Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication

Early tumorigenesis is associated with the engagement of the DNA-damage checkpoint response (DDR). Cell proliferation and transformation induced by oncogene activation are restrained by cellular senescence. It is unclear whether DDR activation and oncogene-induced senescence (OIS) are causally linked. Here we show that senescence, triggered by the expression of an activated oncogene (H-RasV12) in normal human cells, is a consequence of the activation of a robust DDR. Experimental inactivation of DDR abrogates OIS and promotes cell transformation. DDR and OIS are established after a hyper-replicative phase occurring immediately after oncogene expression. Senescent cells arrest with partly replicated DNA and with DNA replication origins having fired multiple times. In vivo DNA labelling and molecular DNA combing reveal that oncogene activation leads to augmented numbers of active replicons and to alterations in DNA replication fork progression. We also show that oncogene expression does not trigger a DDR in the absence of DNA replication. Last, we show that oncogene activation is associated with DDR activation in a mouse model in vivo. We propose that OIS results from the enforcement of a DDR triggered by oncogene-induced DNA hyper-replication.     

Golgi maturation visualized in living yeast

The Golgi apparatus is composed of biochemically distinct early (cis, medial) and late (trans, TGN) cisternae. There is debate about the nature of these cisternae. The stable compartments model predicts that each cisterna is a long-lived structure that retains a characteristic set of Golgi-resident proteins. In this view, secretory cargo proteins are transported by vesicles from one cisterna to the next. The cisternal maturation model predicts that each cisterna is a transient structure that matures from early to late by acquiring and then losing specific Golgi-resident proteins. In this view, secretory cargo proteins traverse the Golgi by remaining within the maturing cisternae. Various observations have been interpreted as supporting one or the other mechanism. Here we provide a direct test of the two models using three-dimensional time-lapse fluorescence microscopy of the yeast Saccharomyces cerevisiae. This approach reveals that individual cisternae mature, and do so at a consistent rate. In parallel, we used pulse-chase analysis to measure the transport of two secretory cargo proteins. The rate of cisternal maturation matches the rate of protein transport through the secretory pathway, suggesting that cisternal maturation can account for the kinetics of secretory traffic.     

Identifying Expensive Trades by Monitoring the Limit Order Book

This paper provides an analysis of the impact of microstructure variables on the transaction costs for split orders on 171 Euronext large cap stocks. First, using the adaptive Lasso selection method, we conduct an exploratory study to identify which microstructure variables best explain the transaction costs of split orders. Then, we propose an ordinal logistic model to classify ex ante transaction costs into buckets. Our empirical work demonstrates that our model performs very well both in‐sample and out‐of‐sample. All the findings show that microstructure information is of great importance for any investor who attempts to manage the execution of split orders throughout the day. Copyright © 2016 John Wiley & Sons, Ltd.     

The diffusion of scientific innovations: A role typology

How do scientific innovations spread within and across scientific communities? In this paper, we propose a general account of the diffusion of scientific innovations. This account acknowledges that novel ideas must be elaborated on and conceptually translated before they can be adopted and applied to field-specific problems. We motivate our account by examining an exemplary case of knowledge diffusion, namely, the early spread of theories of rational decision-making. These theories were grounded in a set of novel mathematical tools and concepts that originated in John von Neumann and Oskar Morgenstern's Theory of Games and Economic Behavior (1944/1947) and subsequently spread widely across the social and behavioral sciences. Introducing a network-based diffusion measure, we trace the spread of those tools and concepts into distinct research areas. We furthermore present an analytically tractable typology for classifying publications according to their roles in the diffusion process. The proposed framework allows for a systematic examination of the conditions under which scientific innovations spread within and across preexisting and newly emerging scientific communities.     

Humpback chub ( Gila cypha ) in the Yampa and Green rivers, Dinosaur National Monument, with observations on roundtail chub ( G. robusta ) and other sympatric fishes

We evaluated distribution, habitat use, spawning, and species associations of the endangered humpback chub ( Gila cypha ) in the Yampa and Green rivers, Dinosaur National Monument, from 1986 to 1989. Adult and juvenile humpback chub were captured in high-gradient reaches of Yampa and Whirlpool canyons where they were rare ( n = 133, G. robusta ) were widely distributed in eddies, pools, runs, and riffles. Humpback chub ( n = 39) and roundtail chub ( n = 242) in reproductive condition were sympatric in eddy habitats during the 5-6 week period following highest spring runoff. River temperatures at this time averaged about 20 C. Nonnative channel catfish ( Ictalurus punctatus ) were abundant in eddies yielding humpback and roundtail chubs, suggesting a potential for negative interactions between the native and introduced fishes.     

