72 research outputs found
Screening robust water infrastructure investments and their trade-offs under global change: A London example
We propose an approach for screening future infrastructure and demand management investments for large water supply systems subject to uncertain future conditions. The approach is demonstrated using the London water supply system. Promising portfolios of interventions (e.g., new supplies, water conservation schemes, etc.) that meet London’s estimated water supply demands in 2035 are shown to face significant trade-offs between financial, engineering and environmental measures of performance. Robust portfolios are identified by contrasting the multi-objective results attained for (1) historically observed baseline conditions versus (2) future global change scenarios. An ensemble of global change scenarios is computed using climate change impacted hydrological flows, plausible water demands, environmentally motivated abstraction reductions, and future energy prices. The proposed multi-scenario trade-off analysis screens for robust investments that provide benefits over a wide range of futures, including those with little change. Our results suggest that 60 percent of intervention portfolios identified as Pareto optimal under historical conditions would fail under future scenarios considered relevant by stakeholders. Those that are able to maintain good performance under historical conditions can no longer be considered to perform optimally under future scenarios. The individual investment options differ significantly in their ability to cope with varying conditions. Visualizing the individual infrastructure and demand management interventions implemented in the Pareto optimal portfolios in multi-dimensional space aids the exploration of how the interventions affect the robustness and performance of the system
Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis
Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatment in vivo. Finally, ex vivo and in vitro experiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS
A systematic, large-scale comparison of transcription factor binding site models
Background The modelling of gene regulation is a major challenge in biomedical
research. This process is dominated by transcription factors (TFs) and
mutations in their binding sites (TFBSs) may cause the misregulation of genes,
eventually leading to disease. The consequences of DNA variants on TF binding
are modelled in silico using binding matrices, but it remains unclear whether
these are capable of accurately representing in vivo binding. In this study,
we present a systematic comparison of binding models for 82 human TFs from
three freely available sources: JASPAR matrices, HT-SELEX-generated models and
matrices derived from protein binding microarrays (PBMs). We determined their
ability to detect experimentally verified “real” in vivo TFBSs derived from
ENCODE ChIP-seq data. As negative controls we chose random downstream exonic
sequences, which are unlikely to harbour TFBS. All models were assessed by
receiver operating characteristics (ROC) analysis. Results While the area-
under-curve was low for most of the tested models with only 47 % reaching a
score of 0.7 or higher, we noticed strong differences between the various
position-specific scoring matrices with JASPAR and HT-SELEX models showing
higher success rates than PBM-derived models. In addition, we found that while
TFBS sequences showed a higher degree of conservation than randomly chosen
sequences, there was a high variability between individual TFBSs. Conclusions
Our results show that only few of the matrix-based models used to predict
potential TFBS are able to reliably detect experimentally confirmed TFBS. We
compiled our findings in a freely accessible web application called ePOSSUM
(http:/mutationtaster.charite.de/ePOSSUM/) which uses a Bayes classifier to
assess the impact of genetic alterations on TF binding in user-defined
sequences. Additionally, ePOSSUM provides information on the reliability of
the prediction using our test set of experimentally confirmed binding sites
Risk-based prioritization of pharmaceuticals in the natural environment in Iraq
Numerous studies have demonstrated the occurrence of pharmaceuticals in the natural environment, raising concerns about their impact on non-target organisms or human health. One region where little is known about the exposure and effects of pharmaceuticals in the environment is Iraq. Due to the high number of pharmaceuticals used by the public health sector in Iraq (hospitals and care centres) and distributed over the counter, there is a need for a systematic approach for identifying substances that should be monitored in the environment in Iraq and assessed in terms of environmental risk. In this study, a risk-based prioritization approach was applied to 99 of the most dispensed pharmaceuticals in three Iraqi cities, Baghdad, Mosul and Basrah. Initially, information on the amounts of pharmaceuticals used in Iraq was obtained. The top used medicines were found to be paracetamol, amoxicillin and metformin with total annual consumption exceeding 1000 tonnes per year. Predicted environmental concentrations (PECs) and predicted no-effect concentrations (PNECs), derived from ecotoxicological end-points and effects related to the therapeutic mode of action, were then used to rank the pharmaceuticals in terms of risks to different environmental compartments. Active pharmaceutical ingredients used as antibiotics, antidepressants and analgesics were identified as the highest priority in surface water, sediment and the terrestrial environment. Antibiotics were also prioritized according to their susceptibility to kill or inhibit the growth of bacteria or to accelerate the evolution and dissemination of antibiotic-resistant genes in water. Future work will focus on understanding the occurrence, fate and effects of some of highly prioritized substances in the environment
Systems Integration of Biodefense Omics Data for Analysis of Pathogen-Host Interactions and Identification of Potential Targets
The NIAID (National Institute for Allergy and Infectious Diseases) Biodefense Proteomics program aims to identify targets for potential vaccines, therapeutics, and diagnostics for agents of concern in bioterrorism, including bacterial, parasitic, and viral pathogens. The program includes seven Proteomics Research Centers, generating diverse types of pathogen-host data, including mass spectrometry, microarray transcriptional profiles, protein interactions, protein structures and biological reagents. The Biodefense Resource Center (www.proteomicsresource.org) has developed a bioinformatics framework, employing a protein-centric approach to integrate and support mining and analysis of the large and heterogeneous data. Underlying this approach is a data warehouse with comprehensive protein + gene identifier and name mappings and annotations extracted from over 100 molecular databases. Value-added annotations are provided for key proteins from experimental findings using controlled vocabulary. The availability of pathogen and host omics data in an integrated framework allows global analysis of the data and comparisons across different experiments and organisms, as illustrated in several case studies presented here. (1) The identification of a hypothetical protein with differential gene and protein expressions in two host systems (mouse macrophage and human HeLa cells) infected by different bacterial (Bacillus anthracis and Salmonella typhimurium) and viral (orthopox) pathogens suggesting that this protein can be prioritized for additional analysis and functional characterization. (2) The analysis of a vaccinia-human protein interaction network supplemented with protein accumulation levels led to the identification of human Keratin, type II cytoskeletal 4 protein as a potential therapeutic target. (3) Comparison of complete genomes from pathogenic variants coupled with experimental information on complete proteomes allowed the identification and prioritization of ten potential diagnostic targets from Bacillus anthracis. The integrative analysis across data sets from multiple centers can reveal potential functional significance and hidden relationships between pathogen and host proteins, thereby providing a systems approach to basic understanding of pathogenicity and target identification
Development of a filter to prevent infections with spore-forming bacteria in injecting drug users
Mouse Rif1 is a regulatory subunit of protein phosphatase 1 (PP1)
International audienceRif1 is a conserved protein that plays essential roles in orchestrating DNA replication timing, controlling nuclear architecture, telomere length and DNA repair. However, the relationship between these different roles, as well as the molecular basis of Rif1 function is still unclear. The association of Rif1 with insoluble nuclear lamina has thus far hampered exhaustive characterization of the associated protein complexes. We devised a protocol that overcomes this problem, and were thus able to discover a number of novel Rif1 interactors, involved in chromatin metabolism and phosphorylation. Among them, we focus here on PP1. Data from different systems have suggested that Rif1-PP1 interaction is conserved and has important biological roles. Using mutagenesis, NMR, isothermal calorimetry and surface plasmon resonance we demonstrate that Rif1 is a high-affinity PP1 adaptor, able to out-compete the well-established PP1-inhibitor I2 in vitro. Our conclusions have important implications for understanding Rif1 diverse roles and the relationship between the biological processes controlled by Rif1
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Differential coexpression analysis of obesity-associated networks in human subcutaneous adipose tissue
Objective: To use a unique obesity-discordant sib-pair study design to combine differential expression analysis, expression quantitative trait loci (eQTLs) mapping and a coexpression regulatory network approach in subcutaneous human adipose tissue to identify genes relevant to the obese state. Study design: Genome-wide transcript expression in subcutaneous human adipose tissue was measured using Affymetrix U133 Plus 2.0 microarrays (Affymetrix, Santa Clara, CA, USA), and genome-wide genotyping data was obtained using an Applied Biosystems (Applied Biosystems; Life Technologies, Carlsbad, CA, USA) SNPlex linkage panel. Subjects: A total of 154 Swedish families ascertained through an obese proband (body mass index (BMI) >30 kg m−2) with a discordant sibling (BMI>10 kg m−2 less than proband). Results: Approximately one-third of the transcripts were differentially expressed between lean and obese siblings. The cellular adhesion molecules (CAMs) KEGG grouping contained the largest number of differentially expressed genes under cis-acting genetic control. By using a novel approach to contrast CAMs coexpression networks between lean and obese siblings, a subset of differentially regulated genes was identified, with the previously GWAS obesity-associated neuronal growth regulator 1 (NEGR1) as a central hub. Independent analysis using mouse data demonstrated that this finding of NEGR1 is conserved across species. Conclusion: Our data suggest that in addition to its reported role in the brain, NEGR1 is also expressed in subcutaneous adipose tissue and acts as a central ‘hub’ in an obesity-related transcript network
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