PNNL-13501 - Pacific Northwest National Laboratory

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Biologically-Based Dose-Response Models for Low Dose Exposures to Chemicals and Radionuclide Mixtures Study Control Number: PN00016/1423 Charles Timchalk, William B. Chrisler, Richard Corley A challenge associated with DOE’s massive cleanup efforts is understanding the impact of concurrent exposures to, or mixtures of, radionuclides and toxic chemicals. Current human health risk assessment procedures are cumbersome, address one chemical or radionuclide at a time, and are oftentimes overly conservative. This research looks at methods to assess health risks from mixtures of chemicals and radionuclides. Project Description In recent years, advances in biologically based models of internal radiation dosimetry and response modeling have provided unique opportunities to understand and predict the human health risks associated with mixed exposures. In a previous study, a representative chemical (benzene that is toxic to the bone marrow) and a bone-seeking radionuclide (yttrium-90 that is capable of irradiating bone marrow and thus causing toxicity), were evaluated for toxicological interactions in the CBA/Ca mouse model (a strain of inbred mice) (Timchalk et al. 2000). The results from these in vivo studies were consistent with previously published reports where benzene and radiation both independently target hematopoiesis. However, the overall biological responses following a co-exposure were complex since benzene and radiation appeared to cause different shifts in the myeloid and erythroid cell populations. A pharmacodynamic model was developed to describe cytotoxicity and cell kinetics following benzene exposure in mice (Scheding et al. 1992; Cox 1996). The model will eventually be adapted to quantitatively evaluate the biological response from a co-exposure to benzene and radiation. Since benzene and radiation share a common target tissue (bone marrow) and toxicological response (hematotoxicity, acute myelogenous leukemia), it is reasonable to anticipate that these two agents, in collaboration, are capable of producing a dose-dependent hematotoxic interaction. The model as described by Scheding et al. (1992) consists of a set of compartments representing specific cell populations including: CFU-S, CFU-E, CFU-GM, and mature erythrocytes and granulocyte/macrophage cells. As depicted in Figure 1, the erythrocytic (CFU-E) and granulocytic (CFU-GM) cell lineage descend from a common progenitor stem cell 38 FY 2000 <strong>Laboratory</strong> Directed Research and Development Annual Report (CFU-S) and the hematopoiesis process (cell differentiation/proliferation) is under feedback control (I). CFU-S stem cells are self-renewing and capable of differentiating into CFU-E or CFU-GM. In addition, CFU-GM and CFU-E progenitors are under feedback control (II) from erythro- and granulopoietic bone marrow cells, respectively. Benzene and radiation are believed to act on all proliferating cell stages and the loss coefficients (KH1, KH2, KG1, KG2, KE1, KE2) will be used to quantify the extent of damage to the various precursor cell populations. I CFU-S II II KH 2 KH 1 CFU-GM KG 1 CFU-E KG 2 Mature Granulocyte Benzene Radiation KE 1 KE 2 Mature Erythrocyte Proliferation Maturation Figure 1. Structure of the pharmacodynamic model for benzene/radiation interaction on hematopoiesis. The model incorporates feedback regulation (I and II) for self-renewal, differentiation, and proliferation. Benzene metabolites and radiation are both assumed to act on proliferating cell stages. Model adapted from Scheding et al. (1992). The focus of this project was to develop an in vitro stem cell culture using bone marrow cells obtained from CBA/Ca mice to evaluate the toxicological response following benzene metabolite and radiation exposures. Development of this in vitro stem cell culture system is needed to experimentally develop and validate pharmacodynamic models of cell injury.
