. Sy2). However, clumpy disc+wind models provide the best fits to the nuclear IR spectral energy distributions (SEDs) of Sy1/1.8/1.9 (median value of log (
N
H
X−ray
cm
−2
) = 21.0 ± 1.0) – specifically, in the near-infrared (NIR) range. The success of the disc+wind models in fitting the NIR emission of Sy1 galaxies is due to the combination of adding large graphite grains to the dust composition and self-obscuration effects caused by the wind at intermediate inclinations. In general, we find that the Seyfert galaxies having unfavourable (favourable) conditions, namely, nuclear hydrogen column density and Eddington ratio, for launching IR dusty polar outflows are best-fitted with smooth, clumpy, and two-phase torus (disc+wind) models, confirming the predictions from simulations. Therefore, our results indicate that the nature of the inner dusty structure in AGN depends on the intrinsic AGN properties.
The objectives were to evaluate (1) the use of 2 types of experimental silos (S) to characterize whole-crop oat (Avena sativa L.) silage with or without addition of an inoculant (I), and (2) the ...effect of inoculation on the microbial community structure of oats ensiled using only plastic bucket silos (BKT). From each of 6 sections in a field, oats were harvested, treated (INO) or not (CON) with inoculant, packed into 19-L BKT or vacuum bags (BG), and ensiled for 217 d. The inoculant added contained Lactobacillus buchneri and Pediococcus pentosaceus (4 × 105 and 1 × 105 cfu/g of fresh oats, respectively). The experimental design was a complete randomized design replicated 6 times. Treatment design was the factorial combination of 2 S × 2 I. Some differences existed between BG versus BKT at silo opening (217 d), including a decreased CP (7.73 vs. 7.04 ± 0.247% of DM) and ethanol (1.93 vs. 1.55 ± 0.155) and increased lactic acid (4.28 vs. 3.65 ± 0.241), respectively. Also, WSC and mold counts were reduced in BG versus BKT for CON (1.78 vs. 2.70 ± 0.162% of DM and 0.8 vs. 2.82 ± 0.409 log cfu/fresh g) but not for INO (∼1.53 and 1.55), respectively. Application of INO increased DM recovery (96.1 vs. 92.9 ± 0.63%), aerobic stability (565 vs. 133 ± 29.2 h), acetic acid (2.38 vs. 1.22 ± 0.116% of DM), and reduced NDF (65.0 vs. 67.0 ± 0.57), ADF (36.7 vs. 38.1 ± 0.60), ethanol (0.63 vs. 2.85 ± 0.155), and yeast counts (1.10 vs. 4.13 ± 0.484 log cfu/fresh g) in INO versus CON, respectively. At d 0, no differences were found for S and I on the nutritional composition and background microbial counts. Leuconostocaceae (82.9 ± 4.27%) and Enterobacteriaceae (15.2 ± 3.52) were the predominant bacterial families and unidentified sequences were predominant for fungi. A higher relative abundance of the Davidiellaceae fungal family (34.3 vs. 19.6 ± 4.47) was observed in INO versus CON. At opening (217 d), INO had a lower relative abundance of Leuconostocaceae (42.3 vs. 95.8 ± 4.64) and higher Lactobacillaceae (57.4 vs. 3.9 ± 4.65) versus CON. Despite several differences were found between BKT and BG, both techniques can be comparable for characterizing effects of INO on the most basic measures used in silage evaluation. The use of inoculant improved oat silage quality partially by a shift in the bacterial community composition during ensiling, which mainly consisted of an increased relative abundance of Lactobacillaceae and reduction of Leuconostocaceae relative to CON.
