Super-Eddington accretion on to the neutron star NGC7793 P13: Broad-band X-ray spectroscopy and ultraluminous X-ray sources

We present a detailed, broad-band X-ray spectral analysis of the ultraluminous X-ray source (ULX) pulsar NGC 7793 P13, a known super-Eddington source, utilizing data from the XMM–Newton, NuSTAR and Chandra observatories. The broad-band XMM–Newton+NuSTAR spectrum of P13 is qualitatively similar to the rest of the ULX sample with broad-band coverage, suggesting that additional ULXs in the known population may host neutron star accretors. Through time-averaged, phase-resolved and multi-epoch studies, we find that two non-pulsed thermal blackbody components with temperatures ∼0.5 and 1.5 keV are required to fit the data below 10 keV, in addition to a third continuum component which extends to higher energies and is associated with the pulsed emission from the accretion column. The characteristic radii of the thermal components appear to be comparable, and are too large to be associated with the neutron star itself, so the need for two components likely indicates the accretion flow outside the magnetosphere is complex. We suggest a scenario in which the thick inner disc expected for super-Eddington accretion begins to form, but is terminated by the neutron star's magnetic field soon after its onset, implying a limit of B ≲ 6 × 1012 G for the dipolar component of the central neutron star's magnetic field. Evidence of similar termination of the disc in other sources may offer a further means of identifying additional neutron star ULXs. Finally, we examine the spectrum exhibited by P13 during one of its unusual ‘off’ states. These data require both a hard power-law component, suggesting residual accretion on to the neutron star, and emission from a thermal plasma, which we argue is likely associated with the P13 system

Discovery of coherent pulsations from the Ultraluminous X-ray Source NGC 7793 P13

We report the detection of coherent pulsations from the ultraluminous X-ray source (ULX) NGC 7793 P13. The ≈0.42 s nearly sinusoidal pulsations were initially discovered in broadband X-ray observations using XMM-Newton and NuSTAR taken in 2016. We subsequently also found pulsations in archival XMM-Newton data taken in 2013 and 2014. The significant (≫5σ) detection of coherent pulsations demonstrates that the compact object in P13 is a neutron star, and given the observed peak luminosity of ≈10⁴⁰ erg s⁻¹ (assuming isotropy), it is well above the Eddington limit for a 1.4 M⨀ accretor. This makes P13 the second ULX known to be powered by an accreting neutron star. The pulse period varies between epochs, with a slow but persistent spin-up over the 2013–2016 period. This spin-up indicates a magnetic field of B ≈ 1.5 × 10¹² G, typical of many Galactic accreting pulsars. The most likely explanation for the extreme luminosity is a high degree of beaming; however, this is difficult to reconcile with the sinusoidal pulse profile.We would like the thank the referee for the helpful comments. M.J.M. acknowledges support from an STFC Ernest Rutherford fellowship and D.B. acknowledges financial support from the French Space Agency (CNES). This research has made use of data obtained with NuSTAR, a project led by Caltech, funded by NASA and managed by NASA/JPL, and has utilized the nustardas software package, jointly developed by the ASDC (Italy) and Caltech (USA). This research has also made use of data obtained with XMM-Newton, an ESA science mission with instruments and contributions directly funded by ESA Member States. This work made use of data supplied by the UK Swift Science Data Centre at the University of Leicester, and also made use of the XRT Data Analysis Software (XRTDAS) developed under the responsibility of the ASI Science Data Center (ASDC), Italy. This research has made use of a collection of ISIS functions (ISISscripts) provided by ECAP/Remeis observatory and MIT (http://www.sternwarte.uni-erlangen.de/isis/). Facilities: NuSTAR - The NuSTAR (Nuclear Spectroscopic Telescope Array) mission, XMM - , Swift -

Computational and Mathematical Modelling of the EGF Receptor System

This chapter gives an overview of computational and mathematical modelling of the EGF receptor system. It begins with a survey of motivations for producing such models, then describes the main approaches that are taken to carrying out such modelling, viz. differential equations and individual-based modelling. Finally, a number of projects that applying modelling and simulation techniques to various aspects of the EGF receptor system are described

An iron K component to the ultrafast outflow in NGC 1313 X-1

We present the detection of an absorption feature at $E$ = 8.77$^{+0.05}_{-0.06}$ keV in the combined X-ray spectrum of the ultraluminous X-ray source NGC 1313 X-1 observed with $\textit{XMM-Newton}$ and $\textit{NuSTAR}$, significant at the 3$\sigma$ level. If associated with blueshifted ionized iron, the implied outflow velocity is ~0.2$c$ for Fe XXVI, or ~0.25$c$ for Fe XXV. These velocities are similar to the ultrafast outflow seen in absorption recently discovered in this source at lower energies by $\textit{XMM-Newton}$, and we therefore conclude that this is an iron component to the same outflow. Photoionization modeling marginally prefers the Fe XXV solution, but in either case the outflow properties appear to be extreme, potentially supporting a super-Eddington hypothesis for NGC 1313 X-1.M.J.M. acknowledges support from an STFC Ernest Rutherford fellowship, C.P. and A.C.F. acknowledge support from ERC Advanced Grant 340442, and D.B. acknowledges financial support from the French Space Agency (CNES). This research has made use of data obtained with NuSTAR, a project led by Caltech, funded by NASA, and managed by NASA/JPL, and has utilized the NUSTARDAS software package, jointly developed by the ASDC (Italy) and Caltech (USA). This research has also made use of data obtained with XMM-Newton, an ESA science mission with instruments and contributions directly funded by ESA Member States

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

BioDMET: a physiologically based pharmacokinetic simulation tool for assessing proposed solutions to complex biological problems

We developed a detailed, whole-body physiologically based pharmacokinetic (PBPK) modeling tool for calculating the distribution of pharmaceutical agents in the various tissues and organs of a human or animal as a function of time. Ordinary differential equations (ODEs) represent the circulation of body fluids through organs and tissues at the macroscopic level, and the biological transport mechanisms and biotransformations within cells and their organelles at the molecular scale. Each major organ in the body is modeled as composed of one or more tissues. Tissues are made up of cells and fluid spaces. The model accounts for the circulation of arterial and venous blood as well as lymph. Since its development was fueled by the need to accurately predict the pharmacokinetic properties of imaging agents, BioDMET is more complex than most PBPK models. The anatomical details of the model are important for the imaging simulation endpoints. Model complexity has also been crucial for quickly adapting the tool to different problems without the need to generate a new model for every problem. When simpler models are preferred, the non-critical compartments can be dynamically collapsed to reduce unnecessary complexity. BioDMET has been used for imaging feasibility calculations in oncology, neurology, cardiology, and diabetes. For this purpose, the time concentration data generated by the model is inputted into a physics-based image simulator to establish imageability criteria. These are then used to define agent and physiology property ranges required for successful imaging. BioDMET has lately been adapted to aid the development of antimicrobial therapeutics. Given a range of built-in features and its inherent flexibility to customization, the model can be used to study a variety of pharmacokinetic and pharmacodynamic problems such as the effects of inter-individual differences and disease-states on drug pharmacokinetics and pharmacodynamics, dosing optimization, and inter-species scaling. While developing a tool to aid imaging agent and drug development, we aimed at accelerating the acceptance and broad use of PBPK modeling by providing a free mechanistic PBPK software that is user friendly, easy to adapt to a wide range of problems even by non-programmers, provided with ready-to-use parameterized models and benchmarking data collected from the peer-reviewed literature

NuStar observations of WISE J1036+0449, a galaxy at z ∼ 1 obscured by hot dust

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 z> 1.5, 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 z˜ 1, 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 ({L}{Bol}≃ 8× {10}46 {erg} {{{s}}}-1). We find evidence of a broadened component in Mg II, which would imply a black hole mass of {M}{BH}≃ 2× {10}8 {M}⊙ and an Eddington ratio of {λ }{Edd}≃ 2.7. 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 {N}{{H}}≃ (2{--}15)× {10}23 {{cm}}-2. The source has an intrinsic 2-10 keV luminosity of ˜ 6× {10}44 {erg} {{{s}}}-1, 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 z≲ 1 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

