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

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

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

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

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

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

A magnetization and 11^{11}B NMR study of Mg1−x_{1-x}Alx_xB2_2 superconductors

We demonstrate for the first time the magnetic field distribution of the pure vortex state in lightly doped Mg$_{1-x}$Al$_x$B$_2$ ($x\leq 0.025$) powder samples, by using $^{11}$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 MgB$_2$. This result correlates nicely with magnetization measurements and is consistent with $\sigma$-band hole driven superconductivity for MgB$_2$

THE INTERNATIONAL RESPONSIBILITIES OF DEVELOPED COUNTRIES IN ADAPTATION TO AND MITIGATION OF CLIMATE CHANGE: AN ETHICAL MANDATE

This article asserts three propositions. First, climate change and/or global warming has (and will continue to have) qualitative differences in its nature and impact on rich and poor countries, thus demonstrating the imperative of adaptation to and mitigation of its effects. Second, the current international environmental regime is insufficient for sensible global distributive justice. What is more, in the absence of an adequate regime the world continues to ignore fundamental ethical issues and the immediate needs of climate-vulnerable countries. Third, the effective preservation of the environment necessitates that developed countries bear the (ethical) responsibility for meeting the costs associated with climate change, and urgently and unremittingly discharge their obligation to assist developing and/or least developed countries in adapting to and mitigating the impact of global warming

11^{11}B NMR study of pure and lightly carbon doped MgB2_2 superconductors

We report a $^{11}$B NMR line shape and spin-lattice relaxation rate ($1/(T_1T)$) study of pure and lightly carbon doped MgB$_{2-x}$C$_{x}$ for $x=0$, 0.02, and 0.04, in the vortex state and in magnetic field of 23.5 kOe. We show that while pure MgB$_2$ exhibits the magnetic field distribution from superposition of the normal and the Abrikosov state, slight replacement of boron with carbon unveils the magnetic field distribution of the pure Abrikosov state. This indicates a considerable increase of $H_{c2}^c$ with carbon doping with respect to pure MgB$_2$. The spin-lattice relaxation rate $1/(T_1T)$ demonstrates clearly the presence of a coherence peak right below $T_c$ in pure MgB$_2$, followed by a typical BCS decrease on cooling. However, at temperatures lower than $\approx 10$K strong deviation from the BCS behavior is observed, probably from residual contribution of the vortex dynamics. In the carbon doped systems both the coherence peak and the BCS temperature dependence of $1/(T_1T)$ weaken, an effect attributed to the gradual shrinking of the $\sigma$ hole cylinders of the Fermi surface with electron doping.Comment: 8 pages, 6 figures, submitted to Phys. Rev.

Simon Terrill: Crowd Theory 2004-18, Perspectives, Notes and Comments

A catalogue publication for a major survey of the monumental Crowd Theory photographs by Melbourne-born, London-based artist Simon Terrill. The publication coincides with an exhibition bringing together all ten Crowd Theory images for the first time, at the Centre for Contemporary Photography, Melbourne. Inside are a range of responses and documents, including images and texts from the time of each event, as well as three newly commissioned essays reflecting on the project

Steering magnet design for a limited space

We compare two extreme designs of steering magnets. The first one is a very thin steering magnet design which occupies only 6 mm in length and can be additionally installed as needed. The other is realized by applying extra coil windings to a quadrupole magnet and does not consume any length. The properties and the features of these steering magnets are discussed

Development of frequency-agile high-repetition-rate CO{sub 2} DIAL systems for long range chemical remote sensing

Issues related to the development of direct detection, long-range CO{sub 2} DIAL systems for chemical detection and identification are presented and discussed including: data handling and display techniques for large, multi-{lambda} data sets, turbulence effects, slant path propagation, and speckle averaging. Data examples from various field campaigns and CO{sub 2} lidar platforms are used to illustrate the issues