Evaluation of the therapeutic potential of ant-TLR4-antibody MTS510 in experimental stroke and significa of different routes of application

Toll-like receptors (TLRs) are central sensors for the inflammatory response in ischemia-reperfusion injury. We therefore investigated whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia. Anti-TLR4/MD2-antibody (mAb clone MTS510) blocked TLR4-induced cell activation in vitro, as reported previously. Here, different routes of MTS510 application in vivo were used to study the effects on stroke outcome up to 2d after occlusion of the middle cerebral artery (MCAO) for 45 min in adult male C57Bl/6 wild-type mice. Improved neurological performance, reduced infarct volumes, and reduced brain swelling showed that intravascular application of MTS510 had a protective effect in the model of 45 min MCAO. Evaluation of potential long-term adverse effects of anti-TLR4-mAb-treament revealed no significant deleterious effect on infarct volumes nor neurological deficit after 14d of reperfusion in a mild model of stroke (15 min MCAO). Interestingly, inhibition of TLR4 resulted in an altered adaptive immune response at 48 hours after reperfusion. We conclude that blocking TLR4 by the use of specific mAb is a promising strategy for stroke therapy. However, long-term studies with increased functional sensitivity, larger sampling sizes and use of other species are required before a clinical use could be envisaged

The Eliashberg Function of Amorphous Metals

A connection is proposed between the anomalous thermal transport properties of amorphous solids and the low-frequency behavior of the Eliashberg function. By means of a model calculation we show that the size and frequency dependence of the phonon mean-free-path that has been extracted from measurements of the thermal conductivity in amorphous solids leads to a sizeable linear region in the Eliashberg function at small frequencies. Quantitative comparison with recent experiments gives very good agreement.Comment: 4pp., REVTeX, 1 uuencoded ps fig. Original posting had a corrupted raw ps fig appended. Published as PRB 51, 689 (1995

Formulating Light Cone QCD on the Lattice

We present the near light cone Hamiltonian $H$ in lattice QCD depending on the parameter $\eta$, which gives the distance to the light cone. Since the vacuum has zero momentum we can derive an effective Hamiltonian $H_{eff}$ from $H$ which is only quadratic in the momenta and therefore solvable by standard methods. An approximate ground state wave functional is determined variationally in the limit $\eta \to 0$.Comment: 48 pages, 8 figure

Conformally Einstein Products and Nearly K\"ahler Manifolds

In the first part of this note we study compact Riemannian manifolds (M,g) whose Riemannian product with R is conformally Einstein. We then consider compact 6--dimensional almost Hermitian manifolds of type W_1+W_4 in the Gray--Hervella classification admitting a parallel vector field and show that (under some regularity assumption) they are obtained as mapping tori of isometries of compact Sasaki-Einstein 5-dimensional manifolds. In particular, we obtain examples of inhomogeneous locally (non-globally) conformal nearly K\"ahler compact manifolds

Nonequilibrium relaxation and scaling properties of the two-dimensional Coulomb glass in the aging regime

We employ Monte Carlo simulations to investigate the two-time density autocorrelation function for the two-dimensional Coulomb glass. We find that the nonequilibrium relaxation properties of this highly correlated disordered system can be described by a full aging scaling ansatz. The scaling exponents are non-universal, and depend on temperature and charge density.Comment: 6 pages, 3 figures included; revised version: corrected exponents, and some additional explanations and references added; to appear in EP

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

While sarcomas account for approximately 1% of malignant tumors of adults, they are particularly more common in children and adolescents affected by cancer. In contrast to malignancies that occur in later stages of life, childhood tumors, including sarcoma, are characterized by a striking paucity of somatic mutations. However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4). Since strong oncogene-dependency has been demonstrated in these entities, direct pharmacological targeting of these fusion oncogenes has been excessively attempted, thus far, with limited success. Despite apparent challenges, our increasing understanding of the neomorphic features of these fusion oncogenes in conjunction with rapid technological advances will likely enable the development of new strategies to therapeutically exploit these neomorphic features and to ultimately turn the \textquotedblundruggable\textquotedbl into first-line target structures. In this review, we provide a broad overview of the current literature on targeting neomorphic features of fusion oncogenes found in Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma, and give a perspective for future developments. Graphical abstract Scheme depicting the different targeting strategies of fusion oncogenes in pediatric fusion-driven sarcomas. Fusion oncogenes can be targeted on their DNA level (1), RNA level (2), protein level (3), and by targeting downstream functions and interaction partners (4)

