Modulational instability of two pairs of counter-propagating waves and energy exchange in two-component media

The dynamics of two pairs of counter-propagating waves in two-component media is considered within the framework of two generally nonintegrable coupled Sine-Gordon equations. We consider the dynamics of weakly nonlinear wave packets, and using an asymptotic multiple-scales expansion we obtain a suite of evolution equations to describe energy exchange between the two components of the system. Depending on the wave packet length-scale vis-a-vis the wave amplitude scale, these evolution equations are either four non-dispersive and nonlinearly coupled envelope equations, or four non-locally coupled nonlinear Schroedinger equations. We also consider a set of fully coupled nonlinear Schroedinger equations, even though this system contains small dispersive terms which are strictly beyond the leading order of the asymptotic multiple-scales expansion method. Using both the theoretical predictions following from these asymptotic models and numerical simulations of the original unapproximated equations, we investigate the stability of plane-wave solutions, and show that they may be modulationally unstable. These instabilities can then lead to the formation of localized structures, and to a modification of the energy exchange between the components. When the system is close to being integrable, the time-evolution is distinguished by a remarkable almost periodic sequence of energy exchange scenarios, with spatial patterns alternating between approximately uniform wavetrains and localized structures.Comment: 35 pages, 13 figure

The association between murine cytomegalovirus induced hepatitis and the accummulation of oval cells

The accumulation of oval cells is an early event in the development of hepatocellular carcinoma induced by certain experimental regimes involving hepatocarcinogens. Oval cells have also been observed during chronic hepatitis induced by alcohol and iron overload. In this study, livers of murine cytomegalovirus (MCMV) infected mice were examined to determine whether hepatitis induced by this virus could initiate oval cell proliferation. BALB/c and C57BL/6 mice were infected with MCMV and studied 4, 8, 10 and 12 months later, alongside control (uninfected) mice. The livers were examined histochemically, immunocytochemically and by in situ hybridization to identify oval cells, inflammatory cells and proliferating cells. Oval cells were seen in the periportal regions of livers from MCMV infected BALB/c mice. These increased in number from 4 to 12 months after infection in parallel with increases in the numbers of inflammatory cells, even though cells expressing MCMV antigens were no longer evident in these samples. Proliferating oval cells and hepatocytes were identified by PCNA staining, indicating an increased level of liver regeneration in the infected livers. C57BL/6 mice are less susceptible to persistent MCMV hepatitis and had fewer oval cells than BALB/c mice. Thus the study demonstrates an association between MCMV induced hepatitis, inflammation, and presence of oval cells

Phase I trial of inducible caspase 9 T cells in adult stem cell transplant demonstrates massive clonotypic proliferative potential and long-term persistence of transgenic Tcells

Purpose: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. Patients and Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 10⁶/kg donor-derived iCasp9-transduced T cells on day + 25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism. Results: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/μL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/μL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur. Conclusions: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.Ping Zhang, Jyothy Raju, Md Ashik Ullah, Raymond Au, Antiopi Varelias, Kate H. Gartlan, Stuart D. Olver, Luke D. Samson, Elise Sturgeon, Nienke Zomerdijk, Judy Avery, Tessa Gargett, Michael P. Brown, Lachlan J. Coin, Devika Ganesamoorthy, Cheryl Hutchins, Gary R. Pratt, Glen A. Kennedy, A. James Morton, Cameron I. Curley, Geoffrey R. Hill, and Siok-Keen Te

CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease

Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17-dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80(+)CSF-1R(+)CD206(+)iNOS(-). Cutaneous cGVHD developed in a CSF-1/CSF-1R-dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r(-/-) mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80(+) macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and king cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti-CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD