Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Lofar low-band antenna observations of the 3C 295 and boötes fields : Source counts and ultra-steep spectrum sources

© 2018 The American Astronomical Society. All rights reserved.We present Low Frequency Array (LOFAR) Low Band observations of the Boötes and 3C 295 fields. Our images made at 34, 46, and 62 MHz reach noise levels of 12, 8, and 5 mJy beam-1, making them the deepest images ever obtained in this frequency range. In total, we detect between 300 and 400 sources in each of these images, covering an area of 17-52 deg2. From the observations, we derive Euclidean-normalized differential source counts. The 62 MHz source counts agree with previous GMRT 153 MHz and Very Large Array 74 MHz differential source counts, scaling with a spectral index of -0.7. We find that a spectral index scaling of -0.5 is required to match up the LOFAR 34 MHz source counts. This result is also in agreement with source counts from the 38 MHz 8C survey, indicating that the average spectral index of radio sources flattens toward lower frequencies. We also find evidence for spectral flattening using the individual flux measurements of sources between 34 and 1400 MHz and by calculating the spectral index averaged over the source population. To select ultra-steep spectrum (α < -1.1) radio sources that could be associated with massive high-redshift radio galaxies, we compute spectral indices between 62 MHz, 153 MHz, and 1.4 GHz for sources in the Boötes field. We cross-correlate these radio sources with optical and infrared catalogs and fit the spectral energy distribution to obtain photometric redshifts. We find that most of these ultra-steep spectrum sources are located in the 0.7 ≲ z ≲ 2.5 range.Peer reviewe

Optimized Trigger for Ultra-High-Energy Cosmic-Ray and Neutrino Observations with the Low Frequency Radio Array

When an ultra-high energy neutrino or cosmic ray strikes the Lunar surface a radio-frequency pulse is emitted. We plan to use the LOFAR radio telescope to detect these pulses. In this work we propose an efficient trigger implementation for LOFAR optimized for the observation of short radio pulses.Comment: Submitted to Nuclear Instruments and Methods in Physics Research Section

First LOFAR observations at very low frequencies of cluster-scale non-thermal emission: the case of Abell 2256

Abell 2256 is one of the best known examples of a galaxy cluster hosting large-scale diffuse radio emission that is unrelated to individual galaxies. It contains both a giant radio halo and a relic, as well as a number of head-tail sources and smaller diffuse steep-spectrum radio sources. The origin of radio halos and relics is still being debated, but over the last years it has become clear that the presence of these radio sources is closely related to galaxy cluster merger events. Here we present the results from the first LOFAR Low band antenna (LBA) observations of Abell 2256 between 18 and 67 MHz. To our knowledge, the image presented in this paper at 63 MHz is the deepest ever obtained at frequencies below 100 MHz in general. Both the radio halo and the giant relic are detected in the image at 63 MHz, and the diffuse radio emission remains visible at frequencies as low as 20 MHz. The observations confirm the presence of a previously claimed ultra-steep spectrum source to the west of the cluster center with a spectral index of -2.3 \pm 0.4 between 63 and 153 MHz. The steep spectrum suggests that this source is an old part of a head-tail radio source in the cluster. For the radio relic we find an integrated spectral index of -0.81 \pm 0.03, after removing the flux contribution from the other sources. This is relatively flat which could indicate that the efficiency of particle acceleration at the shock substantially changed in the last \sim 0.1 Gyr due to an increase of the shock Mach number. In an alternative scenario, particles are re-accelerated by some mechanism in the downstream region of the shock, resulting in the relatively flat integrated radio spectrum. In the radio halo region we find indications of low-frequency spectral steepening which may suggest that relativistic particles are accelerated in a rather inhomogeneous turbulent region.Comment: 13 pages, 13 figures, accepted for publication in A\&A on April 12, 201

Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation

The insulin-like growth factor 2 mRNA-binding proteins 1–3 (IGF2BP1-3, also known as IMP1-3) contribute to the regulation of RNAs in a transcriptome-specific context. Global deletion of the mRNA-binding protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2 or IMP2) in mice causes resistance to obesity and fatty liver–induced by a high-fat diet (HFD), whereas liver-specific IMP2 overexpression results in steatosis. To better understand the role of IMP2 in hepatic triglyceride metabolism, here we crossed mice expressing albumin–Cre with mice bearing a floxed Imp2 gene to generate hepatocyte-specific IMP2-knockout (LIMP2KO) mice. Unexpectedly, the livers of LIMP2KO mice fed an HFD accumulated more triglyceride. Although hepatocyte-specific IMP2 deletion did not alter lipogenic gene expression, it substantially decreased levels of the IMP2 client mRNAs encoding carnitine palmitoyltransferase 1A (CPT1A) and peroxisome proliferator–activated receptor α (PPARα). This decrease was associated with their more rapid turnover and accompanied by significantly diminished rates of palmitate oxidation by isolated hepatocytes and liver mitochondria. HFD-fed control and LIMP2KO mice maintained similar glucose tolerance and insulin sensitivity up to 6 months; however, by 6 months, blood glucose and serum triglycerides in the LIMP2KO mice were modestly elevated, but without evidence of liver damage. In conclusion, hepatocyte-specific IMP2 deficiency promotes modest diet-induced fatty liver by impairing fatty acid oxidation through increased degradation of the IMP2 client mRNAs PPARα and CPT1A. This finding indicates that the previously observed marked protection against fatty liver conferred by global IMP2 deficiency in mice is due entirely to their reduced adiposity

