HANDBOOK OF SHIELDING REQUIREMENTS AND RADIATION CHARACTERISTICS OF ISOTOPIC POWER SOURCES FOR TERRESTRIAL, MARINE, AND SPACE APPLICATIONS

The radiation intensities from shielded and unshielded sources fabricated from seventeen isotopes that show promise for use in isotopic power or radiation applications were calculated. Source sizes in the range of 100 to 20,000 thermal watts were evaluated. All shielded sources were assumed to be attenuated by Fe, Pb, and U; and in those cases where the source also emitted neutrons, neutron and gamma attenuation through water was determined. The isotopes studied and their physical form are as follows: /sup 60/Co (metal), /sup 85/Kr (liquefied gas), /sup 90/Sr (oxide and titanate), Zr-/sup 95/Nb (oxide), / sup 106/Ru (metal), /sup 137/Cs (glass), /sup 144/Ce (ox ide), /sup 147/Pm (oxide), /sup 170/Tm and /sup 171/Tm (both as oxides), /sup 204/Tl (metal), /sup 210/Po (metal matrix with void space for gas collection), /sup 232/U (oxide), /sup 228/Th (oxide matrix with void space for gas collection), /sup 238/Pu (oxide), /sup 242/Cm (oxide matrix with void space for gas collection), and / sup 244/Cm (oxide). The use of the graphical results to calculate separation distance, shield thickness, and shield weight is demonstrated. (auth

MALTE - Model to predict new aerosol formation in the lower troposphere

The manuscript presents a detailed description of the meteorological and chemical code of Malte – a model to predict new aerosol formation in the lower troposphere. The aerosol dynamics are achieved by the new developed UHMA (University of Helsinki Multicomponent Aerosol Model) code with kinetic limited nucleation as responsible mechanism to form new clusters. First results indicate that the model is able to predict the on- and offset of new particle formation as well as the total aerosol number concentrations that were in good agreement with the observations. Further, comparison of predicted and measured H2SO4 concentrations showed a satisfactory agreement. The simulation results indicated that at a certain transitional particle diameter (2–7 nm), organic molecules can begin to contribute significantly to the growth rate compared to sulphuric acid. At even larger particle sizes, organic molecules can dominate the growth rate on days with significant monoterpene concentrations. The intraday vertical evolution of newly formed clusters and particles in two different size ranges resulted in two maxima at the ground. These particles grow around noon to the detectable size range and agree well with measured vertical profiles

Moving constraints as stabilizing controls in classical mechanics

The paper analyzes a Lagrangian system which is controlled by directly assigning some of the coordinates as functions of time, by means of frictionless constraints. In a natural system of coordinates, the equations of motions contain terms which are linear or quadratic w.r.t.time derivatives of the control functions. After reviewing the basic equations, we explain the significance of the quadratic terms, related to geodesics orthogonal to a given foliation. We then study the problem of stabilization of the system to a given point, by means of oscillating controls. This problem is first reduced to the weak stability for a related convex-valued differential inclusion, then studied by Lyapunov functions methods. In the last sections, we illustrate the results by means of various mechanical examples.Comment: 52 pages, 4 figure

A polymerase mechanism-based strategy for viral attenuation and vaccine development

Live, attenuated vaccines have prevented morbidity and mortality associated with myriad viral pathogens. Development of live, attenuated vaccines has traditionally relied on empirical methods, such as growth in nonhuman cells. These approaches require substantial time and expense to identify vaccine candidates and to determine their mechanisms of attenuation. With these constraints, at least a decade is required for approval of a live, attenuated vaccine for use in humans. We recently reported the discovery of an active site lysine residue that contributes to the catalytic efficiency of all nucleic acid polymerases (Castro, C., Smidansky, E. D., Arnold, J. J., Maksimchuk, K. R., Moustafa, I., Uchida, A., Götte, M., Konigsberg, W., and Cameron, C. E. (2009) Nat. Struct. Mol. Biol. 16, 212-218). Here we use a model RNA virus and its polymerase to show that mutation of this residue from lysine to arginine produces an attenuated virus that is genetically stable and elicits a protective immune response. Given the conservation of this residue in all viral polymerases, this study suggests that a universal, mechanism-based strategy may exist for viral attenuation and vaccine development. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc

Vaccine-derived mutation in motif D of poliovirus RNA-dependent RNA polymerase lowers nucleotide incorporation fidelity

All viral RNA-dependent RNA polymerases (RdRps) have a conserved structural element termed motif D. Studies of the RdRp from poliovirus (PV) have shown that a conformational change of motifDleads to efficient and faithful nucleotide addition by bringing Lys-359 into the active site where it serves as a general acid. The RdRp of the Sabin I vaccine strain has Thr-362 changed to Ile. Such a drastic change so close to Lys-359 might alter RdRp function and contribute in some way to the attenuated phenotype of Sabin type I. Here we present our characterization of the T362I RdRp.Wefind that the T362I RdRp exhibits a mutator phenotype in biochemical experiments in vitro. Using NMR, we show that this change in nucleotide incorporation fidelity correlates with a change in the structural dynamics of motif D. A recombinant PV expressing the T362I RdRp exhibits normal growth properties in cell culture but expresses a mutator phenotype in cells. For example, the T362I-containing PV is more sensitive to the mutagenic activity of ribavirin than wildtype PV. Interestingly, the T362I change was sufficient to cause a statistically significant reduction in viral virulence. Collectively, these studies suggest that residues of motif D can be targeted when changes in nucleotide incorporation fidelity are desired. Given the observation that fidelity mutants can serve as vaccine candidates, it may be possible to use engineering of motif D for this purpose

