Science and health for all children with cancer

Each year approximately 429,000 children and adolescents aged 0-19 years are expected to develop cancer. Five-year survival rates exceed 80% for the 45,000 children with cancer in highincome countries (HIC), but are less than 30% for the 384,000 children in low- and middle-income countries (LMIC). Improved survival rates in HIC have been achieved through multidisciplinary care and research, with treatment regimens utilizing mostly generic medicines and optimized risk stratification. Children’s outcomes in LMIC can be improved by adapting effective treatments to local resources and clinical needs, and addressing common problems such as delayed diagnosis and treatment abandonment. By supporting local leaders to increase service capacity and achieve measurable clinical improvements, collaborative partnerships can stimulate governmental and nongovernmental investments. These approaches should bring the new WHO childhood cancer survival target of 60% within reach of all by 2030

Presymptomatic risk assessment for chronic non-communicable diseases

The prevalence of common chronic non-communicable diseases (CNCDs) far overshadows the prevalence of both monogenic and infectious diseases combined. All CNCDs, also called complex genetic diseases, have a heritable genetic component that can be used for pre-symptomatic risk assessment. Common single nucleotide polymorphisms (SNPs) that tag risk haplotypes across the genome currently account for a non-trivial portion of the germ-line genetic risk and we will likely continue to identify the remaining missing heritability in the form of rare variants, copy number variants and epigenetic modifications. Here, we describe a novel measure for calculating the lifetime risk of a disease, called the genetic composite index (GCI), and demonstrate its predictive value as a clinical classifier. The GCI only considers summary statistics of the effects of genetic variation and hence does not require the results of large-scale studies simultaneously assessing multiple risk factors. Combining GCI scores with environmental risk information provides an additional tool for clinical decision-making. The GCI can be populated with heritable risk information of any type, and thus represents a framework for CNCD pre-symptomatic risk assessment that can be populated as additional risk information is identified through next-generation technologies.Comment: Plos ONE paper. Previous version was withdrawn to be updated by the journal's pdf versio

Genomic signatures of population decline in the malaria mosquito Anopheles gambiae

Population genomic features such as nucleotide diversity and linkage disequilibrium are expected to be strongly shaped by changes in population size, and might therefore be useful for monitoring the success of a control campaign. In the Kilifi district of Kenya, there has been a marked decline in the abundance of the malaria vector Anopheles gambiae subsequent to the rollout of insecticide-treated bed nets. To investigate whether this decline left a detectable population genomic signature, simulations were performed to compare the effect of population crashes on nucleotide diversity, Tajima's D, and linkage disequilibrium (as measured by the population recombination parameter ρ). Linkage disequilibrium and ρ were estimated for An. gambiae from Kilifi, and compared them to values for Anopheles arabiensis and Anopheles merus at the same location, and for An. gambiae in a location 200 km from Kilifi. In the first simulations ρ changed more rapidly after a population crash than the other statistics, and therefore is a more sensitive indicator of recent population decline. In the empirical data, linkage disequilibrium extends 100-1000 times further, and ρ is 100-1000 times smaller, for the Kilifi population of An. gambiae than for any of the other populations. There were also significant runs of homozygosity in many of the individual An. gambiae mosquitoes from Kilifi. These results support the hypothesis that the recent decline in An. gambiae was driven by the rollout of bed nets. Measuring population genomic parameters in a small sample of individuals before, during and after vector or pest control may be a valuable method of tracking the effectiveness of interventions

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

Quantifying vertical mixing in estuaries

© 2008 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in Environmental Fluid Mechanics 8 (2008): 495-509, doi:10.1007/s10652-008-9107-2.Estuarine turbulence is notable in that both the dissipation rate and the buoyancy frequency extend to much higher values than in other natural environments. The high dissipation rates lead to a distinct inertial subrange in the velocity and scalar spectra, which can be exploited for quantifying the turbulence quantities. However, high buoyancy frequencies lead to small Ozmidov scales, which require high sampling rates and small spatial aperture to resolve the turbulent fluxes. A set of observations in a highly stratified estuary demonstrate the effectiveness of a vessel-mounted turbulence array for resolving turbulent processes, and for relating the turbulence to the forcing by the Reynolds-averaged flow. The observations focus on the ebb, when most of the buoyancy flux occurs. Three stages of mixing are observed: (1) intermittent and localized but intense shear instability during the early ebb; (2) continuous and relatively homogeneous shear-induced mixing during the mid-ebb, and weakly stratified, boundary-layer mixing during the late ebb. The mixing efficiency as quantified by the flux Richardson number Rf was frequently observed to be higher than the canonical value of 0.15 from Osborn (J Phys Oceanogr 10:83–89, 1980). The high efficiency may be linked to the temporal–spatial evolution of shear instabilities.The funding for this research was obtained from ONR Grant N00014-06-1-0292 and NSF Grant OCE-0729547