Governance and Susceptibility in Conflict Resolution: Possibilities Beyond Control

Governmentality analysis offers a nuanced critique of informal Western conflict resolution by arguing that recently emerged alternatives to adversarial court processes both govern subjects and help to constitute rather than challenge formal regulation. However, this analysis neglects possibilities for transforming governance from within conflict resolution that are suggested by Foucault's contention that there are no relations of power without resistances. To explore this lacuna, I theorise and explore the affective and interpersonal nature of governance in mediation through autoethnographic reflection upon mediation practice, and Levina's insights about the relatedness of selves. The paper argues that two qualitatively different mediator capacities - technical ability and susceptibility - operate in concert to effect liberal governance. Occasionally though, difficulties and failures in mediation practice bring these capacities into tension and reveal the limits of governance. By considering these limits in mediation with Aboriginal Australian people, I argue that the susceptibility of mediator selves contains prospects for mitigating and transforming the very operations of power occurring through conflict resolution. This suggests options for expanded critical thinking about power relations operating through informal processes, and for cultivating a susceptible sensibility to mitigate liberal governance and more ethically respond to difference through conflict resolution

Barriers to Coordination? Examining the Impact of Culture on International Mediation Occurrence and Effectiveness

‘Culture’ features prominently in the literature on international mediation: if belligerents share cultural characteristics, they are likely to have a common understanding and norms. This creates a common identity and makes coordination less costly, which ultimately facilitates mediation occurrence and effectiveness. Surprisingly, existing quantitative research largely neglects any cultural ties the antagonists might share with the mediator. This article addresses this gap by offering one of the first joint analyses of fighting parties’ and mediators’ culture – and the interaction thereof. Based on existing work, a theoretical framework for mediation occurrence and effectiveness is developed and innovative measures for belligerents’ cultural ties and the links to the mediator are used. Contrary to expectations the results suggest that larger cultural distances between antagonists make mediation more likely, while cultural dissimilarities between them and the mediator have the opposite effect. Evidence is also found for a conditional effect between the two culture variables on mediation occurrence

LOFAR discovery of a quiet emission mode in PSR B0823+26

15 pages, 8 figures, 2 tables, accepted for publication in MNRASInternational audiencePSR B0823+26, a 0.53-s radio pulsar, displays a host of emission phenomena over timescales of seconds to (at least) hours, including nulling, subpulse drifting, and mode-changing. Studying pulsars like PSR B0823+26 provides further insight into the relationship between these various emission phenomena and what they might teach us about pulsar magnetospheres. Here we report on the LOFAR discovery that PSR B0823+26 has a weak and sporadically emitting 'quiet' (Q) emission mode that is over 100 times weaker (on average) and has a nulling fraction forty-times greater than that of the more regularly-emitting 'bright' (B) mode. Previously, the pulsar has been undetected in the Q-mode, and was assumed to be nulling continuously. PSR B0823+26 shows a further decrease in average flux just before the transition into the B-mode, and perhaps truly turns off completely at these times. Furthermore, simultaneous observations taken with the LOFAR, Westerbork, Lovell, and Effelsberg telescopes between 110 MHz and 2.7 GHz demonstrate that the transition between the Q-mode and B-mode occurs within one single rotation of the neutron star, and that it is concurrent across the range of frequencies observed

LOFAR MSSS: Detection of a low-frequency radio transient in 400 hrs of monitoring of the North Celestial Pole

We present the results of a four-month campaign searching for low-frequency radio transients near the North Celestial Pole with the Low-Frequency Array (LOFAR), as part of the Multifrequency Snapshot Sky Survey (MSSS). The data were recorded between 2011 December and 2012 April and comprised 2149 11-minute snapshots, each covering 175 deg^2. We have found one convincing candidate astrophysical transient, with a duration of a few minutes and a flux density at 60 MHz of 15-25 Jy. The transient does not repeat and has no obvious optical or high-energy counterpart, as a result of which its nature is unclear. The detection of this event implies a transient rate at 60 MHz of 3.9 (+14.7, -3.7) x 10^-4 day^-1 deg^-2, and a transient surface density of 1.5 x 10^-5 deg^-2, at a 7.9-Jy limiting flux density and ~10-minute time-scale. The campaign data were also searched for transients at a range of other time-scales, from 0.5 to 297 min, which allowed us to place a range of limits on transient rates at 60 MHz as a function of observation duration.Peer reviewedFinal Accepted Versio

Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk

Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk