Pharmacological modulation of early postinfarction remodelling

The response to acute myocardial infarction can be divided into different phases: 1. Acute myocardial infarction induces a sudden decrease of cardiac output related to the size of infarcted area. 2. CompeasatoN phase: A decreased cardiac output evokes activation of compensatory mechanisms, such as the sympathetic nervous system and reninangiotensin- aldosterone sytem. If these mechanisms cannot bring cardiac output back to acceptable levels, structural changes in the heart called hypertrophy and remodeling will follow. 3. Compensated ohase: A relatively stabile phase with (partly) restored cardiac output but with decreased left ventricular function and ejection fraction has been established; a stage compensated heart failure, in which patients are often not recognized. 4. Decompensation ohase: When symptoms of heart failure become overt, decompensation develops driven by the same mechanisms as in the previous phases, but with a very poor prognosis. Therapy during the different phases require different strategies. During phase 1 the objective of therapy is to limit infarct size by establishing reperfusion as quick as possible. Then, theoretically, phase 2 requires stimulation, phase 3 stabilization and support, and phase 4 inhibition of the same ongoing processes. Although still patients at stage 4 are clinically the most important ones, inclination towards earlier intervention is growing. The problem that may arise, however, is that earlier treatment, especially at stage 2 is aimed at the opposite direction as the later therapy. This problem is substantiated by the results of the 2 CONSENSUS trials, where delayed ACE-inhibitor ( enalapril) treatment had clearly beneficial effects (CONSENSUS I), whereas similar treatment during early phases had detrimental effects (CONSENSUS 11)91 • Pharmacological research has mainly focused on stage 4 when congestive heart failure is diagnosed and prognosis becomes very poor. Except for treatment with ACE-inhibitors, prognosis has not benefited substantially from all these research. During this stage, cardiac hypertrophy and remodeling have become a major target for therapy since they are associated with improved prognosis 112• When treatment should be started earlier, that is with ventricular dysfunction but before signs of heart failure, it implies interference with cardiac hypertrophy an

Infrared Spectroscopy of the Diffuse Ionized Halo of NGC 891

We present infrared spectroscopy from the Spitzer Space Telescope at one disk position and two positions at a height of 1 kpc from the disk in the edge-on spiral NGC 891, with the primary goal of studying halo ionization. Our main result is that the [Ne III]/[Ne II] ratio, which provides a measure of the hardness of the ionizing spectrum free from the major problems plaguing optical line ratios, is enhanced in the extraplanar pointings relative to the disk pointing. Using a 2D Monte Carlo-based photo-ionization code which accounts for the effects of radiation field hardening, we find that this trend cannot be reproduced by any plausible photo-ionization model, and that a secondary source of ionization must therefore operate in gaseous halos. We also present the first spectroscopic detections of extraplanar PAH features in an external normal galaxy. If they are in an exponential layer, very rough emission scale-heights of 330-530 pc are implied for the various features. Extinction may be non-negligible in the midplane and reduce these scale-heights significantly. There is little significant variation in the relative emission from the various features between disk and extraplanar environment. Only the 17.4 micron feature is significantly enhanced in the extraplanar gas compared to the other features, possibly indicating a preference for larger PAHs in the halo.Comment: 35 pages in ApJ preprint format, 8 figures, accepted for publication in ApJ. Minor change to Introduction to give appropriate credit to earlier, related wor

