The role of the most luminous, obscured AGN in galaxy assembly at z~2

We present HST WFC3 F160W imaging and infrared spectral energy distributions for twelve extremely luminous, obscured AGN at $1.8<z<2.7$, selected via "Hot, Dust Obscured" mid-infrared colors. Their infrared luminosities span $2-15\times10^{13}$L$_{\odot}$, making them among the most luminous objects in the Universe at $z\sim2$. In all cases the infrared emission is consistent with arising at least in most part from AGN activity. The AGN fractional luminosities are higher than those in either sub-millimeter galaxies, or AGN selected via other mid-infrared criteria. Adopting the $G$, M$_{20}$ and $A$ morphological parameters, together with traditional classification boundaries, infers that three quarters of the sample as mergers. Our sample do not, however, show any correlation between the considered morphological parameters and either infrared luminosity or AGN fractional luminosity. Moreover, their asymmetries and effective radii are distributed identically to those of massive galaxies at $z\sim2$. We conclude that our sample is not preferentially associated with mergers, though a significant merger fraction is still plausible. Instead, we propose that our sample are examples of the massive galaxy population at $z\sim2$ that harbor a briefly luminous, "flickering" AGN, and in which the $G$ and M$_{20}$ values have been perturbed, due to either the AGN, and/or the earliest formation stages of a bulge in an inside-out manner. Furthermore, we find that the mass assembly of the central black holes in our sample leads the mass assembly of any bulge component. Finally, we speculate that our sample represent a small fraction of the immediate antecedents of compact star-forming galaxies at $z\sim2$.Comment: ApJ, accepted. Updated to reflect the accepted versio

Radio Jet Feedback and Star Formation in Heavily Obscured Quasars at Redshifts ~0.3-3, I: ALMA Observations

We present ALMA 870 micron (345 GHz) data for 49 high redshift (0.47<z<2.85), luminous (11.7 < log L(bol) (Lsun) < 14.2) radio-powerful AGN, obtained to constrain cool dust emission from starbursts concurrent with highly obscured radiative-mode black hole (BH) accretion in massive galaxies which possess a small radio jet. The sample was selected from WISE with extremely steep (red) mid-infrared (MIR) colors and with compact radio emission from NVSS/FIRST. Twenty-six sources are detected at 870 microns, and we find that the sample has large mid- to far-infrared luminosity ratios consistent with a dominant and highly obscured quasar. The rest-frame 3 GHz radio powers are 24.7 < log P3.0 GHz (W/Hz) < 27.3, and all sources are radio-intermediate or radio-loud. BH mass estimates are 7.7 < log M(BH) (Msun) < 10.2. The rest frame 1-5 um SEDs are very similar to the "Hot DOGs" (Hot Dust Obscured Galaxies), and steeper (redder) than almost any other known extragalactic sources. ISM masses estimated for the ALMA detected sources are 9.9 < log M(ISM) (Msun) < 11.75 assuming a dust temperature of 30K. The cool dust emission is consistent with star formation rates (SFRs) reaching several thousand Msun/yr, depending on the assumed dust temperature, however we cannot rule out the alternative that the AGN powers all the emission in some cases. Our best constrained source has radiative transfer solutions with ~ equal contributions from an obscured AGN and a young (10-15 Myr) compact starburst.Comment: 29 pages, 8 figures. To appear in Astrophysical Journal. Update on Sept 14 to correct the ALMA proposal id. to ADS/JAO.ALMA#2011.0.00397.S and to add a missing acknowledgemen

Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles

B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase

TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients

<p>Abstract</p> <p>Background</p> <p>Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (<it>DR4</it>) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed <it>DR4 </it>mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC.</p> <p>Methods</p> <p>Frequencies of <it>DR4 </it>gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population.</p> <p>Results</p> <p>Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. <it>DR4 </it>variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10⁶ IU/ml vs. 1.81 ± 0.23 × 10⁶ IU/ml, p = 0.049).</p> <p>Conclusions</p> <p>The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.</p

Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics

Circular economy inspired imaginaries for sustainable innovations

In this chapter, Narayan and Tidström draw on the concept of imaginaries to show how Circular Economy (CE) can facilitate values that enable sustainable innovation. Innovation is key for sustainability, however, understanding and implementing sustainable innovation is challenging, and identifying the kind of actions that could direct sustainable innovations is important. The findings of this study indicate that CE-inspired imaginaries enable collaboration and by relating such imaginaries to common and shared social and cultural values, intermediaries could motivate actors into taking actions that contribute to sustainable innovation.fi=vertaisarvioitu|en=peerReviewed