The importance of lymphotoxin (LT) βR (LTβR) as a regulator of lymphoid organogenesis is well established, but its role in host defense has yet to be fully defined. In this study, we report that mice deficient in LTβR signaling were highly susceptible to infection with murine CMV (MCMV) and early during infection exhibited a catastrophic loss of T and B lymphocytes, although the majority of lymphocytes were themselves not directly infected. Moreover, bone marrow chimeras revealed that lymphocyte survival required LTα expression by hemopoietic cells, independent of developmental defects in lymphoid tissue, whereas LTβR expression by both stromal and hemopoietic cells was needed to prevent apoptosis. The induction of IFN-β was also severely impaired in MCMV-infected LTα−/− mice, but immunotherapy with an agonist LTβR Ab restored IFN-β levels, prevented lymphocyte death, and enhanced the survival of these mice. IFN-αβR−/− mice were also found to exhibit profound lymphocyte death during MCMV infection, thus providing a potential mechanistic link between type 1 IFN induction and lymphocyte survival through a LTαβ-dependent pathway important for MCMV host defense.
In the frequency domain, gradient-based local-optimization methods of waveform inversions have been unsuccessful at inverting subsurface parameters without an accurate starting model. Such methods could not correct automatically for poor starting models because multiple local minima made it difficult to approach the true global minimum. In this study, we compared the behavior of objective functions in the frequency and Laplace domains. Wavefields in the Laplace domain correspond to the zero-frequency component of a damped wavefield; thus, the Laplace-domain waveform inversion can image smooth velocity models. Objective functions in the Laplace-domain inversion have a smoother surface and fewer local minima than in the frequency-domain inversion. We applied the waveform inversion to a 2D slice of the acoustic SEG/EAGE salt model in the Laplace domain and recovered smooth velocity models from inaccurate initial velocity conditions. We also successfully imaged velocities of the salt, SEG overthrust, and Institut Francais du Petrole Marmousi models with the frequency-domain inversion method by using the inverted velocity model of the Laplacedomain inversion as the initial model.
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