Lipid-protein interactions drive membrane protein topogenesis in accordance with the positive inside rule.

Transmembrane domain orientation within some membrane proteins is dependent on membrane lipid composition. Initial orientation occurs within the translocon, but final orientation is determined after membrane insertion by interactions within the protein and between lipid headgroups and protein extramembrane domains. Positively and negatively charged amino acids in extramembrane domains represent cytoplasmic retention and membrane translocation forces, respectively, which are determinants of protein orientation. Lipids with no net charge dampen the translocation potential of negative residues working in opposition to cytoplasmic retention of positive residues, thus allowing the functional presence of negative residues in cytoplasmic domains without affecting protein topology.

Dengue transmission risk maps of the continental United States

Dengue fever is a strictly human and non-human primate disease characterized by a high fever, thrombocytopenia, retro-orbital pain, and severe joint and muscle pain. Over 40% of the world population is at risk. Recent re-emergence of dengue outbreaks in Texas and Florida following the re-introduction of competent Aedes mosquito vectors in the United States have raised growing concerns about the potential for increased occurrences of dengue fever outbreaks throughout the southern United States. Current deficiencies in vector control, active surveillance and awareness among medical practitioners may contribute to a delay in recognizing and controlling a dengue virus outbreak. Previous studies have shown links between low-income census tracts, high population density, and dengue fever within the United States. Areas of low-income and high population density that correlate with the distribution of Aedes mosquitoes result in higher potential for outbreaks. In this retrospective ecologic study, nine maps were generated to model U.S. census tracts’ potential to sustain dengue virus transmission if the virus was introduced into the area. Variables in the model included presence of a competent vector in the county and census tract percent poverty and population density. Thirty states, 1,188 counties, and 34,705 census tracts were included in the analysis. Among counties with Aedes mosquito infestation, the census tracts were ranked high, medium, and low risk potential for sustained transmission of the virus. High risk census tracts were identified as areas having the vector, ≥20% poverty, and ≥500 persons per square mile. Census tracts with either ≥20% poverty or ≥500 persons per square mile and have the vector present are considered moderate risk. Census tracts that have the vector present but have <20% poverty and <500 persons per square mile are considered low risk. Furthermore, counties were characterized as moderate risk if 50% or more of the census tracts in that county were rated high or moderate risk, and high risk if 25% or greater were rated high risk. Extreme risk counties, which were primarily concentrated in Texas and Mississippi, were considered having 50% or greater of the census tracts ranked as high risk. Mapping of geographic areas with potential to sustain dengue virus transmission will support surveillance efforts and assist medical personnel in recognizing potential cases. ^

αvβ8 Integrin Interacts with RhoGDI1 to Regulate Rac1 and Cdc42 Activation and Drive Glioblastoma Cell Invasion

As an interface between the circulatory and central nervous systems, the neurovascular unit is vital to the development and survival of tumors. The malignant brain cancer glioblastoma multiforme (GBM) displays invasive growth behaviors that are major impediments to surgical resection and targeted therapies. Adhesion and signaling pathways that drive GBM cell invasion remain largely uncharacterized. Here we have utilized human GBM cell lines, primary patient samples, and pre-clinical mouse models to demonstrate that integrin αvβ8 is a major driver of GBM cell invasion. β8 integrin is overexpressed in many human GBM cells, with higher integrin expression correlating with increased invasion and diminished patient survival. Silencing β8 integrin in human GBM cells leads to impaired tumor cell invasion due to hyperactivation of the Rho GTPases Rac1 and Cdc42. β8 integrin associates with Rho GDP Dissociation Inhibitor 1 (RhoGDI1), an intracellular signaling effector that sequesters Rho GTPases in their inactive GDP-bound states. Silencing RhoGDI1 expression or uncoupling αvβ8 integrin-RhoGDI1 protein interactions blocks GBM cell invasion due to Rho GTPase hyperactivation. These data reveal for the first time that αvβ8 integrin, via interactions with RhoGDI1, suppresses activation of Rho proteins to promote GBM cell invasiveness. Hence, targeting the αvβ8 integrin-RhoGDI1 signaling axis may be an effective strategy for blocking GBM cell invasion.