Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart.

AIMS: Notch1 signalling in the heart is mainly activated via expression of Jagged1 on the surface of cardiomyocytes. Notch controls cardiomyocyte proliferation and differentiation in the developing heart and regulates cardiac remodelling in the stressed adult heart. Besides canonical Notch receptor activation in signal-receiving cells, Notch ligands can also activate Notch receptor-independent responses in signal-sending cells via release of their intracellular domain. We evaluated therefore the importance of Jagged1 (J1) intracellular domain (ICD)-mediated pathways in the postnatal heart. METHODS AND RESULTS: In cardiomyocytes, Jagged1 releases J1ICD, which then translocates into the nucleus and down-regulates Notch transcriptional activity. To study the importance of J1ICD in cardiac homeostasis, we generated transgenic mice expressing a tamoxifen-inducible form of J1ICD, specifically in cardiomyocytes. Using this model, we demonstrate that J1ICD-mediated Notch inhibition diminishes proliferation in the neonatal cardiomyocyte population and promotes maturation. In the neonatal heart, a response via Wnt and Akt pathway activation is elicited as an attempt to compensate for the deficit in cardiomyocyte number resulting from J1ICD activation. In the stressed adult heart, J1ICD activation results in a dramatic reduction of the number of Notch signalling cardiomyocytes, blunts the hypertrophic response, and reduces the number of apoptotic cardiomyocytes. Consistently, this occurs concomitantly with a significant down-regulation of the phosphorylation of the Akt effectors ribosomal S6 protein (S6) and eukaryotic initiation factor 4E binding protein1 (4EBP1) controlling protein synthesis. CONCLUSIONS: Altogether, these data demonstrate the importance of J1ICD in the modulation of physiological and pathological hypertrophy, and reveal the existence of a novel pathway regulating cardiac homeostasis

Detection of diffuse interstellar bands in M31

We investigate the diffuse interstellar band (DIB) spectrum in the interstellar medium of M31. The DEIMOS spectrograph of the W. M. Keck observatory was used to make optical spectroscopic observations of two supergiant stars, MAG 63885 and MAG 70817, in the vicinity of the OB78 association in M31 where the metallicity is approximately equal to solar. The 5780, 5797, 6203, 6283 and 6613 DIBs are detected in both sightlines at velocities matching the M31 interstellar Na I absorption. The spectra are classified and interstellar reddenings are derived for both stars. Diffuse interstellar band (DIB) equivalent widths and radial velocities are presented. The spectrum of DIBs observed in M31 towards MAG 63885 is found to be similar to that observed in the Milky Way. Towards MAG 70817 the DIB equivalent widths per unit reddening are about three times the Galactic average. Compared to observations elsewhere in the Universe, relative to reddening the M31 ISM in the vicinity of OB78 is apparently a highly favourable environment for the formation of DIB carriers

The Notch pathway controls fibrotic and regenerative repair in the adult heart.

AIMS: In the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown. In the present study, we evaluate, therefore, whether forced activation of the Notch pathway in mesenchymal stromal cells regulates pathological cardiac remodelling. METHODS AND RESULTS: We generated transgenic mice overexpressing the Notch ligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in adjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated Notch sustained cardiac precursor and myocyte proliferation after birth, and led to increased numbers of cardiac myocytes in adult mice. In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-β/connective tissue growth factor-mediated cardiac fibrosis. Most importantly, Notch activation in the stressed adult heart reduced the proliferation of myofibroblasts and stimulated the expansion of stem cell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac precursor cells. CONCLUSIONS: We conclude that Notch is pivotal in the healing process of the injured heart. Specifically, Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, these findings indicate that Notch represents a unique therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cells

A southern hemisphere survey of the 5780 and 6284 {\AA} diffuse interstellar bands: correlation with the extinction

