An oncogenic role for sphingosine kinase 2

While both human sphingosine kinases (SK1 and SK2) catalyze the generation of the pleiotropic signaling lipid sphingosine 1-phosphate, these enzymes appear to be functionally distinct. SK1 has well described roles in promoting cell survival, proliferation and neoplastic transformation. The roles of SK2, and its contribution to cancer, however, are much less clear. Some studies have suggested an antiproliferative/ pro-apoptotic function for SK2, while others indicate it has a prosurvival role and its inhibition can have anti-cancer effects. Our analysis of gene expression data revealed that SK2 is upregulated in many human cancers, but only to a small extent (up to 2.5-fold over normal tissue). Based on these findings, we examined the effect of different levels of cellular SK2 and showed that high-level overexpression reduced cell proliferation and survival, and increased cellular ceramide levels. In contrast, however, low-level SK2 overexpression promoted cell survival and proliferation, and induced neoplastic transformation in vivo. These findings coincided with decreased nuclear localization and increased plasma membrane localization of SK2, as well as increases in extracellular S1P formation. Hence, we have shown for the first time that SK2 can have a direct role in promoting oncogenesis, supporting the use of SK2-specific inhibitors as anti-cancer agents.Heidi A. Neubauer, Duyen H. Pham, Julia R. Zebol, Paul A.B. Moretti, Amanda L. Peterson, Tamara M. Leclercq, Huasheng Chan, Jason A. Powell, Melissa R. Pitman, Michael S. Samuel, Claudine S. Bonder, Darren J. Creek, Briony L. Gliddon and Stuart M. Pitso

A novel tumor-based epithelial-to-mesenchymal transition score that associates with prognosis and metastasis in patients with stage II/III colorectal cancer

It is increasingly appreciated that host factors within the tumor center and microenvironment play a key role in dictating colorectal cancer (CRC) outcomes. As a result, the metastatic process has now been defined as a result of epithelial–mesenchymal transition (EMT). Establishment of the role of EMT within the tumor center and its effect on the tumor microenvironment would be beneficial for prognosis and therapeutic intervention in CRC. The present study assessed five immunohistochemical EMT markers within the tumor center on a 185 Stage II/III CRC patient tissue microarray. In 185 patients with CRC, cytoplasmic snail (HR 1.94 95% confidence interval [CI] 1.15–3.29, p = 0.012) and a novel combined EMT score (HR 3.86 95% CI 2.17–6.86, p < 0.001) were associated with decreased cancer‐specific survival. The combined EMT score was also associated with increased tumor budding (p = 0.046), and systemic inflammation (p = 0.007), as well as decreased memory T‐cells within the stroma (p = 0.030) and at the invasive margin (p = 0.035). Furthermore, the combined EMT score was associated with cancer‐specific survival independent of TNM‐stage (HR 4.12 95% CI 2.30–7.39, p < 0.001). In conclusion, a novel combined EMT score stratifies patient's survival in Stage II/III CRC and associates with key factors of tumor metastasis. Therefore, the combined EMT score could be used to identify patients at risk of micrometastases and who may benefit from standard adjuvant therapy, potentially in combination with EMT blockade

Simulation techniques for cosmological simulations

Modern cosmological observations allow us to study in great detail the evolution and history of the large scale structure hierarchy. The fundamental problem of accurate constraints on the cosmological parameters, within a given cosmological model, requires precise modelling of the observed structure. In this paper we briefly review the current most effective techniques of large scale structure simulations, emphasising both their advantages and shortcomings. Starting with basics of the direct N-body simulations appropriate to modelling cold dark matter evolution, we then discuss the direct-sum technique GRAPE, particle-mesh (PM) and hybrid methods, combining the PM and the tree algorithms. Simulations of baryonic matter in the Universe often use hydrodynamic codes based on both particle methods that discretise mass, and grid-based methods. We briefly describe Eulerian grid methods, and also some variants of Lagrangian smoothed particle hydrodynamics (SPH) methods.Comment: 42 pages, 16 figures, accepted for publication in Space Science Reviews, special issue "Clusters of galaxies: beyond the thermal view", Editor J.S. Kaastra, Chapter 12; work done by an international team at the International Space Science Institute (ISSI), Bern, organised by J.S. Kaastra, A.M. Bykov, S. Schindler & J.A.M. Bleeke

The UK Centre for Astrobiology:A Virtual Astrobiology Centre. Accomplishments and Lessons Learned, 2011-2016

