Theoretical and Experimental Adsorption Studies of Polyelectrolytes on an Oppositely Charged Surface

Using self-assembly techniques, x-ray reflectivity measurements, and computer simulations, we study the effective interaction between charged polymer rods and surfaces. Long-time Brownian dynamics simulations are used to measure the effective adhesion force acting on the rods in a model consisting of a planar array of uniformly positively charged, stiff rods and a negatively charged planar substrate in the presence of explicit monovalent counterions and added monovalent salt ions in a continuous, isotropic dielectric medium. This electrostatic model predicts an attractive polymer-surface adhesion force that is weakly dependent on the bulk salt concentration and that shows fair agreement with a Debye-Huckel approximation for the macroion interaction at salt concentrations near 0.1 M. Complementary x-ray reflectivity experiments on poly(diallyldimethyl ammonium) chloride (PDDA) monolayer films on the native oxide of silicon show that monolayer structure, electron density, and surface roughness are likewise independent of the bulk ionic strength of the solution.Comment: Revtex, prb format; uses amssym

IJEMS: Iowa Joint Experiment in Microgravity Solidification

The Iowa Joint Experiment in Microgravity Solidification (IJEMS) is a cooperative effort between Iowa State University and the University of Iowa to study the formation of metal-matrix composites in a microgravity environment. Of particular interest is the interaction between the solid/liquid interface and the particles in suspension. The experiment is scheduled to fly on STS-69, Space Shuttle Endeavor on August 3, 1995. This project is unique in its heavy student participation and cooperation between the universities involved

Theoretical model for the formation of caveolae and similar membrane invaginations

We study a physical model for the formation of bud-like invaginations on fluid lipid membranes under tension, and apply this model to caveolae formation. We demonstrate that budding can be driven by membrane-bound proteins, provided that they exert asymmetric forces on the membrane that give rise to bending moments. In particular, caveolae formation does not necessarily require forces to be applied by the cytoskeleton. Our theoretical model is able to explain several features observed experimentally in caveolae, where proteins in the caveolin family are known to play a crucial role in the formation of caveolae buds. These include 1), the formation of caveolae buds with sizes in the 100-nm range and 2), that certain N- and C-termini deletion mutants result in vesicles that are an order-of-magnitude larger. Finally, we discuss the possible origin of the morphological striations that are observed on the surfaces of the caveolae

Interactions between proteins bound to biomembranes

We study a physical model for the interaction between general inclusions bound to fluid membranes that possess finite tension, as well as the usual bending rigidity. We are motivated by an interest in proteins bound to cell membranes that apply forces to these membranes, due to either entropic or direct chemical interactions. We find an exact analytic solution for the repulsive interaction between two similar circularly symmetric inclusions. This repulsion extends over length scales of order tens of nanometers, and contrasts with the membrane-mediated contact attraction for similar inclusions on tensionless membranes. For non circularly symmetric inclusions we study the small, algebraically long-ranged, attractive contribution to the force that arises. We discuss the relevance of our results to biological phenomena, such as the budding of caveolae from cell membranes and the striations that are observed on their coats.Comment: 22 pages, 2 figure

Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma.

UNLABELLED: Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial-mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs. SIGNIFICANCE: The molecular-guided therapeutic strategy of combining cabozantinib and sapanisertib restrains ERK activity to effectively suppress growth of renal cell carcinomas, including those unresponsive to immune checkpoint inhibitors