Purpose : In a significant nuclear event, hundreds of thousands of individuals will require rapid triage for absorbed radiation to ensure effective medical treatment and efficient use of medical resources. We are developing a rapid screening method to assess whether an individual received an absorbed dose of ≥2 Gy based on the analysis of a specific panel of blood proteins in a fingerstick blood sample.
Materials and methods : We studied a data set of 1051 human blood samples obtained from radiotherapy patients, normal healthy individuals, and several special population groups. We compared the findings in humans with those from irradiation studies in non-human primates (NHPs).
Results : We identified a panel of three protein biomarkers, salivary alpha amylase (AMY1), Flt3 ligand (FLT3L), and monocyte chemotactic protein 1 (MCP1), which are upregulated in human patients receiving fractionated doses of total body irradiation (TBI) therapy as a treatment for cancer. These proteins exhibited a similar radiation response in NHPs after single acute or fractionated doses of ionizing radiation.
Conclusion : Our work provides confidence in this biomarker panel for biodosimetry triage using fingerstick blood samples and in the use of NHPs as a model for irradiated humans.
National security publications
Evaluation of reaction gap-filling accuracy by randomization
Completion of genome-scale flux-balance models using computational reaction gap-filling is a widely used approach, but its accuracy is not well known.
We report on computational experiments of reaction gap filling in which we generated degraded versions of the EcoCyc-20.0-GEM model by randomly removing flux-carrying reactions from a growing model. We gap-filled the degraded models and compared the resulting gap-filled models with the original model. Gap-filling was performed by the Pathway Tools MetaFlux software using its General Development Mode (GenDev) and its Fast Development Mode (FastDev). We explored 12 GenDev variants including two linear solvers (SCIP and CPLEX) for solving the Mixed Integer Linear Programming (MILP) problems for gap filling; three different sets of linear constraints were applied; and two MILP methods were implemented. We compared these 13 variants according to accuracy, speed, and amount of information returned to the user.
We observed large variation among the performance of the 13 gap-filling variants. Although no variant was best in all dimensions, we found one variant that was fast, accurate, and returned more information to the user. Some gap-filling variants were inaccurate, producing solutions that were non-minimum or invalid (did not enable model growth). The best GenDev variant showed a best average precision of 87% and a best average recall of 61%. FastDev showed an average precision of 71% and an average recall of 59%. Thus, using the most accurate variant, approximately 13% of the gap-filled reactions were incorrect (were not the reactions removed from the model), and 39% of gap-filled reactions were not found, suggesting that curation is still an important aspect of metabolic-model development.
How accurate is automated gap filling of metabolic models?
Reaction gap filling is a computational technique for proposing the addition of reactions to genome-scale metabolic models to permit those models to run correctly. Gap filling completes what are otherwise incomplete models that lack fully connected metabolic networks. The models are incomplete because they are derived from annotated genomes in which not all enzymes have been identified. Here we compare the results of applying an automated likelihood-based gap filler within the Pathway Tools software with the results of manually gap filling the same metabolic model. Both gap-filling exercises were applied to the same genome-derived qualitative metabolic reconstruction for Bifidobacterium longum subsp. longum JCM 1217, and to the same modeling conditions — anaerobic growth under four nutrients producing 53 biomass metabolites.
The solution computed by the gap-filling program GenDev contained 12 reactions, but closer examination showed that solution was not minimal; two of the twelve reactions can be removed to yield a set of ten reactions that enable model growth. The manually curated solution contained 13 reactions, eight of which were shared with the 12-reaction computed solution. Thus, GenDev achieved recall of 61.5% and precision of 66.6%. These results suggest that although computational gap fillers are populating metabolic models with significant numbers of correct reactions, automatically gap-filled metabolic models also contain significant numbers of incorrect reactions.
Our conclusion is that manual curation of gap-filler results is needed to obtain high-accuracy models. Many of the differences between the manual and automatic solutions resulted from using expert biological knowledge to direct the choice of reactions within the curated solution, such as reactions specific to the anaerobic lifestyle of B. longum.
Design and Verification for Transportation System Security
Cyber-security has emerged as a pressing issue for transportation systems. Studies have shown that attackers can attack modern vehicles from a variety of interfaces and gain access to the most safety-critical components. Such threats become even broader and more challenging with the emergence of vehicle-to-vehicle (V2V) and vehicle-to-infrastructure (V2I) communication technologies. Addressing the security issues in transportation systems requires comprehensive approaches that encompass considerations of security mechanisms, safety properties, resource constraints, and other related system metrics. In this work, we propose an integrated framework that combines hybrid modeling, formal verification, and automated synthesis techniques for analyzing the security and safety of transportation systems and carrying out design space exploration of both in-vehicle electronic control systems and vehicle-to-vehicle communications. We demonstrate the ideas of our framework through a case study of cooperative adaptive cruise control.
