Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The effect of spatial throughfall pattern on soil moisture patterns at the hillslope scale

Improving the understanding of the controls on subsurface stormflow generation has been the goal of numerous experimental and modeling studies. However, the effect of the spatial variability of throughfall on soil moisture patterns and subsurface stormflow (SSF) generation has not yet been studied in detail. The objectives of this study are threefold: (1) to investigate the influence of a spatially variable throughfall pattern on soil moisture; (2) to investigate if soil moisture patterns reflect a balance between a throughfall and bedrock topography patterns; and (3) to investigate how this balance changes when soil depth, storm size and slope angle are varied. Virtual experiments are used to address these questions. A virtual experiment is a numerical experiment driven by collective field intelligence. It provides a learning tool to investigate the effect of individual processes in a complex system. In our virtual experiment we combined spatial throughfall data from the Huewelerbach catchment in Luxembourg with the topography of a well-studied hillslope within the Panola Mountain Research Watershed, Georgia, USA. We used HYDRUS-3D as a modeling platform. The virtual experiment shows that throughfall patterns influence soil moisture patterns, but only during and shortly after a storm. With a semi-variogram analysis we showed how the effective range of the soil moisture pattern (i.e., the main descriptor of a spatial pattern in case of a small nugget to sill ratio), is similar to the effective range of the throughfall pattern during the storm and gradually returns to the effective range of the bedrock topography after throughfall has ceased. The same analysis was carried out to investigate how this balance changes due to changes in storm size, soil depth and slope. The analysis showed that the throughfall pattern is more important during large storms on gentle slopes. For steeper slopes the bedrock topography becomes more important.Water ManagementCivil Engineering and Geoscience

New technique to measure forest floor interception: An application in a beech forest in Luxembourg

Civil Engineering and Geoscience

Analytical derivation of the Budyko curve based on rainfall characteristics and a simple evaporation model

The Budyko curve is often used to estimate the actual evaporation as a function of the aridity index in a catchment. Different empirical equations exist to describe this relationship; however, these equations have very limited physical background. The model concept presented in this paper is physically based and uses only measurable parameters. It makes use of two types of evaporation: interception and transpiration. It assumes that interception can be modeled as a threshold process on a daily time scale. If multiplied with the rainfall distribution function, integrated, and multiplied with the expected number of rain days per month, the monthly interception is obtained. In a similar way, the monthly interception can be upscaled to annual interception. Analogous to the interception process, transpiration can be modeled as a threshold process at a monthly time scale and can be upscaled by integration and multiplication with the expected number of rain months. The expected rain days permonth are modeled in two ways: as a fixed proportion of the monthly rainfall and as a power function based on Markov properties of rainfall. The latter is solved numerically. It appears that on an annual basis the analytical model does not differ much from the numerical solution. Hence, the analytical model is used and applied on 10 locations in different climates. This paper shows that the empirical Budyko curve can be constructed on the basis of measurable parameters representing evaporation threshold values and the expected number of rain days and rain months and, in addition, a monthly moisture carryover amount for semiarid zones.Water ManagementCivil Engineering and Geoscience

Understanding catchment behavior through stepwise model concept improvement

Lack of data is one of the main limitations for hydrological modeling. However, it is often used as a justification for over simplifying, poorly performing models. If we want to enhance our understanding of hydrological systems, it is important to fully exploit the information contained in the available data, and to learn from model deficiencies. In this paper, we propose a methodology where we systematically update the model structure, progressively incorporating new hypotheses of catchment behavior. We apply this methodology to the Alzette river basin in Luxembourg, showing how stepwise model improvement helps to identify the behavior of this catchment. We show that the most significant improvement of the evolving model structure is associated to the characterization of antecedent wetness. This is improved accounting for interception, which affects vertical storage distribution, and accounting for rainfall spatial heterogeneity, which influences storage variations in the horizontal dimension. Overall, our results suggested that, due to the damping effect of the basin, the description of fast catchment response benefits more from spatially distributed information than that of slow catchment response.Water ManagementCivil Engineering and Geoscience

Inferring catchment precipitation by doing hydrology backward: A test in 24 small and mesoscale catchments in Luxembourg

The complexity of hydrological systems and the necessary simplification of models describing these systems remain major challenges in hydrological modeling. Kirchner's (2009) approach of inferring rainfall and evaporation from discharge fluctuations by “doing hydrology backward” is based on the assumption that catchment behavior can be conceptualized with a single storage-discharge relationship. Here we test Kirchner's approach using a densely instrumented hydrologic measurement network spanning 24 geologically diverse subbasins of the Alzette catchment in Luxembourg. We show that effective rainfall rates inferred from discharge fluctuations generally correlate well with catchment-averaged precipitation radar estimates in catchments ranging from less than 10 to more than 1000 km2 in size. The correlation between predicted and observed effective precipitation was 0.8 or better in 23 of our 24 catchments, and prediction skill did not vary systematically with catchment size or with the complexity of the underlying geology. Model performance improves systematically at higher soil moisture levels, indicating that our study catchments behave more like simple dynamical systems with unambiguous storage-discharge relationships during wet conditions. The overall mean correlation coefficient for all subbasins for the entire data set increases from 0.80 to 0.95, and the mean bias for all basins decreases from –0.61 to –0.35 mm d?1. We propose an extension of Kirchner's approach that uses in situ soil moisture measurements to distinguish wet and dry catchment conditions.Water ManagementCivil Engineering and Geoscience

Bishop Fulton J. Sheen: America’s public critic of psychoanalysis, 1947–1957

This paper examines the role of Bishop Fulton Sheen in the popularization of Freudian psychoanalysis in the United States during the 1940s and 50s. Social historians argue that Freudian ideas were pervasive in American culture during this period. While their claim speaks mainly to the impact of psychoanalysis on the cultural elite and college educated, they also suggest that Freudian ideas affected ordinary men and women. In the former case, the group impacted is small and not representative of the population as a whole; in the latter, the evidence is sparse and impressionistic. Neglected in their consideration is the influence of Fulton Sheen whose opinions on Freud reached an audience of 30,000,000 during the height of the popularity of his TV show, Life is Worth Living. Sheen\u27s audience was more inclusive and representative of mainstream America. The negative and highly cautionary view of psychoanalysis he presented to many Americans was contrary to that which was promoted to and embraced by many of the college educated and likely shaped both their views of Freud and psychoanalytic therapy