Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma.

Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context-dependent fashion. EfnA5 mediates Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide pre-clinical evidence of druggability of the EFNA5 signalling pathway in GBM xenografts overexpressing Bmi1

Chaos in an Exact Relativistic 3-body Self-Gravitating System

We consider the problem of three body motion for a relativistic one-dimensional self-gravitating system. After describing the canonical decomposition of the action, we find an exact expression for the 3-body Hamiltonian, implicitly determined in terms of the four coordinate and momentum degrees of freedom in the system. Non-relativistically these degrees of freedom can be rewritten in terms of a single particle moving in a two-dimensional hexagonal well. We find the exact relativistic generalization of this potential, along with its post-Newtonian approximation. We then specialize to the equal mass case and numerically solve the equations of motion that follow from the Hamiltonian. Working in hexagonal-well coordinates, we obtaining orbits in both the hexagonal and 3-body representations of the system, and plot the Poincare sections as a function of the relativistic energy parameter $\eta$. We find two broad categories of periodic and quasi-periodic motions that we refer to as the annulus and pretzel patterns, as well as a set of chaotic motions that appear in the region of phase-space between these two types. Despite the high degree of non-linearity in the relativistic system, we find that the the global structure of its phase space remains qualitatively the same as its non-relativisitic counterpart for all values of $\eta$ that we could study. However the relativistic system has a weaker symmetry and so its Poincare section develops an asymmetric distortion that increases with increasing $\eta$. For the post-Newtonian system we find that it experiences a KAM breakdown for $\eta \simeq 0.26$: above which the near integrable regions degenerate into chaos.Comment: latex, 65 pages, 36 figures, high-resolution figures available upon reques

Nuclei, Superheavy Nuclei and Hypermatter in a chiral SU(3)-Modell

A model based on chiral SU(3)-symmetry in nonlinear realisation is used for the investigation of nuclei, superheavy nuclei, hypernuclei and multistrange nuclear objects (so called MEMOs). The model works very well in the case of nuclei and hypernuclei with one Lambda-particle and rules out MEMOs. Basic observables which are known for nuclei and hypernuclei are reproduced satisfactorily. The model predicts Z=120 and N=172, 184 and 198 as the next shell closures in the region of superheavy nuclei. The calculations have been performed in self-consistent relativistic mean field approximation assuming spherical symmetry. The parameters were adapted to known nuclei.Comment: 19 pages, 11 figure

Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation

Early adversity, for example poor caregiving, can have profound effects on emotional development. Orphanage rearing, even in the best circumstances, lies outside of the bounds of a species-typical caregiving environment. The long-term effects of this early adversity on the neurobiological development associated with socio-emotional behaviors are not well understood. Seventy-eight children, who include those who have experienced orphanage care and a comparison group, were assessed. Magnetic resonance imaging (MRI) was used to measure volumes of whole brain and limbic structures (e.g. amygdala, hippocampus). Emotion regulation was assessed with an emotional go-nogo paradigm, and anxiety and internalizing behaviors were assessed using the Screen for Child Anxiety Related Emotional Disorders, the Child Behavior Checklist, and a structured clinical interview. Late adoption was associated with larger corrected amygdala volumes, poorer emotion regulation, and increased anxiety. Although more than 50% of the children who experienced orphanage rearing met criteria for a psychiatric disorder, with a third having an anxiety disorder, the group differences observed in amygdala volume were not driven by the presence of an anxiety disorder. The findings are consistent with previous reports describing negative effects of prolonged orphanage care on emotional behavior and with animal models that show long-term changes in the amygdala and emotional behavior following early postnatal stress. These changes in limbic circuitry may underlie residual emotional and social problems experienced by children who have been internationally adopted

Quantum Size Effect transition in percolating nanocomposite films

We report on unique electronic properties in Fe-SiO2 nanocomposite thin films in the vicinity of the percolation threshold. The electronic transport is dominated by quantum corrections to the metallic conduction of the Infinite Cluster (IC). At low temperature, mesoscopic effects revealed on the conductivity, Hall effect experiments and low frequency electrical noise (random telegraph noise and 1/f noise) strongly support the existence of a temperature-induced Quantum Size Effect (QSE) transition in the metallic conduction path. Below a critical temperature related to the geometrical constriction sizes of the IC, the electronic conductivity is mainly governed by active tunnel conductance across barriers in the metallic network. The high 1/f noise level and the random telegraph noise are consistently explained by random potential modulation of the barriers transmittance due to local Coulomb charges. Our results provide evidence that a lowering of the temperature is somehow equivalent to a decrease of the metal fraction in the vicinity of the percolation limit.Comment: 21 pages, 8 figure

Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma

Epigenetic mechanisms which play an essential role in normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC) are also responsible for some of the changes in the glioblastoma (GBM) genome. Here we develop a strategy to compare the epigenetic and transcriptional make-up of primary GBM cells (GIC) with patient-matched expanded potential stem cell (EPSC)-derived NSC (iNSC). Using a comparative analysis of the transcriptome of syngeneic GIC/iNSC pairs, we identify a glycosaminoglycan (GAG)-mediated mechanism of recruitment of regulatory T cells (Tregs) in GBM. Integrated analysis of the transcriptome and DNA methylome of GBM cells identifies druggable target genes and patient-specific prediction of drug response in primary GIC cultures, which is validated in 3D and in vivo models. Taken together, we provide a proof of principle that this experimental pipeline has the potential to identify patient-specific disease mechanisms and druggable targets in GBM

Accounting for the increasing benefits from scarce ecosystems

Governments are catching up with economic theory and practice by increasingly integrating ecosystem service values into national planning processes, including benefitcost analyses of public policies. Such analyses require information not only about today’s benefits from ecosystem services but also on how benefits change over time. We address a key limitation of existing policy guidance, which assumes that benefits from ecosystem services remain unchanged. We provide a practical rule that is grounded in economic theory and evidence-based as a guideline for how benefits change over time: They rise as societies get richer and even more so when ecosystem services are declining. Our proposal will correct a substantial downward bias in currently used estimates of future ecosystem service values. This will help governments to reflect the importance of ecosystems more accurately in benefit-cost analyses and policy decisions they inform

The solution to the Tullock rent-seeking game when R > 2: mixed-strategy equilibria and mean dissipation rates

In Tullock's rent-seeking model, the probability a player wins the game depends on expenditures raised to the power R. We show that a symmetric mixed-strategy Nash equilibrium exists when R>2, and that overdissipation of rents does not arise in any Nash equilibrium. We derive a tight lower bound on the level of rent dissipation that arises in a symmetric equilibrium when the strategy space is discrete, and show that full rent dissipation occurs when the strategy space is continuous. Our results are shown to be consistent with recent experimental evidence on the dissipation of rents. An earlier version of this paper circulated under the title, No, Virginia, There is No Overdissipation of Rents. We are grateful to Dave Furth and Frans van Winden for stimulating conversations, and for comments provided by workshop participants from the CORE-ULB-KUL IUAP project, Purdue University, Pennsylvania State University, Rijksuniversiteit Limburg, and Washington State University. We also thank Max van de Sande Bakhuyzen and Ben Heijdra for useful discussions, and Geert Gielens for computational assistance. An earlier version of the paper was presented at the ESEM 1992 in Brussels and the Mid-West Mathematical Economics Conference in Pittsburgh. All three authors would like to thank CentER for its hospitality during the formative stages of the paper. The second author has also benefited from the financial support of the Katholieke Universitieit Leuven and the Jay N. Ross Young Faculty Scholar Award at Purdue University. The third author benefitted from visiting IGIER where part of the paper was written. The third author also benefitted from grant IUAP 26 of the Belgian Government

Priority for the Worse Off and the Social Cost of Carbon

The social cost of carbon (SCC) is a monetary measure of the harms from carbon emission. Specifically, it is the reduction in current consumption that produces a loss in social welfare equivalent to that caused by the emission of a ton of CO2. The standard approach is to calculate the SCC using a discounted-utilitarian social welfare function (SWF)—one that simply adds up the well-being numbers (utilities) of individuals, as discounted by a weighting factor that decreases with time. The discounted-utilitarian SWF has been criticized both for ignoring the distribution of well-being, and for including an arbitrary preference for earlier generations. Here, we use a prioritarian SWF, with no time-discount factor, to calculate the SCC in the integrated assessment model RICE. Prioritarianism is a well-developed concept in ethics and theoretical welfare economics, but has been, thus far, little used in climate scholarship. The core idea is to give greater weight to well-being changes affecting worse off individuals. We find substantial differences between the discounted-utilitarian and non-discounted prioritarian SCC