Determination of the X-ray reflection emissivity profile of 1H 0707-495

When considering the X-ray spectrum resulting from the reflection off the surface of accretion discs of AGN, it is necessary to account for the variation in reflected flux over the disc, i.e. the emissivity profile. This will depend on factors including the location and geometry of the X-ray source and the disc characteristics. We directly obtain the emissivity profile of the disc from the observed spectrum by considering the reflection component as the sum of contributions from successive radii in the disc and fitting to find the relative weightings of these components in a relativistically-broadened emission line. This method has successfully recovered known emissivity profiles from synthetic spectra and is applied to XMM-Newton spectra of the Narrow Line Seyfert 1 galaxy 1H 0707-495. The data imply a twice-broken power law form of the emissivity law with a steep profile in the inner regions of the disc (index 7.8) and then a flat region between 5.6rg and 34.8rg before tending to a constant index of 3.3 over the outer regions of the disc. The form of the observed emissivity profile is consistent with theoretical predictions, thus reinforcing the reflection interpretation.Comment: 9 pages, 10 figures. Accepted for publication in MNRA

Models for the X-ray spectra and variability of luminous accreting black holes

The X-ray spectra of luminous Seyfert 1 galaxies often appear to be reflection dominated. In a number of Narrow Line Seyfert 1 (NLS1) galaxies and galactic black holes in the very high state, the variability of the continuum and of the iron line are decoupled, the reflected component being often much less variable than the continuum. These properties have been interpreted as effects of gravitational light bending. In this framework, we present detailed Monte-Carlo simulations of the reflection continuum in the Kerr metric. These calculations confirm that the spectra and variability behaviour of these sources can be reproduced by the light bending model. As an alternative to the light bending model, we show that similar observational properties are expected from radiation pressure dominated discs subject to violent clumping instabilities and, as a result, have a highly inhomogeneous two-phase structure. In this model, most of the observed spectral and variability features originate from the complex geometrical structure of the inner regions of near-Eddington accretion flows and are therefore a signature of accretion physics rather than general relativity

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

SummaryRIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective “hybrid” RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies

Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors

Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pankinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed > 10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity

Gravitational effects on the high energy emission of accreting black holes

We extend the investigation of general relativistic effects on the observed X-ray continuum of Kerr black holes in the context of the light bending model (Miniutti & Fabian, 2004). Assuming a ring-like illuminating source, co-rotating with the underlying accretion disk, we study the shape and normalisation of the primary and disc reflected continuum as well as the dependence of the observed spectrum on the line of sight for various source heights and radii. These calculations are performed using Monte-Carlo methods to compute the angle dependent reflection spectrum from the disc. The effects of general relativity are illustrated by a comparison with Newtonian and Special Relativity calculations. We find that relativistic distortions can strongly affect the shape of the reflected spectrum. Light bending can dramatically increase the observable reflected flux and reduce the primary emission. In addition, multiple reflections due to the reflected photons deflected toward the disc can alter significantly the shape of the spectrum above 10 keV. Large variations of the ring radius at constant height can lead to an (unobserved) anti-correlation between primary and reflected flux. In another side, the variability behaviour of several sources can be reproduced if the ring source radius is small (<5 r_g), and its height varies by a large factor. In particular, a non-linear flux-flux relation, similar to that observed in several sources, can be produced. We compare our model with the flux-flux plot of NGC4051, and find an agreement for low inclination angles (<20 deg.), ring source radius <3 r_g and a height varying between 0.5 to 10 r_g.Comment: 13 pages, 18 figures. Accepted for publication in A&

XMM-Newton and Broad Iron Lines

Iron line emission is common in the X-ray spectra of accreting black holes. When the line emission is broad or variable then it is likely to originate from close to the black hole. X-ray irradiation of the accretion flow by the power-law X-ray continuum produces the X-ray 'reflection' spectrum which includes the iron line. The shape and variability of the iron lines and reflection can be used as a diagnostic of the radius, velocity and nature of the flow. The inner radius of the dense flow corresponds to the innermost stable circular orbit and thus can be used to determine the spin of the black hole. Studies of broad iron lines and reflection spectra offer much promise for understanding how the inner parts of accretion flows (and outflows) around black holes operate. There remains great potential for XMM-Newton to continue to make significant progress in this work. The need for high quality spectra and thus for long exposure times is paramount.Comment: 7 pages, 18 figures, accepted for publication in Astron. Nachr. (ESAC Conference

