Shared and Distinct Functions of the Transcription Factors IRF4 and IRF8 in Myeloid Cell Development

Interferon regulatory factor (IRF) 8 and IRF4 are structurally-related, hematopoietic cell-specific transcription factors that cooperatively regulate the differentiation of dendritic cells and B cells. Whilst in myeloid cells IRF8 is known to modulate growth and differentiation, the role of IRF4 is poorly understood. In this study, we show that IRF4 has activities similar to IRF8 in regulating myeloid cell development. The ectopic expression of IRF4 in myeloid progenitor cells in vitro inhibits cell growth, promotes macrophages, but hinders granulocytic cell differentiation. We also show that IRF4 binds to and activates transcription through the IRF-Ets composite sequence (IECS). Furthermore, we demonstrate that Irf8-/-Irf4-/- mice exhibit a more severe chronic myeloid leukemia (CML)-like disease than Irf8-/- mice, involving a disproportionate expansion of granulocytes at the expense of monocytes/macrophages. Irf4-/- mice, however, display no obvious abnormality in myeloid cell development, presumably because IRF4 is expressed at a much lower level than IRF8 in granulocyte-macrophage progenitors. Our results also suggest that IRF8 and IRF4 have not only common but also specific activities in myeloid cells. Since the expression of both the IRF8 and IRF4 genes is downregulated in CML patients, these results may add to our understanding of CML pathogenesis

ENSO Atmospheric Teleconnections and Their Response to Greenhouse Gas Forcing

This is the final version of the article. Available from AGU via the DOI in this record.El Niño and Southern Oscillation (ENSO) is the most prominent year-to-year climate fluctuation on Earth, alternating between anomalously warm (El Niño) and cold (La Niña) sea surface temperature (SST) conditions in the tropical Pacific. ENSO exerts its impacts on remote regions of the globe through atmospheric teleconnections, affecting extreme weather events worldwide. However, these teleconnections are inherently nonlinear and sensitive to ENSO SST anomaly patterns and amplitudes. In addition, teleconnections are modulated by variability in the oceanic and atmopsheric mean state outside the tropics and by land and sea ice extent. The character of ENSO as well as the ocean mean state have changed since the 1990s, which might be due to either natural variability or anthropogenic forcing, or their combined influences. This has resulted in changes in ENSO atmospheric teleconnections in terms of precipitation and temperature in various parts of the globe. In addition, changes in ENSO teleconnection patterns have affected their predictability and the statistics of extreme events. However, the short observational record does not allow us to clearly distinguish which changes are robust and which are not. Climate models suggest that ENSO teleconnections will change because the mean atmospheric circulation will change due to anthropogenic forcing in the 21st century, which is independent of whether ENSO properties change or not. However, future ENSO teleconnection changes do not currently show strong intermodel agreement from region to region, highlighting the importance of identifying factors that affect uncertainty in future model projections.S. W. Y. is supported by the KoreaMeteorological Administration Researchand Development Program under grant KMIPA2015-2112. Wenju Cai is supported by Earth System and Climate Change Hub of the Australia National Environmental Science Programme, and Centre for Southern Hemisphere Oceans Research, an international collaboration between CSIRO and Qingdao National Laboratory for Marine Sciences and Technology. B. Dewitte acknowledges supports from FONDECYT(1151185) and from LEFE-GMMC. Dietmar Dommenget is supported by ARC Centre of Excellence for Climate System Science (CE110001028)

Ocular Delivery of Compacted DNA-Nanoparticles Does Not Elicit Toxicity in the Mouse Retina

Subretinal delivery of polyethylene glycol-substituted lysine peptide (CK30PEG)-compacted DNA nanoparticles results in efficient gene expression in retinal cells. This work evaluates the ocular safety of compacted DNA nanoparticles. CK30PEG-compacted nanoparticles containing an EGFP expression plasmid were subretinally injected in adult mice (1 µl at 0.3, 1.0 and 3.0 µg/µl). Retinas were examined for signs of inflammation at 1, 2, 4 and 7 days post-injection. Neither infiltration of polymorphonuclear neutrophils or lymphocytes was detected in retinas. In addition, elevation of macrophage marker F4/80 or myeloid marker myeloperoxidase was not detected in the injected eyes. The chemokine KC mRNA increased 3–4 fold in eyes injected with either nanoparticles or saline at 1 day post-injection, but returned to control levels at 2 days post-injection. No elevation of KC protein was observed in these mice. The monocyte chemotactic protein-1, increased 3–4 fold at 1 day post-injection for both nanoparticle and saline injected eyes, but also returned to control levels at 2 days. No elevations of tumor necrosis factor alpha mRNA or protein were detected. These investigations show no signs of local inflammatory responses associated with subretinal injection of compacted DNA nanoparticles, indicating that the retina may be a suitable target for clinical nanoparticle-based interventions

Manipulating the Hype: contemporary art's response to media cliches

Manipulating the Hype addresses art’s reaction to the barrage of signs produced by the media. The paper researches contemporary art’s response to clichéd media stereotypes and elucidates artists’ multifaceted perspective on overtly obvious yet widely embraced paradigms marketed by the media. Contemporary art’s strategic reconfiguration of media stereotypes is a valuable introspection upon the superficiality and impracticability of advertising and entertainment industry constructs. By reconsidering the mediated image, art has the ability to inspire reevaluation of cultural values. The thesis additionally attempts to ascertain the reinterpretation of media stereotypes as a common thread linking principal art movements and historically significant artworks from around the world since 1960. How does contemporary art respond to the extensive cultural influence of the media? Is a reaction to mass media a thematic commonality linking contemporary artists in the age of globalization? Manipulating the Hype is a dual outcome investigation comprised of written thesis and studio practice. The written thesis combines experience from a lengthy professional practice with historical and theoretical research. The visual thesis consists of twelve photographic works taken at on the Big Island of Hawaii. The images juxtapose artificial icons of power from popular culture with the natural force of the active lava flow. The process of research discloses how the advertising and entertainment industries capitalize upon innate human desires through the manipulative proliferation of archetypal imagery. Furthermore, the thesis establishes the widespread retort to media clichés as a palpable commonality in studio practices worldwide. The findings in the research make evident that although contemporary art does not have sufficient influence to reform the media, it can heighten public awareness of media tactics

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201