Authors thank all those individuals, UK research councils, funding agencies, nonprofit organisations, companies and corporations and UK and non-UK government agencies, who have so generously supported our aspirations and hopes over the last 5 years and supported UKCA projects. They include the STFC, the Engineering and Physical Sciences Research Council (EPSRC), the Natural Environmental Research Council (NERC), the EU, the UK Space Agency, NASA, the European Space Agency (ESA), The Crown Estate, Cleveland Potash and others. The Astrobiology Academy has been supported by the UK Space Agency (UKSA), National Space Centre, the Science and Technology Facilities Council (STFC), Dynamic Earth, The Royal Astronomical Society, The Rotary Club (Shetlands) and the NASA Astrobiology Institute.The UK Centre for Astrobiology (UKCA) was set up in 2011 as a virtual center to contribute to astrobiology research, education, and outreach. After 5 years, we describe this center and its work in each of these areas. Its research has focused on studying life in extreme environments, the limits of life on Earth, and implications for habitability elsewhere. Among its research infrastructure projects, UKCA has assembled an underground astrobiology laboratory that has hosted a deep subsurface planetary analog program, and it has developed new flow-through systems to study extraterrestrial aqueous environments. UKCA has used this research backdrop to develop education programs in astrobiology, including a massive open online course in astrobiology that has attracted over 120,000 students, a teacher training program, and an initiative to take astrobiology into prisons. In this paper, we review these activities and others with a particular focus on providing lessons to others who may consider setting up an astrobiology center, institute, or science facility. We discuss experience in integrating astrobiology research into teaching and education activities.Publisher PDFPeer reviewe

Charged-Particle Multiplicities in Charged-Current Neutrino-- and Anti-Neutrino--Nucleus Interactions

The CHORUS experiment, designed to search for $\nu_{\mu}\to\nu_{\tau}$ oscillations, consists of a nuclear emulsion target and electronic detectors. In this paper, results on the production of charged particles in a small sample of charged-current neutrino-- and anti-neutrino--nucleus interactions at high energy are presented. For each event, the emission angle and the ionization features of the charged particles produced in the interaction are recorded, while the standard kinematic variables are reconstructed using the electronic detectors. The average multiplicities for charged tracks, the pseudo-rapidity distributions, the dispersion in the multiplicity of charged particles and the KNO scaling are studied in different kinematical regions. A study of quasi-elastic topologies performed for the first time in nuclear emulsions is also reported. The results are presented in a form suitable for use in the validation of Monte Carlo generators of neutrino--nucleus interactions.Comment: 17 pages, 5 figure

Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma

While the two mammalian sphingosine kinases, SK1 and SK2, both catalyze the generation of pro-survival sphingosine 1-phosphate (S1P), their roles vary dependent on their different subcellular localization. SK1 is generally found in the cytoplasm or at the plasma membrane where it can promote cell proliferation and survival. SK2 can be present at the plasma membrane where it appears to have a similar function to SK1, but can also be localized to the nucleus, endoplasmic reticulum or mitochondria where it mediates cell death. Although SK2 has been implicated in cancer initiation and progression, the mechanisms regulating SK2 subcellular localization are undefined. Here, we report that SK2 interacts with the intermediate chain subunits of the retrograde-directed transport motor complex, cytoplasmic dynein 1 (DYNC1I1 and -2), and we show that this interaction, particularly with DYNC1I1, facilitates the transport of SK2 away from the plasma membrane. DYNC1I1 is dramatically downregulated in patient samples of glioblastoma (GBM), where lower expression of DYNC1I1 correlates with poorer patient survival. Notably, low DYNC1I1 expression in GBM cells coincided with more SK2 localized to the plasma membrane, where it has been recently implicated in oncogenesis. Re-expression of DYNC1I1 reduced plasma membrane-localized SK2 and extracellular S1P formation, and decreased GBM tumor growth and tumor-associated angiogenesis in vivo. Consistent with this, chemical inhibition of SK2 reduced the viability of patient-derived GBM cells in vitro and decreased GBM tumor growth in vivo. Thus, these findings demonstrate a tumor-suppressive function of DYNC1I1, and uncover new mechanistic insights into SK2 regulation which may have implications in targeting this enzyme as a therapeutic strategy in GBM.Heidi A. Neubauer, Melinda N. Tea, Julia R. Zebol, Briony L. Gliddon, Cassandra Stefanidis, Paul A.B. Moretti, Melissa R. Pitman, Maurizio Costabile, Jasreen Kular, Brett W. Stringer, Bryan W. Day, Michael S. Samuel, Claudine S. Bonder, Jason A. Powell, Stuart M. Pitso

BASS XXXVII: the role of radiative feedback in the growth and obscuration properties of nearby supermassive black holes

Galaxie

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele