Disentangling responses to natural stress and human impact gradients in river ecosystems across Europe

1. Rivers are dynamic ecosystems in which both human impacts and climate-driven drying events are increasingly common. These anthropogenic and natural stress ors interact to influence the biodiversity and functioning of river ecosystems. Disentangling ecological responses to these interacting stressors is necessary to guide management actions that support ecosystems adapting to global change. 2. We analysed the independent and interactive effects of human impacts and natu ral drying on aquatic invertebrate communities—a key biotic group used to assess the health of European freshwaters. We calculated biological response metrics representing communities from 406 rivers in eight European countries: taxonomic richness, functional richness and redundancy, and biomonitoring indices that in dicate ecological status. We analysed metrics based on the whole community and on a group of taxa with traits promoting resistance and/or resilience (‘high RR’) to drying. We also examined how responses vary across Europe in relation to climatic aridity. 3. Most community metrics decreased independently in response to impacts and drying. A richness-independent biomonitoring index (the average score per taxon; ASPT) showed particular potential for use in biomonitoring, and should be consid ered alongside new metrics representing high RR diversity, to promote accurate assessment of ecological status. 4. High RR taxonomic richness responded only to impacts, not drying. However, these predictors explained little variance in richness and other high RR metrics, potentially due to low taxonomic richness. Metric responsiveness could thus be enhanced by developing region-specific high RR groups comprising sufficient taxa with sufficiently variable impact sensitivities to indicate ecological status. 5. Synthesis and applications. Metrics are needed to assess the ecological status of dy namic river ecosystems—including those that sometimes dry—and thus to identify priority sites requiring action to tackle the causes of environmental degradation. Our results inform recommendations guiding the development of such metrics. We propose concurrent use of richness-independent ‘average score per taxon’ in dices and metrics that characterize the richness of resistant and resilient taxa. We observed interactions between aridity, impacts and drying, highlighting that these new metrics should be region specific, river type specific and adaptable, promot ing their ability to inform management actions that protect biodiversity in river ecosystems responding to climate change

The Genome of the Chicken DT40 Bursal Lymphoma Cell Line

The chicken DT40 cell line is a widely used model system in the study of multiple cellular processes due to the efficiency of homologous gene targeting. The cell line was derived from a bursal lymphoma induced by avian leukosis virus infection. In this study we characterized the genome of the cell line using whole genome shotgun sequencing and single nucleotide polymorphism array hybridization. The results indicate that wild-type DT40 has a relatively normal karyotype, except for whole chromosome copy number gains, and no karyotype variability within stocks. In a comparison to two domestic chicken genomes and the Gallus gallus reference genome, we found no unique mutational processes shaping the DT40 genome except for a mild increase in insertion and deletion events, particularly deletions at tandem repeats. We mapped coding sequence mutations that are unique to the DT40 genome; mutations inactivating the PIK3R1 and ATRX genes likely contributed to the oncogenic transformation. In addition to a known avian leukosis virus integration in the MYC gene, we detected further integration sites that are likely to de-regulate gene expression. The new findings support the hypothesis that DT40 is a typical transformed cell line with a relatively intact genome; therefore, it is well-suited to the role of a model system for DNA repair and related processes. The sequence data generated by this study, including a searchable de novo genome assembly and annotated lists of mutated genes, will support future research using this cell line

Disentangling responses to natural stress and human impact gradients in river ecosystems across Europe

