CXCL12 retargeting of an adenovirus vector to cancer cells using a bispecific adapter

Ad vectors are promising delivery vehicles for cancer therapeutic interventions. However, their application is limited by promiscuous tissue tropism and hepatotoxicity. This limitation can be avoided by altering the native tropism of Ads so that they can be redirected to the target cells through alternate cellular receptors. The CXCR4 chemokine receptor belongs to a large superfamily of G-protein-coupled receptors and is known to be upregulated in a wide variety of cancers, including breast cancer and melanoma. These receptors have been associated with cancer cell survival, progression, and metastasis. In the current study, an Ad to cancer cells overexpressing CXCR4 by using a bispecific adapter, sCAR-CXCL12, was retargeted. The sCAR-CXCL12 adapter contained the soluble ectodomain form of the native Ad5 receptor (sCAR), which was fused to a mature human chemokine ligand, CXCL12, through a short peptide linker. A dramatic increase in the infectivity of cancer cells using a targeted Ad vector compared with an untargeted vector was observed. Furthermore, sCAR-CXCL12 attenuated Ad infection of liver ex vivo and in vivo and enhanced Ad vector infection of xenograft tumors implanted in immunodeficient SCID-bg mice. Thus, the sCAR-CXCL12 adapter could be used to retarget Ad vectors to chemokine receptor-positive tumors

The Spectral Energy Distribution of Self-gravitating Interstellar Clouds I. Spheres

We derive the spectral energy distribution (SED) of dusty, isothermal, self gravitating, stable and spherical clouds externally heated by the ambient interstellar radiation field. For a given radiation field and dust properties, the radiative transfer problem is determined by the pressure of the surrounding medium and the cloud mass expressed as a fraction of the maximum stable cloud mass above which the clouds become gravitational unstable. To solve the radiative transfer problem a ray-tracing code is used to accurately derive the light distribution inside the cloud. This code considers both non isotropic scattering on dust grains and multiple scattering events. The dust properties inside the clouds are assumed to be the same as in the diffuse interstellar medium in our galaxy. We analyse the effect of the pressure, the critical mass fraction, and the ISRF on the SED and present brightness profiles in the visible, the IR/FIR and the submm/mm regime with the focus on the scattered emission and the thermal emission from PAH-molecules and dust grains.Comment: accepted for publication in ApJS, May 2008, v176n1 issu

Thymic negative selection is functional in NOD mice

Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes. Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection

Fast Mapping of Terahertz Bursting Thresholds and Characteristics at Synchrotron Light Sources

Dedicated optics with extremely short electron bunches enable synchrotron light sources to generate intense coherent THz radiation. The high degree of spatial compression in this so-called low-alpha optics entails a complex longitudinal dynamics of the electron bunches, which can be probed studying the fluctuations in the emitted terahertz radiation caused by the micro-bunching instability ("bursting"). This article presents a "quasi-instantaneous" method for measuring the bursting characteristics by simultaneously collecting and evaluating the information from all bunches in a multi-bunch fill, reducing the measurement time from hours to seconds. This speed-up allows systematic studies of the bursting characteristics for various accelerator settings within a single fill of the machine, enabling a comprehensive comparison of the measured bursting thresholds with theoretical predictions by the bunched-beam theory. This paper introduces the method and presents first results obtained at the ANKA synchrotron radiation facility.Comment: 7 pages, 7 figures, to be published in Physical Review Accelerators and Beam

IRAS03063+5735: A Bowshock Nebula Powered by an Early B Star

Mid-infrared images from the Spitzer Space Telescope Galactic Legacy Infrared MidPlane Survey Extraordinaire program reveal that the infrared source IRAS 03063+5735 is a bowshock nebula produced by an early B star, 2MASS 03101044+5747035. We present new optical spectra of this star, classify it as a B1.5 V, and determine a probable association with a molecular cloud complex at V_LSR=-38 -- -42 km/s in the outer Galaxy near l=140.59 degr, b=-0.250 degr. On the basis of spectroscopic parallax, we estimate a distance of 4.0 +/-1 kpc to both the bowshock nebula and the molecular complex. One plausible scenario is that this a high-velocity runaway star impinging upon a molecular cloud. We identify the HII region and stellar cluster associated with IRAS 03064+5638 at a projected distance of 64 pc as one plausible birth site. The spectrophotometric distance and linkage to a molecular feature provides another piece of data helping to secure the ill-determined rotation curve in the outer Galaxy. As a by-product of spectral typing this star, we present empirical spectral diagnostic diagrams suitable for approximate spectral classification of O and B stars using He lines in the little-used yellow-red portion of the optical spectrum.Comment: Accepted for publication in the Astronomical Journa

Stellar hydrodynamics caught in the act: Asteroseismology with CoRoT and Kepler

Asteroseismic investigations, particularly based on data on stellar oscillations from the CoRoT and Kepler space missions, are providing unique possibilities for investigating the properties of stellar interiors. This constitutes entirely new ways to study the effects of dynamic phenomena on stellar structure and evolution. Important examples are the extent of convection zones and the associated mixing and the direct and indirect effects of stellar rotation. In addition, the stellar oscillations themselves show very interesting dynamic behaviour. Here we discuss examples of the results obtained from such investigations, across the Hertzsprung-Russell diagram.Comment: Proc. IAU Symposium 271, Astrophysical Dynamics: From stars to galaxies, eds N. Brummell, A. S. Brun, M. S. Miesch, Y. Ponty, IAU and Cambridge University Press, in the pres

Circulating C3 is Necessary and Sufficient for Induction of Autoantibody-Mediated Arthritis in a Mouse Model

Objective. For the inflammation characteristic of rheumatoid arthritis, the relative contribution of mediators produced locally in the synovium versus those circulating systemically is unknown. Complement factor C3 is made in rheumatoid synovium and has been proposed to be a crucial driver of inflammation. The aim of this study was to test, in a mouse model of rheumatoid arthritis, whether C3 synthesized within the synovium is important in promoting inflammation. Methods. Radiation bone marrow chimeras between normal and C3−/− mice were constructed in order to generate animals that expressed or lacked expression of C3 only in hematopoietic cells. Parabiotic mice were made by surgically linking C3−/− mice to irradiated wild-type mice to obtain animals having C3 only in the circulation. Arthritis was induced by injection of serum from arthritic K/BxN mice.Results In bone marrow chimeras, synthesis of C3 by radioresistant cells was necessary and sufficient to confer susceptibility to serum-transferred arthritis. Parabionts having C3 only in the circulation remained sensitive to arthritis induction, and the cartilage of these arthritic mice contained deposits of C3. Conclusion. In a mouse model in which the alternative pathway of complement activation is critical to the induction of arthritis by autoantibodies, circulating C3 was necessary and sufficient for arthritis induction.Stem Cell and Regenerative Biolog

The Dust Trail of Comet 67P/Churyumov-Gerasimenko

We report the detection of comet 67P/Churyumov-Gerasimenko's dust trail and nucleus in 24 micron Spitzer Space Telescope images taken February 2004. The dust trail is not found in optical Palomar images taken June 2003. Both the optical and infrared images show a distinct neck-line tail structure, offset from the projected orbit of the comet. We compare our observations to simulated images using a Monte Carlo approach and a dynamical model for comet dust. We estimate the trail to be at least one orbit old (6.6 years) and consist of particles of size >~100 micron. The neck-line is composed of similar sized particles, particles of size but younger in age. Together, our observations and simulations suggest grains 100 micron and larger in size dominate the total mass ejected from the comet. The radiometric effective radius of the nucleus is 1.87 +/- 0.08 km, derived from the Spitzer observation. The Rosetta spacecraft is expected to arrive at and orbit this comet in 2014. Assuming the trail is comprised solely of 1 mm radius grains, we compute a low probability (~10^-3) of a trail grain impacting with Rosetta during approach and orbit insertion.Comment: Accepted for publication in Icaru

FUSE Measurements of Far Ultraviolet Extinction. I. Galactic Sight Lines

We present extinction curves that include data down to far ultraviolet wavelengths (FUV; 1050 - 1200 A) for nine Galactic sight lines. The FUV extinction was measured using data from the Far Ultraviolet Spectroscopic Explorer. The sight lines were chosen for their unusual extinction properties in the infrared through the ultraviolet; that they probe a wide range of dust environments is evidenced by the large spread in their measured ratios of total-to-selective extinction, R_V = 2.43 - 3.81. We find that extrapolation of the Fitzpatrick & Massa relationship from the ultraviolet appears to be a good predictor of the FUV extinction behavior. We find that predictions of the FUV extinction based upon the Cardelli, Clayton & Mathis (CCM) dependence on R_V give mixed results. For the seven extinction curves well represented by CCM in the infrared through ultraviolet, the FUV extinction is well predicted in three sight lines, over-predicted in two sight lines, and under-predicted in 2 sight lines. A Maximum Entropy Method analysis using a simple three component grain model shows that seven of the nine sight lines in the study require a larger fraction of grain materials to be in dust when FUV extinction is included in the models. Most of the added grain material is in the form of small (radii < 200 A) grains.Comment: Accepted for publication in the Astrophysical Journal. 31 pages with 7 figure

Search for the disappearance of muon antineutrinos in the NuMI neutrino beam

We report constraints on antineutrino oscillation parameters that were obtained by using the two MINOS detectors to measure the 7% muon antineutrino component of the NuMI neutrino beam. In the Far Detector, we select 130 events in the charged-current muon antineutrino sample, compared to a prediction of 136.4 ± 11.7(stat)^(+10.2)_(-8.9)(syst) events under the assumption │Δm^2│ = 2.32 X 10^(-3) eV^2, sin^2(2θ) = 1.0