Arbuscular mycorrhizae in thermal-influenced soils in Yellowstone National Park

Mycorrhizae are common plant-fungal symbioses occurring in most land plants. Despite their ubiquity, little is known about the distribution of arbuscular mycorrhizae (AM) in extreme environments. We surveyed for the presence of AM in thermal sites in Yellowstone National Park (YNP) where soils are characterized by extreme pHs, elevated temperatures, and toxic element concentrations. Plants at 5 sites, growing in soils with rooting-zone temperatures up to 48°C and soil pH values as low as 3.4, were mycorrhizal (colonization levels from 4% to 34%). Soils from a sparsely vegetated thermal area and an adjacent, continuously vegetated transition area differed significantly in rooting-zone temperature (35°C vs. 26°C), acidity (pH 3.8 vs. 5.4), electrical conductivity (2.22 vs. 0.49 mmhos cm -1 ), Fe (181.3 vs. 48.5 mg kg -1 ),Mn (7.2 vs. 98.2 mg kg -1 ), and Zn (2.3 vs. 4.5 mg kg -1 ). Mycorrhizal infectivity potential (MIP) was 77% greater in the transition soils, with colonization levels of 26% and 46% in thermal and transition soils, respectively. Furthermore, colonization of Agrostis scabra , Dichanthelium lanuginosum , and Mimulus guttatus was found to be consistently high throughout the growing season (from 48% to 72%). It is possible that AM are essential for plant life on the edge of thermal areas, and that either or both symbionts are specifically adapted to their environment. Further research is required to elucidate AM function in and specific adaptations to YNP's thermal areas.     

Control of signaling molecule range during developmental patterning

Tissue patterning, through the concerted activity of a small number of signaling pathways, is critical to embryonic development. While patterning can involve signaling between neighbouring cells, in other contexts signals act over greater distances by traversing complex cellular landscapes to instruct the fate of distant cells. In this review, we explore different strategies adopted by cells to modulate signaling molecule range to allow correct patterning. We describe mechanisms for restricting signaling range and highlight how such short-range signaling can be exploited to not only control the fate of adjacent cells, but also to generate graded signaling within a field of cells. Other strategies include modulation of signaling molecule action by tissue architectural properties and the use of cellular membranous structures, such as signaling filopodia and exosomes, to actively deliver signaling ligands to target cells. Signaling filopodia can also be deployed to reach out and collect particular signals, thereby precisely controlling their site of action.     

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints.     

MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer

Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.     

Non-mitochondrial complex I proteins in a hydrogenosomal oxidoreductase complex

Trichomonas vaginalis is a unicellular microaerophilic eukaryote that lacks mitochondria yet contains an alternative organelle, the hydrogenosome, involved in pyruvate metabolism. Pathways between the two organelles differ substantially: in hydrogenosomes, pyruvate oxidation is catalysed by pyruvate:ferredoxin oxidoreductase (PFOR), with electrons donated to an [Fe]-hydrogenase which produces hydrogen. ATP is generated exclusively by substrate-level phosphorylation in hydrogenosomes, as opposed to oxidative phosphorylation in mitochondria. PFOR and hydrogenase are found in eubacteria and amitochondriate eukaryotes, but not in typical mitochondria. Analyses of mitochondrial genomes indicate that mitochondria have a single endosymbiotic origin from an alpha-proteobacterial-type progenitor. The absence of a genome in trichomonad hydrogenosomes precludes such comparisons, leaving the endosymbiotic history of this organelle unclear. Although phylogenetic reconstructions of a few proteins indicate that trichomonad hydrogenosomes share a common origin with mitochondria, others do not. Here we describe a novel NADH dehydrogenase module of respiratory complex I that is coupled to the central hydrogenosomal fermentative pathway to form a hydrogenosomal oxidoreductase complex that seems to function independently of quinones. Phylogenetic analyses of hydrogenosomal complex I-like proteins Ndh51 and Ndh24 reveal that neither has a common origin with mitochondrial homologues. These studies argue against a vertical origin of trichomonad hydrogenosomes from the proto-mitochondrial endosymbiont.