The Aster proteins (encoded by the Gramd1a-c genes) contain a ligand-binding fold structurally similar to a START domain and mediate nonvesicular plasma membrane (PM) to endoplasmic reticulum (ER) cholesterol transport. In an effort to develop small molecule modulators of Asters, we identified 20α-hydroxycholesterol (HC) and U18666A as lead compounds. Unfortunately, both 20α-HC and U18666A target other sterol homeostatic proteins, limiting their utility. 20α-HC inhibits sterol regulatory element-binding protein 2 (SREBP2) processing, and U18666A is an inhibitor of the vesicular trafficking protein Niemann-Pick C1 (NPC1). To develop potent and selective Aster inhibitors, we synthesized a series of compounds by modifying 20α-HC and U18666A. Among these, AI (Aster inhibitor)-1l, which has a longer side chain than 20α-HC, selectively bound to Aster-C. The crystal structure of Aster-C in complex with AI-1l suggests that sequence and flexibility differences in the loop that gates the binding cavity may account for the ligand specificity for Aster C. We further identified the U18666A analog AI-3d as a potent inhibitor of all three Aster proteins. AI-3d blocks the ability of Asters to bind and transfer cholesterol in vitro and in cells. Importantly, AI-3d also inhibits the movement of low-density lipoprotein (LDL) cholesterol to the ER, although AI-3d does not block NPC1. This finding positions the nonvesicular Aster pathway downstream of NPC1-dependent vesicular transport in the movement of LDL cholesterol to the ER. Selective Aster inhibitors represent useful chemical tools to distinguish vesicular and nonvesicular sterol transport mechanisms in mammalian cells.

We fabricated three racetrack coils (RC1, RC2, and RC3) from Bi-2212 Rutherford cables (17-strand, thickness × width = 1.44 mm × 7.8 mm, strand diameter = 0.8 mm) and applied overpressure processing heat treatment (OPHT). The quench currents of RC1 and RC2 reached 5268 A and 5781 A, respectively, despite them still, surprisingly, exhibiting some Bi-2212 leakage to the surface. After removing most of the leakages using a simple-to-implement insulation scheme, the quench current of RC3 improved to 6485 A, which is about three times the average quench current of a dozen racetrack coils that had been fabricated and reacted using the conventional 1 bar heat treatment. The results confirm the effectiveness of the OPHT technology and the new leakage control scheme for coils made from Bi-2212 Rutherford cables. Coils exhibited an increased quench current with increasing the current ramp rate from 5 to 200 A s-1; they were quite stable against point and transient disturbances, and were capable of adsorbing persistent Joule heating at ∼80 mW for >15 s before quenching. These behaviors are different from Nb-Ti and Nb3Sn accelerator magnets. Overall, our results provide a critical evaluation and verification of Bi-2212 wire and magnet technologies (wire, insulation, heat treatment, coil fabrication, and coil operation), reveal crucial new stability features of Bi-2212 magnets, and demonstrate technological options for it to become a practical high-field magnet technology.

Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.