The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent type I interferon (IFN) inducer, was evaluated as a chemotherapeutic agent in mouse cancer models and proved to be well tolerated in human cancer clinical trials. Despite its multiple biological functions, DMXAA has not been fully characterized for the potential application as a vaccine adjuvant. In this report, we show that DMXAA does act as an adjuvant due to its unique property as a soluble innate immune activator. Using OVA as a model antigen, DMXAA was demonstrated to improve on the antigen specific immune responses and induce a preferential Th2 (Type-2) response. The adjuvant effect was directly dependent on the IRF3-mediated production of type-I-interferon, but not IL-33. DMXAA could also enhance the immunogenicity of influenza split vaccine which led to significant increase in protective responses against live influenza virus challenge in mice compared to split vaccine alone. We propose that DMXAA can be used as an adjuvant that targets a specific innate immune signaling pathway via IRF3 for potential applications including vaccines against influenza which requires a high safety profile

Optical conductivity of the Hubbard model at finite temperature

The optical conductivity, $\sigma(\omega)$, of the two dimensional one-band Hubbard model is calculated at finite temperature using exact diagonalization techniques on finite clusters. The in-plane d.c. resistivity, $\rho_{ab}$, is also evaluated. We find that at large U/t and temperature T, $\rho_{ab}$ is approximately linear with temperature, in reasonable agreement with experiments on high-T$_c$ superconductors. Moreover, we note that $\sigma(\omega)$ displays charge excitations, a mid-infrared (MIR) band and a Drude peak, also as observed experimentally. The combination of the Drude peak and the MIR oscillator strengths leads to a conductivity that decays slower than $1/\omega^2$ at energies smaller than the insulator gap near half-filling.Comment: 12 pages, 3 figures appended, Revtex version 2.0, preprin

Colossal Magnetoresistance is a Griffiths Singularity

It is now widely accepted that the magnetic transition in doped manganites that show large magnetoresistance is a type of percolation effect. This paper demonstrates that the transition should be viewed in the context of the Griffiths phase that arises when disorder suppresses a magnetic transition. This approach explains unusual aspects of susceptibility and heat capacity data from a single crystal of La$_{0.7}$Ca$_{0.3}$MnO$_{3}.$Comment: 4 page

Charge Dynamics in the Planar t-J Model

The finite-temperature optical conductivity $\sigma(\omega)$ in the planar $t-J$ model is analysed using recently introduced numerical method based on the Lanczos diagonalization of small systems (up to 20 sites), as well as by analytical approaches, including the method of frequency moments and the retraceable-path approximation. Results for a dynamical mobility of a single hole at elevated temperatures $T>t$ reveal a Gaussian-like $\mu(\omega)$ spectra, however with a nonanalytical behavior at low $\omega$. In the single hole response a difference between the ferromagnetic (J=0) and the antiferromagnetic ($J>0$) polaron shows up at $T<J$. At larger dopings numerical results in studied systems are consistent with the thermodynamical behavior for $T>T^*\ge 0.1~t$. $\sigma(\omega)$ spectra show a non-Drude falloff at large frequencies. In particular for `optimum' doping $n_h \sim 0.2$ we obtain in the low-$\omega,T$ regime the relaxation rate $\tau^{-1} \sim 0.6 (\omega+\xi T)$ with $\xi \sim 3$, being consistent with the marginal Fermi liquid concept and experiments. Within the same regime we reproduce the nearly linear variation of dc resistivity $\rho$ with $T$. This behavior is weakly dependent on $J$, provided that $J<t$.Comment: 21 pages of text plus 17 figures, postscrip

Relating the Flow Processes and Bedforms of Steady-State and Waning Density Currents

