AFRP20: New P-Wavespeed Model for the African Mantle Reveals Two Whole-Mantle Plumes Below East Africa and Neoproterozoic Modification of the Tanzania Craton

Africa’s Cenozoic tectonism is often attributed to mantle plumes, particularly below East Africa, but their morphology, number, location, and impact on the African lithosphere are debated. The broad slow wavespeed African Superplume, ubiquitous in large-scale tomographic models, originates below South Africa, reaching the surface somewhere below East Africa. However, whether the diverse East African mantle geochemistry is best reconciled with one heterogeneous upwelling, or current tomographic models lack the resolution to image multiple distinct plumes, remains enigmatic. S-wavespeed tomographic images of Africa are legion, but higher-frequency P-wavespeed whole-mantle models possessing complementary diagnostic capabilities are comparatively lacking. This hinders attempts to disentangle the effects of Cenozoic hotspot tectonism and Pan African (and older) tectonic events on the East African lithosphere. Here we develop a continental-scale P-wave tomographic model capable of resolving structure from upper-to-lower mantle depths using a recently-developed technique to extract absolute arrival-times from noisy, temporary African seismograph deployments. Shallow-mantle wavespeeds are δVP ≈–4% below Ethiopia, but less anomalous (δVP ≥–2%) below other volcanic provinces. The heterogeneous African Superplume reaches the upper mantle below the Kenyan plateau. Below Ethiopia/Afar we image a second sub-vertical slow wavespeed anomaly rooted near the core-mantle boundary outside the African LLVP, meaning multiple disparately sourced whole-mantle plumes may influence East African magmatism. In contrast to other African cratons, wavespeeds below Tanzania are only fast to 90–135km depth. When interpreted alongside Lower Eocene on-craton kimberlites, our results support pervasive metasomatic lithospheric modification caused by subduction during the Neoproterozoic Pan-African orogeny.A. B. and S. C. are funded by the Natural Environment Research Council (NERC) Grant number NE/R010862/1 from PI Cottaar in Cambridge. A. B. was previously funded by the NERC Doctoral Training Partnership: Science and Solutions for a Changing Planet - Grant number NE/L002515/1 at Imperial College. I. B is funded by Natural Environment Research Council Grant number NE/S014136/1

Numerical simulations of the Accretion-Ejection Instability in magnetised accretion disks

The Accretion-Ejection Instability (AEI) described by Tagger & Pellat (1999) is explored numerically using a global 2d model of the inner region of a magnetised accretion disk. The disk is initially currentless but threaded by a vertical magnetic field created by external currents, and frozen in the flow. In agreement with the theory a spiral instability, similar in many ways to those observed in self-gravitating disks, develops when the magnetic field is, within a factor of a few, at equipartition with the disk thermal pressure. Perturbations in the flow build up currents and create a perturbed magnetic field within the disk. The present non-linear simulations give good evidence that such an instability can occur in the inner region of accretion disks, and generate accretion of gas and vertical magnetic flux toward the central object, if the equilibrium radial profiles of density and magnetic flux exceed a critical threshold.Comment: single tar file with GIF figure

Orbital Advection by Interpolation: A Fast and Accurate Numerical Scheme for Super-Fast MHD Flows

In numerical models of thin astrophysical disks that use an Eulerian scheme, gas orbits supersonically through a fixed grid. As a result the time step is sharply limited by the Courant condition. Also, because the mean flow speed with respect to the grid varies with position, the truncation error varies systematically with position. For hydrodynamic (unmagnetized) disks an algorithm called FARGO has been developed that advects the gas along its mean orbit using a separate interpolation substep. This relaxes the constraint imposed by the Courant condition, which now depends only on the peculiar velocity of the gas, and results in a truncation error that is more nearly independent of position. This paper describes a FARGO-like algorithm suitable for evolving magnetized disks. Our method is second order accurate on a smooth flow and preserves the divergence-free constraint to machine precision. The main restriction is that the magnetic field must be discretized on a staggered mesh. We give a detailed description of an implementation of the code and demonstrate that it produces the expected results on linear and nonlinear problems. We also point out how the scheme might be generalized to make the integration of other supersonic/super-fast flows more efficient. Although our scheme reduces the variation of truncation error with position, it does not eliminate it. We show that the residual position dependence leads to characteristic radial variations in the density over long integrations.Comment: 32 pages, 18 figures, accepted for publication in The Astrophysical Journal. Contains an additional appendix providing more details for some of the test problems (to be published as an addendum in the ApJS December 2008, v179n2 issue

