James B. Macelwane Award: Citation and Acceptance of Robert Keith O'Nions

I have the pleasure to introduce Robert Keith O'Nions, a young man of 34, for the Macelwane Award, not because I have had anything to do with his education and research, but because I was a member of the committee this year, and we both originate from the same country. Keith O'Nions earned his B.Sc. from the University of Nottingham in 1966, traveled to Alberta for a Ph.D. in 1969, became a Postdoctoral Fellow in Oslo during 1970, joined the faculty at Oxford from 1971–1975, and moved to his present home at Columbia University in 1975. When the time came to find a citationist [sic] for him it turned out that his colleagues at Lamont-Doherty, who were the obvious choices, were all at sea—and I admit that this is how I feel when I read some of Keith's papers. In a sense, this makes me well-suited for this introduction, because I cannot spend time explaining his research to you. Instead, I will read to you a couple of paragraphs from his nomination for the award, written by an anonymous friend

Latent Epstein-Barr Virus Can Inhibit Apoptosis in B Cells by Blocking the Induction of NOXA Expression

Latent Epstein-Barr virus (EBV) has been shown to protect Burkitt's lymphoma-derived B cells from apoptosis induced by agents that cause damage to DNA, in the context of mutant p53. This protection requires expression of the latency-associated nuclear proteins EBNA3A and EBNA3C and correlates with their ability to cooperate in the repression of the gene encoding the pro-apoptotic, BH3-only protein BIM. Here we confirm that latent EBV in B cells also inhibits apoptosis induced by two other agents – ionomycin and staurosporine – and show that these act by a distinct pathway that involves a p53-independent increase in expression of another pro-apoptotic, BH3-only protein, NOXA. Analyses employing a variety of B cells infected with naturally occurring EBV or B95.8 EBV-BAC recombinant mutants indicated that the block to NOXA induction does not depend on the well-characterized viral latency-associated genes (EBNAs 1, 2, 3A, 3B, 3C, the LMPs or the EBERs) or expression of BIM. Regulation of NOXA was shown to be at least partly at the level of mRNA and the requirement for NOXA to induce cell death in this context was demonstrated by NOXA-specific shRNA-mediated depletion experiments. Although recombinant EBV with a deletion removing the BHRF1 locus – that encodes the BCL2-homologue BHRF1 and three microRNAs – partially abrogates protection against ionomycin and staurosporine, the deletion has no effect on the EBV-mediated block to NOXA accumulation

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Seismic and geochemical evidence for large-scale mantle upwelling beneath the eastern Atlantic and western and central Europe

Seismic tomography and the isotope geochemistry of Cenozoic volcanic rocks suggest the existence of a large, sheet-like region of upwelling in the upper mantle which extends from the eastern Atlantic Ocean to central Europe and the western Mediterranean. A belt of extension and rifting in the latter two areas appears to lie above the intersection of the centre of the upwelling region with the base of the lithosphere. Lead, strontium and neodymium isotope data for all three regions converge on a restricted composition, inferred to be that of the upwelling mantle

Epstein-Barr Virus Nuclear Antigen 3C Facilitates G1-S Transition by Stabilizing and Enhancing the Function of Cyclin D1

EBNA3C, one of the Epstein-Barr virus (EBV)-encoded latent antigens, is essential for primary B-cell transformation. Cyclin D1, a key regulator of G1 to S phase progression, is tightly associated and aberrantly expressed in numerous human cancers. Previously, EBNA3C was shown to bind to Cyclin D1 in vitro along with Cyclin A and Cyclin E. In the present study, we provide evidence which demonstrates that EBNA3C forms a complex with Cyclin D1 in human cells. Detailed mapping experiments show that a small N-terminal region which lies between amino acids 130–160 of EBNA3C binds to two different sites of Cyclin D1- the N-terminal pRb binding domain (residues 1–50), and C-terminal domain (residues 171–240), known to regulate Cyclin D1 stability. Cyclin D1 is short-lived and ubiquitin-mediated proteasomal degradation has been targeted as a means of therapeutic intervention. Here, we show that EBNA3C stabilizes Cyclin D1 through inhibition of its poly-ubiquitination, and also increases its nuclear localization by blocking GSK3β activity. We further show that EBNA3C enhances the kinase activity of Cyclin D1/CDK6 which enables subsequent ubiquitination and degradation of pRb. EBNA3C together with Cyclin D1-CDK6 complex also efficiently nullifies the inhibitory effect of pRb on cell growth. Moreover, an sh-RNA based strategy for knock-down of both cyclin D1 and EBNA3C genes in EBV transformed lymphoblastoid cell lines (LCLs) shows a significant reduction in cell-growth. Based on these results, we propose that EBNA3C can stabilize as well as enhance the functional activity of Cyclin D1 thereby facilitating the G1-S transition in EBV transformed lymphoblastoid cell lines

Bonsai Trees in Your Head: How the Pavlovian System Sculpts Goal-Directed Choices by Pruning Decision Trees

When planning a series of actions, it is usually infeasible to consider all potential future sequences; instead, one must prune the decision tree. Provably optimal pruning is, however, still computationally ruinous and the specific approximations humans employ remain unknown. We designed a new sequential reinforcement-based task and showed that human subjects adopted a simple pruning strategy: during mental evaluation of a sequence of choices, they curtailed any further evaluation of a sequence as soon as they encountered a large loss. This pruning strategy was Pavlovian: it was reflexively evoked by large losses and persisted even when overwhelmingly counterproductive. It was also evident above and beyond loss aversion. We found that the tendency towards Pavlovian pruning was selectively predicted by the degree to which subjects exhibited sub-clinical mood disturbance, in accordance with theories that ascribe Pavlovian behavioural inhibition, via serotonin, a role in mood disorders. We conclude that Pavlovian behavioural inhibition shapes highly flexible, goal-directed choices in a manner that may be important for theories of decision-making in mood disorders

Neural Responses to Truth Telling and Risk Propensity under Asymmetric Information

This research was supported by the Laureate Institute for Brain Research and the William K. Warren Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.Trust is multi-dimensional because it can be characterized by subjective trust, trust antecedent, and behavioral trust. Previous research has investigated functional brain responses to subjective trust (e.g., a judgment of trustworthiness) or behavioral trust (e.g., decisions to trust) in perfect information, where all relevant information is available to all participants. In contrast, we conducted a novel examination of the patterns of functional brain activity to a trust antecedent, specifically truth telling, in asymmetric information, where one individual has more information than others, with the effect of varying risk propensity. We used functional magnetic resonance imaging (fMRI) and recruited 13 adults, who played the Communication Game, where they served as the “Sender” and chose either truth telling (true advice) or lie telling (false advice) regarding the best payment allocation for their partner. Our behavioral results revealed that subjects with recreational high risk tended to choose true advice. Moreover, fMRI results yielded that the choices of true advice were associated with increased cortical activation in the anterior rostral medial and frontopolar prefrontal cortices, middle frontal cortex, temporoparietal junction, and precuneus. Furthermore, when we specifically evaluated a role of the bilateral amygdala as the region of interest (ROI), decreased amygdala response was associated with high risk propensity, regardless of truth telling or lying. In conclusion, our results have implications for how differential functions of the cortical areas may contribute to the neural processing of truth telling.Yeshttp://www.plosone.org/static/editorial#pee