Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Studies of the cardiovascular effects of nociceptin and related peptides

Nociceptin, a novel opioid peptide, and its ORL1 receptor share structural similarities with other opioid ligands and receptors. Although NC exerts evident cardiovascular effects at a central and peripheral level, its role in homeostatic mechanisms and disease states are just beginning to be understood, as only recently selective receptor antagonists became available. In this review, some of the new observations regarding the cardiovascular actions of NC, related peptides and newly synthesized receptor antagonists are discussed

Cardiovascular effects of nociceptin in unanesthetized mice

We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe1c(CH2-NH)Gly2]NC(1–13)NH2 ([F/G]NC(1–13)NH2) in unanesthetized normotensive Swiss Morini mice. Bolus intravenous injection of NC decreased mean blood pressure and heart rate. The hypotensive response to 10 nmol/kg NC lasted ,10 minutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 11463 to 9762 mm Hg at 10 minutes, P,0.01). The latter dose reduced heart rate from 542643 to 479631 beats/min (P,0.05) and increased aortic blood flow by 4165% (P,0.05). Hypotension and bradycardia were also evoked by NC(1–17)NH2 and NC(1–13)NH2 fragments, whereas NC(1–13)OH and NC(1–9)NH2 were ineffective. Thiorphan, an inhibitor of neutral endopeptidase 24.11, enhanced the hypotension induced by NC(1–13)NH2 and revealed the ability of NC(1–13)OH to decrease mean blood pressure. [F/G]NC(1–13)NH2, a recently synthesized antagonist of the NC receptor, did not alter basal mean blood pressure or heart rate, but it prevented the hypotension, bradycardia, and increase in aortic blood flow evoked by NC. In contrast, [F/G]NC(1–13)NH2 did not alter the hypotension induced by bradykinin or endomorphin-1 (a m-receptor agonist), and the bradycardia induced by leu-enkephalin (a d-receptor agonist) or U504885 (a synthetic k-receptor agonist). In conclusion, NC and some of its fragments cause hypotension and bradycardia and increase aortic blood flow in mice, with the NC(1–13) sequence being critical for these biological effects. Our results also demonstrate that the compound [F/G]NC(1–13)NH2 is a potent and selective antagonist of the NC receptor in vivo

Cardiovascular effects of nociceptin in unanesthetized mice

We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe1c(CH2-NH)Gly2]NC(1\u201313)NH2 ([F/G]NC(1\u201313)NH2) in unanesthetized normotensive Swiss Morini mice. Bolus intravenous injection of NC decreased mean blood pressure and heart rate. The hypotensive response to 10 nmol/kg NC lasted ,10 minutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 11463 to 9762 mm Hg at 10 minutes, P,0.01). The latter dose reduced heart rate from 542643 to 479631 beats/min (P,0.05) and increased aortic blood flow by 4165% (P,0.05). Hypotension and bradycardia were also evoked by NC(1\u201317)NH2 and NC(1\u201313)NH2 fragments, whereas NC(1\u201313)OH and NC(1\u20139)NH2 were ineffective. Thiorphan, an inhibitor of neutral endopeptidase 24.11, enhanced the hypotension induced by NC(1\u201313)NH2 and revealed the ability of NC(1\u201313)OH to decrease mean blood pressure. [F/G]NC(1\u201313)NH2, a recently synthesized antagonist of the NC receptor, did not alter basal mean blood pressure or heart rate, but it prevented the hypotension, bradycardia, and increase in aortic blood flow evoked by NC. In contrast, [F/G]NC(1\u201313)NH2 did not alter the hypotension induced by bradykinin or endomorphin-1 (a m-receptor agonist), and the bradycardia induced by leu-enkephalin (a d-receptor agonist) or U504885 (a synthetic k-receptor agonist). In conclusion, NC and some of its fragments cause hypotension and bradycardia and increase aortic blood flow in mice, with the NC(1\u201313) sequence being critical for these biological effects. Our results also demonstrate that the compound [F/G]NC(1\u201313)NH2 is a potent and selective antagonist of the NC receptor in vivo

Differential expression of stromal cell-derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications

Objective. Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF-1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc. Methods. We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF-1 and CXCR4 was assessed by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF-1 and CXCR4 by confocal laser scanning microscopy, RT-PCR, and Western blotting. Results. SDF-1 and CXCR4 were up-regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF-1 in the early stage of disease, with a progressive reduction of SDF-1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF-1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function. Conclusion. Due to its transient expression, SDF-1 could be considered a future therapeutic target to induce new vessel formation in SSc