The Turbulent Interstellar Medium: Insights and Questions from Numerical Models

"The purpose of numerical models is not numbers but insight." (Hamming) In the spirit of this adage, and of Don Cox's approach to scientific speaking, we discuss the questions that the latest generation of numerical models of the interstellar medium raise, at least for us. The energy source for the interstellar turbulence is still under discussion. We review the argument for supernovae dominating in star forming regions. Magnetorotational instability has been suggested as a way of coupling disk shear to the turbulent flow. Models make evident that the unstable wavelengths are very long compared to thermally unstable wavelengths, with implications for star formation in the outer galaxy and low surface brightness disks. The perennial question of the factors determining the hot gas filling factor in a SN-driven medium remains open, in particular because of the unexpectedly strong turbulent mixing at the boundaries of hot cavities seen in the models. The formation of molecular clouds in the turbulent flow is also poorly understood. Dense regions suitable for cloud formation clearly form even in the absence of self-gravity, although their ultimate evolution remains to be computed.Comment: 9 pages in astro-ph version, four reduced resolution color figures, to be published in How Does the Galaxy Work?, eds. E. J. Alfaro, E. P\'erez, J. Franco (Kluwer, Dordrecht

Modeling the Subsurface Structure of Sunspots

While sunspots are easily observed at the solar surface, determining their subsurface structure is not trivial. There are two main hypotheses for the subsurface structure of sunspots: the monolithic model and the cluster model. Local helioseismology is the only means by which we can investigate subphotospheric structure. However, as current linear inversion techniques do not yet allow helioseismology to probe the internal structure with sufficient confidence to distinguish between the monolith and cluster models, the development of physically realistic sunspot models are a priority for helioseismologists. This is because they are not only important indicators of the variety of physical effects that may influence helioseismic inferences in active regions, but they also enable detailed assessments of the validity of helioseismic interpretations through numerical forward modeling. In this paper, we provide a critical review of the existing sunspot models and an overview of numerical methods employed to model wave propagation through model sunspots. We then carry out an helioseismic analysis of the sunspot in Active Region 9787 and address the serious inconsistencies uncovered by \citeauthor{gizonetal2009}~(\citeyear{gizonetal2009,gizonetal2009a}). We find that this sunspot is most probably associated with a shallow, positive wave-speed perturbation (unlike the traditional two-layer model) and that travel-time measurements are consistent with a horizontal outflow in the surrounding moat.Comment: 73 pages, 19 figures, accepted by Solar Physic

Successful Inhibition of Tumor Development by Specific Class-3 Semaphorins Is Associated with Expression of Appropriate Semaphorin Receptors by Tumor Cells

The class-3 semaphorins (sema3s) include seven family members. Six of them bind to neuropilin-1 (np1) or neuropilin-2 (np2) receptors or to both, while the seventh, sema3E, binds to the plexin-D1 receptor. Sema3B and sema3F were previously characterized as tumor suppressors and as inhibitors of tumor angiogenesis. To determine if additional class-3 semaphorins such as sema3A, sema3D, sema3E and sema3G possess anti-angiogenic and anti-tumorigenic properties, we expressed the recombinant full length semaphorins in four different tumorigenic cell lines expressing different combinations of class-3 semaphorin receptors. We show for the first time that sema3A, sema3D, sema3E and sema3G can function as potent anti-tumorigenic agents. All the semaphorins we examined were also able to reduce the concentration of tumor associated blood vessels although the potencies of the anti-angiogenic effects varied depending on the tumor cell type. Surprisingly, there was little correlation between the ability to inhibit tumor angiogenesis and their anti-tumorigenic activity. None of the semaphorins inhibited the adhesion of the tumor cells to plastic or fibronectin nor did they modulate the proliferation of tumor cells cultured in cell culture dishes. However, various semaphorins were able to inhibit the formation of soft agar colonies from tumor cells expressing appropriate semaphorin receptors, although in this case too the inhibitory effect was not always correlated with the anti-tumorigenic effect. In contrast, the anti-tumorigenic effect of each of the semaphorins correlated very well with tumor cell expression of specific signal transducing receptors for particular semaphorins. This correlation was not broken even in cases in which the tumor cells expressed significant concentrations of endogenous semaphorins. Our results suggest that combinations of different class-3 semaphorins may be more effective than single semaphorins in cases in which tumor cells express more than one type of semaphorin receptors

