A nanoliposome delivery system to synergistically trigger TLR4 AND TLR7.

BACKGROUND: Recent reports that TLR4 and TLR7 ligands can synergistically trigger Th1 biased immune responses suggest that an adjuvant that contains both ligands would be an excellent candidate for co-administration with vaccine antigens for which heavily Th1 biased responses are desired. Ligands of each of these TLRs generally have disparate biochemical properties, however, and straightforward co-formulation may represent an obstacle. RESULTS: We show here that the TLR7 ligand, imiquimod, and the TLR4 ligand, GLA, synergistically trigger responses in human whole blood. We combined these ligands in an anionic liposomal formulation where the TLR7 ligand is in the interior of the liposome and the TLR4 ligand intercalates into the lipid bilayer. The new liposomal formulations are stable for at least a year and have an attractive average particle size of around 140 nm allowing sterile filtration. The synergistic adjuvant biases away from Th2 responses, as seen by significantly reduced IL-5 and enhanced interferon gamma production upon antigen-specific stimulation of cells from immunized mice, than any of the liposomal formulations with only one TLR agonist. Qualitative alterations in antibody responses in mice demonstrate that the adjuvant enhances Th1 adaptive immune responses above any adjuvant containing only a single TLR ligand as well. CONCLUSION: We now have a manufacturable, synergistic TLR4/TLR7 adjuvant that is made with excipients and agonists that are pharmaceutically acceptable and will have a straightforward path into human clinical trials.

Visualization of geologic stress perturbations using Mohr diagrams.

Huge salt formations, trapping large untapped oil and gas reservoirs, lie in the deepwater region of the Gulf of Mexico. Drilling in this region is high-risk and drilling failures have led to well abandonments, with each costing tens of millions of dollars. Salt tectonics plays a central role in these failures. To explore the geomechanical interactions between salt and the surrounding sand and shale formations, scientists have simulated the stresses in and around salt diapirs in the Gulf of Mexico using nonlinear finite element geomechanical modeling. In this paper, we describe novel techniques developed to visualize the simulated subsurface stress field. We present an adaptation of the Mohr diagram, a traditional paper-and-pencil graphical method long used by the material mechanics community for estimating coordinate transformations for stress tensors, as a new tensor glyph for dynamically exploring tensor variables within three-dimensional finite element models. This interactive glyph can be used as either a probe or a filter through brushing and linking.