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Ensembl 2014

Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training

Impacts of climate change on plant diseases – opinions and trends

There has been a remarkable scientific output on the topic of how climate change is likely to affect plant diseases in the coming decades. This review addresses the need for review of this burgeoning literature by summarizing opinions of previous reviews and trends in recent studies on the impacts of climate change on plant health. Sudden Oak Death is used as an introductory case study: Californian forests could become even more susceptible to this emerging plant disease, if spring precipitations will be accompanied by warmer temperatures, although climate shifts may also affect the current synchronicity between host cambium activity and pathogen colonization rate. A summary of observed and predicted climate changes, as well as of direct effects of climate change on pathosystems, is provided. Prediction and management of climate change effects on plant health are complicated by indirect effects and the interactions with global change drivers. Uncertainty in models of plant disease development under climate change calls for a diversity of management strategies, from more participatory approaches to interdisciplinary science. Involvement of stakeholders and scientists from outside plant pathology shows the importance of trade-offs, for example in the land-sharing vs. sparing debate. Further research is needed on climate change and plant health in mountain, boreal, Mediterranean and tropical regions, with multiple climate change factors and scenarios (including our responses to it, e.g. the assisted migration of plants), in relation to endophytes, viruses and mycorrhiza, using long-term and large-scale datasets and considering various plant disease control methods

Comprehensive analysis of blood cells and plasma identifies tissue-specific miRNAs as potential novel circulating biomarkers in cattle

Abstract Background The potential of circulating miRNAs as biomarkers of tissue function, both in health and disease, has been extensively demonstrated in humans. In addition, circulating miRNA biomarkers offer significant potential towards improving the productivity of livestock species, however, such potential has been hampered by the absence of information on the nature and source of circulating miRNA populations in these species. In addition, many miRNAs originally proposed as robust biomarkers of a particular tissue or disease in humans have been later shown not to be tissue specific and thus to actually have limited biomarker utility. In this study, we comprehensively analysed miRNA profiles in plasma and cell fractions of blood from cattle with the aim to identify tissue-derived miRNAs which may be useful as biomarkers of tissue function in this important food animal species. Results Using small RNA sequencing, we identified 92 miRNAs with significantly higher expression in plasma compared to paired blood cell samples (n = 4 cows). Differences in miRNA levels between plasma and cell fractions were validated for eight out of 10 miRNAs using RT-qPCR (n = 10 cows). Among miRNAs found to be enriched in plasma, we confirmed miR-122 (liver), miR-133a (muscle) and miR-215 (intestine) to be tissue-enriched, as reported for other species. Profiling of additional miRNAs across different tissues identified the human homologue, miR-802, as highly enriched specifically in liver. Conclusions These results provide novel information on the source of bovine circulating miRNAs and could significantly facilitate the identification of production-relevant tissue biomarkers in livestock. In particular, miR-802, a circulating miRNA not previously identified in cattle, can reportedly regulate insulin sensitivity and lipid metabolism, and thus could potentially provide a specific biomarker of liver function, a key parameter in the context of post-partum negative energy balance in dairy cows

Genetic Diversity and Population Parameters of Sea Otters, Enhydra lutris, before Fur Trade Extirpation from 1741–1911

All existing sea otter, Enhydra lutris, populations have suffered at least one historic population bottleneck stemming from the fur trade extirpations of the eighteenth and nineteenth centuries. We examined genetic variation, gene flow, and population structure at five microsatellite loci in samples from five pre-fur trade populations throughout the sea otter's historical range: California, Oregon, Washington, Alaska, and Russia. We then compared those values to genetic diversity and population structure found within five modern sea otter populations throughout their current range: California, Prince William Sound, Amchitka Island, Southeast Alaska and Washington. We found twice the genetic diversity in the pre-fur trade populations when compared to modern sea otters, a level of diversity that was similar to levels that are found in other mammal populations that have not experienced population bottlenecks. Even with the significant loss in genetic diversity modern sea otters have retained historical structure. There was greater gene flow before extirpation than that found among modern sea otter populations but the difference was not statistically significant. The most dramatic effect of pre fur trade population extirpation was the loss of genetic diversity. For long term conservation of these populations increasing gene flow and the maintenance of remnant genetic diversity should be encouraged