285 research outputs found

    Distinct immune signatures in directly treated and distant tumors result from TLR adjuvants and focal ablation.

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    Both adjuvants and focal ablation can alter the local innate immune system and trigger a highly effective systemic response. Our goal is to determine the impact of these treatments on directly treated and distant disease and the mechanisms for the enhanced response obtained by combinatorial treatments. Methods: We combined RNA-sequencing, flow cytometry and TCR-sequencing to dissect the impact of immunotherapy and of immunotherapy combined with ablation on local and systemic immune components. Results: With administration of a toll-like receptor agonist agonist (CpG) alone or CpG combined with same-site ablation, we found dramatic differences between the local and distant tumor environments, where the directly treated tumors were skewed to high expression of F4/80, Cd11b and Tnf and the distant tumors to enhanced Cd11c, Cd3 and Ifng. When ablation was added to immunotherapy, 100% (n=20/20) of directly treated tumors and 90% (n=18/20) of distant tumors were responsive. Comparing the combined ablation-immunotherapy treatment to immunotherapy alone, we find three major mechanistic differences. First, while ablation alone enhanced intratumoral antigen cross-presentation (up to ~8% of CD45+ cells), systemic cross-presentation of tumor antigen remained low. Combining same-site ablation with CpG amplified cross-presentation in the draining lymph node (~16% of CD45+ cells) compared to the ablation-only (~0.1% of CD45+ cells) and immunotherapy-only cohorts (~10% of CD45+ cells). Macrophages and DCs process and present this antigen to CD8+ T-cells, increasing the number of unique T-cell receptor rearrangements in distant tumors. Second, type I interferon (IFN) release from tumor cells increased with the ablation-immunotherapy treatment as compared with ablation or immunotherapy alone. Type I IFN release is synergistic with toll-like receptor activation in enhancing cytokine and chemokine expression. Expression of genes associated with T-cell activation and stimulation (Eomes, Prf1 and Icos) was 27, 56 and 89-fold higher with ablation-immunotherapy treatment as compared to the no-treatment controls (and 12, 32 and 60-fold higher for immunotherapy-only treatment as compared to the no-treatment controls). Third, we found that the ablation-immunotherapy treatment polarized macrophages and dendritic cells towards a CD169 subset systemically, where CD169+ macrophages are an IFN-enhanced subpopulation associated with dead-cell antigen presentation. Conclusion: While the local and distant responses are distinct, CpG combined with ablative focal therapy drives a highly effective systemic immune response

    Comparing various multi-component global heliosphere models

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    Modeling of the global heliosphere seeks to investigate the interaction of the solar wind with the partially ionized local interstellar medium. Models that treat neutral hydrogen self-consistently and in great detail, together with the plasma, but that neglect magnetic fields, constitute a sub-category within global heliospheric models. There are several different modeling strategies used for this sub-category in the literature. Differences and commonalities in the modeling results from different strategies are pointed out. Plasma-only models and fully self-consistent models from four research groups, for which the neutral species is modeled with either one, three, or four fluids, or else kinetically, are run with the same boundary parameters and equations. They are compared to each other with respect to the locations of key heliospheric boundary locations and with respect to the neutral hydrogen content throughout the heliosphere. In many respects, the models' predictions are similar. In particular, the locations of the termination shock agree to within 7% in the nose direction and to within 14% in the downwind direction. The nose locations of the heliopause agree to within 5%. The filtration of neutral hydrogen from the interstellar medium into the inner heliosphere, however, is model dependent, as are other neutral results including the hydrogen wall. These differences are closely linked to the strength of the interstellar bow shock. The comparison also underlines that it is critical to include neutral hydrogen into global heliospheric models.Comment: 10 pages, 4 figures, submitted to a special section at A&A of an ISSI team "Determination of the physical Hydrogen parameters of the LIC from within the Heliosphere

    Nonthermal Emission from a Supernova Remnant in a Molecular Cloud

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    In evolved supernova remnants (SNRs) interacting with molecular clouds, such as IC 443, W44, and 3C391, a highly inhomogeneous structure consisting of a forward shock of moderate Mach number, a cooling layer, a dense radiative shell and an interior region filled with hot tenuous plasma is expected. We present a kinetic model of nonthermal electron injection, acceleration and propagation in that environment and find that these SNRs are efficient electron accelerators and sources of hard X- and gamma-ray emission. The energy spectrum of the nonthermal electrons is shaped by the joint action of first and second order Fermi acceleration in a turbulent plasma with substantial Coulomb losses. Bremsstrahlung, synchrotron, and inverse Compton radiation of the nonthermal electrons produce multiwavelength photon spectra in quantitative agreement with the radio and the hard emission observed by ASCA and EGRET from IC 443. We distinguish interclump shock wave emission from molecular clump shock wave emission accounting for a complex structure of molecular cloud. Spatially resolved X- and gamma- ray spectra from the supernova remnants IC 443, W44, and 3C391 as might be observed with BeppoSAX, Chandra XRO, XMM, INTEGRAL and GLAST would distinguish the contribution of the energetic lepton component to the gamma-rays observed by EGRET.Comment: 14 pages, 4 figure, Astrophysical Journal, v.538, 2000 (in press

    A magnetization and 11^{11}B NMR study of Mg1x_{1-x}Alx_xB2_2 superconductors

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    We demonstrate for the first time the magnetic field distribution of the pure vortex state in lightly doped Mg1x_{1-x}Alx_xB2_2 (x0.025x\leq 0.025) powder samples, by using 11^{11}B NMR in magnetic fields of 23.5 and 47 kOe. The magnetic field distribution at T=5 K is Al-doping dependent, revealing a considerable decrease of anisotropy in respect to pure MgB2_2. This result correlates nicely with magnetization measurements and is consistent with σ\sigma-band hole driven superconductivity for MgB2_2

    Can the Future Influence the Present?

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    One widely accepted model of classical electrodynamics assumes that a moving charged particle produces both retarded and advanced fields. This formulation first appeared at least 75 years ago. It was popularized in the 1940\u27s by work of Wheeler and Feynman. But the most fundamental question associated with the model has remained unanswered: When (if ever) does the two-body problem have a unique solution? The present paper gives an answer in one special case. Imagine two identical charged particles alone in the universe moving symmetrically along the x axis. One is at x(t) and the other is at −x(t). Their motion is then governed by a system of functional differential equations involving both retarded and advanced arguments. This system together with the Newtonian initial data x(0)=x0\u3e0 and x′(0)=0 has a unique solution for all time provided x0 is sufficiently large. Perhaps the existence and uniqueness proof given for this special case will pave the way for more general results on this curious two-body problem

    The effects of a kappa-distribution in the heliosheath on the global heliosphere and ENA flux at 1 AU

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    We investigate heliosheath energetic neutral atom (ENA) fluxes at keV energies, by assuming that the heliosheath proton distribution can be approximated by a kappa-distribution. The choice of the kappa parameter derives from observational data of the solar wind (SW). This has direct applications to the upcoming IBEX mission. We will look at all-sky ENA maps within the IBEX energy range (10 eV to 6 keV), as well as ENA energy spectra in several directions. We find that the use of kappa, as opposed to a Maxwellian, gives rise to greatly increased ENA fluxes above 1 keV, while medium energy fluxes are somewhat reduced. We show how IBEX data can be used to estimate the spectral slope in the heliosheath, and that the use of kappa reduces the differences between ENA maps at different energies. We also investigate the effect introducing a kappa-distribution has on the global interaction between the SW and the local interstellar medium (LISM), and find that there is generally an increase in energy transport from the heliosphere into the LISM, due to the modified profile of ENA's energies. This results in a termination shock that moves out by 4 AU, a heliopause that moves in by 9 AU and a bow shock 25 AU farther out, in the nose direction

    Site-selective nuclear magnetic relaxation time in a superconducting vortex state

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    The temperature and field dependences of the site-selective nuclear spin relaxation time T_1 around vortices are studied comparatively both for s-wave and d-wave superconductors, based on the microscopic Bogoliubov-de Gennes theory. Reflecting low energy electronic excitations associated with the vortex core, the site selective temperature dependences deviate from those of the zero-field case, and T_1 becomes faster with approaching the vortex core. In the core region, T_1^{-1} has a new peak below the superconducting transition temperature T_c. The field dependence of the overall T_1(T) behaviors for s-wave and d-wave superconductors is investigated and analyzed in terms of the local density of states. The NMR study by the resonance field dependence may be a new method to probe the spatial resolved vortex core structure in various conventional and unconventional superconductors.Comment: 14Pages, 26 figures, revte
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