An X-ray variable absorber within the Broad Line Region in Fairall 51

Fairall 51 is a polar-scattered Seyfert 1 galaxy, a type of active galaxies believed to represent a bridge between unobscured type-1 and obscured type-2 objects. Fairall 51 has shown complex and variable X-ray absorption but only little is known about its origin. In our research, we observed Fairall 51 with the X-ray satellite Suzaku in order to constrain a characteristic time-scale of its variability. We performed timing and spectral analysis of four observations separated by 1.5, 2 and 5.5 day intervals. We found that the 0.5-50 keV broadband X-ray spectra are dominated by a primary power-law emission (with the photon index ~ 2). This emission is affected by at least three absorbers with different ionisations (log(xi) ~ 1-4). The spectrum is further shaped by a reprocessed emission, possibly coming from two regions -- the accretion disc and a more distant scattering region. The accretion disc emission is smeared by the relativistic effects, from which we measured the spin of the black hole as a ~ 0.8 (+-0.2). We found that most of the spectral variability can be attributed to the least ionised absorber whose column density changed by a factor of two between the first (highest-flux) and the last (lowest-flux) observation. A week-long scale of the variability indicates that the absorber is located at the distance ~ 0.05 pc from the centre, i.e., in the Broad Line Region.Comment: 12 pages, 9 figures, accepted to A&

pH homeostasis links the nutrient sensing PKA/TORC1/Sch9 ménage-à-trois to stress tolerance and longevity

The plasma membrane H+-ATPase Pma1 and the vacuolar V-ATPase act in close harmony to tightly control pH homeostasis, which is essential for a vast number of physiological processes. As these main two regulators of pH are responsive to the nutritional status of the cell, it seems evident that pH homeostasis acts in conjunction with nutrient-induced signalling pathways. Indeed, both PKA and the TORC1-Sch9 axis influence the proton pumping activity of the V-ATPase and possibly also of Pma1. In addition, it recently became clear that the proton acts as a second messenger to signal glucose availability via the V-ATPase to PKA and TORC1-Sch9. Given the prominent role of nutrient signalling in longevity, it is not surprising that pH homeostasis has been linked to ageing and longevity as well. A first indication is provided by acetic acid, whose uptake by the cell induces toxicity and affects longevity. Secondly, vacuolar acidity has been linked to autophagic processes, including mitophagy. In agreement with this, a decline in vacuolar acidity was shown to induce mitochondrial dysfunction and shorten lifespan. In addition, the asymmetric inheritance of Pma1 has been associated with replicative ageing and this again links to repercussions on vacuolar pH. Taken together, accumulating evidence indicates that pH homeostasis plays a prominent role in the determination of ageing and longevity, thereby providing new perspectives and avenues to explore the underlying molecular mechanisms.Support via the research grants G.0694.13, G.0A63.15 and SBO-S006617N. We also thank KU Leuven for support by granting the C14/17/063 projectinfo:eu-repo/semantics/publishedVersio

Collaborative Service Blueprinting for Design Thinking: Evaluation of a Digital Prototype

A high degree of innovation is becoming a decisive factor for companies aiming at sustainable competitive advantages. New methods of innovation have become increasingly important in practice. Using such methods in globally operating teams requires location- and time-independent solutions such as web-based collaboration tools. This paper evaluates the ability to digitalize the service innovation method Service Blueprinting using a selfdeveloped prototype. The prototype is evaluated thoroughly in two different studies. In-depth user tests with Design Thinking experts and laymen prove the suitability for Design Thinking and the interaction with the prototype from a HCI perspective. Additionally, we evaluate the acceptance, perceived usefulness and effectiveness quantitatively in the light of the prototype’s collaboration capability. The results indicate the transferability of the required mindset through the digital tool as well as its the acceptance and usefulness. It represents a practical and suitable solution for the digitalizing of Service Blueprinting

X-ray Variability Study of Polar Scattered Seyfert 1 Galaxies

We study 12 Seyfert 1 galaxies with a high level of optical polarization. Optical light emerging from the innermost regions is predominantly scattered in a polar region above the central engine directly in our line of sight. These sources show characteristics of Seyfert 2 galaxies such as, e.g., polarized broad lines. The polarization signatures suggest a viewing angle of 45 degrees classifying them as intermediate Seyfert 1/2 types. The unified model predicts this line of sight to pass through the outer layer of the torus resulting in significant soft X-ray variability due to a strongly varying column density. The aim is to find evidence for this geometrical assumption in the spectral variability of all available historical observations of these sources by XMM-Newton and Swift.Comment: Conference proceedings for the 10th INTEGRAL/BART Workshop on 22-25 April 2013, Karlovy Vary (Carlsbad), Czech Republi

Nebulization of PEGylated recombinant human deoxyribonuclease I using vibrating membrane nebulizers:A technical feasibility study

Recombinant human deoxyribonuclease I (rhDNase, Pulmozyme®) is the most frequently used mucolytic agent for the symptomatic treatment of cystic fibrosis (CF) lung disease. Conjugation of rhDNase to polyethylene glycol (PEG) has been shown to greatly prolong its residence time in the lungs and improve its therapeutic efficacy in mice. To present an added value over current rhDNase treatment, PEGylated rhDNase needs to be efficiently and less frequently administrated by aerosolization and possibly at higher concentrations than existing rhDNase. In this study, the effects of PEGylation on the thermodynamic stability of rhDNase was investigated using linear 20 kDa, linear 30 kDa and 2-armed 40 kDa PEGs. The suitability of PEG30-rhDNase to electrohydrodynamic atomization (electrospraying) as well as the feasibility of using two vibrating mesh nebulizers, the optimized eFlow® Technology nebulizer (eFlow) and Innospire Go, at varying protein concentrations were investigated. PEGylation was shown to destabilize rhDNase upon chemical-induced denaturation and ethanol exposure. Yet, PEG30-rhDNase was stable enough to withstand aerosolization stresses using the eFlow and Innospire Go nebulizers even at higher concentrations (5 mg of protein per ml) than conventional rhDNase formulation (1 mg/ml). High aerosol output (up to 1.5 ml per min) and excellent aerosol characteristics (up to 83% fine particle fraction) were achieved while preserving protein integrity and enzymatic activity. This work demonstrates the technical feasibility of PEG-rhDNase nebulization with advanced vibrating membrane nebulizers, encouraging further pharmaceutical and clinical developments of a long-acting PEGylated alternative to rhDNase for treating patients with CF.</p

Biodistribution and elimination pathways of PEGylated recombinant human deoxyribonuclease I after pulmonary delivery in mice

Conjugation of recombinant human deoxyribonuclease I (rhDNase) to polyethylene glycol (PEG) of 20 to 40 kDa was previously shown to prolong the residence time of rhDNase in the lungs of mice after pulmonary delivery while preserving its full enzymatic activity. This work aimed to study the fate of native and PEGylated rhDNase in the lungs and to elucidate their biodistribution and elimination pathways after intratracheal instillation in mice. In vivo fluorescence imaging revealed that PEG30 kDa-conjugated rhDNase (PEG30-rhDNase) was retained in mouse lungs for a significantly longer period of time than native rhDNase (12 days vs 5 days). Confocal microscopy confirmed the presence of PEGylated rhDNase in lung airspaces for at least 7 days. In contrast, the unconjugated rhDNase was cleared from the lung lumina within 24 h and was only found in lung parenchyma and alveolar macrophages thereafter. Systemic absorption of intact rhDNase and PEG30-rhDNase was observed. However, this was significantly lower for the latter. Catabolism, primarily in the lungs and secondarily systemically followed by renal excretion of byproducts were the predominant elimination pathways for both native and PEGylated rhDNase. Catabolism was nevertheless more extensive for the native protein. On the other hand, mucociliary clearance appeared to play a less prominent role in the clearance of those proteins after pulmonary delivery. The prolonged presence of PEGylated rhDNase in lung airspaces appears ideal for its mucolytic action in patients with cystic fibrosis

The Soft-Excess in Mrk 509: Warm Corona or Relativistic Reflection?

