We identify sources with extremely hard X-ray spectra (i.e., with photon indices of Γ 0.6 ) in the 13 deg2 NuSTAR serendipitous survey, to search for the most highly obscured active galactic nuclei ...(AGNs) detected at > 10 keV . Eight extreme NuSTAR sources are identified, and we use the NuSTAR data in combination with lower-energy X-ray observations (from Chandra, Swift XRT, and XMM-Newton) to characterize the broadband (0.5-24 keV) X-ray spectra. We find that all of the extreme sources are highly obscured AGNs, including three robust Compton-thick (CT; N H > 1.5 × 10 24 cm−2) AGNs at low redshift ( z < 0.1 ) and a likely CT AGN at higher redshift (z = 0.16). Most of the extreme sources would not have been identified as highly obscured based on the low-energy ( < 10 keV) X-ray coverage alone. The multiwavelength properties (e.g., optical spectra and X-ray-mid-IR luminosity ratios) provide further support for the eight sources being significantly obscured. Correcting for absorption, the intrinsic rest-frame 10-40 keV luminosities of the extreme sources cover a broad range, from 5 × 10 42 to 1045 erg s−1. The estimated number counts of CT AGNs in the NuSTAR serendipitous survey are in broad agreement with model expectations based on previous X-ray surveys, except for the lowest redshifts ( z < 0.07 ), where we measure a high CT fraction of f CT obs = 30 − 12 + 16 % . For the small sample of CT AGNs, we find a high fraction of galaxy major mergers (50% 33%) compared to control samples of "normal" AGNs.
Background:
Fatigue is one of the most frequent and disabling symptoms in multiple sclerosis, but its pathophysiological mechanisms are poorly understood. It is in particular unclear whether and how ...fatigue relates to structural and functional brain changes.
Objective:
We aimed to analyse the association of fatigue severity with basal ganglia functional connectivity, basal ganglia volumes, white matter integrity and grey matter density.
Methods:
In 44 patients with relapsing–remitting multiple sclerosis and 20 age- and gender-matched healthy controls, resting-state fMRI, diffusion tensor imaging and voxel-based morphometry was performed.
Results:
In comparison with healthy controls, patients showed alteration of grey matter density, white matter integrity, basal ganglia volumes and basal ganglia functional connectivity. No association of fatigue severity with grey matter density, white matter integrity and basal ganglia volumes was observed within patients. In contrast, fatigue severity was negatively correlated with functional connectivity of basal ganglia nuclei with medial prefrontal cortex, precuneus and posterior cingulate cortex in patients. Furthermore, fatigue severity was positively correlated with functional connectivity between caudate nucleus and motor cortex.
Conclusion:
Fatigue is associated with distinct alterations of basal ganglia functional connectivity independent of overall disability. The pattern of connectivity changes suggests that disruption of motor and non-motor basal ganglia functions, including motivation and reward processing, contributes to fatigue pathophysiology in multiple sclerosis.
Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite (R‐138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with ...roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2‐week washout between periods. Ketoconazole decreased R‐138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34–61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R‐138727 exposure or prasugrel's inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrel's active metabolite AUC0–24 (area under the concentration–time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.
Clinical Pharmacology & Therapeutics (2007) 81, 735–741. doi:10.1038/sj.clpt.6100139; published online 14 March 2007
We discuss the spectral analysis of a sample of 63 active galactic nuclei (AGN) detected above a limiting flux of in the multi-tiered NuSTAR extragalactic survey program. The sources span a redshift ...range (median ). The spectral analysis is performed over the broad 0.5-24 keV energy range, combining NuSTAR with Chandra and/or XMM-Newton data and employing empirical and physically motivated models. This constitutes the largest sample of AGN selected at to be homogeneously spectrally analyzed at these flux levels. We study the distribution of spectral parameters such as photon index, column density ( ), reflection parameter ( ), and 10-40 keV luminosity ( ). Heavily obscured ( ) and Compton-thick (CT; ) AGN constitute ∼25% (15-17 sources) and ∼2-3% (1-2 sources) of the sample, respectively. The observed distribution agrees fairly well with predictions of cosmic X-ray background population-synthesis models (CXBPSM). We estimate the intrinsic fraction of AGN as a function of , accounting for the bias against obscured AGN in a flux-selected sample. The fraction of CT AGN relative to AGN is poorly constrained, formally in the range 2-56% (90% upper limit of 66%). We derived a fraction (fabs) of obscured AGN ( ) as a function of in agreement with CXBPSM and previous X-ray determinations. Furthermore, fabs at and agrees with observational measurements/trends obtained over larger redshift intervals. We report a significant anti-correlation of R with (confirmed by our companion paper on stacked spectra) with considerable scatter around the median R values.
