Involvement of Cyclin K Posttranscriptional Regulation in the Formation of Artemia Diapause Cysts

Background: Artemia eggs tend to develop ovoviviparously to yield nauplius larvae in good rearing conditions; while under adverse situations, they tend to develop oviparously and encysted diapause embryos are formed instead. However, the intrinsic mechanisms regulating this process are not well understood. Principal Finding: This study has characterized the function of cyclin K, a regulatory subunit of the positive transcription elongation factor b (P-TEFb) in the two different developmental pathways of Artemia. In the diapause-destined embryo, Western blots showed that the cyclin K protein was down-regulated as the embryo entered dormancy and reverted to relatively high levels of expression once development resumed, consistent with the fluctuations in phosphorylation of position 2 serines (Ser2) in the C-terminal domain (CTD) of the largest subunit (Rpb1) of RNA polymerase II (RNAP II). Interestingly, the cyclin K transcript levels remained constant during this process. In vitro translation data indicated that the template activity of cyclin K mRNA stored in the postdiapause cyst was repressed. In addition, in vivo knockdown of cyclin K in developing embryos by RNA interference eliminated phosphorylation of the CTD Ser2 of RNAP II and induced apoptosis by inhibiting the extracellular signal-regulated kinase (ERK) survival signaling pathway. Conclusions/Significance: Taken together, these findings reveal a role for cyclin K in regulating RNAP II activity during diapause embryo development, which involves the post-transcriptional regulation of cyclin K. In addition, a further role wa

Primary Black Hole Spin in OJ 287 as Determined by the General Relativity Centenary Flare

OJ 287 is a quasi-periodic quasar with roughly 12 year optical cycles. It displays prominent outbursts that are predictable in a binary black hole model. The model predicted a major optical outburst in 2015 December. We found that the outburst did occur within the expected time range, peaking on 2015 December 5 at magnitude 12.9 in the optical R -band. Based on Swift /XRT satellite measurements and optical polarization data, we find that it included a major thermal component. Its timing provides an accurate estimate for the spin of the primary black hole, ##IMG## [http://ej.iop.org/images/2041-8205/819/2/L37/apjl523055ieqn1.gif] $i =0.313pm 0.01$ . The present outburst also confirms the established general relativistic properties of the system such as the loss of orbital energy to gravitational radiation at the 2% accuracy level, and it opens up the possibility of testing the black hole no-hair theorem with 10% accuracy during the present decade.Peer reviewe

A Search for QPOs in the Blazar OJ287: Preliminary Results from the 2015/2016 Observing Campaign

We analyse the light curve in the R band of the blazar OJ287, gathered during the 2015/2016 observing season. We did a search for quasi-periodic oscillations (QPOs) using several methods over a wide range of timescales. No statistically significant periods were found in the high-frequency domain both in the ground-based data and in Kepler observations. In the longer-period domain, the Lomb–Scargle periodogram revealed several peaks above the 99% significance level. The longest one—about 95 days—corresponds to the innermost stable circular orbit (ISCO) period of the more massive black hole. The 43-day period could be an alias, or it can be attributed to accretion in the form of a two-armed spiral wave.Peer reviewe

Authenticating the Presence of a Relativistic Massive Black Hole Binary in OJ 287 Using Its General Relativity Centenary Flare : Improved Orbital Parameters

Results from regular monitoring of relativistic compact binaries like PSR 1913+16 are consistent with the dominant (quadrupole) order emission of gravitational waves (GWs). We show that observations associated with the binary black hole (BBH) central engine of blazar OJ 287 demand the inclusion of gravitational radiation reaction effects beyond the quadrupolar order. It turns out that even the effects of certain hereditary contributions to GW emission are required to predict impact flare timings of OJ 287. We develop an approach that incorporates this effect into the BBH model for OJ 287. This allows us to demonstrate an excellent agreement between the observed impact flare timings and those predicted from ten orbital cycles of the BBH central engine model. The deduced rate of orbital period decay is nine orders of magnitude higher than the observed rate in PSR 1913+16, demonstrating again the relativistic nature of OJ 287's central engine. Finally, we argue that precise timing of the predicted 2019 impact flare should allow a test of the celebrated black hole "no-hair theorem" at the 10% level.Peer reviewe

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p

Authenticating the Presence of a Relativistic Massive Black Hole Binary in OJ 287 Using Its General Relativity Centenary Flare: Improved Orbital Parameters

© 2018. The American Astronomical Society. All rights reserved. Results from regular monitoring of relativistic compact binaries like PSR 1913+16 are consistent with the dominant (quadrupole) order emission of gravitational waves (GWs). We show that observations associated with the binary black hole (BBH) central engine of blazar OJ 287 demand the inclusion of gravitational radiation reaction effects beyond the quadrupolar order. It turns out that even the effects of certain hereditary contributions to GW emission are required to predict impact flare timings of OJ 287. We develop an approach that incorporates this effect into the BBH model for OJ 287. This allows us to demonstrate an excellent agreement between the observed impact flare timings and those predicted from ten orbital cycles of the BBH central engine model. The deduced rate of orbital period decay is nine orders of magnitude higher than the observed rate in PSR 1913+16, demonstrating again the relativistic nature of OJ 287's central engine. Finally, we argue that precise timing of the predicted 2019 impact flare should allow a test of the celebrated black hole "no-hair theorem" at the 10% level

Authenticating the Presence of a Relativistic Massive Black Hole Binary in OJ 287 Using Its General Relativity Centenary Flare: Improved Orbital Parameters

Results from regular monitoring of relativistic compact binaries like PSR 1913+16 are consistent with the dominant (quadrupole) order emission of gravitational waves (GWs). We show that observations associated with the binary black hole (BBH) central engine of blazar OJ 287 demand the inclusion of gravitational radiation reaction effects beyond the quadrupolar order. It turns out that even the effects of certain hereditary contributions to GW emission are required to predict impact flare timings of OJ 287. We develop an approach that incorporates this effect into the BBH model for OJ 287. This allows us to demonstrate an excellent agreement between the observed impact flare timings and those predicted from ten orbital cycles of the BBH central engine model. The deduced rate of orbital period decay is nine orders of magnitude higher than the observed rate in PSR 1913+16, demonstrating again the relativistic nature of OJ 287's central engine. Finally, we argue that precise timing of the predicted 2019 impact flare should allow a test of the celebrated black hole "no-hair theorem" at the 10% level

Stochastic Modeling of Multiwavelength Variability of the Classical BL Lac Object OJ287 on Timescales Ranging from Decades to Hours

We present the results of our power spectral density analysis for the BL Lac object OJ 287, utilizing the Fermi-LAT survey at high-energy.-rays, Swift-XRT in X-rays, several ground-based telescopes and the Kepler satellite in the optical, and radio telescopes at GHz frequencies. The light curves are modeled in terms of continuous-time autoregressive moving average (CARMA) processes. Owing to the inclusion of the Kepler data, we were able to construct for the first time the optical variability power spectrum of a blazar without any gaps across similar to 6 dex in temporal frequencies. Our analysis reveals that the radio power spectra are of a colored-noise type on timescales ranging from tens of years down to months, with no evidence for breaks or other spectral features. The overall optical power spectrum is also consistent with a colored noise on the variability timescales ranging from 117 years down to hours, with no hints of any quasi-periodic oscillations. The X-ray power spectrum resembles the radio and optical power spectra on the analogous timescales ranging from tens of years down to months. Finally, the.-ray power spectrum is noticeably different from the radio, optical, and X-ray power spectra of the source: we have detected a characteristic relaxation timescale in the Fermi-LAT data, corresponding to similar to 150 days, such that on timescales longer than this, the power spectrum is consistent with uncorrelated (white) noise, while on shorter variability timescales there is correlated (colored) noise