216 research outputs found
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 ATPâpeptide 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 BCRâAbl 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
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 R
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
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
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
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 ( 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 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
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
Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation
Genetic loss of function analysis is a powerful method for the study of protein function. However, some cell biological questions are difficult to address using traditional genetic strategies often due to the lack of appropriate genetic model systems. Here, we present a general strategy for the design and syntheses of molecules capable of inducing the degradation of selected proteins in vivo via the ubiquitinâproteasome pathway. Western blot and fluorometric analyses indicated the loss of two different targets:â green fluorescent protein (GFP) fused with FK506 binding protein (FKBP12) and GFP fused with the androgen receptor (AR), after treatment with PROteolysis TArgeting Chimeric moleculeS (PROTACS) incorporating a FKBP12 ligand and dihydrotestosterone, respectively. These are the first in vivo examples of direct small molecule-induced recruitment of target proteins to the proteasome for degradation upon addition to cultured cells. Moreover, PROTAC-mediated protein degradation offers a general strategy to create âchemical knockouts,â thus opening new possibilities for the control of protein function
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