Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells.

The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5'-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients.

Forceful manipulation with micro air vehicles.

Micro air vehicles (MAVs) are finding use across an expanding range of applications. However, when interacting with the environment, they are limited by the maximum thrust they can produce. Here, we describe FlyCroTugs, a class of robots that adds to the mobility of MAVs the capability of forceful tugging up to 40 times their mass while adhering to a surface. This class of MAVs, which finds inspiration in the prey transportation strategy of wasps, exploits controllable adhesion or microspines to firmly adhere to the ground and then uses a winch to pull heavy objects. The combination of flight and adhesion for tugging creates a class of 100-gram multimodal MAVs that can rapidly traverse cluttered three-dimensional terrain and exert forces that affect human-scale environments. We discuss the energetics and scalability of this approach and demonstrate it for lifting a sensor into a partially collapsed building. We also demonstrate a team of two FlyCroTugs equipped with specialized end effectors for rotating a lever handle and opening a heavy door.

A robotic device using gecko-inspired adhesives can grasp and manipulate large objects in microgravity.

Grasping and manipulating uncooperative objects in space is an emerging challenge for robotic systems. Many traditional robotic grasping techniques used on Earth are infeasible in space. Vacuum grippers require an atmosphere, sticky attachments fail in the harsh environment of space, and handlike opposed grippers are not suited for large, smooth space debris. We present a robotic gripper that can gently grasp, manipulate, and release both flat and curved uncooperative objects as large as a meter in diameter while in microgravity. This is enabled by (i) space-qualified gecko-inspired dry adhesives that are selectively turned on and off by the application of shear forces, (ii) a load-sharing system that scales small patches of these adhesives to large areas, and (iii) a nonlinear passive wrist that is stiff during manipulation yet compliant when overloaded. We also introduce and experimentally verify a model for determining the force and moment limits of such an adhesive system. Tests in microgravity show that robotic grippers based on dry adhesion are a viable option for eliminating space debris in low Earth orbit and for enhancing missions in space.