Estudio de la regulación de la asparraginasa de pino

La asparraginasa (ASPG, EC 3.5.1.1) de plantas pertenece a la familia de Ntn-hidrolasas, enzimas que se sintetizan como un precursor inactivo, el cual es activado mediante un procesamiento autocatalítico que genera dos subunidades (α y β). Estas subunidades forman un tetrámero (αβ)2, que constituye la forma madura de la enzima, en la cual cada subunidad β presenta un residuo nucleófilo (Thr) en su extremo amino como resultado del procesamiento. La asparraginasa está implicada en la movilización del nitrógeno contenido en el grupo amido de la asparragina, el metabolito principal para la reserva y el transporte de nitrógeno en plantas. Nuestro objetivo es determinar cómo se regula esta enzima en pino, tanto a nivel transcripcional como postraduccional. A nivel transcripcional estamos realizando una caracterización estructural y funcional de la región promotora del gen, así como el análisis del patrón de expresión del gen en diferentes tejidos y condiciones. A nivel postraduccional nos hemos centrado en determinar las características del procesado y activación de la ASPG en pino. Debido a los bajos niveles de la proteína en pino, este estudio se abordó con proteína recombinante purificada desde sistemas heterólogos. La expresión de la proteína recombinante de Pinus pinaster en células de E. coli resulta en una proteína inmadura sin capacidad de autocatálisis in vitro, a diferencia de lo que se ha descrito para ASPG de otras especies angiospermas. Por el contrario, la expresión heteróloga en plantas de tabaco genera una proteína madura. En comparación con la estructura primaria de las ASPG de especies cuyo genoma ha sido secuenciado, las ASPG de coníferas presentan una extensión de unos 70 aminoácidos en la posición que precede al residuo nucleófilo, sitio donde ocurre el procesamiento que activa a la enzima. Un análisis mediante espectrometría de masas ha demostrado que esta extensión forma parte de la proteína de Pinus pinaster en su forma madura. En la actualidad estamos analizando el efecto de esta extensión sobre el autoprocesamiento del precursor.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Caracterización de la asparraginasa de pino: implicaciones en el desarrollo del sistema vascular

La asparragina es un metabolito clave en plantas para el transporte y reserva temporal de nitrógeno. La principal vía de movilización del nitrógeno contenido en el grupo amido de la asparragina implica a la enzima asparraginasa (ASPG, EC 3.5.1.1), especialmente en tejidos que demandan altas cantidades de este elemento, tales como semillas en desarrollo y hojas jóvenes. Durante el desarrollo y crecimiento del tronco de los árboles, éstos afrontan un consumo masivo de carbono y nitrógeno para proveer la síntesis de celulosa y lignina. Estudios previos han demostrado que la expresión del gen de asparraginasa en el pino está asociada al intensivo desarrollo del sistema vascular que se produce en el tallo de las plántulas una vez que ésta ha agotado las reservas de la semilla, y que su expresión está confinada a las células de la región del cambium (1). La observación de que este gen se expresa también en células de xilema secundario en diferenciación de árbol adulto sugiere que la ASPG podría jugar un papel importante en el desarrollo vascular y ser de gran relevancia en la producción de biomasa. Aunque conocemos, en líneas generales, la implicación de la asparraginasa en el transporte y movilización de nitrógeno, desconocemos los mecanismos moleculares que controlan espacial y temporalmente su actividad. En nuestro grupo seguimos diferentes aproximaciones para dilucidar el control transcripcional y post-transcripcional de esta enzima y su implicación en el desarrollo del sistema vascular. Nuestros objetivos específicos son determinar las características del procesado y activación de la asparraginasa de pino y los factores que regulan la expresión génica asociada al desarrollo vascular.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. BIO2012-33797, AGL9-12139C0202, AP2010-543

Aspectos estructurales y funcionales de la asparraginasa en pino

La asparragina es un metabolito clave en plantas para el transporte y reserva temporal de nitrógeno. La principal vía de movilización del nitrógeno contenido en el grupo amido de este aminoácido implica a la enzima asparraginasa (ASPG, EC 3.5.1.1), que cataliza la hidrólisis de asparragina a aspartato y amonio. Las asparraginasas de plantas, al igual que todas las enzimas de la familia Ntn-hidrolasas, son sintetizadas como precursores inactivos. La enzima activa es un heterotetrámero con dos tipos distintos de angiospermas se han identificado genes que codifican dos subtipos de asparraginasas (Bruneau et al. 2006), las K+-independientes y las K+-dependientes, con al menos un gen codificante para cada tipo en los genomas que han sido secuenciados. La caracterización de ambos subtipos indica que la forma K+-dependiente sería más eficiente en la movilización del nitrógeno amido de la asparragina bajo condiciones de alta demanda metabólica de nitrógeno (Bruneau et al. 2006), mientras que el papel de las K+-independientes estaría relacionado con su actividad isoaspartil dipeptidasa. Sin embargo, hasta la fecha no se ha realizado una caracterización de las distintas formas presentes y sus funciones en gimnospermas. Una búsqueda en el transcriptoma disponible de Pinus pinaster (Canales et al. 2014) nos permitió identificar un total de tres genes con similitud a asparraginasa. Sólo uno (PpASPG1), identificado previamente por nuestro grupo de investigación (Cañas et al. 2006), presenta mayor similitud con las asparraginasas K+-dependientes. El principal inconveniente para la caracterización de estas proteínas es su baja abundancia. Para soslayar este impedimento se expresaron transitoriamente los tres genes de pino en un sistema heterólogo, se purificaron las proteínas recombinantes y se compararon sus características. Por otro lado, esta aproximación nos ha permitido también estudiar cómo afecta al procesamiento del precursor y a la actividad de la enzima la presencia de una extensión de 70 aminoácidos proteínas ortólogas de especies angiospermas. Finalmente, con el objetivo de dilucidar posibles funciones, hemos realizado un análisis de expresión de los tres genes identificados, así como el aislamiento y análisis del promotor del gen PpASPG1. Referencias Bruneau L. et al (2006) Co-occurrence of both L-asparaginase subtypes in Arabidopsis: At3g16150 encodes a K+-dependent L-asparaginase. Planta, 224:668–679, doi: 10.1007/s00425-006-0245-9. Canales J. et al. (2014) De novo assembly of maritime pine transcriptome: implications for forest breeding and biotechnology. Plant Biotechnology Journal, 12:286–299. doi: 10.1111/pbi.12136. Cañas RA et al. (2006) Coordination of PsAS1 and PsASPG expression controls timing of re-allocated N utilization in hypocotyls of pine seedlings. Planta, 225:1205– 1219. doi: 10.1007/s00425-006-0431-9.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Spatially Resolved Spitzer-IRS Spectroscopy of the Central Region of M82