Approach Hematopoietic (bone marrow) progenitor cell populations will be cultured from CBA/Ca mice according to Farris et al. (1997) and Green et al. (1981). The CBA/Ca mouse was chosen since it is a useful model for benzene-induced leukemia and will be of relevance for understanding the human disease process. In brief, the CFU-S were cultured in conditioned semisolid agar media containing macrophage-colony stimulating factor, interleukin 3, and incubated for up to 12 days at 37°C with various combinations of benzene metabolites (phenol and hydroquinone). At approximately 12 hours prior to counting, the cells were overlaid with a solution of 2-(4-iodophenyl)-3- (4-nitrophenyl)-5-phenyltetrazolium chloride) that is metabolized by viable cells forming a red color for macroscopic quantitation. The CFU-E progenitor cells were cultured in a methycellulose semisolid medium containing 30% fetal bovine serum, 1% bovine serum albumin, and colony stimulating factors erythropoietin as previously described (Farris et al. 1997). Cultures were incubated at 37°C for about 2.5 days and examined by light microscopy, and cell aggregates were scored as colonies. The CFU-GM assay was conducted using the agar culture technique described by Farris and Benjamin (1993). Cultures were incubated for up to 7 days at 37°C with various combinations of benzene metabolites and on day 6, 2-(4-iodophenyl)-3-(4-nitrophenyl)-5phenyltetrazolium chloride was added to the colonies as previously described for the CFU-S assay and colonies were scored. The results of these studies were expressed as number of colonies formed per two femurs and were compared to the response from nontreated cultures. The results were expressed as a percent of control. Similar studies were conducted by exposing stem cells to the 60 Co source available at our <strong>Laboratory</strong>. This gamma radiation source provides an efficient technique for exposing cells at a known radiation dose and dose rate. Studies were also conducted with radiation in combination with benzene metabolites to generate preliminary data on potential interactions in these specific cell types important to the development of both radiation and benzene-induced leukemia. Results and Accomplishments Initial efforts primarily focused on optimizing experimental conditions for isolation and culturing of the bone marrow stem (CFU-S) and progenitor cells (CFU-E and CFU-GM) obtained from naïve mice. Once conditions were optimized, experiments with radiation or benzene metabolites were conducted. The preliminary experiments were designed to determine the doseresponse for bone marrow cell proliferation following exposure to gamma radiation ( 60 Co) and are presented in Figure 2. Cells were exposed to a dose range from 0.01 to 10 Gy. For all three cell populations, a clear doseresponse relationship was established. However, doses greater than 1 Gy decreased colony formation to 11 to 16% of the control response. Based on these results, the radiation doses for the mixed exposures were set at 0.01, 0.1, and 1 Gy. Average +/- SE 80 70 60 50 40 30 20 10 0 Stem Cell Assay Radiation Exposure CFU-E CFU-GM CFU-S Control 0.01 Gy 0.1 Gy 1 Gy 5 Gy 10 Gy Figure 2. Colony formation dose-response for CFU-E, CFU-GM, and CFU-S cells following in vitro exposure to radiation ranging from 0 to 10 Gy from an external 60 Co source The selection of phenol and hydroquinone concentrations for in vitro evaluation in the stem cell assay were based on the results seen in bone marrow cells obtained from Swiss Webster mice (Corti and Snyder 1998). The results obtained with the CFU-S cells following exposure to phenol and HQ at concentrations of 0, 10, 20, and 40 µM and to a mixture of phenol (40 µM) + HQ (10 µM) are presented in Figure 3. These results in CFU-S cells are consistent with the response reported by Corti and Snyder (1998) with CFU-E cells indicating that hydroquinone is more cytotoxic than phenol and that the combined response of hydroquinone and phenol, on CUF-S cells is significantly greater that additive. However, the combined response was not seen with the CFU-GM or CFU-E progenitor cells. The CFU-S cell response to a combined exposure to both radiation and benzene metabolites is presented in Figure 4. Again, the radiation exposure produced a similar dose-response as seen with the preliminary radiation studies, although the inhibition at 1 Gy was less that previously observed. In the absence of radiation treatment, hydroquinone, phenol, and hydroquinone plus Biosciences and Biotechnology 39
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Laboratory Directed Research and De
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Page 9 and 10: Introduction Department of Energy O
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Solution-State Structure and Fold-C
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Plant Root Exudates and Microbial G
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Study Control Number: PN00077/1484
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Summary and Conclusions • The gre
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Jones-Oliveira JB, JS Oliveira, HE
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• securely moves files to a targe
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Plenary invited lecture, “The Ele
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Figure 1. X3DGEN tetrahedral mesh o
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Figure 5a. OSO volume rendering of
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Development of Models of Cell-Signa
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SOS p 23 EGFR Professor Rodland at
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Oliveira JS, JB Jones-Oliveira, and
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Figure 2. Associating a dataset mar
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shown in Figure 1. Simulated result
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HostBuilder: A Tool for the Combina
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Invariant Discretization Methods fo
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Graphics, Inc., workstation. The co
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Mixed Hamiltonian Methods for Geoch
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guyanaite, and grimaldiite (see Fig
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in the Environmental Molecular Scie
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Simulation and Modeling of Electroc
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Summary and Conclusions We implemen
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Since the implementation of the gen
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asis of previous performance, perce
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Bioinformatics for High-Throughput
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Summary and Conclusions In previous
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User Cat - Supervisor (client) Anal
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The second goal was to research way
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Figure 1. A visualization technique
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and interactions. The flexibility o
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Figure 4. A filtered version of Fig
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Development of Modeling Tools for J
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Figure 2. Schematic of experimental
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Integrated Modeling and Simulation
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(a) (b) (c) (d) Figure 1. Results o
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Thurman DA. August 2000. Collaborat
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MARC Input initial m esh and result
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(Johnson 1999; Colligan 1999; Gould
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Modeling of High-Velocity Forming f
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Global divergence error 1 10 -14 0
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that users were unlikely to appreci
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Earth System Science
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the lateral extent of the plume so