© Copyright© 2020 de Cala, Ohata, Dorrell, Naruse, Patacci, Amy, Simmons, McLelland and McCaffrey. The interaction between turbidity currents and mobile substrates can lead to the development of different types of bedforms. Although much research has been conducted on bedform development beneath open channel flows, research into bedform development beneath waning gravity currents is relatively rare. Analysis of density current-related bedform development has therefore relied upon open channel flow phase diagrams. We report on an experimental study designed to assess the development of bedforms under steady and waning saline density currents. The experimental density currents developed stepped density profiles in which a higher-density basal zone was separated from the ambient fluid by a zone of intermediate density; any bedforms that developed were contained within the bottom layer of the current. Under different conditions ripples, dunes, downstream migrating antidunes and long wavelength antidunes were observed to form and could be distinguished based on their interactions and phase relationships with the upper surface of the lower denser layer of the current. Due to limited mixing between the upper and lower layer of the current and maintenance of current momentum, currents set with slowing discharge flow rates maintained a steady flow velocity in the lower layer of the flow. As a result, sustained bedform formative conditions were achieved within this lower layer, while waning current conditions effected the rest of the flow. Under waning currents, it was seen how pre-existing bed states can determine the subsequent evolution of bedforms. This illustrates the limitations of existing phase diagrams as they do not account for trajectory or rate of passage of flows through different bedform phase spaces. In order to establish a reliable quantitative association between the flow regime and the type of bedform development, it is critical to adopt an appropriate Froude number calculation method for stratified flow. The updated density current phase diagram indicates supercritical flow can be achieved at lower flow velocities than for open channel flows due to the effects of reduced gravity. Bedform depositional structures found in outcrop and on the modern sea floor provide data that helps to interpret the hydrodynamic and sedimentological character of the current that formed them. Therefore, understanding the processes involved in bedform development beneath density currents will enable more accurate estimation of the properties of flows

Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(II) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(II) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 ∼ 200 nM)

Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis

Valproic acid (VPA), a histone deacetylase inhibitor, upregulates NKG2D ligands (NKG2DLs) on some monocytic and lymphoid leukemic cells. However, its effect on myeloid leukemia cells and synergistic agents that can augment the effect of VPA remains unknown. Of the various myeloid cell lines examined, OUN-1, a chronic myelogenous leukemia cell line, showed the most prominent upregulation of MICA/B and ULBP2 in response to VPA. The NKG2DL upregulation was observed only in leukemic cells without apoptosis and the effect was abrogated by pretreatment of cells with caffeine, an inhibitor of ATM/ATR. Several activators of ATM/ATR were screened for their effect on NKG2DL expression, but only hydroxyurea (HU) efficiently upregulated both MICA/B and ULPB2 expression on the cell line. VPA and HU synergistically upregulated the NKG2DLs on OUN-1 cells as well as primary leukemic cells from some patients with acute myeloid leukemia. The upregulation of NKG2DLs by VPA and/or HU was associated with increased transcription of each NKG2DL gene. OUN-1 cells treated with VPA + HU were more susceptible to killing by natural killer (NK) cells than untreated cells and the enhanced cytotoxicity of NK cells was blocked by the treatment of NK cells with anti-NKG2D monoclonal antibodies. The same concentrations of VPA and HU did not affect the cytotoxicity of NK cells against OUN-1 cells. These data suggest that VPA and HU might enhance the NK cell-mediated antileukemia effect by increasing the susceptibility of myeloid leukemic cells to NK cells. © 2009 Japanese Cancer Association

A Novel 2D Folding Technique for Enhancing Fermi Surface Signatures in the Momentum Density: Application to Compton Scattering Data from an Al-3at%Li Disordered Alloy

We present a novel technique for enhancing Fermi surface (FS) signatures in the 2D distribution obtained after the 3D momentum density in a crystal is projected along a specific direction in momentum space. These results are useful for investigating fermiology via high resolution Compton scattering and positron annihilation spectroscopies. We focus on the particular case of the (110) projection in an fcc crystal where the standard approach based on the use of the Lock-Crisp-West (LCW) folding theorem fails to give a clear FS image due to the strong overlap with FS images obtained through projection from higher Brillouin zones. We show how these superposed FS images can be disentangled by using a selected set of reciprocal lattice vectors in the folding process. The applicability of our partial folding scheme is illustrated by considering Compton spectra from an Al-3at%Li disordered alloy single crystal. For this purpose, high resolution Compton profiles along nine directions in the (110) plane were measured. Corresponding highly accurate theoretical profiles in Al-3at%Li were computed within the local density approximation (LDA)-based Korringa-Kohn-Rostoker coherent potential approximation (KKR-CPA) first-principles framework. A good level of overall accord between theory and experiment is obtained, some expected discrepancies reflecting electron correlation effects notwithstanding, and the partial folding scheme is shown to yield a clear FS image in the (110) plane in Al-3%Li.Comment: 24 pages, 8 figures, to appear in Phys. Rev.