We present a sample of 10 low-mass active galactic nuclei (AGNs) selected from the 40-month Nuclear Spectroscopic Telescope Array (NuSTAR) serendipitous survey. The sample is selected to have robust ...NuSTAR detections at , to be at , and to have optical r-band magnitudes at least 0.5 mag fainter than an galaxy at its redshift. The median values of absolute magnitude, stellar mass, and 2-10 X-ray luminosity of our sample are , , and erg s−1, respectively. Five objects have detectable broad H emission in their optical spectra, indicating black hole masses of . We find that of the galaxies in our sample do not show AGN-like optical narrow emission lines, and one of the 10 galaxies in our sample, J115851+4243.2, shows evidence for heavy X-ray absorption. This result implies that a non-negligible fraction of low-mass galaxies might harbor accreting massive black holes that are missed by optical spectroscopic surveys and X-ray surveys. The mid-IR colors of our sample also indicate that these optically normal low-mass AGNs cannot be efficiently identified with typical AGN selection criteria based on Wide Field Infrared Survey Explorer colors. While the hard ( keV) X-ray-selected low-mass AGN sample size is still limited, our results show that sensitive NuSTAR observations are capable of probing faint hard X-ray emission originating from the nuclei of low-mass galaxies out to moderate redshift ( ), thus providing a critical step in understanding AGN demographics in low-mass galaxies.
ABSTRACT Hot dust-obscured galaxies (hot DOGs), selected from Wide-Field Infrared Survey Explorer's all-sky infrared survey, host some of the most powerful active galactic nuclei known and may ...represent an important stage in the evolution of galaxies. Most known hot DOGs are located at , due in part to a strong bias against identifying them at lower redshift related to the selection criteria. We present a new selection method that identifies 153 hot DOG candidates at , where they are significantly brighter and easier to study. We validate this approach by measuring a redshift z = 1.009 and finding a spectral energy distribution similar to that of higher-redshift hot DOGs for one of these objects, WISE J1036+0449 ( ). We find evidence of a broadened component in Mg ii, which would imply a black hole mass of and an Eddington ratio of . WISE J1036+0449 is the first hot DOG detected by the Nuclear Spectroscopic Telescope Array, and observations show that the source is heavily obscured, with a column density of . The source has an intrinsic 2-10 keV luminosity of , a value significantly lower than that expected from the mid-infrared/X-ray correlation. We also find that other hot DOGs observed by X-ray facilities show a similar deficiency of X-ray flux. We discuss the origin of the X-ray weakness and the absorption properties of hot DOGs. Hot DOGs at could be excellent laboratories to probe the characteristics of the accretion flow and of the X-ray emitting plasma at extreme values of the Eddington ratio.
ABSTRACT
Possible connections between central black hole (BH) growth and host-galaxy compactness have been found observationally, which may provide insight into BH–galaxy coevolution: compact ...galaxies might have large amounts of gas in their centres due to their high mass-to-size ratios, and simulations predict that high central gas density can boost BH accretion. However, it is not yet clear if BH growth is fundamentally related to the compactness of the host galaxy, due to observational degeneracies between compactness, stellar mass (M⋆) and star formation rate (SFR). To break these degeneracies, we carry out systematic partial-correlation studies to investigate the dependence of sample-averaged BH accretion rate ($\rm \overline{BHAR}$) on the compactness of host galaxies, represented by the surface-mass density, Σe, or the projected central surface-mass density within 1 kpc, Σ1. We utilize 8842 galaxies with H < 24.5 in the five CANDELS fields at z = 0.5–3. We find that $\rm \overline{BHAR}$ does not significantly depend on compactness when controlling for SFR or M⋆ among bulge-dominated galaxies and galaxies that are not dominated by bulges, respectively. However, when testing is confined to star-forming galaxies at z = 0.5–1.5, we find that the $\rm \overline{BHAR}$–Σ1 relation is not simply a secondary manifestation of a primary $\rm \overline{BHAR}$–M⋆ relation, which may indicate a link between BH growth and the gas density within the central 1 kpc of galaxies.
Background: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y12 adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more ...variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized.
Objective: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel.
Methods: Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74).
Results: In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC0–24; P = 0.004) and maximal plasma concentration (Cmax; P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor‐responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC0–24 (P = 0.043), lower Cmax (P = 0.006), lower IPA (P = 0.046) and poor‐responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response.
Conclusions: The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.
ABSTRACT Using observations of the INTErnational Gamma-Ray Astrophysics Laboratory (INTEGRAL), we place upper limits on the gamma-ray and hard X-ray prompt emission associated with the gravitational ...wave event GW150914, which was discovered by the LIGO/Virgo Collaboration. The omnidirectional view of the INTEGRAL/SPI-ACS has allowed us to constrain the fraction of energy emitted in the hard X-ray electromagnetic component for the full high-probability sky region of LIGO triggers. Our upper limits on the hard X-ray fluence at the time of the event range from erg cm−2 to erg cm−2 in the 75 keV-2 MeV energy range for typical spectral models. Our results constrain the ratio of the energy promptly released in gamma-rays in the direction of the observer to the gravitational wave energy E E . We discuss the implication of gamma-ray limits for the characteristics of the gravitational wave source, based on the available predictions for prompt electromagnetic emission.
PDF