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Biogeochemical Processes and Microb
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Analyses of populations of viable a
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The first task was to establish fiv
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purged for 2 minutes. The gas sampl
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developing code architecture to min
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Berkowitz, CM. June 2000. “Atmosp
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environmental monitoring, 2) portab
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corresponded to a current density o
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Enhancing Emissions Pre-Processing
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Environmental Fate and Effects of D
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nitrogen and unpredictable eutrophi
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Figure 1. Ordinary kriging of 2 m d
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precipitation of calcite occurred i
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phenanthrene resistant fraction con
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injection of an immiscible gas phas
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still some key kinetic issues that
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Application of a Crop Model The res
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The Nature, Occurrence, and Origin
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Particle number concentration, 1/cm
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geometry optimized AlOOH and FeOOH
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allowable parameters using thermody
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TCE + 3H + + 3Fe 2+ Fe)=> acetylene
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Use of Shear-Thinning Fluids for In
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concentration of 0.5% AMX was the m
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Roberts AL, LA Totten, WA Arnold, D
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tetra-scale computing, envisioned a
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Energy Technology and Management
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Figure 2. Setup for the second expe
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phase. The algorithms will be teste
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[Pb-212]/[Pb-212] final 100 10 1 0.
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Plasma Particle Dielectric Fiber El
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(species, sub-species, and sex), sp
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Figure 3. Relative risk of bone and
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Development of a Preliminary Physio
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Development of a Virtual Respirator
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Figure 3. Use of the chest cavity a
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Examination of the Use of Diazolumi
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Indoor Air Pathways to Nuclear, Che
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Source Building Release Observed re
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To illustrate the potential impact
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Non-Invasive Biological Monitoring
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Materials Science and Technology
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Figure 1. (a) - (c) Successive magn
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Component Fabrication and Assembly
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Development of a Low-Cost Photoelec
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elaxations, indicating the adequacy
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Promising chemical durability, as m
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Study Control Number : PN98028/1274
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High Power Density Solid Oxide Fuel
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Hybrid Plasma Process for Vacuum De
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Matson DW, PM Martin, WD Bennett, J
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We showed the proof-of-principle ap
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Bandgap Energy (eV) 2.9 2.85 2.8 2.
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Ultrathin Electrolyte Test Results
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Detailed Investigations on Hydrogen
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identified low energy step structur
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Development of Novel Photo-Catalyst
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-2 -1 Energy (eV) 0 1 2 Cu2O SrTiO3
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Here, we perform adsorption and des
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exceed those in the all-metal devic
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Intensity (a.u.) 0 100 200 300 400
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integrated voltage (V) 0.10 0.08 0.
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The first step was to implement thi
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Spontaneous Formation of Cu2O Nano-
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Actinide Chemistry at the Aqueous-M
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to 300°C and 400°C. Unfortunately
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Summary and Conclusions Transmutati
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Advanced Calibration/Registration T
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Figure 1a. Violet filter Figure 1b.
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Autonomous Ultrasonic Probe for Pro
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containing nitrous oxide, an optica
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Chemical Detection Using Cavity Enh
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Figure 3 is a color rendered simula
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appropriate study has been performe
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Exploitation of Conventional Chemic
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Figures 3 and 4 illustrate the impa
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enefits of using a modified spread-
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Single Channel Signal 0.0025 0.0020
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Therefore, in order to extract the
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A next-generation technology is nee
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Wind Dir. Figure 2. Negative ion co
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Volumetric Imaging of Materials by
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amplitude and peak frequency change
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Figure 3. 13 C NMR spectrum of corn
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Approach Two flow loops, one that o
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Modification of Ion Exchange Resins
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Permanganate Treatment for the Deco
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minimized by medium exchange. After
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Figure 1. Thermogravimetric analysi
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Validation and Scale-Up of Monosacc
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Concentration (g/100g solution) Con
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Analysis of High-Volume, Hyper-Dime
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ecent figure of merit values. Shoul
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Probabilistic Methods Development f
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a) Traditional PCA-based process co
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Acronyms and Abbreviations 2-D two-
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