92 research outputs found

    Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

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    The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

    Multi-messenger observations of a binary neutron star merger

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    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

    All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run

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    We present results from a search for gravitational-wave bursts in the data collected by the LIGO and Virgo detectors between July 7, 2009 and October 20, 2010: data are analyzed when at least two of the three LIGO-Virgo detectors are in coincident operation, with a total observation time of 207 days. The analysis searches for transients of duration < 1 s over the frequency band 64-5000 Hz, without other assumptions on the signal waveform, polarization, direction or occurrence time. All identified events are consistent with the expected accidental background. We set frequentist upper limits on the rate of gravitational-wave bursts by combining this search with the previous LIGO-Virgo search on the data collected between November 2005 and October 2007. The upper limit on the rate of strong gravitational-wave bursts at the Earth is 1.3 events per year at 90% confidence. We also present upper limits on source rate density per year and Mpc^3 for sample populations of standard-candle sources. As in the previous joint run, typical sensitivities of the search in terms of the root-sum-squared strain amplitude for these waveforms lie in the range 5 10^-22 Hz^-1/2 to 1 10^-20 Hz^-1/2. The combination of the two joint runs entails the most sensitive all-sky search for generic gravitational-wave bursts and synthesizes the results achieved by the initial generation of interferometric detectors.Comment: 15 pages, 7 figures: data for plots and archived public version at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=70814&version=19, see also the public announcement at http://www.ligo.org/science/Publication-S6BurstAllSky

    Prime-boost immunization of rabbits with HIV-1 gp120 elicits potent neutralization activity against a primary viral isolate

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    <div><p>Development of a vaccine for HIV-1 requires a detailed understanding of the neutralizing antibody responses that can be experimentally elicited to difficult-to-neutralize primary isolates. Rabbits were immunized with the gp120 subunit of HIV-1 JR-CSF envelope (Env) using a DNA-prime protein-boost regimen. We analyzed five sera that showed potent autologous neutralizing activity (IC50s at ∼10<sup>3</sup> to 10<sup>4</sup> serum dilution) against pseudoviruses containing Env from the primary isolate JR-CSF but not from the related isolate JR-FL. Pseudoviruses were created by exchanging each variable and constant domain of JR-CSF gp120 with that of JR-FL or with mutations in putative N-glycosylation sites. The sera contained different neutralizing activities dependent on C3 and V5, C3 and V4, or V4 regions located on the glycan-rich outer domain of gp120. All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4. The JR-CSF gp120 epitopes recognized by the sera are generally distinct from those of several well characterized mAbs (targeting conserved sites on Env) or other type-specific responses (targeting V1, V2, or V3 variable regions). The activity of one serum requires specific glycans that are also important for 2G12 neutralization and this serum blocked the binding of 2G12 to gp120. Our findings show that different fine specificities can achieve potent neutralization of HIV-1, yet this strong activity does not result in improved breadth.</p> </div

    Binary Black Hole Mergers in the first Advanced LIGO Observing Run

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    The first observational run of the Advanced LIGO detectors, from September 12, 2015 to January 19, 2016, saw the first detections of gravitational waves from binary black hole mergers. In this paper we present full results from a search for binary black hole merger signals with total masses up to 100M100 M_\odot and detailed implications from our observations of these systems. Our search, based on general-relativistic models of gravitational wave signals from binary black hole systems, unambiguously identified two signals, GW150914 and GW151226, with a significance of greater than 5σ5\sigma over the observing period. It also identified a third possible signal, LVT151012, with substantially lower significance, which has a 87% probability of being of astrophysical origin. We provide detailed estimates of the parameters of the observed systems. Both GW150914 and GW151226 provide an unprecedented opportunity to study the two-body motion of a compact-object binary in the large velocity, highly nonlinear regime. We do not observe any deviations from general relativity, and place improved empirical bounds on several high-order post-Newtonian coefficients. From our observations we infer stellar-mass binary black hole merger rates lying in the range 9240Gpc3yr19-240 \mathrm{Gpc}^{-3} \mathrm{yr}^{-1}. These observations are beginning to inform astrophysical predictions of binary black hole formation rates, and indicate that future observing runs of the Advanced detector network will yield many more gravitational wave detections

    Observation of Gravitational Waves from a Binary Black Hole Merger

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    On September 14, 2015 at 09:50:45 UTC the two detectors of the Laser Interferometer Gravitational-Wave Observatory simultaneously observed a transient gravitational-wave signal. The signal sweeps upwards in frequency from 35 to 250 Hz with a peak gravitational-wave strain of 1.0 × 10−21. It matches the waveform predicted by general relativity for the inspiral and merger of a pair of black holes and the ringdown of the resulting single black hole. The signal was observed with a matched-filter signal-to-noise ratio of 24 and a false alarm rate estimated to be less than 1 event per 203 000 years, equivalent to a significance greater than 5.1σ. The source lies at a luminosity distance of 410þ160 −180 Mpc corresponding to a redshift z ¼ 0.09þ0.03 −0.04 . In the source frame, the initial black hole masses are 36þ5 −4M⊙ and 29þ4 −4M⊙, and the final black hole mass is 62þ4 −4M⊙, with 3.0þ0.5 −0.5M⊙c2 radiated in gravitational waves. All uncertainties define 90% credible intervals. These observations demonstrate the existence of binary stellar-mass black hole systems. This is the first direct detection of gravitational waves and the first observation of a binary black hole merger
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