Rivers are dynamic ecosystems in which both human impacts and climate-driven drying events are increasingly common. These anthropogenic and natural stress-ors interact to influence the biodiversity and functioning of river ecosystems. Disentangling ecological responses to these interacting stressors is necessary to guide management actions that support ecosystems adapting to global change. We analysed the independent and interactive effects of human impacts and natu-ral drying on aquatic invertebrate communities—a key biotic group used to assess the health of European freshwaters. We calculated biological response metrics representing communities from 406 rivers in eight European countries: taxonomic richness, functional richness and redundancy, and biomonitoring indices that in-dicate ecological status. We analysed metrics based on the whole community and on a group of taxa with traits promoting resistance and/or resilience (‘high RR’) to drying. We also examined how responses vary across Europe in relation to climatic aridity. Most community metrics decreased independently in response to impacts and drying. A richness-independent biomonitoring index (the average score per taxon; ASPT) showed particular potential for use in biomonitoring, and should be consid-ered alongside new metrics representing high RR diversity, to promote accurate assessment of ecological status. High RR taxonomic richness responded only to impacts, not drying. However, these predictors explained little variance in richness and other high RR metrics, potentially due to low taxonomic richness. Metric responsiveness could thus be enhanced by developing region-specific high RR groups comprising sufficient taxa with sufficiently variable impact sensitivities to indicate ecological status.5. Synthesis and applications. Metrics are needed to assess the ecological status of dy-namic river ecosystems—including those that sometimes dry and thus to identify priority sites requiring action to tackle the causes of environmental degradation. Our results inform recommendations guiding the development of such metrics. We propose concurrent use of richness-independent ‘average score per taxon’ indices and metrics that characterize the richness of resistant and resilient taxa. We observed interactions between aridity, impacts and drying, highlighting that these new metrics should be region specific, river type specific and adaptable, promoting their ability to inform management actions that protect biodiversity in river ecosystems responding to climate chang

Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts

Background: Poly-ADP ribose polymerase (PARP) inhibitor-based cancer therapy selectively targets cells with deficient homologous recombination repair. Considering their long-term use in maintenance treatment, any potential mutagenic effect of PARP inhibitor treatment could accelerate the development of resistance or harm non-malignant somatic cells. Methods: We tested the mutagenicity of long-term treatment with the PARP inhibitor niraparib using whole-genome sequencing of cultured cell clones and whole-exome sequencing of patient-derived breast cancer xenografts. Results: We observed no significant increase in the number and alteration in the spectrum of base substitutions, short insertions and deletions and genomic rearrangements upon niraparib treatment of human DLD-1 colon adenocarcinoma cells, wild-type and BRCA1 mutant chicken DT40 lymphoblastoma cells and BRCA1-defective SUM149PT breast carcinoma cells, except for a minor increase in specific deletion classes. We also did not detect any contribution of in vivo niraparib treatment to subclonal mutations arising in breast cancer-derived xenografts. Conclusions: The results suggest that long-term inhibition of DNA repair with PARP inhibitors has no or only limited mutagenic effect. Mutagenesis due to prolonged use of PARP inhibitors in cancer treatment is therefore not expected to contribute to the genetic evolution of resistance, generate significant immunogenic neoepitopes or induce secondary malignancies. © 2018, The Author(s)

DISPERSE, a trait database to assess the dispersal potential of European aquatic macroinvertebrates

Dispersal is an essential process in population and community dynamics, but is difficult to measure in the field. In freshwater ecosystems, information on biological traits related to organisms’ morphology, life history and behaviour provides useful dispersal proxies, but information remains scattered or unpublished for many taxa. We compiled information on multiple dispersal-related biological traits of European aquatic macroinvertebrates in a unique resource, the DISPERSE database. DISPERSE includes nine dispersal-related traits subdivided into 39 trait categories for 480 taxa, including Annelida, Mollusca, Platyhelminthes, and Arthropoda such as Crustacea and Insecta, generally at the genus level. Information within DISPERSE can be used to address fundamental research questions in metapopulation ecology, metacommunity ecology, macroecology and evolutionary ecology. Information on dispersal proxies can be applied to improve predictions of ecological responses to global change, and to inform improvements to biomonitoring, conservation and management strategies. The diverse sources used in DISPERSE complement existing trait databases by providing new information on dispersal traits, most of which would not otherwise be accessible to the scientific community. Measurement(s): dispersal • movement quality • morphological feature • behavioral quality Technology Type(s): digital curation Factor Type(s): taxon Sample Characteristic - Organism: Arthropoda • Mollusca • Annelida Sample Characteristic - Environment: aquatic biome • freshwater biome Sample Characteristic - Location: Europe Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.1314833

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance