Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic ‘client’ proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native ‘carboxylate clamp’ interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H–15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors

A Measurement of Time-Averaged Aerosol Optical Depth using Air-Showers Observed in Stereo by HiRes

Air fluorescence measurements of cosmic ray energy must be corrected for attenuation of the atmosphere. In this paper we show that the air-showers themselves can yield a measurement of the aerosol attenuation in terms of optical depth, time-averaged over extended periods. Although the technique lacks statistical power to make the critical hourly measurements that only specialized active instruments can achieve, we note the technique does not depend on absolute calibration of the detector hardware, and requires no additional equipment beyond the fluorescence detectors that observe the air showers. This paper describes the technique, and presents results based on analysis of 1258 air-showers observed in stereo by the High Resolution Fly's Eye over a four year span.Comment: 7 pages, 3 figures, accepted for publication by Astroparticle Physics Journa

Search for Global Dipole Enhancements in the HiRes-I Monocular Data above 10^{18.5} eV

Several proposed source models for Ultra-High Energy Cosmic Rays (UHECRs) consist of dipole distributions oriented towards major astrophysical landmarks such as the galactic center, M87, or Centaurus A. We use a comparison between real data and simulated data to show that the HiRes-I monocular data for energies above 10^{18.5} eV is, in fact, consistent with an isotropic source model. We then explore methods to quantify our sensitivity to dipole source models oriented towards the Galactic Center, M87, and Centaurus A.Comment: 17 pages, 31 figure

Aperiodicity in one-way Markov cycles and repeat times of large earthquakes in faults

A common use of Markov Chains is the simulation of the seismic cycle in a fault, i.e. as a renewal model for the repetition of its characteristic earthquakes. This representation is consistent with Reid's elastic rebound theory. Here it is proved that in {\it any} one-way Markov cycle, the aperiodicity of the corresponding distribution of cycle lengths is always lower than one. This fact concurs with observations of large earthquakes in faults all over the world

Observation of the Ankle and Evidence for a High-Energy Break in the Cosmic Ray Spectrum

We have measured the cosmic ray spectrum at energies above $10^{17}$ eV using the two air fluorescence detectors of the High Resolution Fly's Eye experiment operating in monocular mode. We describe the detector, PMT and atmospheric calibrations, and the analysis techniques for the two detectors. We fit the spectrum to models describing galactic and extragalactic sources. Our measured spectrum gives an observation of a feature known as the ``ankle'' near $3\times 10^{18}$ eV, and strong evidence for a suppression near $6\times 10^{19}$ eV.Comment: 14 pages, 9 figures. To appear in Physics Letters B. Accepted versio

Science requirement document (SRD) for the European Solar Telescope (EST) (2nd edition, December 2019)

The European Solar Telescope (EST) is a research infrastructure for solar physics. It is planned to be an on-axis solar telescope with an aperture of 4 m and equipped with an innovative suite of spectro-polarimetric and imaging post-focus instrumentation. The EST project was initiated and is driven by EAST, the European Association for Solar Telescopes. EAST was founded in 2006 as an association of 14 European countries. Today, as of December 2019, EAST consists of 26 European research institutes from 18 European countries. The Preliminary Design Phase of EST was accomplished between 2008 and 2011. During this phase, in 2010, the first version of the EST Science Requirement Document (SRD) was published. After EST became a project on the ESFRI roadmap 2016, the preparatory phase started. The goal of the preparatory phase is to accomplish a final design for the telescope and the legal governance structure of EST. A major milestone on this path is to revisit and update the Science Requirement Document (SRD). The EST Science Advisory Group (SAG) has been constituted by EAST and the Board of the PRE-EST EU project in November 2017 and has been charged with the task of providing with a final statement on the science requirements for EST. Based on the conceptual design, the SRD update takes into account recent technical and scientific developments, to ensure that EST provides significant advancement beyond the current state-of-the-art. The present update of the EST SRD has been developed and discussed during a series of EST SAG meetings. The SRD develops the top-level science objectives of EST into individual science cases. Identifying critical science requirements is one of its main goals. Those requirements will define the capabilities of EST and the post-focus instrument suite. The technical requirements for the final design of EST will be derived from the SRD