Modification of the Loss Cone for Energetic Particles
As part of this special issue on control systems for the energy sector, guest editors Sean Peisert and Jonathan Margulies put together a roundtable discussion so readers can learn about the security challenges facing the industrial control system/SCADA world from those who are on the front lines. The discussion touches on some of the hard problems of securing mission-critical systems in the real world, including the challenges of securing 20-year-old legacy infrastructures, defining vendors’ roles and responsibilities in security, and where research and new technologies are needed to fill today’s security gaps.
Evaluation of OMI Operational Standard NO2 Column Retrievals Using in Situ and Surface-Based NO2 Observations
We assess the standard operational nitrogen dioxide (NO2) data product (OMNO2, version 2.1) retrieved from the Ozone Monitoring Instrument (OMI) onboard NASA’s Aura satellite using a combination of aircraft and surface in situ measurements as well as ground-based column measurements at several locations and a bottom-up NOx emission inventory over the continental US. Despite considerable sampling differences, NO2 vertical column densities from OMI are modestly correlated (r = 0.3–0.8) with in situ measurements of tropospheric NO2 from aircraft, ground-based observations of NO2 columns from MAX-DOAS and Pandora instruments, in situ surface NO2measurements from photolytic converter instruments, and a bottom-up NOx emission inventory. Overall, OMI retrievals tend to be lower in urban regions and higher in remote areas, but generally agree with other measurements to within ± 20%. No consistent seasonal bias is evident. Contrasting results between different data sets reveal complexities behind NO2 validation. Monthly mean vertical NO2 profile shapes from the Global Modeling Initiative (GMI) chemistry-transport model (CTM) used in the OMI retrievals are highly consistent with in situ aircraft measurements, but these measured profiles exhibit considerable day-to-day variation, affecting the retrieved daily NO2 columns by up to 40%. This assessment of OMI tropospheric NO2 columns, together with the comparison of OMI-retrieved and model-simulated NO2columns, could offer diagnostic evaluation of the model.
Risks and Myths of Cloud Computing and Cloud Storage
A Framework for Application of Metabolic Modeling in Yeast to Predict the Effects of Nssnv in Human Orthologs
Background
We have previously suggested a method for proteome wide analysis of variation at functional residues wherein we identified the set of all human genes with nonsynonymous single nucleotide variation (nsSNV) in the active site residue of the corresponding proteins. 34 of these proteins were shown to have a 1:1:1 enzyme:pathway:reaction relationship, making these proteins ideal candidates for laboratory validation through creation and observation of specific yeast active site knock-outs and downstream targeted metabolomics experiments. Here we present the next step in the workflow toward using yeast metabolic modeling to predict human metabolic behavior resulting from nsSNV.
Results
For the previously identified candidate proteins, we used the reciprocal best BLAST hits method followed by manual alignment and pathway comparison to identify 6 human proteins with yeast orthologs which were suitable for flux balance analysis (FBA). 5 of these proteins are known to be associated with diseases, including ribose 5-phosphate isomerase deficiency, myopathy with lactic acidosis and sideroblastic anaemia, anemia due to disorders of glutathione metabolism, and two porphyrias, and we suspect the sixth enzyme to have disease associations which are not yet classified or understood based on the work described herein.
Conclusions
Preliminary findings using the Yeast 7.0 FBA model show lack of growth for only one enzyme, but augmentation of the Yeast 7.0 biomass function to better simulate knockout of certain genes suggested physiological relevance of variations in three additional proteins. Thus, we suggest the following four proteins for laboratory validation: delta-aminolevulinic acid dehydratase, ferrochelatase, ribose-5 phosphate isomerase and mitochondrial tyrosyl-tRNA synthetase. This study indicates that the predictive ability of this method will improve as more advanced, comprehensive models are developed. Moreover, these findings will be useful in the development of simple downstream biochemical or mass-spectrometric assays to corroborate these predictions and detect presence of certain known nsSNVs with deleterious outcomes. Results may also be useful in predicting as yet unknown outcomes of active site nsSNVs for enzymes that are not yet well classified or annotated.
Studies of a Prototype Linear Stationary X-Ray Source for Tomosynthesis Imaging
A prototype linear x-ray source to implement stationary source–stationary detector tomosynthesis (TS) imaging has been studied. Potential applications include human breast and small animal imaging. The source is comprised of ten x-ray source elements each consisting of a field emission cathode, electrostatic lens, and target. The electrostatic lens and target are common to all elements. The source elements form x-ray focal spots with minimum diameters of 0.3–0.4 mm at electron beam currents of up to 40 mA with a beam voltage of 40 kV. The x-ray flux versus time was quantified from each source. X-ray bremsstrahlung spectra from tungsten targets were produced using electron beam energies from 35 to 50 keV. The half-value layer was measured to be 0.8, 0.9, and 1.0 mm, respectively, for the 35, 40, and 45 kV tube potentials using the tungsten target. The suppression of voltage breakdown events, particularly during source operation, and the use of a modified form of the standard cold-cathode geometry, enhanced source reliability. The prototype linear source was used to collect tomographic data sets of a mouse phantom using digital TS reconstruction methods and demonstrated a slice-sensitivity profile with a full-width-half-maximum of 1.3 mm. Lastly, preliminary studies of tomographic imaging of flow through the mouse phantom were performed.
