A Replicating Cytomegalovirus-Based Vaccine Encoding a Single Ebola Virus Nucleoprotein CTL Epitope Confers Protection against Ebola Virus

Human outbreaks of hemorrhagic disease caused by Ebola virus (EBOV) are a serious health concern in Central Africa. Great apes (gorillas/chimpanzees) are an important source of EBOV transmission to humans. Candidate EBOV vaccines do not spread from the initial vaccinee. In addition to being highly immunogenic, vaccines based on the cytomegalovirus (CMV) platform have the unique potential to re-infect and disseminate through target populations. To explore the utility of CMV-based vaccines against EBOV, we constructed a mouse CMV (MCMV) vector expressing a region of nucleoprotein (NP) of Zaire ebolavirus (ZEBOV) (MCMV/ZEBOV-NPCTL). MCMV/ZEBOV-NPCTL induced high levels of long-lasting CD8+ T cells against ZEBOV NP in mice. Importantly, all vaccinated animals were protected against lethal ZEBOV challenge. The absence of ZEBOV neutralizing and only low, sporadic levels of total anti-ZEBOV IgG antibodies in protected animals prior to ZEBOV challenge indicate a role, albeit perhaps not exclusive, for CD8+ T cells in mediating protection. This study demonstrates the ability of a CMV-based vaccine approach to protect against ZEBOV, and provides a ‘proof-of-concept’ for the potential for a ‘disseminating’ CMV-based EBOV vaccine to prevent EBOV transmission in wild animal populations

High-charge 10 GeV electron acceleration in a 10 cm nanoparticle-assisted hybrid wakefield accelerator

In an electron wakefield accelerator, an intense laser pulse or charged particle beam excites plasma waves. Under proper conditions, electrons from the background plasma are trapped in the plasma wave and accelerated to ultra-relativistic velocities. We present recent results from a proof-of-principle wakefield acceleration experiment that reveal a unique synergy between a laser-driven and particle-driven accelerator: a high-charge laser-wakefield accelerated electron bunch can drive its own wakefield while simultaneously drawing energy from the laser pulse via direct laser acceleration. This process continues to accelerate electrons beyond the usual decelerating phase of the wakefield, thus reaching much higher energies. We find that the 10-centimeter-long nanoparticle-assisted wakefield accelerator can generate 340 pC, 10.4+-0.6 GeV electron bunches with 3.4 GeV RMS convolved energy spread and 0.9 mrad RMS divergence. It can also produce bunches with lower energy, a few percent energy spread, and a higher charge. This synergistic mechanism and the simplicity of the experimental setup represent a step closer to compact tabletop particle accelerators suitable for applications requiring high charge at high energies, such as free electron lasers or radiation sources producing muon beams

The Vehicle, Fall 1970

Vol. 13, No. 1 Table of Contents A Thought Written in a Locked RoomJudy Huntpage 1 The Eggshell MoonWilliam Probeckpage 2 PoemBarb Parkerpage 3 4/5, May, 1970J. Michael Sainpage 5 A TreeRichard Stickannpage 6 both or noneMichelle Hallpage 6 The TrainSteve Sestinapage 8 Attempted DiscoveryDonald R. Johnsonpage 16 Island of SmokeVerna L. Jonespage 18 AwakeRobert Bladepage 19 PoemMary Klinkerpage 19 In ChurchMuriel Poolpage 21 PoemBarb Parkerpage 21 PoemMichelle Hallpage 22 Pod\u27nerVerna L. Jonespage 23 Rain and Other ThingsCarol Staniecpage 24 PoemAnn Graffpage 24 Examination of StudentdomMelvin Zaloudekpage 26 Women\u27s LiberationTonya Mortonpage 27 Morning Reflections on the Evening NewsPrudence Herberpage 29 Art and Photography Credits Jim Diaspage 4 Mike Dorseypages 7, 20 David Griffithpages 8, 17, 25 Cover PhotographyMark McKinneyhttps://thekeep.eiu.edu/vehicle/1024/thumbnail.jp

NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

INTRODUCTION:Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.METHODS:The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.RESULTS:We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion � hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.CONCLUSION:NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials

Predicting Spatial Patterns of Plant Recruitment Using Animal-Displacement Kernels

For plants dispersed by frugivores, spatial patterns of recruitment are primarily influenced by the spatial arrangement and characteristics of parent plants, the digestive characteristics, feeding behaviour and movement patterns of animal dispersers, and the structure of the habitat matrix. We used an individual-based, spatially-explicit framework to characterize seed dispersal and seedling fate in an endangered, insular plant-disperser system: the endemic shrub Daphne rodriguezii and its exclusive disperser, the endemic lizard Podarcis lilfordi. Plant recruitment kernels were chiefly determined by the disperser's patterns of space utilization (i.e. the lizard's displacement kernels), the position of the various plant individuals in relation to them, and habitat structure (vegetation cover vs. bare soil). In contrast to our expectations, seed gut-passage rate and its effects on germination, and lizard speed-of-movement, habitat choice and activity rhythm were of minor importance. Predicted plant recruitment kernels were strongly anisotropic and fine-grained, preventing their description using one-dimensional, frequency-distance curves. We found a general trade-off between recruitment probability and dispersal distance; however, optimal recruitment sites were not necessarily associated to sites of maximal adult-plant density. Conservation efforts aimed at enhancing the regeneration of endangered plant-disperser systems may gain in efficacy by manipulating the spatial distribution of dispersers (e.g. through the creation of refuges and feeding sites) to create areas favourable to plant recruitment