GW170817: implications for the local kilonova rate and for surveys from ground-based facilities

We compute the local rate of events similar to GRB 170817A, which has been recently found to be associated with a kilonova (KN) outburst. Our analysis finds an observed rate of such events of R_KN∼ 352^{+810}_{-281} Gpc-3 yr-1. After comparing at their face values this density of sGRB outbursts with the much higher density of binary neutron star (BNS) mergers of 1540^{+3200}_{-1220} Gpc-3 yr-1, estimated by LIGO-Virgo collaboration, one can conclude, admittedly with large uncertainty that either only a minor fraction of BNS mergers produces short gamma-ray bursts (sGRB)/KN events or the sGRBs associated with BNS mergers are beamed and observable under viewing angles as large as θ ≲ 40°. Finally, we provide preliminary estimates of the number of sGRB/KN events detected by future surveys carried out with present/future ground-based/space facilities, such as LSST, VST, ZTF, SKA, and THESEUS

Lunar Gravitational-Wave Antenna

Monitoring of vibrational eigenmodes of an elastic body excited by gravitational waves was one of the first concepts proposed for the detection of gravitational waves. At laboratory scale, these experiments became known as resonant-bar detectors first developed by Joseph Weber in the 1960s. Due to the dimensions of these bars, the targeted signal frequencies were in the kHz range. Weber also pointed out that monitoring of vibrations of Earth or Moon could reveal gravitational waves in the mHz band. His Lunar Surface Gravimeter experiment deployed on the Moon by the Apollo 17 crew had a technical failure rendering the data useless. In this article, we revisit the idea and propose a Lunar Gravitational-Wave Antenna (LGWA). We find that LGWA could become an important partner observatory for joint observations with the space-borne, laser-interferometric detector LISA, and at the same time contribute an independent science case due to LGWA's unique features. Technical challenges need to be overcome for the deployment of the experiment, and development of inertial vibration sensor technology lays out a future path for this exciting detector concept.Comment: 29 pages, 17 figure

Inhibition of Melanogenesis by the Pyridinyl Imidazole Class of Compounds: Possible Involvement of the Wnt/β-Catenin Signaling Pathway

While investigating the role of p38 MAPK in regulating melanogenesis, we found that pyridinyl imidazole inhibitors class compounds as well as the analog compound SB202474, which does not inhibit p38 MAPK, suppressed both α-MSH-induced melanogenesis and spontaneous melanin synthesis. In this study, we demonstrated that the inhibitory activity of the pyridinyl imidazoles correlates with inhibition of the canonical Wnt/β-catenin pathway activity. Imidazole-treated cells showed a reduction in the level of Tcf/Lef target genes involved in the β-catenin signaling network, including ubiquitous genes such as Axin2, Lef1, and Wisp1 as well as cell lineage-restricted genes such as microphthalmia-associated transcription factor and dopachrome tautomerase. Although over-expression of the Wnt signaling pathway effector β-catenin slightly restored the melanogenic program, the lack of complete reversion suggested that the imidazoles interfered with β-catenin-dependent transcriptional activity rather than with β-catenin expression. Accordingly, we did not observe any significant change in β-catenin protein expression. The independence of p38 MAPK activity from the repression of Wnt/β-catenin signaling pathway was confirmed by small interfering RNA knockdown of p38 MAPK expression, which by contrast, stimulated β-catenin-driven gene expression. Our data demonstrate that the small molecule pyridinyl imidazoles possess two distinct and opposite mechanisms that modulate β-catenin dependent transcription: a p38 inhibition-dependent effect that stimulates the Wnt pathway by increasing β-catenin protein expression and an off-target mechanism that inhibits the pathway by repressing β-catenin protein functionality. The p38-independent effect seems to be dominant and, at least in B16-F0 cells, results in a strong block of the Wnt/β-catenin signaling pathway

GSK3β inhibition promotes melanogenesis in Mouse B16 Melanoma cells and human normal melanocytes

Glycogen synthase kinase 3beta (GSK3beta) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and the insulin response. GSK3beta also plays a key role in the Wnt/beta-catenin pathway. The master regulator of the pigmentation microphthalmia-associated transcription factor (MITF) is a target for the Wnt pathway, however, to date, the regulatory role of GSK3beta in the control of melanogenesis has not been elucidated. In this study, we evaluated the effect of inhibiting GSK3beta activity on the regulation of melanocyte differentiation. Exposure of the murine melanoma cell line B16 and normal human melanocytes to GSK3beta specific inhibitors (SB216763, SB415286, BIO, and LiCl) resulted in a dose-dependent accumulation of beta-catenin. This is associated with the induction of melanocyte differentiation-associated markers such as melanin synthesis, tyrosinase activity, and expression of tyrosinase and the microphthalmia-associated transcription factor. Attenuation of GSK3beta activity has an inhibitory effect on cell growth, and this was accompanied by morphological changes. Moreover, treatment of B16 cells with a siRNA targeted against beta-catenin completely abolished the promelanogenic effect of GSK3beta inhibition, however, the overexpression of a constitutively active mutant form of beta-catenin (pCS2beta-cat-mut) only slightly increased the degree of pigmentation. These results demonstrated that GSK3beta is implicated in the regulation of melanogenesis and that pharmacological inhibition of its activity could increase melanin synthesis through mechanisms probably not restricted to Wnt/beta-catenin pathway activation

Regulation of Wnt/β-catenin signaling by pyridinyl imidazoles.

<p>(A) Inhibition of the β-catenin/Tcf/Lef1-responsive luciferase reporter gene by PI compounds. The pTK-Renilla was inserted as an internal control. Twenty-four hours after transfection, cells were treated with PI compounds (SB202474, SB202190, SB203580, SB220025, PD169316 20 µM: MAPK Inh III 10 µM) for 6 h. Firefly luciferase activity, normalized to the corresponding renilla luciferase activity was expressed as fold decrease compared with control cells. Values represent mean ± SD of three representative experiments performed in duplicate. (B) Semi-qunatitative real-time PCR was used to measure Wnt/β-catenin-target genes Axin2, Lef1 and Wisp1 mRNAs expression in B16-F0 cells after 6 h of treatments with PI compounds. The graphs show fold differences in transcript abundance in comparison with untreated cells. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033021#s2" target="_blank">Results</a> shown were normalized by the β-actin mRNA levels. The data show the mean±SD of three experiments performed in triplicate. *P≤0.05; #P≤0.01 versus control. (C) Expression of β-catenin in B16-F0 cells after 6 h of treatment with PI compounds (SB202474, SB202190, SB203580, SB220025, PD169316 20 µM: MAPK Inh III 10 µM). Total cellular proteins (30 µg/lane) were subject to 10% SDS-PAGE. Variation of loading was determined by blotting with anti-β-tubulin antibody. Western blot assays are representative of at least three experiments. (D) Immunofluorescence analysis of β-catenin. B16-F0 cells were grown on glass coverslips and then treated with SB202474, PD169316 (20 µM) or DMSO respectively. Six hours later, cells were fixed and analyzed by immunofluorescence labelling with a mouse monoclonal anti-β-catenin followed by Alexa-Fluor-546-conjugated goat anti-mouse IgG antibody. Nuclei were labelled with bisbenzidine (DAPI). Original magnification 20×.</p

Analysis of the role of Mitf expression in pyridinyl imidazoles-dependent melanogenesis inhibition.

<p>(A) To B16-F0 melanoma cells were transiently transfected with a plasmid encoding for Mitf cDNA (pCAAG-mi-S) or a control construct carrying Mitf cDNA in antisense orientation (pCAAG-mi-AS). Following incubation with α-MSH (0.1 µM) in presence of pyridinyl imidazoles (SB202474, SB202190, SB203580, SB220025, PD169316 20 µM: MAPK Inh III 10 µM) for 72 h, or not, the extracellular and intracellular levels of melanin were determined as described above. The data show the mean±SD of three experiments performed in duplicate. (B–C) Analysis of luciferase activity of the Mitf melanocyte-specific promoter (M promoter) in the presence of pyridinyl imidazoles in B16-F0 and HeLa cells. Twenty-four hours after transient transfection cells were treated with PI compounds in presence (C) or not (B) of α-MSH (0.1 µM) (B16-F0) or forskolin (1 µM) (HeLa). Luciferase activity was assayed after 6 h of treatment. Firefly luciferase activity, normalized to the corrisponding renilla luciferase activity was expressed as fold change compared with control cells. Values represent mean ± SD of three representative experiments performed in duplicate.</p

Effect of pyridinyl imidazoles compounds on melanin synthesis in B16-F0 melanoma cells.

<p>(A) Following incubation with α-MSH (0.1 µM) and increasing concentrations (1, 2.5, 5, 10, 20 µM) of pyridinyl imidazoles for 72 h, the extracellular and intracellular levels of melanin were determined separately by measuring the absorbance at 405 nm. Standard curves of synthetic melanin were used to extrapolate the absolute values of melanin content. The total amount of melanin was calculated for each experimental point by adding the extracellular and intracellular melanin values after normalization for protein content. Total melanin produced at the end-point by control (DMSO-treated cells) and hormone-stimulated cells (α-MSH plus DMSO-treated cells) is reported for comparison. (B) B16-F0 cells were also treated with pyridinyl imidazoles compounds for 96 h in absence of α-MSH. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033021#s2" target="_blank">Results</a> are expressed as percentage of untreated control samples. The data show the mean±SD of three experiments performed in duplicate. *P≤0.05; #P≤0.01 versus control.</p