612 research outputs found
A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in sorsby's fundus dystrophy
Sorsby’s fundus dystrophy (SFD) is a dominantly inherited
degenerative disease of the retina that leads to
loss of vision in middle age. It has been shown to be
caused by mutations in the gene for tissue inhibitor of
metalloproteinases-3 (TIMP-3). Five different mutations
have previously been identified, all introducing an extra
cysteine residue into exon 5 (which forms part of the
C-terminal domain) of the TIMP-3 molecule; however,
the significance of these mutations to the disease phenotype
was unknown. In this report, we describe the
expression of several of these mutated genes, together
with a previously unreported novel TIMP-3 mutation
from a family with SFD that results in truncation of
most of the C-terminal domain of the molecule. Despite
these differences, all of these molecules are expressed
and exhibit characteristics of the normal protein, including
inhibition of metalloproteinases and binding to
the extracellular matrix. However, unlike wild-type
TIMP-3, they all form dimers. These observations, together
with the recent finding that expression of TIMP-3
is increased, rather than decreased, in eyes from patients
with SFD, provides compelling evidence that
dimerized TIMP-3 plays an active role in the disease
process by accumulating in the eye. Increased expression
of TIMP-3 is also observed in other degenerative
retinal diseases, including the more severe forms of agerelated
macular degeneration, the most common cause
of blindness in the elderly in developed countries. We
hypothesize that overexpression of TIMP-3 may prove to
be a critical step in the progression of a variety of degenerative
retinopathies
An Isocurvature Mechanism for Structure Formation
We examine a novel mechanism for structure formation involving initial number
density fluctuations between relativistic species, one of which then undergoes
a temporary downward variation in its equation of state and generates
superhorizon-scale density fluctuations. Isocurvature decaying dark matter
models (iDDM) provide concrete examples. This mechanism solves the
phenomenological problems of traditional isocurvature models, allowing iDDM
models to fit the current CMB and large-scale structure data, while still
providing novel behavior. We characterize the decaying dark matter and its
decay products as a single component of ``generalized dark matter''. This
simplifies calculations in decaying dark matter models and others that utilize
this mechanism for structure formation.Comment: 4 pages, 3 figures, submitted to PRD (rapid communications
Is the evidence for dark energy secure?
Several kinds of astronomical observations, interpreted in the framework of
the standard Friedmann-Robertson-Walker cosmology, have indicated that our
universe is dominated by a Cosmological Constant. The dimming of distant Type
Ia supernovae suggests that the expansion rate is accelerating, as if driven by
vacuum energy, and this has been indirectly substantiated through studies of
angular anisotropies in the cosmic microwave background (CMB) and of spatial
correlations in the large-scale structure (LSS) of galaxies. However there is
no compelling direct evidence yet for (the dynamical effects of) dark energy.
The precision CMB data can be equally well fitted without dark energy if the
spectrum of primordial density fluctuations is not quite scale-free and if the
Hubble constant is lower globally than its locally measured value. The LSS data
can also be satisfactorily fitted if there is a small component of hot dark
matter, as would be provided by neutrinos of mass 0.5 eV. Although such an
Einstein-de Sitter model cannot explain the SNe Ia Hubble diagram or the
position of the `baryon acoustic oscillation' peak in the autocorrelation
function of galaxies, it may be possible to do so e.g. in an inhomogeneous
Lemaitre-Tolman-Bondi cosmology where we are located in a void which is
expanding faster than the average. Such alternatives may seem contrived but
this must be weighed against our lack of any fundamental understanding of the
inferred tiny energy scale of the dark energy. It may well be an artifact of an
oversimplified cosmological model, rather than having physical reality.Comment: 12 pages, 5 figures; to appear in a special issue of General
Relativity and Gravitation, eds. G.F.R. Ellis et al; Changes: references
reformatted in journal style - text unchange
Limits on the gravity wave contribution to microwave anisotropies
We present limits on the fraction of large angle microwave anisotropies which
could come from tensor perturbations. We use the COBE results as well as
smaller scale CMB observations, measurements of galaxy correlations, abundances
of galaxy clusters, and Lyman alpha absorption cloud statistics. Our aim is to
provide conservative limits on the tensor-to-scalar ratio for standard
inflationary models. For power-law inflation, for example, we find T/S<0.52 at
95% confidence, with a similar constraint for phi^p potentials. However, for
models with tensor amplitude unrelated to the scalar spectral index it is still
currently possible to have T/S>1.Comment: 23 pages, 7 figures, accepted for publication in Phys. Rev. D.