We present a new database of 5780.5 and 6283.8 {\AA} DIB measurements and also study their correlation with the reddening. The database is based on high-resolution, high-quality spectra of early-type nearby stars located in the southern hemisphere at an average distance of 300 pc. Equivalent widths of the two DIBs were determined by means of a realistic continuum fitting and synthetic atmospheric transmissions. For all stars that possess a precise measurement of their color excess, we compare the DIBs and the extinction. We find average linear relationships of the DIBS and the color excess that agree well with those of a previous survey of northern hemisphere stars closer than 550 pc. This similarity shows that there is no significant spatial dependence of the average relationship in the solar neighborhood within $\simeq$ 600 pc. A noticeably different result is our higher degree of correlation of the two DIBs with the extinction. We demonstrate that it is simply due to the lower temperature and intrinsic luminosity of our targets. Using cooler target stars reduces the number of outliers, especially for nearby stars, confirming that the radiation field of UV bright stars has a significant influence on the DIB strength. We have used the cleanest data to compute updated DIB shapes.Comment: Astronomy & Astrophysics (in press

Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways.

The adult mammalian heart has poor regenerative capacity. In contrast, the zebrafish heart retains a robust capacity for regeneration into adulthood. These distinct responses are consequences of a differential utilization of evolutionary-conserved gene regulatory networks in the damaged heart. To systematically identify miRNA-dependent networks controlling cardiac repair following injury, we performed comparative gene and miRNA profiling of the cardiac transcriptome in adult mice and zebrafish. Using an integrated approach, we show that 45 miRNA-dependent networks, involved in critical biological pathways, are differentially modulated in the injured zebrafish vs. mouse hearts. We study, more particularly, the miR-26a-dependent response. Therefore, miR-26a is down-regulated in the fish heart after injury, whereas its expression remains constant in the mouse heart. Targets of miR-26a involve activators of the cell cycle and Ezh2, a component of the polycomb repressive complex 2 (PRC2). Importantly, PRC2 exerts repressive functions on negative regulators of the cell cycle. In cultured neonatal cardiomyocytes, inhibition of miR-26a stimulates, therefore, cardiomyocyte proliferation. Accordingly, miR-26a knockdown prolongs the proliferative window of cardiomyocytes in the post-natal mouse heart. This novel strategy identifies a series of miRNAs and associated pathways, in particular miR-26a, which represent attractive therapeutic targets for inducing repair in the injured heart

Negative Ions in Space

Until a decade ago, the only anion observed to play a prominent role in astrophysics was H–. The bound–free transitions in H– dominate the visible opacity in stars with photospheric temperatures less than 7000 K, including the Sun. The H– anion is also believed to have been critical to the formation of molecular hydrogen in the very early evolution of the Universe. Once H₂ formed, about 500 000 years after the Big Bang, the expanding gas was able to lose internal gravitational energy and collapse to form stellar objects and “protogalaxies”, allowing the creation of heavier elements such as C, N, and O through nucleosynthesis. Although astronomers had considered some processes through which anions might form in interstellar clouds and circumstellar envelopes, including the important role that polycyclic aromatic hydrocarbons might play in this, it was the detection in 2006 of rotational line emission from C₆H– that galvanized a systematic study of the abundance, distribution, and chemistry of anions in the interstellar medium. In 2007, the Cassini mission reported the unexpected detection of anions with mass-to-charge ratios of up to ˜10 000 in the upper atmosphere of Titan; this observation likewise instigated the study of fundamental chemical processes involving negative ions among planetary scientists. In this article, we review the observations of anions in interstellar clouds, circumstellar envelopes, Titan, and cometary comae. We then discuss a number of processes by which anions can be created and destroyed in these environments. The derivation of accurate rate coefficients for these processes is an essential input for the chemical kinetic modeling that is necessary to fully extract physics from the observational data. We discuss such models, along with their successes and failings, and finish with an outlook on the future

Time-dependent density functional study of the electronic spectra of oligoacenes in the charge states -1, 0, +1, and +2