Lentiviral Hematopoietic Stem Cell Gene Therapy Corrects Murine Pompe Disease

Pompe disease is an autosomal recessive lysosomal storage disorder characterized by progressive muscle weakness. The disease is caused by mutations in the acid α-glucosidase (GAA) gene. Despite the currently available enzyme replacement therapy (ERT), roughly half of the infants with Pompe disease die before the age of 3 years. Limitations of ERT are immune responses to the recombinant enzyme, incomplete correction of the disease phenotype, lifelong administration, and inability of the enzyme to cross the blood-brain barrier. We previously reported normalization of glycogen in heart tissue and partial correction of the skeletal muscle phenotype by ex vivo hematopoietic stem cell gene therapy. In the present study, using a codon-optimized GAA (GAAco), the enzyme levels resulted in close to normalization of glycogen in heart, muscles, and brain, and in complete normalization of motor function. A large proportion of microglia in the brain was shown to be GAA positive. All astrocytes contained the enzyme, which is in line with mannose-6-phosphate receptor expression and the key role in glycogen storage and glucose metabolism. The lentiviral vector insertion site analysis confirmed no preference for integration near proto-oncogenes. This correction of murine Pompe disease warrants further development toward a cure of the human condition.This publication reports that stem cell gene therapy using a codon-optimized gene encoding acid α-glucosidase (GAA) cures the mouse model of Pompe disease, a lysosomal storage disorder

Meson Exchange Currents in (e,e'p) recoil polarization observables

A study of the effects of meson-exchange currents and isobar configurations in $A(\vec{e},e'\vec{p})B$ reactions is presented. We use a distorted wave impulse approximation (DWIA) model where final-state interactions are treated through a phenomenological optical potential. The model includes relativistic corrections in the kinematics and in the electromagnetic one- and two-body currents. The full set of polarized response functions is analyzed, as well as the transferred polarization asymmetry. Results are presented for proton knock-out from closed-shell nuclei, for moderate to high momentum transfer.Comment: 44 pages, 18 figures. Added physical arguments explaining the dominance of OB over MEC, and a summary of differences with previous MEC calculations. To be published in PR

Structural dynamics as a contributor to error-prone replication by an RNA-dependent RNA polymerase

RNA viruses encoding high- or low-fidelity RNA-dependent RNA polymerases (RdRp) are attenuated. The ability to predict residues of the RdRp required for faithful incorporation of nucleotides represents an essential step in any pipeline intended to exploit perturbed fidelity as the basis for rational design of vaccine candidates. We used x-ray crystallography, molecular dynamics simulations,NMRspectroscopy, and pre-steady-state kinetics to compare a mutator (H273R) RdRp from poliovirus to the wild-type (WT) enzyme. We show that the nucleotide-binding site toggles between the nucleotide binding-occluded and nucleotide binding-competent states. The conformational dynamics between these states were enhanced by binding to primed template RNA. For the WT, the occluded conformation was favored; for H273R, the competent conformation was favored. The resonance for Met-187 in our NMR spectra reported on the ability of the enzyme to check the correctness of the bound nucleotide. Kinetic experiments were consistent with the conformational dynamics contributing to the established pre-incorporation conformational change and fidelity checkpoint. For H273R, residues comprising the active site spent more time in the catalytically competent conformation and were more positively correlated than the WT. We propose that by linking the equilibrium between the binding-occluded and binding-competent conformations of the nucleotide-binding pocket and other active-site dynamics to the correctness of the bound nucleotide, faithful nucleotide incorporation is achieved. These studies underscore the need to apply multiple biophysical and biochemical approaches to the elucidation of the physical basis for polymerase fidelity

Channel Coupling in A(e⃗,e′N⃗)BA(\vec{e},e' \vec{N})B Reactions

The sensitivity of momentum distributions, recoil polarization observables, and response functions for nucleon knockout by polarized electrons to channel coupling in final-state interactions is investigated using a model in which both the distorting and the coupling potentials are constructed by folding density-dependent effective interactions with nuclear transition densities. Calculations for $^{16}$O are presented for 200 and 433 MeV ejectile energies, corresponding to proposed experiments at MAMI and TJNAF, and for $^{12}$C at 70 and 270 MeV, corresponding to experiments at NIKHEF and MIT-Bates. The relative importance of charge exchange decreases as the ejectile energy increases, but remains significant for 200 MeV. Both proton and neutron knockout cross sections for large recoil momenta, $p_m > 300$ MeV/c, are substantially affected by inelastic couplings even at 433 MeV. Significant effects on the cross section for neutron knockout are also predicted at smaller recoil momenta, especially for low energies. Polarization transfer for proton knockout is insensitive to channel coupling, even for fairly low ejectile energies, but polarization transfer for neutron knockout retains nonnegligible sensitivity to channel coupling for energies up to about 200 MeV. The present results suggest that possible medium modifications of neutron and proton electromagnetic form factors for $Q^2 \gtrsim 0.5 (GeV/c)^2$ can be studied using recoil polarization with relatively little sensitivity due to final state interactions.Comment: Substantially revised version accepted by Phys. Rev. C; shortened to 49 pages including 21 figure