We present high spatial resolution (~ 35 parsec) 5-38 um spectra of the central region of M82, taken with the Spitzer Infrared Spectrograph. From these spectra we determined the fluxes and equivalent widths of key diagnostic features, such as the [NeII]12.8um, [NeIII]15.5um, and H_2 S(1)17.03um lines, and the broad mid-IR polycyclic aromatic hydrocarbon (PAH) emission features in six representative regions and analysed the spatial distribution of these lines and their ratios across the central region. We find a good correlation of the dust extinction with the CO 1-0 emission. The PAH emission follows closely the ionization structure along the galactic disk. The observed variations of the diagnostic PAH ratios across M82 can be explained by extinction effects, within systematic uncertainties. The 16-18um PAH complex is very prominent, and its equivalent width is enhanced outwards from the galactic plane. We interpret this as a consequence of the variation of the UV radiation field. The EWs of the 11.3um PAH feature and the H_2 S(1) line correlate closely, and we conclude that shocks in the outflow regions have no measurable influence on the H_2 emission. The [NeIII]/[NeII] ratio is on average low at ~0.18, and shows little variations across the plane, indicating that the dominant stellar population is evolved (5 - 6 Myr) and well distributed. There is a slight increase of the ratio with distance from the galactic plane of M82 which we attribute to a decrease in gas density. Our observations indicate that the star formation rate has decreased significantly in the last 5 Myr. The quantities of dust and molecular gas in the central area of the galaxy argue against starvation and for negative feedback processes, observable through the strong extra-planar outflows.Comment: 15 pages, 12 figures, 3 tables, ApJ, emulateap

The Physical Conditions in Starbursts Derived from Bayesian Fitting of Mid-IR SEDS: 30 Doradus as a Template

To understand and interpret the observed Spectral Energy Distributions (SEDs) of starbursts, theoretical or semi-empirical SED models are necessary. Yet, while they are well-founded in theory, independent verification and calibration of these models, including the exploration of possible degeneracies between their parameters, are rarely made. As a consequence, a robust fitting method that leads to unique and reproducible results has been lacking. Here we introduce a novel approach based on Bayesian analysis to fit the Spitzer-IRS spectra of starbursts using the SED models proposed by Groves et al. (2008). We demonstrate its capabilities and verify the agreement between the derived best fit parameters and actual physical conditions by modelling the nearby, well-studied, giant HII region 30 Dor in the LMC. The derived physical parameters, such as cluster mass, cluster age, ISM pressure and covering fraction of photodissociation regions, are representative of the 30 Dor region. The inclusion of the emission lines in the modelling is crucial to break degeneracies. We investigate the limitations and uncertainties by modelling sub-regions, which are dominated by single components, within 30 Dor. A remarkable result for 30 Doradus in particular is a considerable contribution to its mid-infrared spectrum from hot ({\simeq} 300K) dust. The demonstrated success of our approach will allow us to derive the physical conditions in more distant, spatially unresolved starbursts.Comment: 17 pages, 10 figures. Accepted por publication in the Astrophysical Journa

