Use of Gas Electron Multiplier (GEM) Detectors for an Advanced X-ray Monitor

We describe a concept for a NASA SMEX Mission in which Gas Electron Multiplier (GEM) detectors, developed at CERN, are adapted for use in X-ray astronomy. These detectors can be used to obtain moderately large detector area and two-dimensional photon positions with sub mm accuracy in the range of 1.5 to 15 keV. We describe an application of GEMs with xenon gas, coded mask cameras, and simple circuits for measuring event positions and for anticoincidence rejection of particle events. The cameras are arranged to cover most of the celestial sphere, providing high sensitivity and throughput for a wide variety of cosmic explosions. At longer timescales, persistent X-ray sources would be monitored with unprecedented levels of coverage. The sensitivity to faint X-ray sources on a one-day timescale would be improved by a factor of 6 over the capability of the RXTE All Sky Monitor.Comment: 10 pages, 5 figs., in X-Ray and Gamma Ray Instrumentation for Astronomy XI, SPIE conference, San Diego, Aug. 200

Nod2 Suppresses Borrelia burgdorferi Mediated Murine Lyme Arthritis and Carditis through the Induction of Tolerance

The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen. The intracellular, cytosolic receptor Nod2 has been shown to play varying roles in either enhancing or attenuating inflammation in response to different infectious agents. We examined the role of Nod2 in responses to B. burgdorferi. In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM) resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells. However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice. We explored multiple potential mechanisms for the paradoxical response in in vivo versus in vitro systems and found that prolonged stimulation with a Nod2 ligand, muramyl dipeptide (MDP), resulted in tolerance to stimulation by B. burgdorferi. This tolerance was lost with stimulation of Nod2 deficient cells that cannot respond to MDP. Cytokine patterns in the tolerance model closely paralleled cytokine profiles in infected Nod2 deficient mice. We propose a model where Nod2 has an enhancing role in activating inflammation in early infection, but moderates inflammation after prolonged exposure to the organism through induction of tolerance

Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis

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A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation

Nod1 and Nod2 are intracellular proteins that are involved in host recognition of specific bacterial molecules and are genetically associated with several inflammatory diseases. Nod1 and Nod2 stimulation activates NF-κB through RICK, a caspase-recruitment domain-containing kinase. However, the mechanism by which RICK activates NF-κB in response to Nod1 and Nod2 stimulation is unknown. Here we show that RICK is conjugated with lysine-63-linked polyubiquitin chains at lysine 209 (K209) located in its kinase domain upon Nod1 or Nod2 stimulation and by induced oligomerization of RICK. Polyubiquitination of RICK at K209 was essential for RICK-mediated IKK activation and cytokine/chemokine secretion. However, RICK polyubiquitination did not require the kinase activity of RICK or alter the interaction of RICK with NEMO, a regulatory subunit of IκB kinase (IKK). Instead, polyubiquitination of RICK was found to mediate the recruitment of TAK1, a kinase that was found to be essential for Nod1-induced signaling. Thus, RICK polyubiquitination links TAK1 to IKK complexes, a critical step in Nod1/Nod2-mediated NF-κB activation