Background and purpose:
The endocannabinoid N‐arachidonoylethanolamide (anandamide) is co‐synthesized with other N‐acylethanolamides, namely N‐palmitoylethanolamide (PEA) and N‐oleoylethanolamide ...(OEA), which have been shown to potentiate anandamide responses (so‐called ‘entourage effects’) in non‐vascular tissues. It remains unclear whether such interactions occur in the circulation.
Experimental approach:
In rat isolated small mesenteric arteries, the effects of PEA and OEA on relaxation to anandamide and tissue contents of the N‐acylethanolamides were examined under myographic conditions.
Key results:
Anandamide‐induced relaxation was potentiated by pretreatment with PEA (10 μM) or OEA (1 μM), or in combination. The potentiation by PEA and OEA was endothelium‐independent and abolished by treatment with capsaicin (10 μM), which desensitizes the transient receptor potential vanilloid type 1 (TRPV1) receptor system, or by the TRPV1 receptor antagonist, N‐(3‐methoxyphenyl)‐4‐chlorocinnamide (SB366791) (2 μM). It was also observed at molar ratios of anandamide and PEA (or OEA) similar to those found in mesenteric arteries. PEA and inhibition of anandamide hydrolysis by 3′‐carbamoyl‐biphenyl‐3‐yl‐cyclohexylcarbamate (URB597) (1 μM) additively potentiated anandamide responses. On the other hand, PEA and OEA also induced vasorelaxation per se (rank order of potency: anandamide>OEA>PEA), but relaxation to the three N‐acylethanolamides displayed different sensitivity to treatment with capsaicin, SB366791 and URB597. For example, relaxations to anandamide and OEA, but not PEA, were attenuated by both capsaicin and SB366791.
Conclusion and implications:
This study shows that PEA and OEA potentiate relaxant responses to anandamide through TRPV1 receptors in rat small mesenteric arteries. The congeners also induce vasorelaxation per se, suggesting a function for the N‐acylethanolamides in vascular control.
British Journal of Pharmacology (2008) 155, 837–846; doi:10.1038/bjp.2008.324; published online 11 August 2008
A radio counterpart to a neutron star merger Hallinan, G.; Corsi, A.; Mooley, K. P. ...
Science (American Association for the Advancement of Science),
12/2017, Letnik:
358, Številka:
6370
Journal Article
Recenzirano
Odprti dostop
Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the ...outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultrarelativistic jet, viewed off-axis, or a cocoon of mildly relativistic ejecta. Within 100 days of the merger, the radio light curves will enable observers to distinguish between these models, and the angular velocity and geometry of the debris will be directly measurable by very long baseline interferometry.
The aim of this subgroup analysis of the Mabthera International Trial Group study was to evaluate the impact of chemotherapy and rituximab in primary mediastinal B-cell lymphoma (PMBCL) in comparison ...to other diffuse large B-cell lymphoma (DLBCL).
Patients were randomly assigned to six cycles of CHOP-like regimens with or without rituximab.
Of 824 patients enrolled, 87 had PMBCL and 627 other types of DLBCL. Rituximab increased the rates of complete remission (unconfirmed) in both PMBCL (from 54% to 80%, P = 0.015) and DLBCL (from 72% to 87%, P < 0.001). In PMBCL, rituximab virtually eliminated progressive disease (PD) (2.5% versus 24%, P < 0.001), whereas without rituximab, PD was more frequent in PMBCL than in DLBCL (24% versus 10%, P = 0.010). With a median observation time of 34 months, 3-year event-free survival (EFS) was improved by rituximab for PMBCL (78% versus 52%, P = 0.012) and for DLBCL (81% versus 61%, P < 0.001). Overall survival benefit was similar for DLBCL (93% versus 85%, P < 0.001) and PMBCL (89% versus 78%, P = 0.158).
In young patients with PMBCL (age-adjusted International Prognostic Index 0–1), rituximab added to six cycles of CHOP-like chemotherapy increases response rate and EFS to the same extent as other DLBCL. The combination of rituximab with CHOP chemotherapy is an effective treatment in PMBCL with good prognosis features.
