CD40 ligand induced cytotoxicity in carcinoma cells is enhanced by inhibition of metalloproteinase cleavage and delivery via a conditionally-replicating adenovirus

Background CD40 and its ligand (CD40L) play a critical role in co-ordinating immune responses. CD40 is also expressed in lymphoid malignancies and a number of carcinomas. In carcinoma cells the physiological outcome of CD40 ligation depends on the level of receptor engagement with low levels promoting cell survival and high levels inducing cell death. The most profound induction of cell death in carcinoma cells is induced by membrane-bound rather than recombinant soluble CD40L, but like other TNF family ligands, it is cleaved from the membrane by matrix metalloproteinases. Results We have generated a replication-deficient adenovirus expressing a mutant CD40L that is resistant to metalloproteinase cleavage such that ligand expression is retained at the cell membrane. Here we show that the mutated, cleavage-resistant form of CD40L is a more potent inducer of apoptosis than wild-type ligand in CD40-positive carcinoma cell lines. Since transgene expression via replication-deficient adenovirus vectors in vivo is low, we have also engineered a conditionally replicating E1A-CR2 deleted adenovirus to express mutant CD40L, resulting in significant amplification of ligand expression and consequent enhancement of its therapeutic effect. Conclusions Combined with numerous studies demonstrating its immunotherapeutic potential, these data provide a strong rationale for the exploitation of the CD40-CD40L pathway for the treatment of solid tumours

The structures of E. coli NfsA bound to the antibiotic nitrofurantoin; to 1,4-benzoquinone and to FMN

NfsA is a dimeric flavoprotein that catalyses the reduction in nitroaromatics and quinones by NADPH. This reduction is required for the activity of nitrofuran antibiotics. The crystal structure of free Escherichia coli NfsA and several homologues have been determined previously, but there is no structure of the enzyme with ligands. We present here crystal structures of oxidised E. coli NfsA in the presence of several ligands, including the antibiotic nitrofurantoin. Nitrofurantoin binds with the furan ring, rather than the nitro group that is reduced, near the N5 of the FMN. Molecular dynamics simulations show that this orientation is only favourable in the oxidised enzyme, while potentiometry suggests that little semiquinone is formed in the free protein. This suggests that the reduction occurs by direct hydride transfer from FMNH(−) to nitrofurantoin bound in the reverse orientation to that in the crystal structure. We present a model of nitrofurantoin bound to reduced NfsA in a viable hydride transfer orientation. The substrate 1,4-benzoquinone and the product hydroquinone are positioned close to the FMN N5 in the respective crystal structures with NfsA, suitable for reaction, but are mobile within the active site. The structure with a second FMN, bound as a ligand, shows that a mobile loop in the free protein forms a phosphate-binding pocket. NfsA is specific for NADPH and a similar conformational change, forming a phosphate-binding pocket, is likely to also occur with the natural cofactor

The Outer Disks of Early-Type Galaxies. I. Surface-Brightness Profiles of Barred Galaxies

We present a study of 66 barred, early-type (S0-Sb) disk galaxies, focused on the disk surface brightness profile outside the bar region and the nature of Freeman Type I and II profiles, their origins, and their possible relation to disk truncations. This paper discusses the data and their reduction, outlines our classification system, and presents $R$-band profiles and classifications for all galaxies in the sample. The profiles are derived from a variety of different sources, including the Sloan Digital Sky Survey (Data Release 5). For about half of the galaxies, we have profiles derived from more than one telescope; this allows us to check the stability and repeatability of our profile extraction and classification. The vast majority of the profiles are reliable down to levels of mu_R ~ 27 mag arcsec^-2; in exceptional cases, we can trace profiles down to mu_R > 28. We can typically follow disk profiles out to at least 1.5 times the traditional optical radius R_25; for some galaxies, we find light extending to ~ 3 R_25. We classify the profiles into three main groups: Type I (single-exponential), Type II (down-bending), and Type III (up-bending). The frequencies of these types are approximately 27%, 42%, and 24%, respectively, plus another 6% which are combinations of Types II and III. We further classify Type II profiles by where the break falls in relation to the bar length, and in terms of the postulated mechanisms for breaks at large radii ("classical trunction" of star formation versus the influence of the Outer Lindblad Resonance of the bar). We also classify the Type III profiles by the probable morphology of the outer light (disk or spheroid). Illustrations are given for all cases. (Abridged)Comment: 41 pages, 26 PDF figures. To appear in the Astronomical Journal. Version with full-resolution figures available at http://www.mpe.mpg.de/~erwin/research

X-Pipeline: An analysis package for autonomous gravitational-wave burst searches

Autonomous gravitational-wave searches -- fully automated analyses of data that run without human intervention or assistance -- are desirable for a number of reasons. They are necessary for the rapid identification of gravitational-wave burst candidates, which in turn will allow for follow-up observations by other observatories and the maximum exploitation of their scientific potential. A fully automated analysis would also circumvent the traditional "by hand" setup and tuning of burst searches that is both labourious and time consuming. We demonstrate a fully automated search with X-Pipeline, a software package for the coherent analysis of data from networks of interferometers for detecting bursts associated with GRBs and other astrophysical triggers. We discuss the methods X-Pipeline uses for automated running, including background estimation, efficiency studies, unbiased optimal tuning of search thresholds, and prediction of upper limits. These are all done automatically via Monte Carlo with multiple independent data samples, and without requiring human intervention. As a demonstration of the power of this approach, we apply X-Pipeline to LIGO data to search for gravitational-wave emission associated with GRB 031108. We find that X-Pipeline is sensitive to signals approximately a factor of 2 weaker in amplitude than those detectable by the cross-correlation technique used in LIGO searches to date. We conclude with the prospects for running X-Pipeline as a fully autonomous, near real-time triggered burst search in the next LSC-Virgo Science Run.Comment: 18 pages, 10 figures. Minor edits and clarifications; added more background on gravitational waves and detectors. To appear in New Journal of Physics

What the disjunctivist is right about

There is a traditional conception of sensory experience on which the experiences one has looking at, say, a cat could be had by someone merely hallucinating a cat. Disjunctivists take issue with this conception on the grounds that it does not enable us to understand how perceptual knowledge is possible. In particular, they think, it does not explain how it can be that experiences gained in perception enable us to be in ‘cognitive contact’ with objects and facts. I develop this chal- lenge to the traditional conception and then show that it is possible to accommo- date an adequate account of cognitive contact in keeping with the traditional conception. One upshot of the discussion is that experiences do not bear the explanatory burden placed upon them by disjunctivists

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit