The eukaryotic cell membrane is connected to a dense actin rich cortex. We present FCS and STED experiments showing that dense membrane bound actin networks have severe influence on lipid phase separation. A minimal actin cortex was bound to a supported lipid bilayer via biotinylated lipid streptavidin complexes (pinning sites). In general, actin binding to ternary membranes prevented macroscopic liquid-ordered and liquid-disordered domain formation, even at low temperature. Instead, depending on the type of pinning lipid, an actin correlated multi-domain pattern was observed. FCS measurements revealed hindered diffusion of lipids in the presence of an actin network. To explain our experimental findings, a new simulation model is proposed, in which the membrane composition, the membrane curvature, and the actin pinning sites are all coupled. Our results reveal a mechanism how cells may prevent macroscopic demixing of their membrane components, while at the same time regulate the local membrane composition.DOI: http://dx.doi.org/10.7554/eLife.01671.001

Substructure within the liquid-ordered phase of lipid bilayers is reported, composed of saturated hydrocarbon chains packed with local hexagonal order, separated by interstitial regions enriched in cholesterol and unsaturated chains. The structure, identified during 10 msec all-atom molecular dynamics simulation of liquid-ordered/liquid-disordered coexistence (Lo/Ld), is confirmed by comparison to 2H NMR quadropolar splittings. The balance of cholesterolrich to local hexagonal order is proposed to control the partitioning of membrane components into the Lo region. Understanding how mechanisms present in the cell membrane _ such as crowding or coupling to the cytoskeleton _ shift the balance of cholesterol rich substructure should help resolve partitioning in bilayers and cell membranes.

We present computer simulations of a membrane in which the local composition is coupled to the local membrane curvature. At high temperatures (i.e., above the temperature of macroscopic phase separation), finite-sized transient domains are observed, reminiscent of lipid rafts. The domain size is in the range of hundred nanometers, and set by the membrane elastic properties. These findings are in line with the notion of the membrane as a curvature-induced microemulsion. At low temperature, the membrane phase separates. The transition to the phase-separated regime is continuous and belongs to the two-dimensional Ising universality class when the coupling to curvature is weak, but becomes first-order for strong curvature-composition coupling.

No abstract

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2-targeting agents have been incorporated into the treatment paradigms for HER2overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. Herein we discuss two patients with gallbladder carcinoma (GBC) and a third with ampullary carcinoma who were able to achieve marked responses to HER2-directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2-directed therapy beyond breast and gastroesophageal cancers. The Oncologist 2021;9999:• • KEY POINTS• Current guidelines recommend molecular assessment for HER2-oversexpression exclusively in breast and gastric adenocarcinoma • The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 is detected and treatment with HER2-directed therapy resulted in robust responses • These cases exemplify responsiveness of non-breast/gastric histologies to HER2-directed therapies, highlighting several promising new settings for these agents • Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options