Helium is expected to be present in the massive ejecta of some hydrogen-poor superluminous supernovae (SLSN-I). However, until now only one event has been identified with He features in its ...photospheric spectra (PTF10hgi). We present the discovery of a new He-rich SLSN-I, ZTF19aawfbtg (SN2019hge), at z = 0.0866. This event has more than 10 optical spectra at phases from −41 to +103 days relative to the peak, most of which match well with that of PTF10hgi. Confirmation comes from a near-IR spectrum taken at +34 days, revealing He i features with P-Cygni profiles at 1.083 and 2.058 m. Using the optical spectra of PTF10hgi and SN2019hge as templates, we examined 70 other SLSNe-I discovered by Zwicky Transient Facility in the first two years of operation and found five additional SLSNe-I with distinct He-features. The excitation of He i atoms in normal core-collapse supernovae requires nonthermal radiation, as proposed by previous studies. These He-rich events cannot be explained by the traditional 56Ni mixing model because of their blue spectra, high peak luminosities, and long rise timescales. Magnetar models offer a possible solution since pulsar winds naturally generate high-energy particles, potential sources of nonthermal excitation. An alternative model is the interaction between the ejecta and dense H-poor circumstellar material, which may be supported by observed undulations in the light curves. These six SLSNe-Ib have relatively low-peak luminosities (rest frame Mg = −20.06 0.16).
Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical ...opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.
The Zwicky Transient Facility (ZTF) is performing a three-day cadence survey of the visible northern sky (∼3π) with newly found transient candidates announced via public alerts. The ZTF Bright ...Transient Survey (BTS) is a large spectroscopic campaign to complement the photometric survey. BTS endeavors to spectroscopically classify all extragalactic transients with mpeak ≤ 18.5 mag in either the gZTF or rZTF filters, and publicly announce said classifications. BTS discoveries are predominantly supernovae (SNe), making this the largest flux-limited SN survey to date. Here we present a catalog of 761 SNe, classified during the first nine months of ZTF (2018 April 1-2018 December 31). We report BTS SN redshifts from SN template matching and spectroscopic host-galaxy redshifts when available. We analyze the redshift completeness of local galaxy catalogs, the redshift completeness fraction (RCF; the ratio of SN host galaxies with known spectroscopic redshift prior to SN discovery to the total number of SN hosts). Of the 512 host galaxies with SNe Ia, 227 had previously known spectroscopic redshifts, yielding an RCF estimate of 44% 4%. The RCF decreases with increasing distance and decreasing galaxy luminosity (for z < 0.05, or ∼200 Mpc, RCF 0.6). Prospects for dramatically increasing the RCF are limited to new multifiber spectroscopic instruments or wide-field narrowband surveys. Existing galaxy redshift catalogs are only ∼50% complete at r 16.9 mag. Pushing this limit several magnitudes deeper will pay huge dividends when searching for electromagnetic counterparts to gravitational wave events or sources of ultra-high-energy cosmic rays or neutrinos.
The low rate of approval of novel anti-cancer agents underscores the need for better preclinical models of therapeutic response as neither xenografts nor early-generation genetically engineered mouse ...models (GEMMs) reliably predict human clinical outcomes. Whereas recent, sporadic GEMMs emulate many aspects of their human disease counterpart more closely, their ability to predict clinical therapeutic responses has never been tested systematically. We evaluated the utility of two state-of-the-art, mutant Kras-driven GEMMs--one of non-small-cell lung carcinoma and another of pancreatic adenocarcinoma--by assessing responses to existing standard-of-care chemotherapeutics, and subsequently in combination with EGFR and VEGF inhibitors. Standard clinical endpoints were modeled to evaluate efficacy, including overall survival and progression-free survival using noninvasive imaging modalities. Comparisons with corresponding clinical trials indicate that these GEMMs model human responses well, and lay the foundation for the use of validated GEMMs in predicting outcome and interrogating mechanisms of therapeutic response and resistance.
