Testing Gravity with Pulsars in the SKA Era

The Square Kilometre Array (SKA) will use pulsars to enable precise measurements of strong gravity effects in pulsar systems, which yield tests of gravitational theories that cannot be carried out anywhere else. The Galactic census of pulsars will discover dozens of relativistic pulsar systems, possibly including pulsar -- black hole binaries which can be used to test the "cosmic censorship conjecture" and the "no-hair theorem". Also, the SKA's remarkable sensitivity will vastly improve the timing precision of millisecond pulsars, allowing probes of potential deviations from general relativity (GR). Aspects of gravitation to be explored include tests of strong equivalence principles, gravitational dipole radiation, extra field components of gravitation, gravitomagnetism, and spacetime symmetries.Comment: 20 pages, 4 figures, to be published in: "Advancing Astrophysics with the Square Kilometre Array", Proceedings of Science, PoS(AASKA14)04

Photometric Supernova Cosmology with BEAMS and SDSS-II

Supernova cosmology without spectroscopic confirmation is an exciting new frontier which we address here with the Bayesian Estimation Applied to Multiple Species (BEAMS) algorithm and the full three years of data from the Sloan Digital Sky Survey II Supernova Survey (SDSS-II SN). BEAMS is a Bayesian framework for using data from multiple species in statistical inference when one has the probability that each data point belongs to a given species, corresponding in this context to different types of supernovae with their probabilities derived from their multi-band lightcurves. We run the BEAMS algorithm on both Gaussian and more realistic SNANA simulations with of order 10^4 supernovae, testing the algorithm against various pitfalls one might expect in the new and somewhat uncharted territory of photometric supernova cosmology. We compare the performance of BEAMS to that of both mock spectroscopic surveys and photometric samples which have been cut using typical selection criteria. The latter typically are either biased due to contamination or have significantly larger contours in the cosmological parameters due to small data-sets. We then apply BEAMS to the 792 SDSS-II photometric supernovae with host spectroscopic redshifts. In this case, BEAMS reduces the area of the (\Omega_m,\Omega_\Lambda) contours by a factor of three relative to the case where only spectroscopically confirmed data are used (297 supernovae). In the case of flatness, the constraints obtained on the matter density applying BEAMS to the photometric SDSS-II data are \Omega_m(BEAMS)=0.194\pm0.07. This illustrates the potential power of BEAMS for future large photometric supernova surveys such as LSST.Comment: 25 pages, 15 figures, submitted to Ap

Wavelength-Gated Photochemical Synthesis of Phenalene Diimides

Herein, we pioneer a wavelength‐gated synthesis route to phenalene diimides. Consecutive Diels–Alder reactions of methylisophthalaldehydes and maleimides afford hexahydro‐phenalene‐1,6‐diol diimides via 5‐formyl‐hexahydro‐benzo[f]isoindoles as the intermediate. Both photoreactions are efficient (82–99 % yield) and exhibit excellent diastereoselectivity (62–98 % d.r.). The wavelength‐gated nature of the stepwise reaction enables the modular construction of phenalene diimide scaffolds by choice of substrate and wavelength. Importantly, this synthetic methodology opens a facile avenue to a new class of persistent phenalenyl diimide neutral radicals, constituting a versatile route to spin‐active molecules

Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

The expression of hyperpolarization activated cyclic nucleotide gated (HCN) channels in the rat ovary are dependent on the type of cell and the reproductive age of the animal: a laboratory investigation

<p>Abstract</p> <p>Background</p> <p>Aim of this study was to test the hypothesis that levels of hyperpolarization activated cyclic nucleotide gated channels 1 to 4 (HCN1-4) are linked to the reproductive age of the ovary.</p> <p>Methods</p> <p>Young, adult, and reproductively aged ovaries were collected from Sprague-Dawley rats. RT-PCR and western blot analysis of ovaries was performed to investigate the presence of mRNA and total protein for HCN1-4. Immunohistochemistry with semiquantitative H score analysis was performed using whole ovarian histologic sections.</p> <p>Results</p> <p>RT-PCR analysis showed the presence of mRNA for HCN1-4. Western blot analysis revealed HCN1-3 proteins in all ages of ovarian tissues. Immunohistochemistry with H score analysis demonstrated distinct age-related changes in patterns of HCN1-3 in the oocytes, granulosa cells, theca cells, and corpora lutea. HCN4 was present only in the oocytes, with declining levels during the reproduction lifespan.</p> <p>Conclusion</p> <p>The evidence presented here demonstrates cell-type and developmental age patterns of HCN1-4 channel expression in rat ovaries. Based on this, we hypothesize that HCN channels have functional significance in rat ovaries and may have changing roles in reproductive aging.</p

Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-Controlled Study of Telotristat Ethyl

Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful. Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment. Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥ 30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo. Implications: Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl

AIC, BIC, Bayesian evidence against the interacting dark energy model

Recent astronomical observations have indicated that the Universe is in the phase of accelerated expansion. While there are many cosmological models which try to explain this phenomenon, we focus on the interacting $\Lambda$CDM model where the interaction between the dark energy and dark matter sectors takes place. This model is compared to its simpler alternative---the $\Lambda$CDM model. To choose between these models the likelihood ratio test was applied as well as the model comparison methods (employing Occam's principle): the Akaike information criterion (AIC), the Bayesian information criterion (BIC) and the Bayesian evidence. Using the current astronomical data: SNIa (Union2.1), $h(z)$, BAO, Alcock--Paczynski test and CMB we evaluated both models. The analyses based on the AIC indicated that there is less support for the interacting $\Lambda$CDM model when compared to the $\Lambda$CDM model, while those based on the BIC indicated that there is the strong evidence against it in favor the $\Lambda$CDM model. Given the weak or almost none support for the interacting $\Lambda$CDM model and bearing in mind Occam's razor we are inclined to reject this model.Comment: LaTeX svjour3, 12 pages, 3 figure

Increased pain intensity is associated with greater verbal communication difficulty and increased production of speech and co-speech gestures

Effective pain communication is essential if adequate treatment and support are to be provided. Pain communication is often multimodal, with sufferers utilising speech, nonverbal behaviours (such as facial expressions), and co-speech gestures (bodily movements, primarily of the hands and arms that accompany speech and can convey semantic information) to communicate their experience. Research suggests that the production of nonverbal pain behaviours is positively associated with pain intensity, but it is not known whether this is also the case for speech and co-speech gestures. The present study explored whether increased pain intensity is associated with greater speech and gesture production during face-to-face communication about acute, experimental pain. Participants (N = 26) were exposed to experimentally elicited pressure pain to the fingernail bed at high and low intensities and took part in video-recorded semi-structured interviews. Despite rating more intense pain as more difficult to communicate (t(25) = 2.21, p = .037), participants produced significantly longer verbal pain descriptions and more co-speech gestures in the high intensity pain condition (Words: t(25) = 3.57, p = .001; Gestures: t(25) = 3.66, p = .001). This suggests that spoken and gestural communication about pain is enhanced when pain is more intense. Thus, in addition to conveying detailed semantic information about pain, speech and co-speech gestures may provide a cue to pain intensity, with implications for the treatment and support received by pain sufferers. Future work should consider whether these findings are applicable within the context of clinical interactions about pain