Monoamine oxidase-A modulates apoptotic cell death induced by staurosporine in human neuroblastoma cells

Monoamine oxidases (MAOs) are mitochondrial enzymes which control the levels of neurotransmitters in the brain and dietary amines in peripheral tissues via oxidative deamination. MAO has also been implicated in cell signalling. In this study, we describe the MAO-A isoform as functional in apoptosis induced by staurosporine (STS) in human dopaminergic neuroblastoma cells (SH-SY5Y). Increased levels of MAO-A activity were induced by STS, accompanied by increased MAO-A protein and activation of the initiator of the intrinsic pathway, caspase 9, and the executioner caspase 3. MAO-A mRNA levels were unaffected by STS, suggesting that changes in MAO-A protein are due to post-transcriptional events. Two unrelated MAO-A inhibitors reduced caspase activation. STS treatment resulted in sustained activation of the mitogen-activated protein kinase pathway enzymes extracellular regulated kinase, c-jun terminal kinase and p38, and depletion of the anti-apoptotic protein Bcl-2. These changes were significantly reversed by MAO inhibition. Production of reactive oxygen species was increased following STS exposure, which was blocked by both MAO inhibition and the antioxidant N-acetylcysteine. Therefore our data provide evidence that MAO-A, through its production of reactive oxygen species as a by-product of its catalytic activity on the mitochondrial surface, is recruited by the cell to enhance apoptotic signalling

Correlated optical, X-ray, and $-ray flaring activity seen with INTEGRAL during the 2015 outburst of V404 Cygni

Reproduced with permission from Astronomy & Astrophysics. © 2015 ESO.After 25 years of quiescence, the microquasar V404 Cyg entered a new period of activity in June 2015. This X-ray source is known to undergo extremely bright and variable outbursts seen at all wavelengths. It is therefore an object of prime interest to understand the accretion-ejection connections. These can, however, only be probed through simultaneous observations at several wavelengths. We made use of the INTEGRAL instruments to obtain long, almost uninterrupted observations from 2015 June 20th, 15:50 UTC to June 25th, 4:05 UTC, from the optical V-band, up to the soft γ-rays. V404 Cyg was extremely variable in all bands, with the detection of 18 flares with fluxes exceeding 6 Crab (20--40 keV) within 3 days. The flare recurrence can be as short as ∼ 20~min from peak to peak. A model-independent analysis shows that the >6 Crab flares have a hard spectrum. A simple 10--400 keV spectral analysis of the off-flare and flare periods shows that the variation in intensity is likely to be due to variations of a cut-off power law component only. The optical flares seem to be at least of two different types: one occurring in simultaneity with the X-ray flares, the other showing a delay greater than 10 min. The former could be associated with X-ray reprocessing by either an accretion disk or the companion star. We suggest that the latter are associated with plasma ejections that have also been seen in radio.Peer reviewe

Is the plateau state in GRS 1915+105 equivalent to canonical hard states?

GRS1915+105 is a very peculiar black hole binary that exhibits accretion-related states that are not observed in any other stellar-mass black hole system. One of these states, however -- referred to as the plateau state -- may be related to the canonical hard state of black hole X-ray binaries. Both the plateau and hard state are associated with steady, relatively lower X-ray emission and flat/inverted radio emission, that is sometimes resolved into compact, self-absorbed jets. However, while generally black hole binaries quench their jets when the luminosity becomes too high, GRS1915+105 seems to sustain them despite the fact that it accretes at near- or super-Eddington rates. In order to investigate the relationship between the plateau and the hard state, we fit two multi-wavelength observations using a steady-state outflow-dominated model, developed for hard state black hole binaries. The data sets consist of quasi-simultaneous observations in radio, near-infrared and X-ray bands. Interestingly, we find both significant differences between the two plateau states, as well as between the best-fit model parameters and those representative of the hard state. We discuss our interpretation of these results, and the possible implications for GRS 1915+105's relationship to canonical black hole candidates.Comment: accepted for publication in MNRA

Evidence for a compact jet dominating the broadband spectrum of the black hole accretor XTE J1550-564