Complex relationships among personality traits, job characteristics, and work behaviors

The aim of the study was to investigate the additive, mediating, and moderating effects of personality traits and job characteristics on work behaviors. Job applicants (N = 161) completed personality questionnaires measuring extraversion, neuroticism, achievement motivation, and experience seeking. One and a half years later, supervisors rated the applicants' job performance, and the job incumbents completed questionnaires about skill variety, autonomy, and feedback, work stress, job satisfaction, work self-efficacy, and propensity to leave. LISREL was used to test 15 hypotheses. Perceived feedback mediated the relationship between achievement motivation and job performance. Extraversion predicted work self-efficacy and job satisfaction. Work stress mediated the relationship between neuroticism and job satisfaction. Job satisfaction and experience seeking were related to propensity to leave. Autonomy, skill variety, and feedback were related to job satisfaction

A Likelihood Method for Measuring the Ultrahigh Energy Cosmic Ray Composition

Air fluorescence detectors traditionally determine the dominant chemical composit ion of the ultrahigh energy cosmic ray flux by comparing the averaged slant depth of the shower maximum, $X_{max}$, as a function of energy to the slant depths expect ed for various hypothesized primaries. In this paper, we present a method to make a direct measurement of the expected mean number of protons and iron by comparing the shap es of the expected $X_{max}$ distributions to the distribution for data. The advantages of this method includes the use of information of the full distribution and its ability to calculate a flux for various cosmic ray compositi ons. The same method can be expanded to marginalize uncertainties due to choice of spectra, hadronic models and atmospheric parameters. We demonstrate the technique with independent simulated data samples from a parent sample of protons and iron. We accurately predict the number of protons and iron in the parent sample and show that the uncertainties are meaningful.Comment: 11 figures, 22 pages, accepted by Astroparticle Physic

Alternative Methods to Finding Patterns in HiRes Stereo Data

In this paper Ultra High Energy Cosmic Rays UHECRs data observed by the HiRes fluorescence detector in stereo mode is analyzed to search for events in the sky with an arrival direction lying on a great circle. Such structure is known as the arc structure. The arc structure is expected when the charged cosmic rays pass through the galactic magnetic field. The arcs searched for could represent a broad or a small scale anisotropy depending on the proposed source model for the UHECRs. The Arcs in this paper are looked for using Hough transform were Hough transform is a technique used to looking for patterns in images. No statistically significant arcs were found in this study

CMAG: a mission to study and monitor the inner corona magnetic field

Measuring magnetic fields in the inner corona, the interface between the solar chromosphere and outer corona, is of paramount importance if we aim to understand the energetic transformations taking place there, and because it is at the origin of processes that lead to coronal heating, solar wind acceleration, and of most of the phenomena relevant to space weather. However, these measurements are more difficult than mere imaging because polarimetry requires differential photometry. The coronal magnetograph mission (CMAG) has been designed to map the vector magnetic field, line-of-sight velocities, and plane-of-the-sky velocities of the inner corona with unprecedented spatial and temporal resolutions from space. This will be achieved through full vector spectropolarimetric observations using a coronal magnetograph as the sole instrument on board a spacecraft, combined with an external occulter installed on another spacecraft. The two spacecraft will maintain a formation flight distance of 430 m for coronagraphic observations, which requires a 2.5 m occulter disk radius. The mission will be preferentially located at the Lagrangian L5 point, offering a significant advantage for solar physics and space weather research. Existing ground-based instruments face limitations such as atmospheric turbulence, solar scattered light, and long integration times when performing coronal magnetic field measurements. CMAG overcomes these limitations by performing spectropolarimetric measurements from space with an external occulter and high-image stability maintained over time. It achieves the necessary sensitivity and offers a spatial resolution of 2.5″ and a temporal resolution of approximately one minute, in its nominal mode, covering the range from 1.02 solar radii to 2.5 radii. CMAG relies on proven European technologies and can be adapted to enhance any other solar mission, offering potential significant advancements in coronal physics and space weather modeling and monitoring