A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain

The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180° with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP–peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR–Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain

Time dependence of the electron and positron components of the cosmic radiation measured by the PAMELA experiment between July 2006 and December 2015

Cosmic-ray electrons and positrons are a unique probe of the propagation of cosmic rays as well as of the nature and distribution of particle sources in our Galaxy. Recent measurements of these particles are challenging our basic understanding of the mechanisms of production, acceleration and propagation of cosmic rays. Particularly striking are the differences between the low energy results collected by the space-borne PAMELA and AMS-02 experiments and older measurements pointing to sign-charge dependence of the solar modulation of cosmic-ray spectra. The PAMELA experiment has been measuring the time variation of the positron and electron intensity at Earth from July 2006 to December 2015 covering the period for the minimum of solar cycle 23 (2006-2009) till the middle of the maximum of solar cycle 24, through the polarity reversal of the heliospheric magnetic field which took place between 2013 and 2014. The positron to electron ratio measured in this time period clearly shows a sign-charge dependence of the solar modulation introduced by particle drifts. These results provide the first clear and continuous observation of how drift effects on solar modulation have unfolded with time from solar minimum to solar maximum and their dependence on the particle rigidity and the cyclic polarity of the solar magnetic field.Comment: 11 pages, 2 figure

Time dependence of the e^- flux measured by PAMELA during the July 2006 - December 2009 solar minimum

Precision measurements of the electron component in the cosmic radiation provide important information about the origin and propagation of cosmic rays in the Galaxy not accessible from the study of the cosmic-ray nuclear components due to their differing diffusion and energy-loss processes. However, when measured near Earth, the effects of propagation and modulation of galactic cosmic rays in the heliosphere, particularly significant for energies up to at least 30 GeV, must be properly taken into account. In this paper the electron (e^-) spectra measured by PAMELA down to 70 MeV from July 2006 to December 2009 over six-months time intervals are presented. Fluxes are compared with a state-of-the-art three-dimensional model of solar modulation that reproduces the observations remarkably well.Comment: 40 pages, 18 figures, 1 tabl

Geomagnetically trapped, albedo and solar energetic particles: trajectory analysis and flux reconstruction with PAMELA

The PAMELA satellite experiment is providing comprehensive observations of the interplanetary and magnetospheric radiation in the near-Earth environment. Thanks to its identification capabilities and the semi-polar orbit, PAMELA is able to precisely measure the energetic spectra and the angular distributions of the different cosmic-ray populations over a wide latitude region, including geomagnetically trapped and albedo particles. Its observations comprise the solar energetic particle events between solar cycles 23 and 24, and the geomagnetic cutoff variations during magnetospheric storms. PAMELA's measurements are supported by an accurate analysis of particle trajectories in the Earth's magnetosphere based on a realistic geomagnetic field modeling, which allows the classification of particle populations of different origin and the investigation of the asymptotic directions of arrival.Comment: Accepted for publication in Advances in Space Research, 2016. 21 pages, 7 figure

Search for anisotropies in cosmic-ray positrons detected by the PAMELA experiment

The PAMELA detector was launched on board of the Russian Resurs-DK1 satellite on June 15, 2006. Data collected during the first four years have been used to search for large-scale anisotropies in the arrival directions of cosmic-ray positrons. The PAMELA experiment allows for a full sky investigation, with sensitivity to global anisotropies in any angular window of the celestial sphere. Data samples of positrons in the rigidity range 10 GV $\leq$ R $\leq$ 200 GV were analyzed. This article discusses the method and the results of the search for possible local sources through analysis of anisotropy in positron data compared to the proton background. The resulting distributions of arrival directions are found to be isotropic. Starting from the angular power spectrum, a dipole anisotropy upper limit \delta = 0.166 at 95% C.L. is determined. Additional search is carried out around the Sun. No evidence of an excess correlated with that direction was found.Comment: The value of the dipole anisotropy upper limit has been changed. The method is correct but there was a miscalculation in the relative formul

PAMELA's measurements of geomagnetic cutoff variations during solar energetic particle events

