A Monte Carlo Model of Uncertainty in a Deterministic Hazardous Waste Transportation Risk Assessment

This thesis is aimed at developing and applying advanced modeling tools in the prediction of risk to the general public from transportation of chemical waste on public highways. The modeling tools developed can then be used to compare alternative waste management scenarios. The application considered is related to the transport of hazardous waste generated by the United States Department of Energy (DOE) to current treatment, storage, and disposal facilities. DOE is currently considering four different scenarios. The application considered can be more specifically defined as an analysis of the risk to the general public from transporting the 63 shipments of DOE generated hazardous waste designated as poison by inhalation hazards (PIH), potentially resulting in fatality, by the United States Department of Transportation (DOT) [Title 49, Code of Federal Regulations (Part 173.132)] in the 1992 fiscal year. The analysis is based on current transportation practices employed by DOE. Once the modeling tools have been developed to perform this analysis, similar analysis can be routinely carried out for other health end-points (carcinogenic effects and other adverse health effects other than cancer and lethality) and other waste management scenarios. Two types of tools have been developed, deterministic and probabilistic. Using the probabilistic modeling tool, a cumulative probability distribution of number of people impacted can be developed (for this application impacted means number of individuals experiencing potentially life-threatening health effects due to inhalation of a DOE generated PIH released as a result of a truck transportation accident). The probabilistic modeling tool developed is based upon a Monte Carlo analysis accounting for the uncertainties in the variables involved in the modeling process. The deterministic tool developed provides a simplified version of the probabilistic model such that the prediction will be one risk value which should approximate the mean of the cumulative probability distribution developed by the probabilistic model. Both the deterministic and probabilistic modeling tools require the modeling of the consequence of a release of hazardous waste. The consequence is the result of source term accident modeling (i.e., resulting from a truck accident spill) along with dispersion modeling. The source term modeling employs the use of (1) distributions of meteorological data supplied by the National Weather Service at over 60 locations uniformly distributed around the continental United States and (2) a detailed study on the US DOT HMIRS (Hazardous Materials Information Reporting System) database which encompasses information on thousands of hazardous material transportation accidents since the 1970\u27s. The study of the HMIRS database led to probability distributions on the release amounts (by transport container), breach fractions and accident time (by hour and month). A health criteria, presented at WM-94 by Hartman et. al. (1994), is used in the dispersion modeling to define human health impacts from the concentration history at each downwind location. Reasonable single values for all modeling parameters were used in the deterministic model, whereas probability distributions for release estimates and accident meteorological conditions were used for release amounts and meteorology in the probabilistic model. Realistic scenarios for the transportation accident itself were developed accounting for mixtures of chemicals released as is likely to occur. It was found that the cumulative probability distribution of the number of individuals with potentially life-threatening health effects, is highly skewed. The probability that no individuals will have potentially life-threatening health effects from these 63 shipments is greater than 99%. Therefore the median (the 50-th percentile) of the distribution is 0, and all of the non-zero potentially life-threatening health effects are contained in the upper tail of the cumulative probability distribution (less than 1% chance of occurrence). Table 1 below presents some summary statistics compiled from the distribution. Only 3 (of the 63) shipments had the potential to affect more than 500 people in a single accident. Furthermore, only 14 shipments had the potential to affect more than 100 people. Eliminating, or at least altering the waste management of these shipments, could dramatically reduce risks by reducing the probabilities for a catastrophic accident in which more than 100 people are affected. An additional observation is that the mean of the cumulative probability distribution, 3.48E-4, is located at the 99.947-th percentile and the result of the deterministic calculations of risk, 1.74E-4 (½ of the mean), is located at the 99.941-th percentile. The Monte Carlo analysis helped to provide a great deal of perspective on the deterministic risk value. The fact that there is such a large probability of zero risk and an extremely small probability of a high risk scenario can be very useful in the decision making process

Mapping the Hsp90 Genetic Interaction Network in Candida albicans Reveals Environmental Contingency and Rewired Circuitry

The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, and evolution. Hsp90 interacts with ∼10% of the proteome in the model yeast Saccharomyces cerevisiae, while only two interactions have been identified in Candida albicans, the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time

Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data

We report a quasi-differential upper limit on the extremely-high-energy (EHE) neutrino flux above $5\times 10^{6}$ GeV based on an analysis of nine years of IceCube data. The astrophysical neutrino flux measured by IceCube extends to PeV energies, and it is a background flux when searching for an independent signal flux at higher energies, such as the cosmogenic neutrino signal. We have developed a new method to place robust limits on the EHE neutrino flux in the presence of an astrophysical background, whose spectrum has yet to be understood with high precision at PeV energies. A distinct event with a deposited energy above $10^{6}$ GeV was found in the new two-year sample, in addition to the one event previously found in the seven-year EHE neutrino search. These two events represent a neutrino flux that is incompatible with predictions for a cosmogenic neutrino flux and are considered to be an astrophysical background in the current study. The obtained limit is the most stringent to date in the energy range between $5 \times 10^{6}$ and $5 \times 10^{10}$ GeV. This result constrains neutrino models predicting a three-flavor neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\ {\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}$at$10^9\ {\rm GeV}$. A significant part of the parameter-space for EHE neutrino production scenarios assuming a proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review

