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

Biological Rhythms Workshop I: Introduction to Chronobiology

In this chapter, we present a series of four articles derived from a Introductory Workshop on Biological Rhythms presented at the 72nd Annual Cold Spring Harbor Symposium on Quantitative Biology: Clocks and Rhythms. A diverse range of species, from cyanobacteria to humans, evolved endogenous biological clocks that allow for the anticipation of daily variations in light and temperature. The ability to anticipate environmental variation promotes optimal performance and survival. In the first article, Introduction to Chronobiology, we present a brief historical timeline of how circadian concepts and terminology have emerged since the early observation of daily leaf movement in plants made by an astronomer in the 1700s. Workshop Part IA provides an overview of the molecular basis for rhythms generation in several key model organisms, Workshop Part IB focuses on how biology built a brain clock capable of coordinating the daily timing of essential brain and physiological processes, and Workshop Part IC gives key insight into how researchers study sleep and rhythms in humans

Prey naiveté to invasive lionfish Pterois volitans on Caribbean coral reefs

Native prey can be particularly vulnerable to consumption by exotic predators. Prey naiveté, the failure to recognize a novel predator due to lack of recent co-evolutionary history, likely facilitates the disproportionate impact that some exotic predators exert on prey populations. Lionfish Pterois volitans, exotic predators from the Pacific, have invaded coral reefs and other coastal habitats along the western Atlantic. Prey naiveté towards novel lionfish was tested in field experiments and with observations using closest approach distance as the anti-predator response. We quantified the distance of prey fishes to exotic lionfish in both the Atlantic and Pacific (invasive and native ranges of lionfish) as well as to native predators in the Atlantic. In the Atlantic, experiments indicated that Haemulon plumierii, prey of lionfish, generally display a closer approach distance to exotic than to native predators, and field observations of free-ranging fish revealed that at least 5 other species of small fishes (Halichoeres bivitattus, Halichoeres garnoti, Scarus taeniopterus, Stegastes leucostictus and Thalassoma bifasciatum) also might exhibit limited predatoravoidance behaviour towards invasive lionfish. We also found that 3 families of small fish (Labridae, Pomacentridae and Scaridae) maintained greater distances from lionfish in the Pacific compared with the Atlantic in both experimental and field observations. These results suggest prey naiveté to exotic lionfish by at least 8 species of fish (Abudefduf saxatilis, H. plumierii, H. bivitattus, H. garnoti, S. taeniopterus, Sparisoma aurofrenatum, S. leucostictus and T. bifasciatum) in the Atlantic, which could be contributing to the rapid expansion of this invasive species by enhancing its fitness and reproductive output through high predation efficiency

The JCMT Legacy Survey of the Gould Belt: a first look at Orion B with HARP

‘The definitive version is available at www3.interscience.wiley.com '. Copyright Royal Astronomical Society.The Gould Belt Legacy Survey will survey nearby star-forming regions (within 500 pc), using Heterodyne Array Receiver Programme (HARP), Submillimetre Common-User Bolometer Array 2 and Polarimeter 2 on the James Clerk Maxwell Telescope. This paper describes the initial data obtained using HARP to observe 12CO, 13CO and C18O J= 3 → 2 towards two regions in Orion B, NGC 2024 and NGC 2071. We describe the physical characteristics of the two clouds, calculating temperatures and opacities utilizing all the three isotopologues. We find good agreement between temperatures calculated from CO and from dust emission in the dense, energetic regions. We determine the mass and energetics of the clouds, and of the high-velocity material seen in 12CO emission, and compare the relative energetics of the high- and low-velocity material in the two clouds. We present a clumpfind analysis of the 13CO condensations. The slope of the condensation mass functions, at the high-mass ends, is similar to the slope of the initial mass function.Peer reviewe

Representation of the Community Earth System Model (CESM1) CAM4-chem within the Chemistry-Climate Model Initiative (CCMI)

The Community Earth System Model (CESM1) CAM4-chem has been used to perform the Chemistry Climate Model Initiative (CCMI) reference and sensitivity simulations. In this model, the Community Atmospheric Model version 4 (CAM4) is fully coupled to tropospheric and stratospheric chemistry. Details and specifics of each configuration, including new developments and improvements are described. CESM1 CAM4-chem is a low-top model that reaches up to approximately 40km and uses a horizontal resolution of 1.9° latitude and 2.5° longitude. For the specified dynamics experiments, the model is nudged to Modern-Era Retrospective Analysis for Research and Applications (MERRA) reanalysis. We summarize the performance of the three reference simulations suggested by CCMI, with a focus on the last 15 years of the simulation when most observations are available. Comparisons with selected data sets are employed to demonstrate the general performance of the model. We highlight new data sets that are suited for multi-model evaluation studies. Most important improvements of the model are the treatment of stratospheric aerosols and the corresponding adjustments for radiation and optics, the updated chemistry scheme including improved polar chemistry and stratospheric dynamics and improved dry deposition rates. These updates lead to a very good representation of tropospheric ozone within 20% of values from available observations for most regions. In particular, the trend and magnitude of surface ozone is much improved compared to earlier versions of the model. Furthermore, stratospheric column ozone of the Southern Hemisphere in winter and spring is reasonably well represented. All experiments still underestimate CO most significantly in Northern Hemisphere spring and show a significant underestimation of hydrocarbons based on surface observations

Planck-Scale Physics and Neutrino Masses

We discuss gravitationally induced masses and mass splittings of Majorana, Zeldovich-Konopinski-Mahmoud and Dirac neutrinos. Among other implications, these effects can provide a solution of the solar neutrino puzzle. In particular, we show how this may work in the 17 keV neutrino picture.Comment: 10 pages, IC/92/79, SISSA-83/92/EP, LMU-04/92 (the preprint number has been corrected; no other changes

The influence of νh11/2 occupancy on the magnetic moments of collective 21+ states in A∼100 fission fragments

AbstractThe magnetic moments of Iπ=21+ states in even–even A∼100 fission fragments have been measured using the Gammasphere array, using the technique of time-integral perturbed angular correlations. The data are interpreted within the context of the interacting boson model (IBA2) leading to the suggestion of a strong νh11/2 component in the deformed 21+ states of this region

Planck scale effects in neutrino physics

We study the phenomenology and cosmology of the Majoron (flavon) models of three active and one inert neutrino paying special attention to the possible (almost) conserved generalization of the Zeldovich-Konopinski-Mahmoud lepton charge. Using Planck scale physics effects which provide the breaking of the lepton charge, we show how in this picture one can incorporate the solutions to some of the central issues in neutrino physics such as the solar and atmospheric neutrino puzzles, dark matter and a 17 keV neutrino. These gravitational effects induce tiny Majorana mass terms for neutrinos and considerable masses for flavons. The cosmological demand for the sufficiently fast decay of flavons implies a lower limit on the electron neutrino mass in the range of 0.1-1 eV.Comment: 24 pages, 1 figure (not included but available upon request), LaTex, IC/92/196, SISSA-140/92/EP, LMU-09/9

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

Coexistence of 'alpha+ 208Pb' cluster structures and single-particle excitations in 212Po

Excited states in 212Po have been populated by alpha transfer using the 208Pb(18O,14C) reaction at 85MeV beam energy and studied with the EUROBALL IV gamma multidetector array. The level scheme has been extended up to ~ 3.2 MeV excitation energy from the triple gamma coincidence data. Spin and parity values of most of the observed states have been assigned from the gamma angular distributions and gamma -gamma angular correlations. Several gamma lines with E(gamma) < 1 MeV have been found to be shifted by the Doppler effect, allowing for the measurements of the associated lifetimes by the DSAM method. The values, found in the range [0.1-0.6] ps, lead to very enhanced E1 transitions. All the emitting states, which have non-natural parity values, are discussed in terms of alpha-208Pb structure. They are in the same excitation-energy range as the states issued from shell-model configurations.Comment: 21 pages, 19 figures, corrected typos, revised arguments in Sect. III