Mechanistic relationship among mutagenicity, skin sensitization, and skin carcinogenicity.

Twenty organic Salmonella mutagens, seven of which (including benzo[a]pyrene) are established skin carcinogens, and one of which (2-chloroethanol) is a well-defined noncarcinogen to skin, have been evaluated for skin-sensitizing activity using the local lymph node assay. The relative mutagenicity of the agents to Salmonella was also established. Fourteen of the chemicals were positive in the local lymph node assay, including the seven skin carcinogens. 2-Chloroethanol was inactive as a sensitizing agent. We suggest that a variety of factors contributes to the lack of sensitizing activity of the remaining six bacterial mutagens: extremes of intrinsic chemical reactivity, high water solubility reducing dermal translocation, and inappropriate dermal metabolism. Two reference skin-sensitizing agents (an oxazolinone and fluorescein isothiocyanate) were established as in vitro clastogens after their recognition as nonmutagens to Salmonella. These data imply that mutagenicity, rather than simply activity in the Salmonella assay, is a primary stimulus for electrophilic sensitization and carcinogenic initiation in the skin. We conclude that genotoxicity data for an agent can provide indications of the agent's potential to induce skin sensitization and that genotoxins which are skin-sensitizing agents have an enhanced potential to initiate skin carcinogenesis. We suggest that common, albeit individually distinct, structure-activity relationships underpin genotoxicity, skin sensitization, and the initiation of skin carcinogenesis. These relationships should simplify the hazard evaluation of chemicals and contribute to a reduction in animal usage. Several predictions of skin carcinogenicity are made based on the data presented

Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

MHO1, an Evolutionarily Conserved Gene, Is Synthetic Lethal with PLC1; Mho1p Has a Role in Invasive Growth

The novel protein Memo (Mediator of ErbB2 driven cell motility) was identified in a screen for ErbB2 interacting proteins and found to have an essential function in cell motility. Memo is evolutionarily conserved with homologs found in all branches of life; the human and yeast proteins have a similarity of >50%. In the present study we used the model organism S. cerevisiae to characterize the Memo-homologue Mho1 (Yjr008wp) and to investigate its function in yeast. In a synthetic lethal screen we found MHO1 as a novel synthetic lethal partner of PLC1, which encodes the single phospholipase C in yeast. Double-deleted cells lacking MHO1 and PLC1, proliferate for up to ten generations. Introduction of human Memo into the memoΔplc1Δ strain rescued the synthetic lethal phenotype suggesting that yeast and human proteins have similar functions. Mho1 is present in the cytoplasm and the nucleus of yeast cells; the same distribution of Memo was found in mammalian cells. None of the Memo homologues have a characteristic nuclear localization sequence, however, a conserved nuclear export sequence is found in all. In mammalian cells, blocking nuclear export with Leptomycin B led to nuclear Memo accumulation, suggesting that it is actively exported from the nucleus. In yeast MHO1 expression is induced by stress conditions. Since invasive growth in S. cerevisiea is also stress-induced, we tested Mho1's role in this response. MHO1 deletion had no effect on invasion induced by nutrient deprivation, however, Mho1 overexpression blocked the invasive ability of yeast cells, suggesting that Mho1 might be acting in a dominant negative manner. Taken together, our results show that MHO1 is a novel synthetic lethal interactor with PLC1, and that both gene products are required for proliferation. Moreover, a role for Memo in cell motility/invasion appears to be conserved across species