We present the analysis of the first NuSTAR observations ($\sim 220$ ks), simultaneous with the last SUZAKU observations ($\sim 50$ ks), of the active galactic nucleus of the bright Seyfert 1 galaxy Mrk 509. The time-averaged spectrum in the $1-79$ keV X-ray band is dominated by a power-law continuum ($\Gamma\sim 1.8-1.9$), a strong soft excess around 1 keV, and signatures of X-ray reflection in the form of Fe K emission ($\sim 6.4$ keV), an Fe K absorption edge ($\sim 7.1$ keV), and a Compton hump due to electron scattering ($\sim 20-30$ keV). We show that these data can be described by two very different prescriptions for the soft excess: a warm ($kT\sim 0.5-1$ keV) and optically thick ($\tau\sim10-20$) Comptonizing corona, or a relativistically blurred ionized reflection spectrum from the inner regions of the accretion disk. While these two scenarios cannot be distinguished based on their fit statistics, we argue that the parameters required by the warm corona model are physically incompatible with the conditions of standard coronae. Detailed photoionization calculations show that even in the most favorable conditions, the warm corona should produce strong absorption in the observed spectrum. On the other hand, while the relativistic reflection model provides a satisfactory description of the data, it also requires extreme parameters, such as maximum black hole spin, a very low and compact hot corona, and a very high density for the inner accretion disk. Deeper observations of this source are thus necessary to confirm the presence of relativistic reflection, and to further understand the nature of its soft excess.Comment: Accepted for publication in ApJ, 18 pages, 7 figure

The yeast protein kinase Sch9 adjusts V-ATPase assembly/disassembly to control pH homeostasis and longevity in response to glucose availability

The evolutionary conserved TOR complex 1 controls growth in response to the quality and quantity of nutrients such as carbon and amino acids. The protein kinase Sch9 is the main TORC1 effector in yeast. However, only few of its direct targets are known. In this study, we performed a genome-wide screening looking for mutants which require Sch9 function for their survival and growth. In this way, we identified multiple components of the highly conserved vacuolar proton pump (V-ATPase) which mediates the luminal acidification of multiple biosynthetic and endocytic organelles. Besides a genetic interaction, we found Sch9 also physically interacts with the V- ATPase to regulate its assembly state in response to glucose availability and TORC1 activity. Moreover, the interaction with the V-ATPase has consequences for ageing as it allowed Sch9 to control vacuolar pH and thereby trigger either lifespan extension or lifespan shortening. Hence, our results provide insights into the signaling mechanism coupling glucose availability, TORC1 signaling, pH homeostasis and longevity. As both Sch9 and the V-ATPase are highly conserved and implicated in various pathologies, these results offer fertile ground for further research in higher eukaryotes

Implications of the Warm Corona and Relativistic Reflection Models for the Soft Excess in Mrk 509

We present the analysis of the first Nuclear Spectroscopic Telescope Array observations (~220 ks), simultaneous with the last Suzaku observations (~50 ks), of the active galactic nucleus of the bright Seyfert 1 galaxy Mrk 509. The time-averaged spectrum in the 1–79 keV X-ray band is dominated by a power-law continuum (Γ ~ 1.8–1.9), a strong soft excess around 1 keV, and signatures of X-ray reflection in the form of Fe K emission (~6.4 keV), an Fe K absorption edge (~7.1 keV), and a Compton hump due to electron scattering (~20–30 keV). We show that these data can be described by two very different prescriptions for the soft excess: a warm (kT ~ 0.5–1 keV) and optically thick (τ ~ 10–20) Comptonizing corona or a relativistically blurred ionized reflection spectrum from the inner regions of the accretion disk. While these two scenarios cannot be distinguished based on their fit statistics, we argue that the parameters required by the warm corona model are physically incompatible with the conditions of standard coronae. Detailed photoionization calculations show that even in the most favorable conditions, the warm corona should produce strong absorption in the observed spectrum. On the other hand, while the relativistic reflection model provides a satisfactory description of the data, it also requires extreme parameters, such as maximum black hole spin, a very low and compact hot corona, and a very high density for the inner accretion disk. Deeper observations of this source are thus necessary to confirm the presence of relativistic reflection and further understand the nature of its soft excess