DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.     

Rapid cloning of high-affinity human monoclonal antibodies against influenza virus

Pre-existing neutralizing antibody provides the first line of defence against pathogens in general. For influenza virus, annual vaccinations are given to maintain protective levels of antibody against the currently circulating strains. Here we report that after booster vaccination there was a rapid and robust influenza-specific IgG+ antibody-secreting plasma cell (ASC) response that peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells. These ASCs could be distinguished from influenza-specific IgG+ memory B cells that peaked 14-21 days after vaccination and averaged 1% of all B cells. Importantly, as much as 80% of ASCs purified at the peak of the response were influenza specific. This ASC response was characterized by a highly restricted B-cell receptor (BCR) repertoire that in some donors was dominated by only a few B-cell clones. This pauci-clonal response, however, showed extensive intraclonal diversification from accumulated somatic mutations. We used the immunoglobulin variable regions isolated from sorted single ASCs to produce over 50 human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains with high affinity. This strategy demonstrates that we can generate multiple high-affinity mAbs from humans within a month after vaccination. The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine. However, we found that most of the influenza-virus-specific mAbs showed the highest affinity for the current vaccine strain. Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination.     

Bridging the Gap Between the Theory and Practices of Stakeholder Participation in Integrated Vulnerability Assessments of Climate Change

In the international climate regime, integrated vulnerability assessments have become the most prominent method of investigating the potential effects of climate change. Vulnerability assessments typically operate on a local to regional level, where it is most likely to inform subsequent decision making. To cope with the inherent complexity of the climate change problem, the corresponding uncertainties and the aim of producing useful and actionable knowledge various degrees of stakeholder participation have become a critical part of participatory integrated vulnerability assessments. The present study relies upon Fiorino’s (Sci Technol Hum Values 15(2):226–243, 1990) heuristic distinctions between the normative, instrumental and substantive rationales of participation, and it investigates two internationally renowned case studies to demonstrate the consequences of the design and conduct of participatory processes. An analysis of the interplay of the purposes and practices of stakeholder integration points to four fundamental challenges of participatory integrated assessments: knowledge integration, interest convergence, causality and representation. At the end two exit options are discussed, which aim to overcome some obstacles of using the concept of participation in the assessment efforts. This paper therefore goes beyond the typical analyses of ways to better organize and steer the process of stakeholder participation and wants to make a contribution to improve future integrated vulnerability assessments of climate change.     

Allee effects and pulsed invasion by the gypsy moth

Biological invasions pose considerable threats to the world's ecosystems and cause substantial economic losses. A prime example is the invasion of the gypsy moth in the United States, for which more than $194 million was spent on management and monitoring between 1985 and 2004 alone. The spread of the gypsy moth across eastern North America is, perhaps, the most thoroughly studied biological invasion in the world, providing a unique opportunity to explore spatiotemporal variability in rates of spread. Here we describe evidence for periodic pulsed invasions, defined as regularly punctuated range expansions interspersed among periods of range stasis. We use a theoretical model with parameter values estimated from long-term monitoring data to show how an interaction between strong Allee effects (negative population growth at low densities) and stratified diffusion (most individuals disperse locally, but a few seed new colonies by long-range movement) can explain the invasion pulses. Our results indicate that suppressing population peaks along range borders might greatly slow invasion.     

Suppression of star formation in early-type galaxies by feedback from supermassive black holes

Detailed high-resolution observations of the innermost regions of nearby galaxies have revealed the presence of supermassive black holes. These black holes may interact with their host galaxies by means of 'feedback' in the form of energy and material jets; this feedback affects the evolution of the host and gives rise to observed relations between the black hole and the host. Here we report observations of the ultraviolet emissions of massive early-type galaxies. We derive an empirical relation for a critical black-hole mass (as a function of velocity dispersion) above which the outflows from these black holes suppress star formation in their hosts by heating and expelling all available cold gas. Supermassive black holes are negligible in mass compared to their hosts but nevertheless seem to play a critical role in the star formation history of galaxies.     

Stream denitrification across biomes and its response to anthropogenic nitrate loading

Anthropogenic addition of bioavailable nitrogen to the biosphere is increasing and terrestrial ecosystems are becoming increasingly nitrogen-saturated, causing more bioavailable nitrogen to enter groundwater and surface waters. Large-scale nitrogen budgets show that an average of about 20-25 per cent of the nitrogen added to the biosphere is exported from rivers to the ocean or inland basins, indicating that substantial sinks for nitrogen must exist in the landscape. Streams and rivers may themselves be important sinks for bioavailable nitrogen owing to their hydrological connections with terrestrial systems, high rates of biological activity, and streambed sediment environments that favour microbial denitrification. Here we present data from nitrogen stable isotope tracer experiments across 72 streams and 8 regions representing several biomes. We show that total biotic uptake and denitrification of nitrate increase with stream nitrate concentration, but that the efficiency of biotic uptake and denitrification declines as concentration increases, reducing the proportion of in-stream nitrate that is removed from transport. Our data suggest that the total uptake of nitrate is related to ecosystem photosynthesis and that denitrification is related to ecosystem respiration. In addition, we use a stream network model to demonstrate that excess nitrate in streams elicits a disproportionate increase in the fraction of nitrate that is exported to receiving waters and reduces the relative role of small versus large streams as nitrate sinks.