There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug ...reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new ‘pharmaco-metabonomic’ approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.
Mastitis is among the main reasons women cease breastfeeding, which leads to them supplementing breast milk with artificial formula. In farm animals, mastitis results in significant economic losses ...and the premature culling of some animals. Nevertheless, researchers do not know enough about the effect of inflammation on the mammary gland. This article discusses the changes to DNA methylation in mouse mammary tissue caused by lipopolysaccharide-induced inflammation (4 h post-injection of lipopolysaccharide). We analysed the expression of some genes related to mammary gland function, epigenetic regulation, and the immune response. The analysis focused on three comparisons: inflammation during the first lactation, inflammation during second lactation with no history of inflammation, and inflammation during second lactation with previous inflammation. We identified differentially methylated cytosines (DMCs), differentially methylated regions (DMRs), and some differentially expressed genes (DEGs) for each comparison. The three comparisons shared some DEGs; however, few DMCs and only one DMR were shared. These observations suggest that inflammation is one of several factors affecting epigenetic regulation during successive lactations. Furthermore, the comparison between animals in second lactation with and without inflammation, with no inflammation history during first lactation showed a different pattern compared to the other conditions in this experiment. This indicates that inflammation history plays an important role in determining epigenetic changes. The data presented in this study suggest that lactation rank and previous inflammation history are equally important when explaining mammary tissue gene expression and DNA methylation changes.
Abbreviations: RRBS, reduced representation bisulfite sequencing; RT-qPCR, real-time quantitative polymerase chain reaction; MEC, mammary epithelial cells; TSS, transcription start site; TTS, transcription termination site; UTR, untranslated region; SINE, short interspersed nuclear element; LINE, long interspersed nuclear element; CGI, CpG island; DEG, differentially expressed gene; DMC, differentially methylated cytosine; DMR, differentially methylated region; GO term, gene ontology term; MF, molecular function; BP, biological process
A large body of research shows that biodiversity loss can reduce ecosystem functioning. However, much of the evidence for this relationship is drawn from biodiversity-ecosystem functioning ...experiments in which biodiversity loss is simulated by randomly assembling communities of varying species diversity, and ecosystem functions are measured. This random assembly has led some ecologists to question the relevance of biodiversity experiments to real-world ecosystems, where community assembly or disassembly may be non-random and influenced by external drivers, such as climate, soil conditions or land use. Here, we compare data from real-world grassland plant communities with data from two of the largest and longest-running grassland biodiversity experiments (the Jena Experiment in Germany and BioDIV in the United States) in terms of their taxonomic, functional and phylogenetic diversity and functional-trait composition. We found that plant communities of biodiversity experiments cover almost all of the multivariate variation of the real-world communities, while also containing community types that are not currently observed in the real world. Moreover, they have greater variance in their compositional features than their real-world counterparts. We then re-analysed a subset of experimental data that included only ecologically realistic communities (that is, those comparable to real-world communities). For 10 out of 12 biodiversity-ecosystem functioning relationships, biodiversity effects did not differ significantly between the full dataset of biodiversity experiments and the ecologically realistic subset of experimental communities. Although we do not provide direct evidence for strong or consistent biodiversity-ecosystem functioning relationships in real-world communities, our results demonstrate that the results of biodiversity experiments are largely insensitive to the exclusion of unrealistic communities and that the conclusions drawn from biodiversity experiments are generally robust.
Mastitis is among the main reasons women cease breastfeeding. In farm animals, mastitis results in significant economic losses and the premature culling of some animals. Nevertheless, the effect of ...inflammation on the mammary gland is not completely understood. This article discusses the changes to DNA methylation in mouse mammary tissue caused by lipopolysaccharide-induced inflammation after in vivo intramammary challenges and the differences in DNA methylation between 1
st
and 2
nd
lactations. Lactation rank induces 981 differential methylations of cytosines (DMCs) in mammary tissue. Inflammation in 1
st
lactation compared to inflammation in 2
nd
lactation results in the identification of 964 DMCs. When comparing inflammation in 1
st
vs. 2
nd
lactations with previous inflammation history, 2590 DMCs were identified. Moreover, Fluidigm PCR data show changes in the expression of several genes related to mammary function, epigenetic regulation, and the immune response. We show that the epigenetic regulation of two successive physiological lactations is not the same in terms of DNA methylation and that the effect of lactation rank on DNA methylation is stronger than that of the onset of inflammation. The conditions presented here show that few DMCs are shared between comparisons, suggesting a specific epigenetic response depending on lactation rank, the presence of inflammation, and even whether the cells had previously suffered inflammation. In the long term, this information could lead to a better understanding of the epigenetic regulation of lactation in both physiological and pathological conditions.
Abbreviations: RRBS, reduced representation bisulphite sequencing; RT-qPCR, real-time quantitative polymerase chain reaction; MEC, mammary epithelial cells; MaSC, mammary stem cell; TSS, transcription start site; TTS, transcription termination site; UTR, untranslated region; SINE, short interspersed nuclear element; LINE, long interspersed nuclear element; CGI, CpG island; DEG, differentially expressed gene; DMC, differentially methylated cytosine; DMR, differentially methylated region; GO term, gene ontology term; MF, molecular function; BP, biological process
Pollinators benefit from increasing floral resources in agricultural landscapes, which could be an underexplored co‐benefit of mass‐flowering crop cultivation. However, the impacts of mass‐flowering ...crops on pollinator communities are complex and appear to be context‐dependent, mediated by factors such as crop flowering time and the availability of other flower resources in the landscape. A synthesis of research is needed to develop management recommendations for effective pollinator conservation in agroecosystems.
By combining 22 datasets from 13 publications conducted in nine temperate countries (20 European, 2 North American), we investigated if mass‐flowering crop flowering time (early or late season), bloom state (during or after crop flowering) and extent of non‐crop habitat cover in the landscape moderated the effect of mass‐flowering crop cover on wild pollinator abundance and species richness in mass‐flowering crop and non‐crop habitats.
During bloom, wild bee abundance and richness are negatively related to mass‐flowering crop cover. Dilution effects were predominant in crop habitats and early in the season, except for bumblebees, which declined with mass‐flowering crop cover irrespective of habitat or season. Late in the season and in non‐crop habitats, several of these negative relationships were either absent or reversed. Late‐season mass‐flowering crop cover is positively related to honeybee abundance in crop habitats and to other bee abundance in non‐crop habitats. These results indicate that crop‐adapted species, like honeybees, move to forage and concentrate on late‐season mass‐flowering crops at a time when flower availability in the landscape is limited, potentially alleviating competition for flower resources in non‐crop habitats. We found no evidence of pollinators moving from mass‐flowering crop to non‐crop habitats after crop bloom.
Synthesis and applications: Our results confirm that increasing early‐season mass‐flowering crop cover dilutes wild pollinators in crop habitats during bloom. We find that dilution effects were absent late in the season. While mass‐flowering crop cultivation alone is unlikely to be sufficient for maintaining pollinators, as part of carefully designed diverse crop rotations or mixtures combined with the preservation of permanent non‐crop habitats, it might provide valuable supplementary food resources for pollinators in temperate agroecosystems, particularly later in the season when alternative flower resources are scarce.
Our results confirm that increasing early‐season mass‐flowering crop cover dilutes wild pollinators in crop habitats during bloom. We find that dilution effects were absent late in the season. While mass‐flowering crop cultivation alone is unlikely to be sufficient for maintaining pollinators, as part of carefully designed diverse crop rotations or mixtures combined with the preservation of permanent non‐crop habitats, it might provide valuable supplementary food resources for pollinators in temperate agroecosystems, particularly later in the season when alternative flower resources are scarce.