Theory of Exciton Migration and Field-Induced Dissociation in Conjugated Polymers

The interplay of migration, recombination, and dissociation of excitons in disordered media is studied theoretically in the low temperature regime. An exact expression for the photoluminescence spectrum is obtained. The theory is applied to describe the electric field-induced photoluminescence-quenching experiments by Kersting et al. [Phys. Rev. Lett. 73, 1440 (1994)] and Deussen et al. [Synth. Met. 73, 123 (1995)] on conjugated polymer systems. Good agreement with experiment is obtained using an on-chain dissociation mechanism, which implies a separation of the electron-hole pair along the polymer chain.Comment: 4 pages, RevTeX, 2 Postscript figure

On dispersive energy transport and relaxation in the hopping regime

A new method for investigating relaxation phenomena for charge carriers hopping between localized tail states has been developed. It allows us to consider both charge and energy {\it dispersive} transport. The method is based on the idea of quasi-elasticity: the typical energy loss during a hop is much less than all other characteristic energies. We have investigated two models with different density of states energy dependencies with our method. In general, we have found that the motion of a packet in energy space is affected by two competing tendencies. First, there is a packet broadening, i.e. the dispersive energy transport. Second, there is a narrowing of the packet, if the density of states is depleting with decreasing energy. It is the interplay of these two tendencies that determines the overall evolution. If the density of states is constant, only broadening exists. In this case a packet in energy space evolves into Gaussian one, moving with constant drift velocity and mean square deviation increasing linearly in time. If the density of states depletes exponentially with decreasing energy, the motion of the packet tremendously slows down with time. For large times the mean square deviation of the packet becomes constant, so that the motion of the packet is ``soliton-like''.Comment: 26 pages, RevTeX, 10 EPS figures, submitted to Phys. Rev.

Strategies for Enhancing the Dielectric Constant of Organic Materials

High dielectric constant organic semiconductors, often obtained by the use of ethylene glycol (EG) side chains, have gained attention in recent years in the efforts of improving the device performance for various applications. Dielectric constant enhancements due to EGs have been demonstrated extensively, but various effects, such as the choice of the particular molecule and the frequency and temperature regime, that determine the extent of this enhancement require further understanding. In this work, we study these effects by means of polarizable molecular dynamics simulations on a carefully selected set of fullerene derivatives with EG side chains. The selection allows studying the dielectric response in terms of both the number and length of EG chains and also the choice of the group connecting the fullerene to the EG chain. The computed time- and frequency-dependent dielectric responses reveal that the experimentally observed rise of the dielectric constant within the kilo/megahertz regime for some molecules is likely due to the highly stretched dielectric response of the EGs: the initial sharp increase over the first few nanoseconds is followed by a smaller but persistent increase in the range of microseconds. Additionally, our computational protocol allows the separation of different factors that contribute to the overall dielectric constant, providing insights to make several molecular design guides for future organic materials in order to enhance their dielectric constant further

Monte-Carlo Simulations of the Dynamical Behavior of the Coulomb Glass

We study the dynamical behavior of disordered many-particle systems with long-range Coulomb interactions by means of damage-spreading simulations. In this type of Monte-Carlo simulations one investigates the time evolution of the damage, i.e. the difference of the occupation numbers of two systems, subjected to the same thermal noise. We analyze the dependence of the damage on temperature and disorder strength. For zero disorder the spreading transition coincides with the equilibrium phase transition, whereas for finite disorder, we find evidence for a dynamical phase transition well below the transition temperature of the pure system.Comment: 10 pages RevTeX, 8 Postscript figure