Data from the PAMELA satellite experiment were used to measure the geomagnetic cutoff for high-energy ($\gtrsim$ 80 MeV) protons during the solar particle events on 2006 December 13 and 14. The variations of the cutoff latitude as a function of rigidity were studied on relatively short timescales, corresponding to single spacecraft orbits (about 94 minutes). Estimated cutoff values were cross-checked with those obtained by means of a trajectory tracing approach based on dynamical empirical modeling of the Earth's magnetosphere. We find significant variations in the cutoff latitude, with a maximum suppression of about 6 deg for $\sim$80 MeV protons during the main phase of the storm. The observed reduction in the geomagnetic shielding and its temporal evolution were compared with the changes in the magnetosphere configuration, investigating the role of IMF, solar wind and geomagnetic (Kp, Dst and Sym-H indexes) variables and their correlation with PAMELA cutoff results.Comment: Conference: The 34th International Cosmic Ray Conference (ICRC2015), 30 July - 6 August, 2015, The Hague, The Netherlands, Volume: PoS(ICRC2015)28

Time dependence of the proton flux measured by PAMELA during the July 2006 - December 2009 solar minimum

The energy spectra of galactic cosmic rays carry fundamental information regarding their origin and propagation. These spectra, when measured near Earth, are significantly affected by the solar magnetic field. A comprehensive description of the cosmic radiation must therefore include the transport and modulation of cosmic rays inside the heliosphere. During the end of the last decade the Sun underwent a peculiarly long quiet phase well suited to study modulation processes. In this paper we present proton spectra measured from July 2006 to December 2009 by PAMELA. The large collected statistics of protons allowed the time variation to be followed on a nearly monthly basis down to 400 MV. Data are compared with a state-of-the-art three-dimensional model of solar modulation.Comment: 17 pages, 5 figures, 1 table, to appear in Astrophysical Journal. Corrected two elements of Table

Solar energetic particle events: trajectory analysis and flux reconstruction with PAMELA

The PAMELA satellite experiment is providing first direct measurements of Solar Energetic Particles (SEPs) with energies from about 80 MeV to several GeV in near-Earth space, bridging the low energy data by other space-based instruments and the Ground Level Enhancement (GLE) data by the worldwide network of neutron monitors. Its unique observational capabilities include the possibility of measuring the flux angular distribution and thus investigating possible anisotropies. This work reports the analysis methods developed to estimate the SEP energy spectra as a function of the particle pitch-angle with respect to the Interplanetary Magnetic Field (IMF) direction. The crucial ingredient is provided by an accurate simulation of the asymptotic exposition of the PAMELA apparatus, based on a realistic reconstruction of particle trajectories in the Earth's magnetosphere. As case study, the results for the May 17, 2012 event are presented.Comment: Conference: The 34th International Cosmic Ray Conference (ICRC2015), 30 July - 6 August, 2015, The Hague, The Netherlands, Volume: PoS(ICRC2015)08

Trapped proton fluxes at low Earth orbits measured by the PAMELA experiment

We report an accurate measurement of the geomagnetically trapped proton fluxes for kinetic energy above > 70 MeV performed by the PAMELA mission at low Earth orbits (350-610 km). Data were analyzed in the frame of the adiabatic theory of charged particle motion in the geomagnetic field. Flux properties were investigated in detail, providing a full characterization of the particle radiation in the South Atlantic Anomaly region, including locations, energy spectra and pitch angle distributions. PAMELA results significantly improve the description of the Earth's radiation environment at low altitudes placing important constraints on the trapping and interaction processes, and can be used to validate current trapped particle radiation models.Comment: 22 pages, 5 figure

Measurement of boron and carbon fluxes in cosmic rays with the PAMELA experiment

The propagation of cosmic rays inside our galaxy plays a fundamental role in shaping their injection spectra into those observed at Earth. One of the best tools to investigate this issue is the ratio of fluxes for secondary and primary species. The boron-to-carbon (B/C) ratio, in particular, is a sensitive probe to investigate propagation mechanisms. This paper presents new measurements of the absolute fluxes of boron and carbon nuclei, as well as the B/C ratio, from the PAMELA space experiment. The results span the range 0.44 - 129 GeV/n in kinetic energy for data taken in the period July 2006 - March 2008