The AMADEUS system described in this article is integrated into the ANTARES neutrino telescope in the Mediterranean Sea and aims at the investigation of techniques for acoustic detection of neutrinos ...in the deep sea. Installed at water depths between 2000 and 2400m, its acoustic sensors employ piezo-electric elements for the broad-band recording of signals with frequencies ranging up to 125 kHz with typical sensitivities around −145 dB re. 1V/μPa (including preamplifier). Completed in May 2008, AMADEUS consists of six "acoustic clusters", each comprising six acoustic sensors that are arranged at distances of roughly 1m from each other. Three acoustic clusters each are installed along two vertical mechanical structures (so-called lines) of the ANTARES detector at a horizontal distance of 240m. Vertical spacings within a line range from 15m to 125m. Each cluster contains custom-designed electronics boards to amplify and digitise the acoustic data from the sensors. The data transmission to shore is done via optical fibres, using the TCP/IP protocol. An on-shore computer cluster, currently consisting of four dedicated servers, is used to process, filter and store the selected data. The daily volume of recorded data is about 10 - 20 GByte. The system is operating continuously and automatically, requiring only little human intervention. AMADEUS allows for extensive studies of both transient signals and ambient noise in the deep sea as well as signal correlations on several length scales and localisation of acoustic point sources. Thus the system is excellently suited to assess the background conditions that affect the measurement of bipolar pulses expected to originate from neutrino interactions. This in turn allows for feasibility studies of a future large-scale acoustic neutrino telescope in the Mediterranean Sea.
Experiments showed that biodiversity increases grassland productivity and nutrient exploitation, potentially reducing fertiliser needs. Enhancing biodiversity could improve P-use efficiency of ...grasslands, which is beneficial given that rock-derived P fertilisers are expected to become scarce in the future. Here, we show in a biodiversity experiment that more diverse plant communities were able to exploit P resources more completely than less diverse ones. In the agricultural grasslands that we studied, management effects either overruled or modified the driving role of plant diversity observed in the biodiversity experiment. Nevertheless, we show that greater above- (plants) and belowground (mycorrhizal fungi) biodiversity contributed to tightening the P cycle in agricultural grasslands, as reduced management intensity and the associated increased biodiversity fostered the exploitation of P resources. Our results demonstrate that promoting a high above- and belowground biodiversity has ecological (biodiversity protection) and economical (fertiliser savings) benefits. Such win-win situations for farmers and biodiversity are crucial to convince farmers of the benefits of biodiversity and thus counteract global biodiversity loss.
Gamma-ray bursts (GRB) sign energetic explosions in the Universe, occurring at cosmological distances. Multi-wavelength observations of GRB allow to study their properties and to use them as ...cosmological tools. In 2012 the space borne gamma-ray telescope ECLAIRs is expected to provide accurate GRB localizations on the sky in near real-time, necessary for ground-based follow-up observations. Led by CEA Saclay, France, the project is currently in its technical design phase. ECLAIRs is optimized to detect highly red-shifted GRB thanks to a 4 keV low energy threshold. A coded mask telescope with a 1024 cm^2 detection plane of 80x80 CdTe pixels permanently observes a 2 sr sky field. The on-board trigger detects GRB using count-rate increase monitors on multiple time-scales and cyclic images. It computes sky images in the 4-50 keV energy range by de-convolving detector plane images with the mask pattern and localizes newly detected sources with <10 arcmin accuracy. While individual GRB photons are available hours later, GRB alerts are transmitted over a VHF network within seconds to ground, in particular to robotic follow-up telescopes, which refine GRB localizations to the level needed by large spectroscopic telescopes. This paper describes the ECLAIRs concept, with emphasis on the GRB triggering scheme.
The charged trigger system of NA48 at CERN Anvar, S.; Bugeon, F.; Debu, P. ...
IEEE transactions on nuclear science,
1998-Aug., 1998-8-00, Volume:
45, Issue:
4
Journal Article
Peer reviewed
Open access
The NA48 charged trigger is a mixed hardware and software real time processing system intended to detect the interesting configurations of K/sup 0/ charged decays. It achieves real-time event ...building, track reconstruction and kinematics computation on drift chamber data at an event rate of 100 kHz and within a maximum decision latency of 100 /spl mu/s. The system uses data driven, FPGA-based coordinate builders, a hardware event builder based on a crossbar switch, and a farm of up to 16 event processors for its software part. It has been installed and operated at CERN since 1995. After a description of the constraints and architecture of the various subsystems, the paper will give an account of the results and performance of the system based on the 1996/1997 runs. More specifically, the replacement of the present DSP-based implementation of the processing farm by RISC processors will be discussed.
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