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

Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2

The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo

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 $K^+/\pi^- = 0.161 \pm 0.002 {\rm (stat)} \pm 0.024 {\rm (syst)}$ and $K^-/\pi^- = 0.146 \pm 0.002 {\rm (stat)} \pm 0.022 {\rm (syst)}$ for the most central collisions. The $K^+/\pi^-$ ratio is lower than the same ratio observed at the SPS while the $K^-/\pi^-$ is higher than the SPS result. Both ratios are enhanced by about 50% relative to p+p and $\bar{\rm p}$+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