Context. Although studying outflows in the host galaxies of active galactic nuclei (AGNs) have moved to the forefront of extragalactic astronomy in recent years, estimating the energy associated with ...these outflows has been a major challenge. Determining the energy associated with an outflow often involves an assumption of uniform density in the narrow line region (NLR), which spans a wide range in the literature, leading to large systematic uncertainties in energy estimation. Aims. In this paper we present electron density maps for a sample of outflowing and non-outflowing Seyfert galaxies at z < 0.02 drawn from the Siding Spring Southern Seyfert Spectroscopic Snapshot Survey (S7) and try to understand the origin and values of the observed density structures to reduce the systematic uncertainties in outflow energy estimation. Methods. We use the ratio of the S IIλ6716,6731 emission lines to derive spatially resolved electron densities (≲50–2000 cm−3). Using optical Integral Field Unit observations from the Wide Field Spectrograph (WiFeS), we are able to measure densities across the central 2–5 kpc of the selected AGN host galaxies. We compare the density maps with the positions of the H II regions derived from the narrow Hα component, ionization maps from O III and spatially resolved BPT diagrams to infer the origin of the observed density structures. We also use the electron density maps to construct density profiles as a function of distance from the central AGN. Results. We find a spatial correlation between the sites of high star formation and high electron density for targets without an active ionized outflow. The non-outflowing targets also show an exponential drop in the electron density as a function of distance from the centre, with a mean exponential index of ∼0.15. The correlation between the star forming sites and electron density ceases for targets with an outflow. The density within the outflowing medium is not uniform and shows both low- and high-density sites, most likely due to the presence of shocks and highly turbulent medium. We compare these results in the context of previous results obtained from fibre and slit spectra.
We present a detailed characterization of the 849 broad-line quasars from the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project. Our quasar sample covers a redshift range of 0.1 < z < ...4.5 and is flux-limited to iPSF < 21.7 without any other cuts on quasar properties. The main sample characterization includes: (1) spectral measurements of the continuum and broad emission lines for individual objects from the coadded first-season spectroscopy in 2014, (2) identification of broad and narrow absorption lines in the spectra, and (3) optical variability properties for continuum and broad lines from multi-epoch spectroscopy. We provide improved systemic redshift estimates for all quasars and demonstrate the effects of the signal-to-noise ratio on the spectral measurements. We compile measured properties for all 849 quasars along with supplemental multi-wavelength data for subsets of our sample from other surveys. The SDSS-RM sample probes a diverse range in quasar properties and shows well-detected continuum and broad-line variability for many objects from first-season monitoring data. The compiled properties serve as the benchmark for follow-up work based on SDSS-RM data. The spectral fitting tools are made public along with this work.
We present accretion disk structure measurements from continuum lags in the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project. Lags are measured using the JAVELIN software from the ...first-year SDSS-RM g and i photometry, resulting in well-defined lags for 95 quasars, 33 of which have lag S/N > 2 . We also estimate lags using the ICCF software and find consistent results, though with larger uncertainties. Accretion disk structure is fit using a Markov chain Monte Carlo approach, parameterizing the measured continuum lags as a function of disk size normalization, wavelength, black hole mass, and luminosity. In contrast with previous observations, our best-fit disk sizes and color profiles are consistent (within 1.5 ) with the Shakura & Sunyaev analytic solution. We also find that more massive quasars have larger accretion disks, similarly consistent with the analytic accretion disk model. The data are inconclusive on a correlation between disk size and continuum luminosity, with results that are consistent with both no correlation and the Shakura & Sunyaev expectation. The continuum lag fits have a large excess dispersion, indicating that our measured lag errors are underestimated and/or our best-fit model may be missing the effects of orientation, spin, and/or radiative efficiency. We demonstrate that fitting disk parameters using only the highest-S/N lag measurements biases best-fit disk sizes to be larger than the disk sizes recovered using a Bayesian approach on the full sample of well-defined lags.
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