We present a systematic theoretical study of the five smallest oligoacenes (naphthalene, anthracene, tetracene, pentacene, and hexacene) in their anionic,neutral, cationic, and dicationic charge states. We used density functional theory (DFT) to obtain the ground-state optimised geometries, and time-dependent DFT (TD-DFT) to evaluate the electronic absorption spectra. Total-energy differences enabled us to evaluate the electron affinities and first and second ionisation energies, the quasiparticle correction to the HOMO-LUMO energy gap and an estimate of the excitonic effects in the neutral molecules. Electronic absorption spectra have been computed by combining two different implementations of TD-DFT: the frequency-space method to study general trends as a function of charge-state and molecular size for the lowest-lying in-plane long-polarised and short-polarised $\pi\to\pi^\star$ electronic transitions, and the real-time propagation scheme to obtain the whole photo-absorption cross-section up to the far-UV. Doubly-ionised PAHs are found to display strong electronic transitions of $\pi\to\pi^\star$ character in the near-IR, visible, and near-UV spectral ranges, like their singly-charged counterparts. While, as expected, the broad plasmon-like structure with its maximum at about 17-18 eV is relatively insensitive to the charge-state of the molecule, a systematic decrease with increasing positive charge of the absorption cross-section between about 6 and about 12 eV is observed for each member of the class.Comment: 38 pages, 11 figures, 7 tables, accepted for publication in Chemical Physic

The Gaia-ESO Survey : Extracting diffuse interstellar bands from cool star spectra: DIB-based interstellar medium line-of-sight structures at the kpc scale

Date of Acceptance: 05/10/2014Aims. We study how diffuse interstellar bands (DIBs) measured toward distance-distributed target stars can be used to locate dense interstellar (IS) clouds in the Galaxy and probe a line-of-sight (LOS) kinematical structure, a potentially useful tool when gaseous absorption lines are saturated or not available in the spectral range. Cool target stars are numerous enough for this purpose. Methods. We devised automated DIB-fitting methods appropriate for cool star spectra and multiple IS components. The data were fitted with a combination of a synthetic stellar spectrum, a synthetic telluric transmission, and empirical DIB profiles. The initial number of DIB components and their radial velocity were guided by HI 21 cm emission spectra, or, when available in the spectral range, IS neutral sodium absorption lines. For NaI, radial velocities of NaI lines and DIBs were maintained linked during a global simultaneous fit. In parallel, stellar distances and extinctions were estimated self-consistently by means of a 2D Bayesian method from spectroscopically-derived stellar parameters and photometric data. Results. We have analyzed Gaia-ESO Survey (GES) spectra of 225 stars that probe between ∼2 and 10 kpc long LOS in five different regions of the Milky Way. The targets are the two CoRoT fields, two open clusters (NGC 4815 and γ Vel), and the Galactic bulge. Two OGLE fields toward the bulge observed before the GES are also included (205 target stars). Depending on the observed spectral intervals, we extracted one or more of the following DIBs: λλ 6283.8, 6613.6, and 8620.4. For each field, we compared the DIB strengths with the Bayesian distances and extinctions, and the DIB Doppler velocities with the HI emission spectra. Conclusions. For all fields, the DIB strength and the target extinction are well correlated. For targets that are widely distributed in distance, marked steps in DIBs and extinction radial distance profiles match each other and broadly correspond to the expected locations of spiral arms. For all fields, the DIB velocity structure agrees with HI emission spectra, and all detected DIBs correspond to strong NaI lines. This illustrates how DIBs can be used to locate the Galactic interstellar gas and to study its kinematics at the kpc scale, as illustrated by Local and Perseus Arm DIBs that differ by ≳∼30 km s-1, in agreement with HI emission spectra. On the other hand, if most targets are located beyond the main absorber, DIBs can trace the differential reddening within the field.Peer reviewedFinal Accepted Versio