Antiangiogenic properties of selected ruthenium(III) complexes that are nitric oxide scavengers

The nitric oxide synthase (NOS) pathway has been clearly demonstrated to regulate angiogenesis. Increased levels of NO correlate with tumour growth and spreading in different experimental and human cancers. Drugs interfering with the NOS pathway may be useful in angiogenesis-dependent tumours. The aim of this study was to pharmacologically characterise certain ruthenium-based compounds, namely NAMI-A, KP1339, and RuEDTA, as potential NO scavengers to be used as antiangiogenic/antitumour agents. NAMI-A, KP1339 and RuEDTA were able to bind tightly and inactivate free NO in solution. Formation of ruthenium-NO adducts was documented by electronic absorption, FT-IR spectroscopy and (1)H-NMR. Pretreatment of rabbit aorta rings with NAMI-A, KP1339 or RuEDTA reduced endothelium-dependent vasorelaxation elicited by acetylcholine. This effect was reversed by 8-Br-cGMP. The key steps of angiogenesis, endothelial cell proliferation and migration stimulated by vascular endothelial growth factor (VEGF) or NO donor drugs, were blocked by NAMI-A, KP1339 and RuEDTA, these compounds being devoid of any cytotoxic activity. When tested in vivo, NAMI-A inhibited angiogenesis induced by VEGF. It is likely that the antitumour properties previously observed for ruthenium-based NO scavengers, such as NAMI-A, are related to their NO-related antiangiogenic propertie

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference

Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds

BACKGROUND: Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. CONCLUSIONS/SIGNIFICANCE: A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds

Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The datasets generated during this study are available at EGA under study ID EGAS00001003780. The codes generated during this study and all supplementary tables are available at GitLab https://gitlab.com/dseyres/extremephenotype.Background: This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature. Methods/Results: We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, six months after bariatric surgery revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. Netosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Conclusions: We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features.British Heart FoundationMedical Research Council (MRC)Wellcome TrustNational Institute for Health Research (NIHR)Isaac Newton fellowshipJohn and Lucille Van Geest Foundatio

The Herschel-SPIRE Legacy Survey (HSLS): the scientific goals of a shallow and wide submillimeter imaging survey with SPIRE

A large sub-mm survey with Herschel will enable many exciting science opportunities, especially in an era of wide-field optical and radio surveys and high resolution cosmic microwave background experiments. The Herschel-SPIRE Legacy Survey (HSLS), will lead to imaging data over 4000 sq. degrees at 250, 350, and 500 micron. Major Goals of HSLS are: (a) produce a catalog of 2.5 to 3 million galaxies down to 26, 27 and 33 mJy (50% completeness; 5 sigma confusion noise) at 250, 350 and 500 micron, respectively, in the southern hemisphere (3000 sq. degrees) and in an equatorial strip (1000 sq. degrees), areas which have extensive multi-wavelength coverage and are easily accessible from ALMA. Two thirds of the of the sources are expected to be at z > 1, one third at z > 2 and about a 1000 at z > 5. (b) Remove point source confusion in secondary anisotropy studies with Planck and ground-based CMB data. (c) Find at least 1200 strongly lensed bright sub-mm sources leading to a 2% test of general relativity. (d) Identify 200 proto-cluster regions at z of 2 and perform an unbiased study of the environmental dependence of star formation. (e) Perform an unbiased survey for star formation and dust at high Galactic latitude and make a census of debris disks and dust around AGB stars and white dwarfs

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

Measurement of the B0s →J/ψη lifetime

Using a data set corresponding to an integrated luminosity of 3 fb−1, collected by the LHCb experiment in pp collisions at centre-of-mass energies of 7 and 8 TeV, the effective lifetime in the Bs0→J/ψη decay mode, τeff, is measured to be τeff=1.479±0.034 (stat)±0.011 (syst) ps. Assuming CP conservation, τeff corresponds to the lifetime of the light Bs0 mass eigenstate. This is the first measurement of the effective lifetime in this decay mode

Measurement of D s ^± production asymmetry in pp collisions at √s=7 and 8 TeV

The inclusive $D_s^{\pm}$ production asymmetry is measured in $pp$ collisions collected by the LHCb experiment at centre-of-mass energies of $\sqrt{s} =7$ and 8 TeV. Promptly produced $D_s^{\pm}$ mesons are used, which decay as $D_s^{\pm}\to\phi\pi^{\pm}$, with $\phi\to K^+K^-$. The measurement is performed in bins of transverse momentum, $p_{\rm T}$, and rapidity, $y$, covering the range $2.5<p_{\rm T}<25.0$ GeV$/c$ and $2.0<y<4.5$. No kinematic dependence is observed. Evidence of nonzero $D_s^{\pm}$ production asymmetry is found with a significance of 3.3 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2018-010.htm

Observation of B+c → D0K+ decays

Using proton-proton collision data corresponding to an integrated luminosity of 3.0 fb−1, recorded by the LHCb detector at center-of-mass energies of 7 and 8 TeV, the B+ c → D0K+ decay is observed with a statistical significance of 5.1 standard deviations. By normalizing to B+ → D¯ 0π+ decays, a measurement of the branching fraction multiplied by the production rates for B+ c relative to B+ mesons in the LHCb acceptance is obtained, R D 0 K = ( f c / f u ) × B ( B + c → D 0 K + ) = ( 9. 3 + 2.8 − 2.5 ± 0.6 ) × 10 − 7, where the first uncertainty is statistical and the second is systematic. This decay is expected to proceed predominantly through weak annihilation and penguin amplitudes, and is the first B+ c decay of this nature to be observed

Measurement of the B_{s}^{0}→μ^{+}μ^{-} Branching Fraction and Effective Lifetime and Search for B^{0}→μ^{+}μ^{-} Decays.

A search for the rare decays B_{s}^{0}→μ^{+}μ^{-} and B^{0}→μ^{+}μ^{-} is performed at the LHCb experiment using data collected in pp collisions corresponding to a total integrated luminosity of 4.4  fb^{-1}. An excess of B_{s}^{0}→μ^{+}μ^{-} decays is observed with a significance of 7.8 standard deviations, representing the first observation of this decay in a single experiment. The branching fraction is measured to be B(B_{s}^{0}→μ^{+}μ^{-})=(3.0±0.6_{-0.2}^{+0.3})×10^{-9}, where the first uncertainty is statistical and the second systematic. The first measurement of the B_{s}^{0}→μ^{+}μ^{-} effective lifetime, τ(B_{s}^{0}→μ^{+}μ^{-})=2.04±0.44±0.05  ps, is reported. No significant excess of B^{0}→μ^{+}μ^{-} decays is found, and a 95% confidence level upper limit, B(B^{0}→μ^{+}μ^{-})<3.4×10^{-10}, is determined. All results are in agreement with the standard model expectations