Evaluation of a biodegradable microparticulate polymer as a carrier for Burkholderia pseudomallei subunit vaccines in a mouse model of melioidosis.

Melioidosis, a potentially lethal disease of humans and animals, is caused by the soil-dwelling bacterium Burkholderia pseudomallei. Due to B. pseudomallei's classification as a Tier 1 Select Agent, there is substantial interest in the development of an effective vaccine. Yet, despite decades of research, no effective target, adjuvant or delivery vehicle capable of inducing protective immunity against B. pseudomallei infection has been identified. We propose a microparticulate delivery vehicle comprised of the novel polymer acetalated dextran (Ac-DEX). Ac-DEX is an acid-sensitive biodegradable carrier that can be fabricated into microparticles (MPs) that are relatively stable at pH 7.4, but rapidly degrade after phagocytosis by antigen presenting cells where the pH can drop to 5.0. As compared to other biomaterials, this acid sensitivity has been shown to enhance cross presentation of subunit antigens. To evaluate this platform as a delivery system for a melioidosis vaccine, BALB/c mice were vaccinated with Ac-DEX MPs separately encapsulating B. pseudomallei whole cell lysate and the toll-like receptor (TLR) 7/8 agonist resiquimod. This vaccine elicited a robust antibody response that included both Th1 and Th2 immunity. Following lethal intraperitoneal challenge with B. pseudomallei 1026b, vaccinated mice demonstrated a significant delay to time of death compared to untreated mice. The formulation, however, demonstrated incomplete protection indicating that lysate protein offers limited value as an antigen. Nevertheless, our Ac-DEX MPs may offer an effective delivery vehicle for a subunit B. psuedomallei vaccine.

Continuous improvement of H-mode discharge performance with progressively increasing lithium coatings in the National Spherical Torus Experiment.

Lithium wall coatings have been shown to reduce recycling, improve energy confinement, and suppress edge localized modes in the National Spherical Torus Experiment. Here, we show that these effects depend continuously on the amount of predischarge lithium evaporation. We observed a nearly monotonic reduction in recycling, decrease in electron transport, and modification of the edge profiles and stability with increasing lithium. These correlations challenge basic expectations, given that even the smallest coatings exceeded that needed for a nominal thickness of the order of the implantation range.

Triggered confinement enhancement and pedestal expansion in high-confinement-mode discharges in the national spherical torus experiment.

We report observation of a new high performance regime in discharges in the National Spherical Torus Experiment, where the H mode edge "pedestal" temperature doubles and the energy confinement increases by 50%. The spontaneous transition is triggered by a large edge-localized mode, either natural or externally triggered by 3D fields. The transport barrier grows inward from the edge, with a doubling of both the pedestal pressure width and the spatial extent of steep radial electric field shear. The dynamics suggest that 3D fields could be applied to reduce edge transport in fusion devices.

Attacker-defender models and road network vulnerability.

The reliability of road networks depends directly on their vulnerability to disruptive incidents, ranging in severity from minor disruptions to terrorist attacks. This paper presents a game theoretic approach to the analysis of road network vulnerability. The approach posits predefined disruption, attack or failure scenarios and then considers how to use the road network so as to minimize the maximum expected loss in the event of one of these scenarios coming to fruition. A mixed route strategy is adopted, meaning that the use of the road network is determined by the worst scenario probabilities. This is equivalent to risk-averse route choice. A solution algorithm suitable for use with standard traffic assignment software is presented, thereby enabling the use of electronic road navigation networks. A variant of this algorithm suitable for risk-averse assignment is developed. A numerical example relating to the central London road network is presented. The results highlight points of vulnerability in the road network. Applications of this form of network vulnerability analysis together with improved solution methods are discussed.

Efficient generation of closed magnetic flux surfaces in a large spherical tokamak using coaxial helicity injection.

A method of coaxial helicity injection has successfully produced a closed flux current without the use of the central solenoid in the NSTX device, on a size scale closer to a spherical torus reactor, for a proof-of-principle demonstration of this concept. For the first time, a remarkable 60 times current multiplication factor was achieved. Grad-Shafranov plasma equilibrium reconstructions are used to verify the existence of closed flux current. In some discharges the generated current persists for a surprisingly long time approximately 400 ms.

Observation of plasma toroidal-momentum dissipation by neoclassical toroidal viscosity.

Dissipation of plasma toroidal angular momentum is observed in the National Spherical Torus Experiment due to applied nonaxisymmetric magnetic fields and their plasma-induced increase by resonant field amplification and resistive wall mode destabilization. The measured decrease of the plasma toroidal angular momentum profile is compared to calculations of nonresonant drag torque based on the theory of neoclassical toroidal viscosity. Quantitative agreement between experiment and theory is found when the effect of toroidally trapped particles is included.

Design and synthesis of fluorinated RXR modulators.

Fluorinated trienoic acid analogues of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their ability to bind RXRalpha and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the position of fluorination, and improvement in pharmacological profile was demonstrated in some cases.

Characteristics of the first H-mode discharges in the national spherical torus experiment.

We report observations of the first low-to-high ( L-H) confinement mode transitions in the National Spherical Torus Experiment. The H-mode energy confinement time increased over reference discharges transiently by 100-200%, as high as approximately 100 ms. This confinement time is approximately 2 times higher than predicted by a multimachine scaling. Thus the confinement time of spherical tori has been extended to a record high value, leading to an eventual revision of confinement scalings. Finally, the power threshold for H-mode access is >10x higher than predicted by an international scaling from conventional aspect-ratio tokamaks, which could lead to new understanding of H-mode transition dynamics.

Pharmacological characterization of LY335979: a potent cyclopropyldibenzosuberane modulator of P-glycoprotein.

The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.