Effets relativistes sur l'émission haute énergie des trous noirs

Many recent observations show the existence of the relativistic effects in the black hole radiation (broad iron line, variability).I present the numerical tools for consistent calculations of the relativistic effects (gravitational shift, light bending effect) in the X and gamma rays radiation process around the black holes. These calculations based on Monte-Carlo methods allow to take the angular dependence of the source emission into account. Optimization methods are also presented because the calculation time can become considerably important. These numerical tools are applied to study the behavior of photons and leptons in the Kerr geometry, the influence of the source's position relative to the black hole centre and of the emission angle, as well as the observational effects on the emission of the disc located in the equatorial plane. The study uses an axisymmetric model consisting of a ring-like X-rays source above an accretion disc around a rotating black hole. The observed spectra are the superposition of the primary component directly from the source and the reflection component from the disc. The shape, the normalization, and the angular dependence of both components are investigated by varying the source radius and the distance between the source and the disc. The general relativistic effects are illustrated by a comparison with Newtonian and Special Relativity calculations. The multiple reflections are taken into account for the reflected photons returning to the disc by the light bending effects and their influence quantified. Finally, in order to compare our results with the observations, we investigated the relation between the primary component and the reflection component predicted by the model when the source position varies. The obtained results can reproduce the relation established from the observed data from NGC 4051, and give information on the variation of the source position. I have demonstrated that the relativistic effects are very important in the regions close to black holes and can not be neglected in the high energy emission spectra. I show as well how the relevant numerical tools (including optimization methods) can be integrated in numerical radiative transfer calculations.Plusieurs observations récentes semblent montrer l'existence d'effets relativistes dans l'émission des trous noirs (raie de fluorescence du Fer large, variabilité). Je présente des outils numériques pour calculer les effets relativistes (le décalage gravitationnel, la courbure de l'espace-temps) de manière cohérente dans les processus de rayonnement X et gamma autour des trous noirs. Ces codes basés sur des méthodes Monte-Carlo permettent de prendre en compte la dépendance angulaire de l'émission de la source. Les méthodes d'optimisation des codes sont aussi présentées car les temps de calcul peuvent devenir considérablement élevés. Ces outils sont appliqués pour étudier le comportement des photons et des leptons en métrique de Kerr, l'influence de la position de la source par rapport au trou noir et de l'angle d'émission, ainsi que les effets observables sur l'émission d'un disque localisé dans le plan équatorial. Le modèle axisymétrique utilisé comprend une source X en forme d'anneau située au dessus d'un disque d'accrétion autour d'un trou noir en rotation. Les spectres observés sont la superposition de la composante primaire, observée directement de la source, et de la composante réfléchie par le disque. La forme, la normalisation et la dépendance angulaire des deux composantes sont étudiées en faisant varier le rayon de l'anneau et la distance entre la source et le disque. Les effets de la relativité générale sont mis en évidence par comparaison avec les résultats obtenus en métrique Newtonienne et en relativité restreinte. Les réflexions multiples sont prises en compte, pour les photons réfléchis qui retournent vers le disque d'accrétion en raison de la courbure de l'espace, et leur influence quantifiée. Finalement, afin de confronter nos calculs aux observations, nous avons regardé la relation prédite par notre modèle, entre la composante directe et la composante réfléchie, quand la position de la source varie. Les résultats obtenus reproduisent bien les données reportées pour la source NGC4051, et donnent alors des informations sur la variation de la position de la source. J'ai donc démontré que les effets relativistes sont très importants dans la région proche du trou noir et ne peuvent être négligés dans les spectres d'émission à haute énergie. Je montre également comment les outils numériques correspondants (incluant des méthodes d'optimisation) peuvent être incorporés dans les codes de transfert de rayonnemen

Structure-Based Design of Selective RIPK1 and RIPK2 Inhibitors

Kinases regulate various biological functions by post-translational phosphorylation of proteins. Kinase dysfunction is associated with many pathological conditions. Therefore, kinase inhibitors have become an important class of drugs and chemical biology probes for mechanistic studies of diseases. This dissertation focuses on a structural-based design of selective RIPK1 and RIPK2 inhibitors using various approaches. Chapter 1 presents an introduction to protein kinases and a review of kinase inhibitor types for understanding the rationale and design of selective RIPK1 and RIPK2 inhibitors. Chapter 2 describes two design strategies to potent and selective RIPK1 inhibition. The first strategy involves modifications of ponatinib, a type II Abl kinase inhibitor, exploiting differences in the steric and hydrophilic characteristics of Abl and RIPK1 gatekeeper residues. An introduction of tert-butyl on the central phenyl (CS5) caused unfavorable interactions with Abl’s gatekeeper and resulted in significantly improved selectivity for RIPK1 versus Abl/RIPK2/RIPK3. To improve cellular activity, a hybridization strategy linking ponatinib and Nec-1, a type III RIPK1 inhibitor, was pursued. PN10 displayed selectivity for RIPK1 inhibition and better RIPK1 cellular activity than either Nec-1 or ponatinib. In Chapter 3, strategies to develop selective type II RIPK2 inhibitors based on regorafenib, a VEGFR inhibitor, are presented. The first strategy is based on structural differences between RIPK2 and VEGFR around allosteric hydrophobic pocket and gatekeeper residues. The second strategy targeted the activation loop, a region of kinases with diverse amino acid sequences. CSR35 was identified and shown to form an interaction with the activation loop. A RIPK2CSR35 co-crystal structure revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in CSR35 and Lys169. Chapter 4 presents a hybridization strategy between ALK2 type I inhibitor LDN-214117 and B-Raf type I½ inhibitor PLX4032 as an approach to conformational distinct αC-helix-displacing RIPK2 inhibitors. Potent and selective RIPK2 inhibitors (CSLP43 and CSLP37) were achieved through modifications of the trimethoxyphenyl in LDN-214117 that occupies the hydrophobic pocket in RIPK2 next to the αC-helix. RIPK2inhibitor co-crystal structures of several derivatives suggested that they bind in a type I mode. However, further analysis of CSLP43 and CSLP37 is warranted since they display greater cellular potency.Chemistry, Department o

Effets relativistes sur l'émission haute énergie des trous noirs

TOULOUSE3-BU Sciences (315552104) / SudocTOULOUSE-Observ. Midi Pyréné (315552299) / SudocSudocFranceF