Discovery and validation of a novel inhibitor of HYPE-mediated AMPylation.

Adenosyl monophosphate (AMP)ylation (the covalent transfer of an AMP from Adenosine Triphosphate (ATP) onto a target protein) is catalyzed by the human enzyme Huntingtin Yeast Interacting Partner E (HYPE)/FicD to regulate its substrate, the heat shock chaperone binding immunoglobulin protein (BiP). HYPE-mediated AMPylation of BiP is critical for maintaining proteostasis in the endoplasmic reticulum and mounting a unfolded protein response in times of proteostatic imbalance. Thus, manipulating HYPE's enzymatic activity is a key therapeutic strategy toward the treatment of various protein misfolding diseases, including neuropathy and early-onset diabetes associated with two recently identified clinical mutations of HYPE. Herein, we present an optimized, fluorescence polarization-based, high-throughput screening (HTS) assay to discover activators and inhibitors of HYPE-mediated AMPylation. After challenging our HTS assay with over 30,000 compounds, we discovered a novel AMPylase inhibitor, I2.10. We also determined a low micromolar IC50 for I2.10 and employed biorthogonal counter-screens to validate its efficacy against HYPE's AMPylation of BiP. Further, we report low cytotoxicity of I2.10 on human cell lines. We thus established an optimized, high-quality HTS assay amenable to tracking HYPE's enzymatic activity at scale, and provided the first novel small-molecule inhibitor capable of perturbing HYPE-directed AMPylation of BiP in vitro. Our HTS assay and I2.10 compound serve as a platform for further development of HYPE-specific small-molecule therapeutics.

High-Fidelity Ion State Detection Using Trap-Integrated Avalanche Photodiodes.

Integrated technologies greatly enhance the prospects for practical quantum information processing and sensing devices based on trapped ions. High-speed and high-fidelity ion state readout is critical for any such application. Integrated detectors offer significant advantages for system portability and can also greatly facilitate parallel operations if a separate detector can be incorporated at each ion-trapping location. Here, we demonstrate ion quantum state detection at room temperature utilizing single-photon avalanche diodes (SPADs) integrated directly into the substrate of silicon ion trapping chips. We detect the state of a trapped Sr^{+} ion via fluorescence collection with the SPAD, achieving 99.92(1)% average fidelity in 450 µs, opening the door to the application of integrated state detection to quantum computing and sensing utilizing arrays of trapped ions.

Lynx x-ray microcalorimeter.

Lynx is an x-ray telescope, one of four large satellite mission concepts currently being studied by NASA to be a flagship mission. One of Lynx's three instruments is an imaging spectrometer called the Lynx x-ray microcalorimeter (LXM), an x-ray microcalorimeter behind an x-ray optic with an angular resolution of 0.5 arc sec and ∼2 m2 of area at 1 keV. The LXM will provide unparalleled diagnostics of distant extended structures and, in particular, will allow the detailed study of the role of cosmic feedback in the evolution of the Universe. We discuss the baseline design of LXM and some parallel approaches for some of the key technologies. The baseline sensor technology uses transition-edge sensors, but we also consider an alternative approach using metallic magnetic calorimeters. We discuss the requirements for the instrument, the pixel layout, and the baseline readout design, which uses microwave superconducting quantum interference devices and high-electron mobility transistor amplifiers and the cryogenic cooling requirements and strategy for meeting these requirements. For each of these technologies, we discuss the current technology readiness level and our strategy for advancing them to be ready for flight. We also describe the current system design, including the block diagram, and our estimate for the mass, power, and data rate of the instrument.

Integrated GaN photonic circuits on silicon (100) for second harmonic generation.

We demonstrate second order optical nonlinearity in a silicon architecture through heterogeneous integration of single-crystalline gallium nitride (GaN) on silicon (100) substrates. By engineering GaN microrings for dual resonance around 1560 nm and 780 nm, we achieve efficient, tunable second harmonic generation at 780 nm. The χ2 nonlinear susceptibility is measured to be as high as 16 ± 7 pm/V. Because GaN has a wideband transparency window covering ultraviolet, visible and infrared wavelengths, our platform provides a viable route for the on-chip generation of optical wavelengths in both the far infrared and near-UV through a combination of χ2 enabled sum-/difference-frequency processes.