Interactions between misfolded protein oligomers and membranes: A central topic in neurodegenerative diseases?

AbstractThe deposition of amyloid material has been associated with many different diseases. Although these diseases are very diverse the amyloid material share many common features such as cross-β-sheet structure of the backbone of the proteins deposited. Another common feature of the aggregation process for a wide variety of proteins is the presence of prefibrillar oligomers. These oligomers are linked to the cytotoxicity occurring during the aggregation of proteins. These prefibrillar oligomers interact extensively with lipid membranes and in some cases leads to destabilization of lipid membranes. This interaction is however highly dependent on the nature of both the oligomer and the lipids. Anionic lipids are often required for interaction with the lipid membrane while increased exposure of hydrophobic patches from highly dynamic protein oligomers are structural determinants of cytotoxicity of the oligomers. To explore the oligomer lipid interaction in detail the interaction between oligomers of α-synuclein and the 4th fasciclin-1 domain of TGFBIp with lipid membranes will be examined here. For both proteins the dynamic species are the ones causing membrane destabilization and the membrane interaction is primarily seen when the lipid membranes contain anionic lipids. Hence the dynamic nature of oligomers with exposed hydrophobic patches alongside the presence of anionic lipids could be essential for the cytotoxicity observed for prefibrillar oligomers in general. This article is part of a Special Issue entitled: Lipid–protein interactions

Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice

In a mouse model of respiratory tract infection by Bordetella pertussis, bacteria multiply in the airways over the first week and are then cleared over the next 3–4 weeks by the host immune response. Pertussis toxin (PT), a virulence factor secreted exclusively by B. pertussis, promotes bacterial growth in the airways by suppression and modulation of host immune responses. By comparison of wild type and PT-deficient strains, we examined the role of PT in modulating airway cytokine and chemokine responses affecting neutrophil recruitment during B. pertussis infection in mice. We found that, despite early inhibition of neutrophil recruitment by PT, high numbers of neutrophils were recruited to the airways by 4 days post-infection with the wild type strain, but not with the PT-deficient strain, and that this correlated with upregulation of neutrophil-attracting chemokine gene expression. In addition, there was similar upregulation of genes expressing the cytokines IL-17A (IL-17), TNF-α and IFN-γ, indicating a mixed Th1/Th17 response. Expression of IL-6, a cytokine involved in Th17 induction, was upregulated earlier than the IL-17 response. We showed that PT, rather than bacterial numbers, was important for induction of these responses. Flow cytometric analysis revealed that the IL-17-producing cells were macrophages and neutrophils as well as T cells, and were present predominantly in the airways rather than the lung tissue. Antibody neutralization of IL-17 significantly reduced chemokine gene expression and neutrophil recruitment to the airways, but only modestly increased peak bacterial loads. These data indicate that PT stimulates inflammatory responses by induction of Th1- and Th17-associated cytokines, including IL-17, during B. pertussis infection in mice, but a role for IL-17 in protection against the infection remains to be established

Swath Mapping Data Management Within the National Oceanic and Atmospheric Administration

In 1983, the United States proclaimed the establishment of a maritime Exclusive Economic Zone (EEZ) extending beyond the territorial sea to a distance of 200 nautical miles from its coastline. The proclamation reserved for the U.S. the sovereign right to explore for, exploit, conserve, and manage all natural resources within this new 3.4 million square nautical mile territory, an area roughly 1.2 times the total U.S. land mass. In order to help determine the characteristics and resources of the U.S. EEZ, a detailed program was developed to systematically map the entire area using multi-beam swath sounding systems. The program is under the direction of the National Oceanic and Atmospheric Administration (NOAA), United States Department of Commerce. Field operations commenced in early 1984 as two NOAA ships, equipped with advanced bathymetric swath mapping and precision navigation capabilities, began surveying off the coast of central California. Two additional ships have been added since and, to date, 36,000 square nautical miles of bathymetric mapping have been completed, a product of 95,000 lineal nautical miles of swath sounding. With such an enormous amount of data produced by swath mapping systems, the necessity for a comprehensive data management program was recognized early in the project. This paper describes the two-level data management system that has evolved, the lower level utilized aboard NOAA ships that acquire and initially process swath data, and the upper level employed by the Ocean Mapping Section, which is responsible for receiving, verifying, final processing and archiving all bathymetric swath data

Topology Optimization of Two Fluid Heat Exchangers

A method for density-based topology optimization of heat exchangers with two fluids is proposed. The goal of the optimization process is to maximize the heat transfer from one fluid to the other, under maximum pressure drop constraints for each of the fluid flows. A single design variable is used to describe the physical fields. The solid interface and the fluid domains are generated using an erosion-dilation based identification technique, which guarantees well-separated fluids, as well as a minimum wall thickness between them. Under the assumption of laminar steady flow, the two fluids are modelled separately, but in the entire computational domain using the Brinkman penalization technique for ensuring negligible velocities outside of the respective fluid subdomains. The heat transfer is modelled using the convection-diffusion equation, where the convection is driven by both fluid flows. A stabilized finite element discretization is used to solve the governing equations. Results are presented for two different problems: a two-dimensional example illustrating and verifying the methodology; and a three-dimensional example inspired by shell-and-tube heat exchangers. The optimized designs for both cases show an improved heat transfer compared to the baseline designs. For the shell-and-tube case, the full freedom topology optimization approach is shown to yield performance improvements of up to 113% under the same pressure drop