20 research outputs found
On the interaction of microquasar jets with stellar winds
Strong interactions between jets and stellar winds at binary system spatial
scales could occur in high-mass microquasars. We study here, mainly from a
dynamical but also a radiative point of view, the collision between a dense
stellar wind and a mildly relativistic hydrodynamical jet of supersonic
nature.}{We have performed numerical 2-dimensional simulations of jets, with
cylindrical and planar (slab) symmetry, crossing the stellar wind material.
From the results of the simulations, we derive estimates of the particle
acceleration efficiency, using first order Fermi acceleration theory, and give
some insight on the possible radiative outcomes. We find that, during jet
launching, the jet head generates a strong shock in the wind. During and after
this process, strong recollimation shocks can occur due to the initial
overpressure of the jet with its environment. The conditions in all these
shocks are convenient to accelerate particles up to TeV energies, which
can lead to leptonic (synchrotron and inverse Compton) and hadronic
(proton-proton) radiation. In principle, the cylindrical jet simulations show
that the jet is stable, and can escape from the system even for relatively low
power. However, when accounting for the wind ram pressure, the jet can be bent
and disrupted for power \la 10^{36} erg s.Comment: Accepted for publication in Astronomy & Astrophysic
Theoretical overview on high-energy emission in microquasars
Microquasar (MQ) jets are sites of particle acceleration and synchrotron
emission. Such synchrotron radiation has been detected coming from jet regions
of different spatial scales, which for the instruments at work nowadays appear
as compact radio cores, slightly resolved radio jets, or (very) extended
structures. Because of the presence of relativistic particles and dense photon,
magnetic and matter fields, these outflows are also the best candidates to
generate the very high-energy (VHE) gamma-rays detected coming from two of
these objects, LS 5039 and LS I +61 303, and may be contributing significantly
to the X-rays emitted from the MQ core. In addition, beside electromagnetic
radiation, jets at different scales are producing some amount of leptonic and
hadronic cosmic rays (CR), and evidences of neutrino production in these
objects may be eventually found. In this work, we review on the different
physical processes that may be at work in or related to MQ jets. The jet
regions capable to produce significant amounts of emission at different
wavelengths have been reduced to the jet base, the jet at scales of the order
of the size of the system orbital semi-major axis, the jet middle scales (the
resolved radio jets), and the jet termination point. The surroundings of the
jet could be sites of multiwavelegnth emission as well, deserving also an
insight. We focus on those scenarios, either hadronic or leptonic, in which it
seems more plausible to generate both photons from radio to VHE and high-energy
neutrinos. We briefly comment as well on the relevance of MQ as possible
contributors to the galactic CR in the GeV-PeV range.Comment: Astrophysics & Space Science, in press (invited talk in the
conference: The multimessenger approach to the high-energy gamma-ray
sources", Barcelona/Catalonia, in July 4-7); 10 pages, 6 figures, 2 tables
(one reference corrected
Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening.
In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR), it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis, making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action
Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening
In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR), it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis, making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action
Hoe gevoelig is de acountant voor variabele managementbeloning?
In dit onderzoek wordt ingegaan op de invloed van variabele beloningen voor de CEO en/of CFO op de verwerking van door de accountant geconstateerde controleverschillen. In dit onderzoek is geanalyseerd of een variabele beloning van invloed is op het constateren en het corrigeren van controleverschillen. Uit de onderzoeksresultaten volgt dat het aantal geconstateerde controleverschillen niet hoger is indien een variabele beloning aanwezig is. Uit de onderzoeksresultaten volgt voorts dat subjectieve controleverschillen minder vaak gecorrigeerd worden indien sprake is van variabele beloning. Aanvullend concluderen wij dat grotere controleverschillen minder vaak gecorrigeerd worden indien een variabele beloning aanwezig is. De gebruiker van de jaarrekening heeft doorgaans geen goed inzicht in de aard en omvang van niet-gecorrigeerde verschillen. Een mogelijke oplossing hiervoor is het vermelden van grotere niet-gecorrigeerde controleverschillen in de controleverklaring. Accountantsorganisaties kunnen overwegen bij een kwaliteitsonderzoek een specifiek aandachtspunt mee te nemen bij opdrachten waar sprake is van variabele managementbeloning
A novel signaling pathway controlling induced systemic resistance in arabidopsis
Plants have the ability to acquire an enhanced level of resistance to pathogen attack after being exposed to specific biotic stimuli. In Arabidopsis, nonpathogenic, root-colonizing Pseudomonas fluorescens bacteria trigger an induced systemic resistance (ISR) response against infection by the bacterial leaf pathogen P. syringae pv tomato. In contrast to classic, pathogen-induced systemic acquired resistance (SAR), this rhizobacteria-mediated ISR response is independent of salicylic acid accumulation and pathogenesis-related gene activation. Using the jasmonate response mutant jar1, the ethylene response mutant etr1, and the SAR regulatory mutant npr1, we demonstrate that signal transduction leading to P. fluorescens WCS417r-mediated ISR requires responsiveness to jasmonate and ethylene and is dependent on NPR1. Similar to P. fluorescens WCS417r, methyl jasmonate and the ethylene precursor 1-aminocyclopropane-1-carboxylate were effective in inducing resistance against P.s. tomato in salicylic acid-nonaccumulating NahG plants. Moreover, methyl jasmonate-induced protection was blocked in jar1, etr1, and npr1 plants, whereas 1-aminocyclopropane-1-carboxylate-induced protection was affected in etr1 and npr1 plants but not in jar1 plants. Hence, we postulate that rhizobacteria-mediated ISR follows a novel signaling pathway in which components from the jasmonate and ethylene response are engaged successively to trigger a defense reaction that, like SAR, is regulated by NPR1. We provide evidence that the processes downstream of NPR1 in the ISR pathway are divergent from those in the SAR pathway, indicating that NPR1 differentially regulates defense responses, depending on the signals that are elicited during induction of resistance
A novel signaling pathway controlling induced systemic resistance in Arabidopsis.
Plants have the ability to acquire an enhanced level of resistance to pathogen attack after being exposed to specific biotic stimuli. In Arabidopsis, nonpathogenic, root-colonizing Pseudomonas fluorescens bacteria trigger an induced systemic resistance (ISR) response against infection by the bacterial leaf pathogen P. syringae pv tomato. In contrast to classic, pathogen-induced systemic acquired resistance (SAR), this rhizobacteria-mediated ISR response is independent of salicylic acid accumulation and pathogenesis-related gene activation. Using the jasmonate response mutant jar1, the ethylene response mutant etr1, and the SAR regulatory mutant npr1, we demonstrate that signal transduction leading to P. fluorescens WCS417r-mediated ISR requires responsiveness to jasmonate and ethylene and is dependent on NPR1. Similar to P. fluorescens WCS417r, methyl jasmonate and the ethylene precursor 1-aminocyclopropane-1-carboxylate were effective in inducing resistance against P. s. tomato in salicylic acid-nonaccumulating NahG plants. Moreover, methyl jasmonate-induced protection was blocked in jar1, etr1, and npr1 plants, whereas 1-aminocyclopropane-1-carboxylate-induced protection was affected in etr1 and npr1 plants but not in jar1 plants. Hence, we postulate that rhizobacteria-mediated ISR follows a novel signaling pathway in which components from the jasmonate and ethylene response are engaged successively to trigger a defense reaction that, like SAR, is regulated by NPR1. We provide evidence that the processes downstream of NPR1 in the ISR pathway are divergent from those in the SAR pathway, indicating that NPR1 differentially regulates defense responses, depending on the signals that are elicited during induction of resistance