This paper describes the science motivation, measurement objectives, performance requirements, detailed design, approach and implementation, and calibration of the four Hot Plasma Composition Analyzers (HPCA) for the Magnetospheric Multiscale mission. The HPCA is based entirely on electrostatic optics combining an electrostatic energy analyzer with a carbon-foil based time-of-flight analyzer. In order to fulfill mission requirements, the HPCA incorporates three unique technologies that give it very wide dynamic range capabilities essential to measuring minor ion species in the presence of extremely high proton fluxes found in the region of magnetopause reconnection. Dynamic range is controlled primarily by a novel radio frequency system analogous to an RF mass spectrometer. The RF, in combination with capabilities for high TOF event processing rates and high current micro-channel plates, ensures the dynamic range and sensitivity needed for accurate measurements of ion fluxes between ∼1 eV and 40 keV that are expected in the region of In order to calibrate the four HPCA instruments we have developed a unique ion calibration system. The system delivers a multi-species beam resolved to M/ M ∼ 100 and current densities between 0.05 and 200 pA/cm 2 with a stability of ±5 %. The entire system is controlled by a dedicated computer synchronized with the HPCA ground support equipment. This approach results not only in accurate calibration but also in a comprehensive set of coordinated instrument and auxiliary data that makes analysis straightforward and ensures archival of all relevant data.

Like many coactivators, the GACKIX domain of the master coactivator CBP/p300 recognizes transcriptional activators of diverse sequence composition via dynamic binding surfaces. The conformational dynamics of GACKIX that underlie its function also render it especially challenging for structural characterization. We find that the ligand discovery strategy of Tethering is an effective method for identifying small molecule fragments that stabilize the GACKIX domain and enables, for the first time, the crystallographic characterization of this important motif. The 2.0 Å resolution structure of GACKIX complexed to a small molecule was further analyzed by molecular dynamics simulations, revealing the importance of specific side chain motions that remodel the activator binding site in order to accommodate binding partners of distinct sequence and size. More broadly, these results suggest that Tethering can be a powerful strategy for identifying small molecule stabilizers of conformationally malleable proteins, thus facilitating their structural characterization and accelerating the discovery of small molecule modulators.

In the kinase field, there are many widely held tenets about conformation-selective inhibitors that have yet to be validated using controlled experiments. We have designed, synthesized, and characterized a series of kinase inhibitor analogues of dasatinib, an FDA-approved kinase inhibitor that binds the active conformation. This inhibitor series includes two Type II inhibitors that bind the DFG-out inactive conformation and two inhibitors that bind the αC-helix-out inactive conformation. Using this series of compounds, we analyze the impact that conformation-selective inhibitors have on target binding and kinome-wide selectivity.

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Space weather including solar activity and background plasma sets up spacecraft conditions that can magnify the threat from hypervelocity impacts. Hypervelocity impactors include both meteoroids, traveling between 11 and 72 km/s, and orbital debris, with typical impact speeds of 10 km/s. When an impactor encounters a spacecraft, its kinetic energy is converted over a very short timescale into energy of vaporization and ionization, resulting in a small, dense plasma. This plasma can produce radio frequency (RF) emission, causing electrical anomalies within the spacecraft. In order to study this phenomenon, we conducted ground-based experiments to study hypervelocity impact plasmas using a Van de Graaff dust accelerator. Iron projectiles ranging from 10 À16 g to 10 À11 g were fired at speeds of up to 70 km/s into a variety of target materials under a range of surface charging conditions representative of space weather effects. Impact plasmas associated with bare metal targets as well as spacecraft materials were studied. Plasma expansion models were developed to determine the composition and temperature of the impact plasma, shedding light on the plasma dynamics that can lead to spacecraft electrical anomalies. The dependence of these plasma properties on target material, impact speed, and surface charge was analyzed. Our work includes three major results. First, the initial temperature of the impact plasma is at least an order of magnitude lower than previously reported, providing conditions more favorable for sustained RF emission. Second, the composition of impact plasmas from glass targets, unlike that of impact plasmas from tungsten, has low dependence on impact speed, indicating a charge production mechanism that is significant down to orbital debris speeds. Finally, negative ion formation has a strong dependence on target material. These new results can inform the design and operation of spacecraft in order to mitigate future impact-related space weather anomalies and failures. V