ΔNp73 antisense activates PUMA and induces apoptosis in neuroblastoma cells

The p73 gene codes for various different protein isoforms. They include proteins expressed under the control of the P1 promoter that contain a transactivation domain and are similar in function to p53 (TAp73 isoforms), as well as proteins regulated by the P2 promoter that lack this domain and function as dominant negative inhibitors of TAp73 and p53 (ΔNp73 isoforms). Whereas TAp73 functions as a tumor suppressor with pro-apoptotic function, ΔNp73 is likely to prevent the induction of apoptosis in tumor cells and to participate in oncogenesis. Here we used a loss-of-function strategy to assess the role of ΔNp73 in SH-SY5Y neuroblastoma cells. An antisense oligonucleotide designed to target ΔNp73 mRNA, but not TAp73, was used to effectively downregulate this transcript. ΔNp73 downregulation was accompanied by increased levels of the pro-apoptotic BH3 family member PUMA at the mRNA and protein level, and by conformational activation of BAX which translocated to mitochondria. These ΔNp73 antisense-mediated alterations led to the induction of apoptosis as detected by decreased cell viability, augmented DNA fragmentation and increased caspase-3 activity in cell lysates. Our results demonstrate the cytoprotective role of ΔNp73 in neuroblastoma and suggest its use as a target for molecular intervention therap

Did Galaxy Assembly and Supermassive Black-Hole Growth go hand-in-hand?

In this paper, we address whether the growth of supermassive black-holes has kept pace with the process of galaxy assembly. For this purpose, we first searched the Hubble Ultra Deep Field (HUDF) for "tadpole galaxies", which have a knot at one end and an extended tail. They appear dynamically unrelaxed -- presumably early-stage mergers -- and make up ~6% of the field galaxy population. Their redshift distribution follows that of field galaxies, indicating that -- if tadpole galaxies are indeed dynamically young -- the process of galaxy assembly generally kept up with the reservoir of field galaxies as a function of epoch. Next, we present a search for HUDF objects with point-source components that are optically variable (at the >~3.0 sigma level) on timescales of weeks--months. Among 4644 objects to i_AB=28.0 mag (10 sigma), 45 have variable point-like components, which are likely weak AGN. About 1% of all field objects show variability for 0.1 < z < 4.5, and their redshift distribution is similar to that of field galaxies. Hence supermassive black-hole growth in weak AGN likely also kept up with the process of galaxy assembly. However, the faint AGN sample has almost no overlap with the tadpole sample, which was predicted by recent hydrodynamical numerical simulations. This suggests that tadpole galaxies are early-stage mergers, which likely preceded the ``turn-on'' of the AGN component and the onset of visible point-source variability by >~1 Gyr.Comment: 9 pages, Latex2e requires 'elsart' and 'elsart3' (included), 10 postscript figures. To appear in the Proceedings of the Leiden Workshop on "QSO Host Galaxies: Evolution and Environment", eds. P.D. Barthel & D.B. Sanders (New Astron. Rev., 2006

The LBDS Hercules sample of mJy radio sources at 1.4 GHz - II. Redshift distribution, radio luminosity function, and the high-redshift cut-off

{Abridged} A combination of spectroscopy and broadband photometric redshifts has been used to find the complete redshift distribution of the Hercules sample of millijansky radio sources. These data have been used to examine the evolution of the radio luminosity function (RLF) and its high-redshift cut-off. New redshifts have been measured for eleven sources, and a further ten upper limits are given. The total number of sources with known redshifts in the sample is now 47 (65%). We calculated broadband photometric redshifts for the remaining one-third of the sample. For the luminosity range probed by the present study (P_1.4 > 10^24.5 W/Hz/sr), we use the V/V_max test to show conclusively that there is a deficit of high-redshift (z > 2-2.5) objects. Comparison with the model RLFs of Dunlop & Peacock (1990) shows that our data can now exclude pure luminosity evolution. Two of the models of DP90, and the RLF deduced by direct binning of the data, both favour a luminosity dependence for the high-redshift cut-off, with lower-luminosity sources (P_1.4 \simeq 10^24 W/Hz/sr) in decline by z \simeq 1-1.5 while higher-luminosity sources (P_1.4 \simeq 10^{25-26} W/Hz/sr) decline in comoving number density beyond z \simeq 2-2.5.Comment: Revised version submitted to MNRAS. 16 pages, 12 figure

Interrupting prolonged sitting with frequent short bouts of light-intensity activity in people with type 1 diabetes improves glycaemic control without increasing hypoglycaemia: The SIT-LESS randomised controlled trial

Aim To examine the impact of interrupting prolonged sitting with frequent short bouts of light-intensity activity on glycaemic control in people with type 1 diabetes (T1D). Materials and Methods In total, 32 inactive adults with T1D [aged 27.9 ± 4.7 years, 15 men, diabetes duration 16.0 ± 6.9 years and glycated haemoglobin 8.4 ± 1.4% (68 ± 2.3 mmol/mol)] underwent two 7-h experimental conditions in a randomised crossover fashion with >7-day washout consisting of: uninterrupted sitting (SIT), or, interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals (SIT-LESS). Standardised mixed-macronutrient meals were administered 3.5 h apart during each condition. Blinded continuous glucose monitoring captured interstitial glucose responses during the 7-h experimental period and for a further 48-h under free-living conditions. Results SIT-LESS reduced total mean glucose (SIT 8.2 ± 2.6 vs. SIT-LESS 6.9 ± 1.7 mmol/L, p = .001) and increased time in range (3.9-10.0 mmol/L) by 13.7% (SIT 71.5 ± 9.5 vs. SIT-LESS 85.1 ± 7.1%, p = .002). Hyperglycaemia (>10.0 mmol/L) was reduced by 15.0% under SIT-LESS (SIT 24.2 ± 10.8 vs. SIT-LESS 9.2 ± 6.4%, p = .002), whereas hypoglycaemia exposure (<3.9 mmol/L) (SIT 4.6 ± 3.0 vs. SIT-LESS 6.0 ± 6.0%, p = .583) was comparable across conditions. SIT-LESS reduced glycaemic variability (coefficient of variation %) by 7.8% across the observation window (p = .021). These findings were consistent when assessing discrete time periods, with SIT-LESS improving experimental and free-living postprandial, whole-day and night-time glycaemic outcomes (p < .05). Conclusions Interrupting prolonged sitting with frequent short bouts of light-intensity activity improves acute postprandial and 48-h glycaemia in adults with T1D. This pragmatic strategy is an efficacious approach to reducing sedentariness and increasing physical activity levels without increasing risk of hypoglycaemia in T1D

Solid-state additive manufacturing for metallized optical fiber integration

The formation of smart, Metal Matrix Composite (MMC) structures through the use of solid-state Ultrasonic Additive Manufacturing (UAM) is currently hindered by the fragility of uncoated optical fibers under the required processing conditions. In this work, optical fibers equipped with metallic coatings were fully integrated into solid Aluminum matrices using processing parameter levels not previously possible. The mechanical performance of the resulting manufactured composite structure, as well as the functionality of the integrated fibers, was tested. Optical microscopy, Scanning Electron Microscopy (SEM) and Focused Ion Beam (FIB) analysis were used to characterize the interlaminar and fiber/matrix interfaces whilst mechanical peel testing was used to quantify bond strength. Via the integration of metallized optical fibers it was possible to increase the bond density by 20–22%, increase the composite mechanical strength by 12–29% and create a solid state bond between the metal matrix and fiber coating; whilst maintaining full fiber functionality

Observing Supermassive Black Holes across cosmic time: from phenomenology to physics

In the last decade, a combination of high sensitivity, high spatial resolution observations and of coordinated multi-wavelength surveys has revolutionized our view of extra-galactic black hole (BH) astrophysics. We now know that supermassive black holes reside in the nuclei of almost every galaxy, grow over cosmological times by accreting matter, interact and merge with each other, and in the process liberate enormous amounts of energy that influence dramatically the evolution of the surrounding gas and stars, providing a powerful self-regulatory mechanism for galaxy formation. The different energetic phenomena associated to growing black holes and Active Galactic Nuclei (AGN), their cosmological evolution and the observational techniques used to unveil them, are the subject of this chapter. In particular, I will focus my attention on the connection between the theory of high-energy astrophysical processes giving rise to the observed emission in AGN, the observable imprints they leave at different wavelengths, and the methods used to uncover them in a statistically robust way. I will show how such a combined effort of theorists and observers have led us to unveil most of the SMBH growth over a large fraction of the age of the Universe, but that nagging uncertainties remain, preventing us from fully understating the exact role of black holes in the complex process of galaxy and large-scale structure formation, assembly and evolution.Comment: 46 pages, 21 figures. This review article appears as a chapter in the book: "Astrophysical Black Holes", Haardt, F., Gorini, V., Moschella, U and Treves A. (Eds), 2015, Springer International Publishing AG, Cha

Magnetic Field Amplification in Galaxy Clusters and its Simulation

We review the present theoretical and numerical understanding of magnetic field amplification in cosmic large-scale structure, on length scales of galaxy clusters and beyond. Structure formation drives compression and turbulence, which amplify tiny magnetic seed fields to the microGauss values that are observed in the intracluster medium. This process is intimately connected to the properties of turbulence and the microphysics of the intra-cluster medium. Additional roles are played by merger induced shocks that sweep through the intra-cluster medium and motions induced by sloshing cool cores. The accurate simulation of magnetic field amplification in clusters still poses a serious challenge for simulations of cosmological structure formation. We review the current literature on cosmological simulations that include magnetic fields and outline theoretical as well as numerical challenges.Comment: 60 pages, 19 Figure

Horizontal Branch Stars: The Interplay between Observations and Theory, and Insights into the Formation of the Galaxy

We review HB stars in a broad astrophysical context, including both variable and non-variable stars. A reassessment of the Oosterhoff dichotomy is presented, which provides unprecedented detail regarding its origin and systematics. We show that the Oosterhoff dichotomy and the distribution of globular clusters (GCs) in the HB morphology-metallicity plane both exclude, with high statistical significance, the possibility that the Galactic halo may have formed from the accretion of dwarf galaxies resembling present-day Milky Way satellites such as Fornax, Sagittarius, and the LMC. A rediscussion of the second-parameter problem is presented. A technique is proposed to estimate the HB types of extragalactic GCs on the basis of integrated far-UV photometry. The relationship between the absolute V magnitude of the HB at the RR Lyrae level and metallicity, as obtained on the basis of trigonometric parallax measurements for the star RR Lyrae, is also revisited, giving a distance modulus to the LMC of (m-M)_0 = 18.44+/-0.11. RR Lyrae period change rates are studied. Finally, the conductive opacities used in evolutionary calculations of low-mass stars are investigated. [ABRIDGED]Comment: 56 pages, 22 figures. Invited review, to appear in Astrophysics and Space Scienc

Late Ebola virus relapse causing meningoencephalitis: a case report

Background: There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods: A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings: On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation: Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern