121 research outputs found
In depth analysis of kinase cross screening data to identify CaMKK2 inhibitory scaffolds
The calcium/calmodulin‐dependent protein kinase kinase 2 (CAMKK2) activates CAMK1, CAMK4, AMPK, and AKT, leading to numerous physiological responses. The deregulation of CAMKK2 is linked to several diseases, suggesting the utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work, we demonstrate that STO‐609, frequently described as a selective inhibitor for CAMKK2, potently inhibits a significant number of other kinases. Through an analysis of literature and public databases, we have identified other potent CAMKK2 inhibitors and verified their activities in differential scanning fluorimetry and enzyme inhibition assays. These inhibitors are potential starting points for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology.252CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP465651/2014-32013/50724-5; 2014/50897-0; 2019/14275-
Further Evidence Suggestive of a Solar Influence on Nuclear Decay Rates
Recent analyses of nuclear decay data show evidence of variations suggestive
of a solar influence. Analyses of datasets acquired at the Brookhaven National
Laboratory (BNL) and at the Physikalisch-Technische Bundesanstalt (PTB) both
show evidence of an annual periodicity and of periodicities with sidereal
frequencies in the neighborhood of 12.25 year^{-1} (at a significance level
that we have estimated to be 10^{-17}). It is notable that this implied
rotation rate is lower than that attributed to the solar radiative zone,
suggestive of a slowly rotating solar core. This leads us to hypothesize that
there may be an "inner tachocline" separating the core from the radiative zone,
analogous to the "outer tachocline" that separates the radiative zone from the
convection zone. The Rieger periodicity (which has a period of about 154 days,
corresponding to a frequency of 2.37 year^{-1}) may be attributed to an r-mode
oscillation with spherical-harmonic indices l=3, m=1, located in the outer
tachocline. This suggests that we may test the hypothesis of a solar influence
on nuclear decay rates by searching BNL and PTB data for evidence of a
"Rieger-like" r-mode oscillation, with l=3, m=1, in the inner tachocline. The
appropriate search band for such an oscillation is estimated to be 2.00-2.28
year^{-1}. We find, in both datasets, strong evidence of a periodicity at 2.11
year^{-1}. We estimate that the probability of obtaining these results by
chance is 10^{-12}.Comment: 12 pages, 6 figures, v2 has a color corrected Fig 6, a corrected
reference, and a corrected typ
Power Spectrum Analysis of Physikalisch-Technische Bundesanstalt Decay-Rate Data: Evidence for Solar Rotational Modulation
Evidence for an anomalous annual periodicity in certain nuclear decay data
has led to speculation concerning a possible solar influence on nuclear
processes. We have recently analyzed data concerning the decay rates of Cl-36
and Si-32, acquired at the Brookhaven National Laboratory (BNL), to search for
evidence that might be indicative of a process involving solar rotation.
Smoothing of the power spectrum by weighted-running-mean analysis leads to a
significant peak at frequency 11.18/yr, which is lower than the equatorial
synodic rotation rates of the convection and radiative zones. This article
concerns measurements of the decay rates of Ra-226 acquired at the
Physikalisch-Technische Bundesanstalt (PTB) in Germany. We find that a similar
(but not identical) analysis yields a significant peak in the PTB dataset at
frequency 11.21/yr, and a peak in the BNL dataset at 11.25/yr. The change in
the BNL result is not significant since the uncertainties in the BNL and PTB
analyses are estimated to be 0.13/yr and 0.07/yr, respectively. Combining the
two running means by forming the joint power statistic leads to a highly
significant peak at frequency 11.23/yr. We comment briefly on the possible
implications of these results for solar physics and for particle physics.Comment: 15 pages, 13 figure
Horizontal Branch Stars: The Interplay between Observations and Theory, and Insights into the Formation of the Galaxy
We review HB stars in a broad astrophysical context, including both variable
and non-variable stars. A reassessment of the Oosterhoff dichotomy is
presented, which provides unprecedented detail regarding its origin and
systematics. We show that the Oosterhoff dichotomy and the distribution of
globular clusters (GCs) in the HB morphology-metallicity plane both exclude,
with high statistical significance, the possibility that the Galactic halo may
have formed from the accretion of dwarf galaxies resembling present-day Milky
Way satellites such as Fornax, Sagittarius, and the LMC. A rediscussion of the
second-parameter problem is presented. A technique is proposed to estimate the
HB types of extragalactic GCs on the basis of integrated far-UV photometry. The
relationship between the absolute V magnitude of the HB at the RR Lyrae level
and metallicity, as obtained on the basis of trigonometric parallax
measurements for the star RR Lyrae, is also revisited, giving a distance
modulus to the LMC of (m-M)_0 = 18.44+/-0.11. RR Lyrae period change rates are
studied. Finally, the conductive opacities used in evolutionary calculations of
low-mass stars are investigated. [ABRIDGED]Comment: 56 pages, 22 figures. Invited review, to appear in Astrophysics and
Space Scienc
Demonstration of the temporal matter-wave Talbot effect for trapped matter waves
We demonstrate the temporal Talbot effect for trapped matter waves using
ultracold atoms in an optical lattice. We investigate the phase evolution of an
array of essentially non-interacting matter waves and observe matter-wave
collapse and revival in the form of a Talbot interference pattern. By using
long expansion times, we image momentum space with sub-recoil resolution,
allowing us to observe fractional Talbot fringes up to 10th order.Comment: 17 pages, 7 figure
Kaon Production and Kaon to Pion Ratio in Au+Au Collisions at \snn=130 GeV
Mid-rapidity transverse mass spectra and multiplicity densities of charged
and neutral kaons are reported for Au+Au collisions at \snn=130 GeV at RHIC.
The spectra are exponential in transverse mass, with an inverse slope of about
280 MeV in central collisions. The multiplicity densities for these particles
scale with the negative hadron pseudo-rapidity density. The charged kaon to
pion ratios are and
for the most central collisions. The ratio is lower than the same
ratio observed at the SPS while the is higher than the SPS result.
Both ratios are enhanced by about 50% relative to p+p and +p
collision data at similar energies.Comment: 6 pages, 3 figures, 1 tabl
Phi meson production in Au+Au and p+p collisions at sqrt (s)=200 GeV
We report the STAR measurement of Phi meson production in Au+Au and p+p
collisions at sqrt (s)=200 GeV. Using the event mixing technique, the Phi
spectra and yields are obtained at mid-rapidity for five centrality bins in
Au+Au collisions and for non-singly-diffractive p+p collisions. It is found
that the Phi transverse momentum distributions from Au+Au collisions are better
fitted with a single-exponential while the p+p spectrum is better described by
a double-exponential distribution. The measured nuclear modification factors
indicate that Phi production in central Au+Au collisions is suppressed relative
to peripheral collisions when scaled by the number of binary collisions. The
systematics of versus centrality and the constant Phi/K- ratio versus beam
species, centrality, and collision energy rule out kaon coalescence as the
dominant mechanism for Phi production.Comment: 6 pages, 3 figures, submitted to Phys. Rev. Let
Azimuthal anisotropy at RHIC: the first and fourth harmonics
We report the first observations of the first harmonic (directed flow, v_1),
and the fourth harmonic (v_4), in the azimuthal distribution of particles with
respect to the reaction plane in Au+Au collisions at the Relativistic Heavy Ion
Collider (RHIC). Both measurements were done taking advantage of the large
elliptic flow (v_2) generated at RHIC. From the correlation of v_2 with v_1 it
is determined that v_2 is positive, or {\it in-plane}. The integrated v_4 is
about a factor of 10 smaller than v_2. For the sixth (v_6) and eighth (v_8)
harmonics upper limits on the magnitudes are reported.Comment: 6 pages with 3 figures, as accepted for Phys. Rev. Letters The data
tables are at
http://www.star.bnl.gov/central/publications/pubDetail.php?id=3
Pion, kaon, proton and anti-proton transverse momentum distributions from p+p and d+Au collisions at GeV
Identified mid-rapidity particle spectra of , , and
from 200 GeV p+p and d+Au collisions are reported. A
time-of-flight detector based on multi-gap resistive plate chamber technology
is used for particle identification. The particle-species dependence of the
Cronin effect is observed to be significantly smaller than that at lower
energies. The ratio of the nuclear modification factor () between
protons and charged hadrons () in the transverse momentum
range GeV/c is measured to be
(stat)(syst) in minimum-bias collisions and shows little
centrality dependence. The yield ratio of in minimum-bias d+Au
collisions is found to be a factor of 2 lower than that in Au+Au collisions,
indicating that the Cronin effect alone is not enough to account for the
relative baryon enhancement observed in heavy ion collisions at RHIC.Comment: 6 pages, 4 figures, 1 table. We extended the pion spectra from
transverse momentum 1.8 GeV/c to 3. GeV/
Comprehensive characterization of the Published Kinase Inhibitor Set
Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome
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