The diversity-generating benefits of a prokaryotic adaptive immune system

Published onlineJOURNAL ARTICLEProkaryotic CRISPR-Cas adaptive immune systems insert spacers derived from viruses and other parasitic DNA elements into CRISPR loci to provide sequence-specific immunity. This frequently results in high within-population spacer diversity, but it is unclear if and why this is important. Here we show that, as a result of this spacer diversity, viruses can no longer evolve to overcome CRISPR-Cas by point mutation, which results in rapid virus extinction. This effect arises from synergy between spacer diversity and the high specificity of infection, which greatly increases overall population resistance. We propose that the resulting short-lived nature of CRISPR-dependent bacteria-virus coevolution has provided strong selection for the evolution of sophisticated virus-encoded anti-CRISPR mechanisms.S.v.H. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 660039. E.R.W. received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under Research Executive Agency grant agreement number 327606. E.R.W., A.B. and M.B. also acknowledge the Natural Environment Research Council, the Biotechnology and Biological Sciences Research Council, the Royal Society, the Leverhulme Trust, the Wellcome Trust and the AXA research fund for funding. J.M.B.-D. was supported by the University of California San Francisco Program for Breakthrough in Biomedical Research, the Sandler Foundation, and a National Institutes of Health Director’s Early Independence Award (DP5-OD021344). H.C. was funded by the Erasmus+ programme (European Union), the Explora’Sup programme (Région Rhône-Alpes) and the Centre Régional des Œuvres Universitaires et Scolaires (CROUS; French State)

Of monkeys and men:Impatience in perceptual decision-making

For decades sequential sampling models have successfully accounted for human and monkey decision-making, relying on the standard assumption that decision makers maintain a pre-set decision standard throughout the decision process. Based on the theoretical argument of reward rate maximization, some authors have recently suggested that decision makers become increasingly impatient as time passes and therefore lower their decision standard. Indeed, a number of studies show that computational models with an impatience component provide a good fit to human and monkey decision behavior. However, many of these studies lack quantitative model comparisons and systematic manipulations of rewards. Moreover, the often-cited evidence from single-cell recordings is not unequivocal and complimentary data from human subjects is largely missing. We conclude that, despite some enthusiastic calls for the abandonment of the standard model, the idea of an impatience component has yet to be fully established; we suggest a number of recently developed tools that will help bring the debate to a conclusive settlement

Mood and cognition in healthy older European adults: the Zenith study

YesBackground: The study aim was to determine if state and trait intra-individual measures of everyday affect predict cognitive functioning in healthy older community dwelling European adults (n = 387), aged 55-87 years. Methods: Participants were recruited from centres in France, Italy and Northern Ireland. Trait level and variability in positive and negative affect (PA and NA) were assessed using self-administered PANAS scales, four times a day for four days. State mood was assessed by one PANAS scale prior to assessment of recognition memory, spatial working memory, reaction time and sustained attention using the CANTAB computerized test battery. Results: A series of hierarchical regression analyses were carried out, one for each measure of cognitive function as the dependent variable, and socio-demographic variables (age, sex and social class), state and trait mood measures as the predictors. State PA and NA were both predictive of spatial working memory prior to looking at the contribution of trait mood. Trait PA and its variability were predictive of sustained attention. In the final step of the regression analyses, trait PA variability predicted greater sustained attention, whereas state NA predicted fewer spatial working memory errors, accounting for a very small percentage of the variance (1-2%) in the respective tests. Conclusion: Moods, by and large, have a small transient effect on cognition in this older sample

Incremental grouping of image elements in vision

One important task for the visual system is to group image elements that belong to an object and to segregate them from other objects and the background. We here present an incremental grouping theory (IGT) that addresses the role of object-based attention in perceptual grouping at a psychological level and, at the same time, outlines the mechanisms for grouping at the neurophysiological level. The IGT proposes that there are two processes for perceptual grouping. The first process is base grouping and relies on neurons that are tuned to feature conjunctions. Base grouping is fast and occurs in parallel across the visual scene, but not all possible feature conjunctions can be coded as base groupings. If there are no neurons tuned to the relevant feature conjunctions, a second process called incremental grouping comes into play. Incremental grouping is a time-consuming and capacity-limited process that requires the gradual spread of enhanced neuronal activity across the representation of an object in the visual cortex. The spread of enhanced neuronal activity corresponds to the labeling of image elements with object-based attention