[abridged] The black hole X-ray binary XTE J1550-564 was monitored extensively at X-ray, optical and infrared wavelengths throughout its outburst in 2000. We show that it is possible to separate the optical/near-infrared (OIR) jet emission from the OIR disc emission. Focussing on the jet component, we find that as the source fades in the X-ray hard state, the OIR jet emission has a spectral index consistent with optically thin synchrotron emission (alpha ~ -0.6 to -0.7, where F_nu \propto nu^alpha). This jet emission is tightly and linearly correlated with the X-ray flux; L_OIR,jet \propto L_X^(0.98 +- 0.08) suggesting a common origin. This is supported by the OIR, X-ray and OIR to X-ray spectral indices being consistent with a single power law (alpha = -0.73). Ostensibly the compact, synchrotron jet could therefore account for ~ 100 % of the X-ray flux at low luminosities in the hard state. At the same time, (i) an excess is seen over the power law decay of the X-ray flux at the point in which the jet would start to dominate, (ii) the X-ray spectrum slightly softens, which seems to be due to a high energy cut-off or break shifting to a lower energy, and (iii) the X-ray rms variability increases. This may be the strongest evidence to date of synchrotron emission from the compact, steady jet dominating the X-ray flux of an X-ray binary. For XTE J1550-564, this is likely to occur within the luminosity range ~ (2 e-4 - 2 e-3) L_Edd on the hard state decline of this outburst. However, on the hard state rise of the outburst and initially on the hard state decline, the synchrotron jet can only provide a small fraction (~ a few per cent) of the X-ray flux. Both thermal Comptonization and the synchrotron jet can therefore produce the hard X-ray power law in accreting black holes.Comment: MNRAS accepted, 12 pages, 9 figure

When size really does matter - providing PrEP across Queensland

Background: Providing universal access to PrEP across Queensland, the 2nd largest and 3rd most populous state in Australia has provided unique challenges. Queensland has 22.5% of Australia’s total land area, compared to the 14.4% of New South Wales, Victoria and Tasmania combined. Queensland is also less centralised with 50% of the population living outside the state capital and 25% outside of the south eastern region. Notably, this population distribution is reflected in HIV diagnoses with 24% of new diagnoses in 2015 coming from Health Service Areas outside of the south east. Method: The unique service models, buildings, personalities, communities and clinical capacity of regional services has required bespoke solutions to implement QPrEPd in these sites. Many sites have not taken part in clinical trials before and required additional support. Additionally, the barriers to access found in more conservative services and communities has required the implementation team to advocate and educate for universal PrEP provision. Protocol modification has enabled nurses to manage ongoing PrEP provision in services with limited medical officer support. Results: Eleven study sites are outside of the south east corner; 7 public sexual health services, 3 general practices in Cairns and one Aboriginal Medical Service in Toowoomba. These sites have enrolled 18.5% of the all participants. The remaining 11 sites in the south east corner are include 5 general practices, including one run through a community based organisation, 5 public sexual health clinics and one private hospital. Overall, nearly 63% of the participants have enrolled at general practice sites. Conclusions: While this project has provided access to PrEP throughout much of Queensland, gaps remain. The key limitation in regional areas where there is no public sexual health service is the lack of S100 prescribing general practitioners. In order to expand access other service delivery models are being explored

A Glass Polyalkenoate Cement Carrier for Bone Morphogenetic Proteins

This work considers a glass polyalkenoate cement (GPC)-based carrier for the effective delivery of bone morphogenetic proteins (BMPs) at an implantation site. A 0.12 CaO–0.04 SrO–0.36 ZnO–0.48 SiO2 based glass and poly(acrylic acid) (PAA, Mw 213,000) were employed for the fabrication of the GPC. The media used for the water source in the GPC reaction was altered to produce a series of GPCs. The GPC liquid media was either 100 % distilled water with additions of albumin at 0, 2, 5 and 8 wt% of the glass content, 100 % formulation buffer (IFB), and 100 % BMP (150 µg rhBMP-2/ml IFB). Rheological properties, compressive strength, ion release profiles and BMP release were evaluated. Working times (Tw) of the formulated GPCs significantly increased with the addition of 2 % albumin and remained constant with further increases in albumin content or IFB solutions. Setting time (Ts) experienced an increase with 2 and 5 % albumin content, but a decrease with 8 % albumin. Changing the liquid source to IFB containing 5 % albumin had no significant effect on Ts compared to the 8 % albumin-containing BT101. Replacing the albumin with IFB/BMP-2 did not significantly affect Tw. However, Ts increased for the BT101_BMP-2 containing GPCs, compared to all other samples. The compressive strength evaluated 1 day post cement mixing was not affected significantly by the incorporation of BMPs, but the ion release did increase from the cements, particularly for Zn and Sr. The GPCs released BMP after the first day, which decreased in content during the following 6 days. This study has proven that BMPs can be immobilized into GPCs and may result in novel materials for clinical applications