We present 31.5 ...m imaging photometry of 11 nearby Seyfert galaxies observed from the Stratospheric Observatory For Infrared Astronomy (SOFIA) using the Faint Object infraRed CAmera for the SOFIA ...Telescope (FORCAST). We tentatively detect extended 31 ...m emission for the first time in our sample. In combination with this new data set, subarcsecond resolution 1-18 ...m imaging and 7.5-13 ...m spectroscopic observations were used to compute the nuclear spectral energy distribution (SED) of each galaxy. We found that the turnover of the torus emission does not occur at wavelengths less than or equal to 31.5 ...m, which we interpret as a lower-limit for the wavelength of peak emission. We used Clumpy torus models to fit the nuclear infrared (IR) SED and infer trends in the physical parameters of the AGN torus for the galaxies in the sample. Including the 31.5 ...m nuclear flux in the SED (1) reduces the number of clumpy torus models compatible with the data, and (2) modifies the model output for the outer radial extent of the torus for 10 of the 11 objects. Specifically, six (60 per cent) objects show a decrease in radial extent while four (40 per cent) show an increase. We find torus outer radii ranging from <1 to 8.4 pc. (ProQuest: ... denotes formulae/symbols omitted.)
We examine star formation activity in a distant (z < 0.1) and flux-limited sample of quasars (QSOs). Midinfrared (MIR) spectral diagnostics at high spatial resolution (∼0.4 arcsec) yield star ...formation rates (SFRs) in the inner regions (∼300 pc-1 kpc) for 13 of 20 of the sample members. We group these objects according to the size probed by the high angular resolution spectroscopy, with characteristic scales of <0.7 and ∼0.7-1 kpc. Using the polycyclic aromatic hydrocarbon (PAH) feature at 11.3 m, we measure SFRs around 0.2 and 1.6 M yr−1. We also measure the larger aperture PAH-derived SFRs in the individual IRS/Spitzer spectra of the sample and obtain a clear detection in ∼58% of them. We compare smaller and larger aperture measurements and find that they are similar, suggesting that star formation activity in these QSOs is more centrally concentrated, with the inner region ( 1 kpc) accounting for the majority of star formation measured on these scales, and that PAH molecules can be present in most local MIR-bright QSOs within a few hundred parsecs from the central engine. By comparison with merger simulations, we find that our estimation of the SFR and black hole (BH) accretion rates are consistent with a scenario in which the star formation activity is centrally peaked as predicted by simulations.
Finding strategies to use the swim bladder of farmed totoaba (
) is of the utmost need to reduce waste. Fish swim bladders are rich in collagen; hence, extracting collagen is a promising alternative ...with benefits for aquaculture of totoaba and the environment. The elemental biochemical composition of totoaba swim bladders, including their proximate and amino acid compositions, was determined. Pepsin-soluble collagen (PSC) was used to extract collagen from swim bladders, and its characteristics were analyzed. Alcalase and papain were used for the preparation of collagen hydrolysates. Swim bladders contained 95% protein, 2.4% fat, and 0.8% ash (on a dry basis). The essential amino acid content was low, but the functional amino acid content was high. The PSC yield was high, at 68% (dry weight). The amino acid composition profile, electrophoretic pattern, and structural integrity analyses of the isolated collagen suggested it is a typical type-I collagen with high purity. The denaturalization temperature was 32.5 °C, probably attributable to the imino acid content (205 residues/1000 residues). Papain-hydrolysates (≤3 kDa) of this collagen exhibited higher radical scavenging activity than Alcalase-hydrolysates. The swim bladder from the farmed totoaba could be an ideal source to produce high-quality type I collagen and may be considered an alternative to conventional collagen sources or bioactive peptides.
Disruption of the histone modification patterns is one of the most common features of human tumors. However, few genetic alterations in the histone modifier genes have been described in ...tumorigenesis. Herein we show that the histone methyltransferase SETDB1 undergoes gene amplification in non-small and small lung cancer cell lines and primary tumors. The existence of additional copies of the SETDB1 gene in these transformed cells is associated with higher levels of the corresponding mRNA and protein. From a functional standpoint, the depletion of SETDB1 expression in amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases the tumor invasiveness. The increased gene dosage of SETDB1 is also associated with enhanced sensitivity to the growth inhibitory effect mediated by the SETDB1-interfering drug mithramycin. Overall, the findings identify SETDB1 as a bona fide oncogene undergoing gene amplification-associated activation in lung cancer and suggest its potential for new therapeutic strategies.
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