The Mid-IR Properties of Starburst Galaxies from Spitzer-IRS Spectroscopy

We present 5-38um mid-infrared spectra at a spectral resolution of R~65-130 of a large sample of 22 starburst nuclei taken with the Infrared Spectrograph IRS on board the Spitzer Space Telescope. The spectra show a vast range in starburst SEDs. The silicate absorption ranges from essentially no absorption to heavily obscured systems with an optical depth of tau(9.8um)~5. The spectral slopes can be used to discriminate between starburst and AGN powered sources. The monochromatic continuum fluxes at 15um and 30um enable a remarkably accurate estimate of the total infrared luminosity of the starburst. We find that the PAH equivalent width is independent of the total starburst luminosity L_IR as both continuum and PAH feature scale proportionally. However, the luminosity of the 6.2um feature scales with L_IR and can be used to approximate the total infrared luminosity of the starburst. Although our starburst sample covers about a factor of ten difference in the [NeIII]/[NeII] ratio, we found no systematic correlation between the radiation field hardness and the PAH equivalent width or the 7.7um/11.3um PAH ratio. These results are based on spatially integrated diagnostics over an entire starburst region, and local variations may be ``averaged out''. It is presumably due to this effect that unresolved starburst nuclei with significantly different global properties appear spectrally as rather similar members of one class of objects.Comment: 22 pages, accepted for publication in ApJ, a high-resolution version is available from http://www.strw.leidenuniv.nl/~brandl/IRS_starbursts.pd

A Spitzer high resolution mid-infrared spectral atlas of starburst galaxies

We present an atlas of Spitzer/IRS high resolution (R~600) 10-37um spectra for 24 well known starburst galaxies. The spectra are dominated by fine-structure lines, molecular hydrogen lines, and emission bands of polycyclic aromatic hydrocarbons. Six out of the eight objects with a known AGN component show emission of the high excitation [NeV] line. This line is also seen in one other object (NGC4194) with, a priori, no known AGN component. In addition to strong polycyclic aromatic hydrocarbon emission features in this wavelength range (11.3, 12.7, 16.4um), the spectra reveal other weak hydrocarbon features at 10.6, 13.5, 14.2um, and a previously unreported emission feature at 10.75um. An unidentified absorption feature at 13.7um is detected in many of the starbursts. We use the fine-structure lines to derive the abundance of neon and sulfur for 14 objects where the HI 7-6 line is detected. We further use the molecular hydrogen lines to sample the properties of the warm molecular gas. Several basic diagrams characterizing the properties of the sample are also shown. We have combined the spectra of all the pure starburst objects to create a high S/N template, which is available to the community.Comment: 25 pages (emulate apj), 6 tables, 14 figures, Accepted for publication in ApJ

Polycyclic aromatic hydrocarbon processing in a hot gas

Context: PAHs are thought to be a ubiquitous and important dust component of the interstellar medium. However, the effects of their immersion in a hot (post-shock) gas have never before been fully investigated. Aims: We study the effects of energetic ion and electron collisions on PAHs in the hot post-shock gas behind interstellar shock waves. Methods: We calculate the ion-PAH and electron-PAH nuclear and electronic interactions, above the carbon atom loss threshold, in H II regions and in the hot post-shock gas, for temperatures ranging from 10^3 to 10^8 K. Results: PAH destruction is dominated by He collisions at low temperatures (T < 3x10^4 K), and by electron collisions at higher temperatures. Smaller PAHs are destroyed faster for T < 10^6 K, but the destruction rates are roughly the same for all PAHs at higher temperatures. The PAH lifetime in a tenuous hot gas (n_H ~ 0.01 cm^-3, T ~ 10^7 K), typical of the coronal gas in galactic outflows, is found to be about thousand years, orders of magnitude shorter than the typical lifetime of such objects. Conclusions: In a hot gas, PAHs are principally destroyed by electron collisions and not by the absorption of X-ray photons from the hot gas. The resulting erosion of PAHs occurs via C_2 loss from the periphery of the molecule, thus preserving the aromatic structure. The observation of PAH emission from a million degree, or more, gas is only possible if the emitting PAHs are ablated from dense, entrained clumps that have not yet been exposed to the full effect of the hot gas.Comment: 16 pages, 11 figures, 3 tables, typos corrected and PAH acronym in the title substituted with full name to match version published in Astronomy and Astrophysic