Expression of excess receptors and negative feedback control of signal pathways are required for rapid activation and prompt cessation of signal transduction

Cellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors. Receptors are often expressed in excess, and cells are activated when a small number of receptors bind ligands. Intracellular signal proteins are act

Living on a Flare: Relativistic Reflection in V404 Cyg Observed by NuSTAR during Its Summer 2015 Outburst

We present first results from a series of $\textit{NuSTAR}$ observations of the black hole X-ray binary V404 Cyg obtained during its summer 2015 outburst, primarily focusing on observations during the height of this outburst activity. The $\textit{NuSTAR}$ data show extreme variability in both the flux and spectral properties of the source. This is partly driven by strong and variable line-of-sight absorption, similar to previous outbursts. The latter stages of this observation are dominated by strong flares, reaching luminosities close to Eddington. During these flares, the central source appears to be relatively unobscured and the data show clear evidence for a strong contribution from relativistic reflection, providing a means to probe the geometry of the innermost accretion flow. Based on the flare properties, analogies with other Galactic black hole binaries, and also the simultaneous onset of radio activity, we argue that this intense X-ray flaring is related to transient jet activity during which the ejected plasma is the primary source of illumination for the accretion disk. If this is the case, then our reflection modeling implies that these jets are launched in close proximity to the black hole (as close as a few gravitational radii), consistent with expectations for jet launching models that tap either the spin of the central black hole, or the very innermost accretion disk. Our analysis also allows us to place the first constraints on the black hole spin for this source, which we find to be ${a}^{* }\gt 0.92$ (99% statistical uncertainty, based on an idealized lamp-post geometry).D.J.W., P.G., and M.J.M. acknowledge support from STFC Ernest Rutherford fellowships (grant ST/J003697/2). K.P.M. acknowledges support from the Hintze Foundation. A.L.K. acknowledges support from NASA through an Einstein Postdoctoral Fellowship (grant number PF4-150125) awarded by the Chandra X-ray Center, operated by the Smithsonian Astrophysical Observatory for NASA under contract NAS8-03060. A.C.F. acknowledges support from ERC Advanced Grant 340442. L.N. wishes to acknowledge the Italian Space Agency (ASI) for Financial support by ASI/INAF grant I/037/12/0-011/13. This research has made use of data obtained with NuSTAR, a project led by Caltech, funded by NASA and managed by NASA/JPL, and has utilized the NUSTARDAS software package, jointly developed by the ASDC (Italy) and Caltech (USA). This research has also made use of data from AMI, which is supported by the ERC, and we thank the AMI staff for scheduling these radio observations

Positional Information Generated by Spatially Distributed Signaling Cascades

The temporal and stationary behavior of protein modification cascades has been extensively studied, yet little is known about the spatial aspects of signal propagation. We have previously shown that the spatial separation of opposing enzymes, such as a kinase and a phosphatase, creates signaling activity gradients. Here we show under what conditions signals stall in the space or robustly propagate through spatially distributed signaling cascades. Robust signal propagation results in activity gradients with long plateaus, which abruptly decay at successive spatial locations. We derive an approximate analytical solution that relates the maximal amplitude and propagation length of each activation profile with the cascade level, protein diffusivity, and the ratio of the opposing enzyme activities. The control of the spatial signal propagation appears to be very different from the control of transient temporal responses for spatially homogenous cascades. For spatially distributed cascades where activating and deactivating enzymes operate far from saturation, the ratio of the opposing enzyme activities is shown to be a key parameter controlling signal propagation. The signaling gradients characteristic for robust signal propagation exemplify a pattern formation mechanism that generates precise spatial guidance for multiple cellular processes and conveys information about the cell size to the nucleus