168 research outputs found
Adenovirus-based phospholamban antisense expression as a novel approach to improve cardiac contractile dysfunction: comparison of a constitutive viral versus an endothelin-1-responsive cardiac promoter
BACKGROUND: A decrease in sarcoplasmic reticulum Ca(2+) pump (SERCA2)
activity is believed to play a role in the impairment of diastolic
function of the failing heart. Because the expression ratio of
phospholamban (PL) to SERCA2 may be a target to improve contractile
dysfunction, a PL antisense RNA strategy was developed under the control
of either a constitutive cytomegalovirus (CMV) or an inducible atrial
natriuretic factor (ANF) promoter. The latter is upregulated in
hypertrophied and failing heart, allowing "induction-by-disease" gene
therapy. METHODS AND RESULTS: Part of the PL cDNA was cloned in antisense
and sense directions into adenovectors under the control of either a CMV
(Ad5CMVPLas and Ad5CMVPLs, respectively) or ANF (Ad5ANFPLas and Ad5ANFPLs,
respectively) promoter. Infection of cultured rat neonatal cardiomyocytes
with Ad5CMVPLas reduced PL mRNA to 30+/-7% of baseline and PL protein to
24+/-3% within 48 and 72 hours, respectively. The effects were vector dose
dependent. Ad5CMVPLas increased the Ca(2+) sensitivity of SERCA2 and
reduced the time to 50% recovery of the Ca(2+) transient. A decrease of PL
protein was also achieved by infection with Ad5ANFPLas, and the presence
of the hypertrophic stimulus, endothelin-1, led to enhanced downregulation
of PL. The adenovectors expressing PL sense RNA had no effect on any of
the tested parameters. CONCLUSIONS: Vector-mediated PL antisense RNA
expression may become a feasible approach to modulate myocyte Ca(2+)
homeostasis in the failing heart. The inducible ANF promoter for the first
time offers the perspective for induction-by-disease gene therapy, ie,
selective expression of therapeutic genes in hypertrophied and failing
cardiomyocytes
On the relative Contribution of high-redshift Galaxies and Active Galactic Nuclei to Reionization
In this paper we discuss the contribution of different astrophysical sources
to the ionization of neutral hydrogen at different redshifts. We critically
revise the arguments in favour/against a substantial contribution of Active
Galactic Nuclei (AGNs) and/or Lyman Break Galaxies (LBGs) to the reionization
of the Universe at z>5. We consider extrapolations of the high-z QSO and LBG
luminosity functions and their redshift evolution as well as indirect
constraints on the space density of lower luminosity Active Galactic Nuclei
based on the galaxy stellar mass function. Since the hypothesis of a
reionization due to LBGs alone requires a significant contribution of faint
dwarf galaxies and a LyC photon escape fraction (f_esc) of the order of ~20%,
in tension with present observational constraints, we examine under which
hypothesis AGNs and LBGs may provide a combined relevant contribution to the
reionization. We show that a relatively steep faint-end of the AGN luminosity
function, consistent with present constraints, provides a relevant (although
sub-dominant) contribution, thus allowing us to recover the required ionizing
photon rates with f_esc~5% up to z~7. At higher redshifts, we test the case for
a luminosity-dependent f_esc scenario and we conclude that, if the observed
LBGs are indeed characterized by very low f_esc, values of the order of
f_esc~70% are needed for objects below our detection threshold, for this galaxy
population to provide a substantial contribution to reionization. Clearly, the
study of the properties of faint sources (both AGNs and LBGs) is crucial.Comment: 9 pages, 7 figures, MNRAS accepte
DOGS: Reaction-Driven de novo Design of Bioactive Compounds
We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties
A High Yield of New Sightlines for the Study of Intergalactic Helium: Far-UV-Bright Quasars from SDSS, GALEX, and HST
Investigations of He II Ly-alpha (304 A rest) absorption toward a half-dozen
quasars at z~3-4 have demonstrated the great potential of helium studies of the
IGM, but the current critically small sample size of clean sightlines for the
He II Gunn-Peterson test limits confidence in cosmological inferences, and a
larger sample is required. Although the unobscured quasar sightlines to high
redshift are extremely rare, SDSS DR6 provides thousands of z>2.8 quasars. We
have cross-correlated these SDSS quasars with GALEX GR2/GR3 to establish a
catalog of 200 higher-confidence (~70% secure) cases of quasars at z=2.8-5.1
potentially having surviving far-UV (restframe) flux. We also catalog another
112 likely far-UV-bright quasars from GALEX cross-correlation with other
(non-SDSS) quasar compilations. Reconnaissance UV prism observations with HST
of 24 of our SDSS/GALEX candidates confirm 12 as detected in the far-UV, with
at least 9 having flux extending to very near the He II break; with refinements
our success rate is even higher. Our SDSS/GALEX selection approach is thereby
confirmed to be an order of magnitude more efficient than previous He II quasar
searches, more than doubles the number of spectroscopically confirmed clean
sightlines to high redshift, and provides a resource list of hundreds of
high-confidence sightlines for upcoming He II and other far-UV studies from
HST. Our reconnaissance HST prism spectra suggest some far-UV diversity,
confirming the need to obtain a large sample of independent quasar sightlines
across a broad redshift range to assess such issues as the epoch(s) of helium
reionization, while averaging over individual-object pathology and/or cosmic
variance.Comment: 32 pages, 7 figures, accepted by Ap
The line-of-sight proximity effect in individual quasar spectra
We exploit a set of high signal-to-noise (~70), low-resolution (R~800) quasar
spectra to search for the signature of the so-called proximity effect in the HI
Ly alpha forest. Our sample consists of 17 bright quasars in the redshift range
2.7<z<4.1. Analysing the spectra with the flux transmission technique, we
detect the proximity effect in the sample at high significance. We use this to
estimate the average intensity of the metagalactic UV background, assuming it
to be constant over this redshift range. We obtain a value of J =
(9+-4)x10^{-22}ergcm^{-2}s^{-1}Hz^{-1}sr^{-1}, in good agreement with previous
measurements at similar z. We then apply the same procedure to individual lines
of sight, finding a significant deficit in the effective optical depth close to
the emission redshift in every single object except one (which by a different
line of evidence does nevertheless show a noticeable proximity effect). Thus,
we clearly see the proximity effect as a universal phenomenon associated with
individual quasars. Using extensive Monte-Carlo simulations to quantify the
error budget, we assess the expected statistical scatter in the strength of the
proximity effect due to shot noise (cosmic variance). The observed scatter is
larger than the predicted one, so that additional sources of scatter are
required. We rule out a dispersion of spectral slopes as a significant
contributor. Possible effects are long time-scale variability of the quasars
and/or gravitational clustering of Ly alpha forest lines. We speculate on the
possibility of using the proximity effect as a tool to constrain individual
quasar ages, finding that ages between ~10^6 and ~10^8 yrs might produce a
characteristic signature in the optical depth profile towards the QSO. We
identify one possible candidate for this effect in our sample.Comment: A&A accepted for publication, 14 pages, 24 figures (including 17
online figures
The stellar content of the Hamburg/ESO survey. V. The metallicity distribution function of the Galactic halo
We determine the metallicity distribution function (MDF) of the Galactic halo
by means of a sample of 1638 metal-poor stars selected from the Hamburg/ESO
objective-prism survey (HES). The sample was corrected for minor biases
introduced by the strategy for spectroscopic follow-up observations of the
metal-poor candidates, namely "best and brightest stars first". [...] We
determined the selection function of the HES, which must be taken into account
for a proper comparison between the HES MDF with MDFs of other stellar
populations or those predicted by models of Galactic chemical evolution. The
latter show a reasonable agreement with the overall shape of the HES MDF for
[Fe/H] > -3.6, but only a model of Salvadori et al. (2007) with a critical
metallicity for low-mass star formation of Z_cr = 10^{-3.4} * Z_Sun reproduces
the sharp drop at [Fe/H] ~-3.6 present in the HES MDF. [...] A comparison of
the MDF of Galactic globular clusters and of dSph satellites to the Galaxy
shows qualitative agreement with the halo MDF, derived from the HES, once the
selection function of the latter is included. However, statistical tests show
that the differences between these are still highly significant. [ABSTRACT
ABRIDGED]Comment: Accepted for publication in A&
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