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

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