Characterization of a Human Cell Line Stably Over-Expressing the Candidate Oncogene, Dual Specificity Phosphatase 12

Analysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the "driver" gene(s) within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21-1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6) and the dual specificity phosphatase 12 (dusp12). While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized.To evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over-expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1) which is implicated in metastasis.Collectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer

BACKGROUND: Delta-like ligand 4 (Dll4) is a Notch ligand that is upregulated by hypoxia and vascular endothelial growth factor-A (VEGF-A) and is reported to have a role in tumor angiogenesis. Evidence from xenograft studies suggests that inhibiting Dll4-Notch signalling may overcome resistance to anti-VEGF therapy. The aim of this study was to characterise the expression of Dll4 in colon cancer and to assess whether it is associated with markers of hypoxia and prognosis. METHOD: In all, 177 colon cancers were represented in tissue microarrays. Immunohistochemistry was performed using validated antibodies against Dll4, VEGF, hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and carbonic anhydrase 9 (CA9). RESULTS: The expression of Dll4 was observed preferentially in the endothelium of 71% (125 out of 175) of colon cancers, but not in the endothelium adjacent to normal mucosa (none out of 107, P<0.0001). The expression of VEGF was significantly associated with HIF-2alpha (P<0.0001) and Dll4 (P=0.010). Only HIF-2alpha had a significant multivariate prognostic effect (hazard ratio 1.61, 95% confidence interval 1.01-2.57). Delta-like ligand 4 was also expressed by neoplastic cells, particularly neoplastic goblet cells. CONCLUSION: Endothelial expression of Dll4 is not a prognostic factor, but is significantly associated with VEGF. Assessing endothelial Dll4 expression may be critical in predicting response to anti-VEGF therapies

High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response

Abstract The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. We show here that glioma stem cells (GSCs) express low levels of MKP1, a dual-specificity phosphatase, which acts as a negative inhibitor of JNK, ERK1/2, and p38 MAPK, while induction of high levels of MKP1 expression are associated with differentiation of GSC. Notably, we find that high levels of MKP1 correlate with a subset of glioblastoma patients with better prognosis and overall increased survival. Gain of expression studies demonstrated that elevated MKP1 impairs self-renewal and induces differentiation of GSCs while reducing tumorigenesis in vivo. Moreover, we identified that MKP1 is epigenetically regulated and that it mediates the anti-tumor activity of histone deacetylase inhibitors (HDACIs) alone or in combination with temozolomide. In summary, this study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma

Impact of Anti-Inflammatory Agents on the Gene Expression Profile of Stimulated Human Neutrophils: Unraveling Endogenous Resolution Pathways

Adenosine, prostaglandin E2, or increased intracellular cyclic AMP concentration each elicit potent anti-inflammatory events in human neutrophils by inhibiting functions such as phagocytosis, superoxide production, adhesion and cytokine release. However, the endogenous molecular pathways mediating these actions are poorly understood. In the present study, we examined their impact on the gene expression profile of stimulated neutrophils. Purified blood neutrophils from healthy donors were stimulated with a cocktail of inflammatory agonists in the presence of at least one of the following anti-inflammatory agents: adenosine A2A receptor agonist CGS 21680, prostaglandin E2, cyclic-AMP-elevating compounds forskolin and RO 20-1724. Total RNA was analyzed using gene chips and real-time PCR. Genes encoding transcription factors, enzymes and regulatory proteins, as well as secreted cytokines/chemokines showed differential expression. We identified 15 genes for which the anti-inflammatory agents altered mRNA levels. The agents affected the expression profile in remarkably similar fashion, suggesting a central mechanism limiting cell activation. We have identified a set of genes that may be part of important resolution pathways that interfere with cell activation. Identification of these pathways will improve understanding of the capacity of tissues to terminate inflammatory responses and contribute to the development of therapeutic strategies based on endogenous resolution