Explore the vast range of titles available.

Protease-activatable retroviral vectors offer the possibility of targeted gene transfer into cancer cells expressing a unique set of proteases as, for example, the matrix metalloproteases (MMPs). However, it is difficult to predict which substrate sequence will be optimally cleaved by a given tumour cell type. Therefore, we developed a novel approach that allows the selection of MMP-activatable retroviruses from libraries of viruses displaying combinatorially diversified protease substrates. Starting from a virus harbouring a standard MMP-2 substrate motif, after only two consecutive cycles of diversification and in vivo selection, MMP-activatable viruses were recovered. Biochemical characterization of the selected viruses revealed that their linker peptides showed a considerably increased sensitivity for MMP-2 cleavage, and interestingly also improved the particle incorporation rate of the Env protein. Owing to the optimized linker peptide, the selected viruses exhibited a greatly enhanced spreading efficiency through human fibrosarcoma cells, while having retained the dependency on MMP activation. Moreover, cell entry efficiency and virus titres were considerably improved as compared to the parental virus displaying the standard MMP-2 substrate. The results presented imply that retroviral protease substrate libraries allow the definition of MMP substrate specificities under in vivo conditions as well as the generation of optimally adapted tumour-specific viruses.

A significant fraction of the energy density of the interstellar medium is in the form of high-energy charged particles (cosmic rays) 1 . The origin of these particles remains uncertain. Although it is generally accepted that the only sources capable of supplying the energy required to accelerate the bulk of Galactic cosmic rays are supernova explosions, and even though the mechanism of particle acceleration in expanding supernova remnant (SNR) shocks is thought to be well understood theoretically 2 , 3 , unequivocal evidence for the production of high-energy particles in supernova shells has proven remarkably hard to find. Here we report on observations of the SNR RX J1713.7 - 3946 (G347.3 - 0.5), which was discovered by ROSAT 4 in the X-ray spectrum and later claimed as a source of high-energy γ-rays 5 , 6 of TeV energies (1 TeV = 10 12  eV). We present a TeV γ-ray image of the SNR: the spatially resolved remnant has a shell morphology similar to that seen in X-rays, which demonstrates that very-high-energy particles are accelerated there. The energy spectrum indicates efficient acceleration of charged particles to energies beyond 100 TeV, consistent with current ideas of particle acceleration in young SNR shocks.

Viruses conditionally replicating in cancer cells form an attractive novel class of antitumoral agents. To engineer such viruses infectivity can be coupled with proteolytic activity of the target cell by modifying the envelope (Env) protein of murine leukaemia virus (MLV) with blocking domains that prevent cell entry unless they are cleaved off by tumour-associated proteases like the matrix metalloproteases (MMP). Here we show that MLV variants selectively spreading through MMP-positive cells can be evolved from virus libraries, in which a standard MMP-2 substrate peptide connecting the blocking domain CD40L with the Env protein was diversified. Passaging the virus library on human fibrosarcoma or glioma cell lines resulted in the selection of about 10 virus clones, of which the three most frequent ones were shown to become activated by MMPs and to be replication competent on MMP-positive cells only. On these cells, the selected linker peptides improved the spreading by several orders of magnitude in vitro , as well as in tumour xenografts in vivo , approaching the kinetic of the unmodified wild-type virus. The data suggest that retroviral protease substrate libraries form a potent tool for the engineering of viruses conditionally replicating in a given cancer cell type of interest.

The molecular atmosphere has a number of windows where it is effectively transparent to electromagnetic radiation, one of these being in the infrared 8–14 micron region. The presence of clouds and aerosols, which are more effective emitters of infrared radiation, in the atmosphere show up as an increase in the effective brightness temperature compared to the clear sky. This talk will cover the results from operating a scanning radiometer at the H.E.S.S. site in Namibia in determining atmospheric conditions.

The accretion of matter onto a massive black hole is believed to feed the relativistic plasma jets found in many active galactic nuclei (AGN). Although some AGN accelerate particles to energies exceeding 10¹² electron volts and are bright sources of very-high-energy (VHE) γ-ray emission, it is not yet known where the VHE emission originates. Here we report on radio and VHE observations of the radio galaxy Messier 87, revealing a period of extremely strong VHE γ-ray flares accompanied by a strong increase of the radio flux from its nucleus. These results imply that charged particles are accelerated to very high energies in the immediate vicinity of the black hole.

AbstractThe High Energy Stereoscopic System (H.E.S.S.) consists of four 12m diameter imaging Cherenkov telescopes, and is presently under construction in the Khomas Highland region of Namibia, 1.8 km above sea level (23∘16′18′′ S, 16∘30′00′′ E). The H.E.S.S. telescopes provide very good angular resolution and background rejection capability resulting in a sensitivity ~ 10 mCrab with an energy threshold of around 100 GeV. The first two telescopes are currently operating, and the array will be complete in early 2004. This paper provides a description of the H.E.S.S. telescopes and reports preliminary results obtained with the first telescope. PACS: 95.55.Ka X- and gamma ray telescopes and instrumentation – 95.55.Pw Astronomical observations: gamma ray

Monitoring of high energy cosmic ray neutrons is of particular interest for cosmic ray water Cherenkov detectors as intense bundles of delayed neutrons have been found to arrive after the initial passage of a high energy air shower. In this paper we explore the possibility of building large-area high-energy neutron monitors using gadolinium-loaded Water Cherenkov Detectors (WCDs). GEANT4 simulations of photon production in WCDs are used to estimate the maximum detection efficiency for a hypothetical system. Requiring a series of neutron induced gamma ray flashes distributed over an extended period of time (up to 20s) was shown to be an effective way to discriminate high energy neutron interactions from other backgrounds. Results suggest that neutron detection efficiencies of 4-15% may be possible using a gadolinium-loaded detection system above 200 MeV. The magnitude of gadolinium loading was also shown to significantly modify the timing response of the simulated detector.

Blazars are a subclass of active galactic nuclei (AGN) that have a relativistic jet with a small viewing angle towards the observer. Recent results based on hadronic scenarios have motivated an ongoing discussion of how a blazar can produce high energy neutrinos during a flaring state and which scenario can successfully describe the observed gamma-ray behaviour. Markarian 421 is one of the closest and brightest objects in the extragalactic gamma-ray sky and showed flaring activity over a 14-day period in March 2010. In this work, we describe the performed analysis of Fermi-LAT data from the source focused on the MeV range (100 MeV - 1 GeV), and study the possibility of a contribution coming from the \\(p\\) interactions between protons and MeV SSC target photons to fit the very high energy (VHE) gamma-ray emission. The fit results were compared with two leptonic models (one-zone and two-zone) using the Akaike Information Criteria (AIC) test, which evaluates goodness-of-fit alongside the simplicity of the model. In all cases the photohadronic model was favoured as a better fit description in comparison to the one-zone leptonic model, and with respect to the two-zone model in the majority of cases. Our results show the potential of a photohadronic contribution to a lepto-hadronic origin of gamma-ray flux of blazars. Future gamma-ray observations above tens of TeV and below 100 MeV in energy will be crucial to test and discriminate between models.

Very high energy γ-rays probe the long-standing mystery of the origin of cosmic rays. Produced in the interactions of accelerated particles in astrophysical objects, they can be used to image cosmic particle accelerators. A first sensitive survey of the inner part of the Milky Way with the High Energy Stereoscopic System (HESS) reveals a population of eight previously unknown firmly detected sources of very high energy γ-rays. At least two have no known radio or x-ray counterpart and may be representative of a new class of \"dark\" nucleonic cosmic ray sources.

The design, construction and operation of the University of Durham ground-based gamma ray telescope is discussed. The telescope has been designed to detect gamma rays in the ≤ 200 GeV region and to achieve good discrimination between gamma ray and hadron initiated showers in the higher energy region (≳ 300 GeV). The telescope was commissioned in 1995 and a description of its design and operation is presented, together with a verification of the telescope's performance.