Lipids, Lipoproteins, and Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. While excellent treatment has emerged for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. A prominent age-related change is the accumulation of neutral lipid in normal Bruch's membrane (BrM) throughout adulthood and also disease-related BrM accumulations called basal deposits and drusen. AMD lesion formation has thus been conceptualized as sharing mechanisms with atherosclerotic plaque formation, where low-density lipoprotein (LDL) retention within the arterial wall initiates a cascade of pathologic events. However, we do not yet understand how lipoproteins contribute to AMD. This paper explores how systemic and local production of lipoproteins might contribute to the pathogenesis of AMD

Hyperstrong Radio-Wave Scattering in the Galactic Center. II. A Likelihood Analysis of Free Electrons in the Galactic Center

The scattering diameters of Sgr A* and several nearby OH masers (~ 1" at 1 GHz) indicate that a region of enhanced scattering is along the line of sight to the Galactic center. We combine radio-wave scattering data and free-free emission and absorption measurements in a likelihood analysis that constrains the following parameters of the GC scattering region: The GC-scattering region separation, d; the angular extent of the region, \psi_l; the outer scale on which density fluctuations occur, l_0; and the gas temperature, T. The maximum likelihood estimates of these parameters are d = 133_{-80}^{+200} pc, 0.5 degrees <= \psi_l <~ 1 degrees, and (l_0/1 pc)^{2/3}T^{-1/2} = 10^{-7 +/- 0.8}. As host media for the scattering, we consider the photoionized surface layers of molecular clouds and the interfaces between molecular clouds and the 10^7 K ambient gas. We are unable to make an unambiguous determination, but we favor an interface model in which the scattering medium is hot (T ~ 10^6 K) and dense (n_e ~ 10 cm^{-3}). The GC scattering region produces a 1 GHz scattering diameter for an extragalactic source of 90", if the region is a single screen, or 180", if the region wraps around the GC, as appears probable. We modify the Taylor-Cordes model for the Galactic distribution of free electrons in order to include an explicit GC component. Pulsars seen through this region will have a dispersion measure of approximately 2000 pc cm^{-3}, of which 75% arises from the GC component. We stress the uniqueness of the GC scattering region, probably resulting from the high-pressure environment in the GC.Comment: 39 pages with 9 PostScript figures; LaTeX2e with AASTeX macro aaspp4, to be published in Ap

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD

Poly(β-Amino Ester)-Nanoparticle Mediated Transfection of Retinal Pigment Epithelial Cells In Vitro and In Vivo

A variety of genetic diseases in the retina, including retinitis pigmentosa and leber congenital amaurosis, might be excellent targets for gene delivery as treatment. A major challenge in non-viral gene delivery remains finding a safe and effective delivery system. Poly(beta-amino ester)s (PBAEs) have shown great potential as gene delivery reagents because they are easily synthesized and they transfect a wide variety of cell types with high efficacy in vitro. We synthesized a combinatorial library of PBAEs and evaluated them for transfection efficacy and toxicity in retinal pigment epithelial (ARPE-19) cells to identify lead polymer structures and transfection formulations. Our optimal polymer (B5-S5-E7 at 60 w/w polymer∶DNA ratio) transfected ARPE-19 cells with 44±5% transfection efficacy, significantly higher than with optimized formulations of leading commercially available reagents Lipofectamine 2000 (26±7%) and X-tremeGENE HP DNA (22±6%); (p<0.001 for both). Ten formulations exceeded 30% transfection efficacy. This high non-viral efficacy was achieved with comparable cytotoxicity (23±6%) to controls; optimized formulations of Lipofectamine 2000 and X-tremeGENE HP DNA showed 15±3% and 32±9% toxicity respectively (p>0.05 for both). Our optimal polymer was also significantly better than a gold standard polymeric transfection reagent, branched 25 kDa polyethyleneimine (PEI), which achieved only 8±1% transfection efficacy with 25±6% cytotoxicity. Subretinal injections using lyophilized GFP-PBAE nanoparticles resulted in 1.1±1×103-fold and 1.5±0.7×103-fold increased GFP expression in the retinal pigment epithelium (RPE)/choroid and neural retina respectively, compared to injection of DNA alone (p = 0.003 for RPE/choroid, p<0.001 for neural retina). The successful transfection of the RPE in vivo suggests that these nanoparticles could be used to study a number of genetic diseases in the laboratory with the potential to treat debilitating eye diseases

Observation of Hadronic W Decays in t-tbar Events with the Collider Detector at Fermilab

We observe hadronic W decays in t-tbar -> W (-> l nu) + >= 4 jet events using a 109 pb-1 data sample of p-pbar collisions at sqrt{s} = 1.8 TeV collected with the Collider Detector at Fermilab (CDF). A peak in the dijet invariant mass distribution is obtained that is consistent with W decay and inconsistent with the background prediction by 3.3 standard deviations. From this peak we measure the W mass to be 77.2 +- 4.6 (stat+syst) GeV/c^2. This result demonstrates the presence of two W bosons in t-tbar candidates in the W (-> l nu) + >= 4 jet channel.Comment: 20 pages, 4 figures, submitted to PR

Measurement of the lepton charge asymmetry in W-boson decays produced in p-pbar collisions

We describe a measurement of the charge asymmetry of leptons from W boson decays in the rapidity range 0 enu, munu events from 110+/-7 pb^{-1}of data collected by the CDF detector during 1992-95. The asymmetry data constrain the ratio of d and u quark momentum distributions in the proton over the x range of 0.006 to 0.34 at Q2 \approx M_W^2. The asymmetry predictions that use parton distribution functions obtained from previously published CDF data in the central rapidity region (0.0<|y_l|<1.1) do not agree with the new data in the large rapidity region (|y_l|>1.1).Comment: 13 pages, 3 tables, 1 figur

Search for Narrow Diphoton Resonances and for gamma-gamma+W/Z Signatures in p\bar p Collisions at sqrt(s)=1.8 TeV

We present results of searches for diphoton resonances produced both inclusively and also in association with a vector boson (W or Z) using 100 pb^{-1} of p\bar p collisions using the CDF detector. We set upper limits on the product of cross section times branching ratio for both p\bar p\to\gamma\gamma + X and p\bar p\to\gamma\gamma + W/Z. Comparing the inclusive production to the expectations from heavy sgoldstinos we derive limits on the supersymmetry-breaking scale sqrt{F} in the TeV range, depending on the sgoldstino mass and the choice of other parameters. Also, using a NLO prediction for the associated production of a Higgs boson with a W or Z boson, we set an upper limit on the branching ratio for H\to\gamma\gamma. Finally, we set a lower limit on the mass of a `bosophilic' Higgs boson (e.g. one which couples only to \gamma, W, and Z$ bosons with standard model couplings) of 82 GeV/c^2 at 95% confidence level.Comment: 30 pages, 11 figure

Measurement of the Associated γ+μ±\gamma + \mu^\pm Production Cross Section in ppˉp \bar p Collisions at s=1.8\sqrt{s} = 1.8 TeV

We present the first measurement of associated direct photon + muon production in hadronic collisions, from a sample of 1.8 TeV $p \bar p$ collisions recorded with the Collider Detector at Fermilab. Quantum chromodynamics (QCD) predicts that these events are primarily from the Compton scattering process $cg \to c\gamma$, with the final state charm quark producing a muon. Hence this measurement is sensitive to the charm quark content of the proton. The measured cross section of $29\pm 9 pb^{-1}$ is compared to a leading-order QCD parton shower model as well as a next-to-leading-order QCD calculation.Comment: 12 pages, 4 figures Added more detailed description of muon background estimat

Measurement of the top quark mass and top-antitop production cross section from dilepton events at the Collider Detector at Fermilab

We present an analysis of dilepton events originating from top-antitop production in proton-antiproton collisions at sqrt{s}=1.8 TeV at the Fermilab Tevatron Collider. The sample corresponds to an integrated luminosity of 109+-7 pb^{-1}. We observe 9 candidate events, with an estimated background of 2.4+-0.5 events. We determine the mass of the top quark to be M_top = 161+-17(stat.)+-10(syst.) GeV/c^2. In addition we measure a top-antitop production cross section of 8.2+4.4-3.4 pb (where M_top = 175 GeV/c^2 has been assumed for the acceptance estimate).Comment: 6 pages of text, 3 figure