Synthesis, Decomposition and Characterization of Fe and Ni Sulfides and Fe and CO Nanoparticles for Aerospace Applications

We describe several related studies where simple iron, nickel, and cobalt complexes were prepared, decomposed, and characterized for aeronautics (Fischer-Tropsch catalysts) and space (high-fidelity lunar regolith simulant additives) applications. We describe the synthesis and decomposition of several new nickel dithiocarbamate complexes. Decomposition resulted in a somewhat complicated product mix with NiS predominating. The thermogravimetric analysis of fifteen tris(diorganodithiocarbamato)iron(III) has been investigated. Each undergoes substantial mass loss upon pyrolysis in a nitrogen atmosphere between 195 and 370 C, with major mass losses occurring between 279 and 324 C. Steric repulsion between organic substituents generally decreased the decomposition temperature. The product of the pyrolysis was not well defined, but usually consistent with being either FeS or Fe2S3 or a combination of these. Iron nanoparticles were grown in a silica matrix with a long-term goal of introducing native iron into a commercial lunar dust simulant in order to more closely simulate actual lunar regolith. This was also one goal of the iron and nickel sulfide studies. Finally, cobalt nanoparticle synthesis is being studied in order to develop alternatives to crude processing of cobalt salts with ceramic supports for Fischer-Tropsch synthesis

Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms

KT acknowledges receipt of a mandate of Industrial Research Fund (IOFm/05/022). JB acknowledges funding from the European Research Council Advanced Award 3400867/RAPLODAPT and the Israel Science Foundation grant # 314/13 (www.isf.il). NG acknowledges the Wellcome Trust and MRC for funding. CD acknowledges funding from the Agence Nationale de Recherche (ANR-10-LABX-62-IBEID). CJN acknowledges funding from the National Institutes of Health R35GM124594 and R21AI125801. AW is supported by the Wellcome Trust Strategic Award (grant 097377), the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen MaCA: outside this study MaCA has received personal speaker’s honoraria the past five years from Astellas, Basilea, Gilead, MSD, Pfizer, T2Candida, and Novartis. She has received research grants and contract work paid to the Statens Serum Institute from Astellas, Basilea, Gilead, MSD, NovaBiotics, Pfizer, T2Biosystems, F2G, Cidara, and Amplyx. CAM acknowledges the Wellcome Trust and the MRC MR/N006364/1. PVD, TC and KT acknowledge the FWO research community: Biology and ecology of bacterial and fungal biofilms in humans (FWO WO.009.16N). AAB acknowledges the Deutsche Forschungsgemeinschaft – CRC FungiNet.Peer reviewedPublisher PD

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

Exploring the Trypanosoma brucei Hsp83 Potential as a Target for Structure Guided Drug Design

Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite

A leaky umbrella has little value:evidence clearly indicates the serotonin system is implicated in depression

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

Primordial Nucleosynthesis with a Decaying Tau Neutrino

A comprehensive study of the effect of an unstable tau neutrino on primordial nucleosynthesis is presented. The standard code for nucleosynthesis is modified to allow for a massive decaying tau neutrino whose daughter products include neutrinos, photons, $e^\pm$ pairs, and/or noninteracting (sterile) daughter products. Tau-neutrino decays influence primordial nucleosynthesis in three distinct ways: (i) the energy density of the decaying tau neutrino and its daughter products affect the expansion rate tending to increase $^4$He, D, and $^3$He production; (ii) electromagnetic (EM) decay products heat the EM plasma and dilute the baryon-to-photon ratio tending to decrease $^4$He production and increase D and $^3$He production; and (iii) electron neutrinos and antineutrinos produced by tau-neutrino decays increase the weak rates that govern the neutron-to-proton ratio, leading to decreased $^4$He production for short lifetimes (\la 30\sec) and masses less than about 10\MeV and increased $^4$He production for long lifetimes or large masses. The precise effect of a decaying tau neutrino on the yields of primordial nucleosynthesis and the mass-lifetime limits that follow depend crucially upon decay mode. We identify four generic decay modes that serve to bracket the wider range of possibilities:Comment: 27 pages, Latex, 12 Figures avaiable on request, FNAL--Pub--93/236-

Effect of Virulence Factors on the Photodynamic Inactivation of Cryptococcus neoformans

Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance.Fundação de Amparo à Pesquisa do Estado de São Paulo (2010/13313–9