Calculations extended to blue spectral index, Fig. 6 added, discussion of
results expande
Chemical evolution of the Galactic bulge as traced by microlensed dwarf and subgiant stars: II. Ages, metallicities, detailed elemental abundances, and connections to the Galactic thick disc
Is cosmology consistent?
We perform a detailed analysis of the latest CMB measurements (including
BOOMERaNG, DASI, Maxima and CBI), both alone and jointly with other
cosmological data sets involving, e.g., galaxy clustering and the Lyman Alpha
Forest. We first address the question of whether the CMB data are internally
consistent once calibration and beam uncertainties are taken into account,
performing a series of statistical tests. With a few minor caveats, our answer
is yes, and we compress all data into a single set of 24 bandpowers with
associated covariance matrix and window functions. We then compute joint
constraints on the 11 parameters of the ``standard'' adiabatic inflationary
cosmological model. Out best fit model passes a series of physical consistency
checks and agrees with essentially all currently available cosmological data.
In addition to sharp constraints on the cosmic matter budget in good agreement
with those of the BOOMERaNG, DASI and Maxima teams, we obtain a heaviest
neutrino mass range 0.04-4.2 eV and the sharpest constraints to date on gravity
waves which (together with preference for a slight red-tilt) favors
``small-field'' inflation models.Comment: Replaced to match accepted PRD version. 14 pages, 12 figs. Tiny
changes due to smaller DASI & Maxima calibration errors. Expanded neutrino
and tensor discussion, added refs, typos fixed. Combined CMB data, window and
covariance matrix at http://www.hep.upenn.edu/~max/consistent.html or from
[email protected]
Detection Limits for Super-Hubble Suppression of Causal Fluctuations
We investigate to what extent future microwave background experiments might
be able to detect a suppression of fluctuation power on large scales in flat
and open universe models. Such suppression would arise if fluctuations are
generated by causal processes, and a measurement of a small suppression scale
would be problematic for inflation models, but consistent with many defect
models. More speculatively, a measurement of a suppression scale of the order
of the present Hubble radius could provide independent evidence for a
fine-tuned inflation model leading to a low-density universe. We find that,
depending on the primordial power spectrum, a suppression scale modestly larger
than the visible Horizon can be detected, but that the detectability drops very
rapidly with increasing scale. For models with two periods of inflation, there
is essentially no possibility of detecting a causal suppression scale.Comment: 8 pages, 4 figures, revtex, In Press Physical Review D 200
Constraints from Inflation on Scalar-Tensor Gravity Theories
We show how observations of the perturbation spectra produced during
inflation may be used to constrain the parameters of general scalar-tensor
theories of gravity, which include both an inflaton and dilaton field. An
interesting feature of these models is the possibility that the curvature
perturbations on super-horizon scales may not be constant due to non-adiabatic
perturbations of the two fields. Within a given model, the tilt and relative
amplitude of the scalar and tensor perturbation spectra gives constraints on
the parameters of the gravity theory, which may be comparable with those from
primordial nucleosynthesis and post-Newtonian experiments.Comment: LaTeX (with RevTex) 19 pages, 8 uuencoded figures appended, also
available on WWW via http://star.maps.susx.ac.uk/index.htm
Kinetics of active surface-mediated diffusion in spherically symmetric domains
We present an exact calculation of the mean first-passage time to a target on
the surface of a 2D or 3D spherical domain, for a molecule alternating phases
of surface diffusion on the domain boundary and phases of bulk diffusion. We
generalize the results of [J. Stat. Phys. {\bf 142}, 657 (2011)] and consider a
biased diffusion in a general annulus with an arbitrary number of regularly
spaced targets on a partially reflecting surface. The presented approach is
based on an integral equation which can be solved analytically. Numerically
validated approximation schemes, which provide more tractable expressions of
the mean first-passage time are also proposed. In the framework of this minimal
model of surface-mediated reactions, we show analytically that the mean
reaction time can be minimized as a function of the desorption rate from the
surface.Comment: Published online in J. Stat. Phy
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