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WRN is unique among the five human RecQ DNA helicases by having a functional exonuclease domain (WRN-exo) and being defective in the premature aging and cancer-related disorder Werner syndrome. Here, we characterize WRN-exo crystal structures, biochemical activity and participation in DNA end-joining. Metal ion complex structures, active site mutations and activity assays reveal a two-metal-ion mediated nuclease mechanism. The DNA end-binding Ku70/80 complex specifically stimulates WRN-exo activity, and structure-based mutational inactivation of WRN-exo alters DNA end-joining in human cells. We furthermore establish structural and biochemical similarities of WRN-exo to DnaQ family replicative proofreading exonucleases, with WRN-specific adaptations consistent with dsDNA specificity and functionally important conformational changes. These results indicate WRN-exo is a human DnaQ family member and support analogous proof-reading activities that are stimulated by Ku70/80 with implications for WRN functions in age related pathologies and maintenance of genomic integrity.

Erythroid progenitors differentiate in erythroblastic islands, bone marrow niches composed of erythroblasts surrounding a central macrophage. Evidence suggests that within islands adhesive interactions regulate erythropoiesis and apoptosis. We are exploring whether erythroid intercellular adhesion molecule-4 (ICAM-4), animmunoglobulin superfamily member, participates in island formation. Earlier, we identified alpha V integrins as ICAM-4 counter receptors. Since macrophages express alpha V, ICAM-4 potentially mediates island attachments. To test this, we generated ICAM-4 knockout mice and developed quantitative, live cell techniques for harvesting intact islands and for reforming islands in vitro. We observed a 47 percent decrease in islands reconstituted from ICAM-4 null marrow compared to wild type. We also found a striking decrease in islands formed in vivo in knockout mice. Further, peptides that block ICAM-4 alpha V adhesion produced a 53-57 percent decrease in reconstituted islands, strongly suggesting that ICAM-4 binding to macrophage alpha V functions in island integrity. Importantly, we documented that alpha V integrin is expressed in macrophages isolated from erythro blastic islands. Collectively, these data provide convincing evidence that ICAM-4 is critical in erythroblastic island formation via ICAM-4/alpha V adhesion and also demonstrate that the novel experimental strategies we developed will be valuable in exploring molecular mechanisms of erythroblastic …

Several technological options have been proposed to stabilize atmospheric concentrations of CO{sub 2}. One proposed remedy is to separate and capture CO{sub 2} from fossil-fuel power plants and other stationary industrial sources and to inject the CO{sub 2} into deep subsurface formations for long-term storage and sequestration. Characterization of geologic formations for sequestration of large quantities of CO{sub 2} needs to be carefully considered to ensure that sites are suitable for long-term storage and that there will be no adverse impacts to human health or the environment. The Intergovernmental Panel on Climate Change (IPCC) Special Report on Carbon Dioxide Capture and Storage (Final Draft, October 2005) states that ''Site characterization, selection and performance prediction are crucial for successful geological storage. Before selecting a site, the geological setting must be characterized to determine if the overlying cap rock will provide an effective seal, if there is a sufficiently voluminous and permeable storage formation, and whether any abandoned or active wells will compromise the integrity of the seal. Moreover, the availability of good site characterization data is critical for the reliability of models''. This International Symposium on Site Characterization for CO{sub 2} Geological Storage (CO2SC) addresses the particular issue of site characterization …

The nucleation and coalescence of silver islands on coated glass was investigated by in-situ measurements of the sheet resistance. Sub-monolayer amounts of transition metals (Nb, Ti, Ni, Cr, Zr, Ta, and Mo) were deposited prior to the deposition of silver. It was found that some, but not all, of the transition metals lead to coalescence of silver at nominally thinner films with smoother topology. The smoothing effect of the transition metal at sub-monolayer thickness can be explained by a thermodynamic model of surface energies.

One of the outstanding issues in the quantum instanton (QI) theory (or any transition state-type theory) for thermal rate constants of chemical reactions is the choice of an appropriate ''dividing surface'' (DS) that separates reactants and products. (In the general version of the QI theory, there are actually two dividing surfaces involved.) This paper shows one simple and general way for choosing DS's for use in QI Theory, namely using the family of (hyper) planes normal to the minimum energy path (MEP) on the potential energy surface at various distances s along it. Here the reaction coordinate is not one of the dynamical coordinates of the system (which will in general be the Cartesian coordinates of the atoms), but rather simply a parameter which specifies the DS. It is also shown how this idea can be implemented for an N-atom system in 3d space in a way that preserves overall translational and rotational invariance. Numerical application to a simple system (the colliner H + H{sub 2} reaction) is presented to illustrate the procedure.

In this contribution we will describe a technology path to very high quality coatings fabricated in the vacuum of space. To accomplish the ambitious goals set out in NASA's Lunar-Mars proposal, advanced thin-film deposition technology will be required. The ability to deposit thin-film coatings in the vacuum of lunar-space could be extremely valuable for executing this new space mission. Developing lightweight space-based deposition technology (goal:<300 g, including power supply) will enable the future fabrication and repair of flexible large-area space antennae and fixed telescope mirrors for lunar-station observatories. Filtered Cathodic Arc (FCA) is a proven terrestrial energetic thin-film deposition technology that does not need any processing gas but is well suited for ultra-high vacuum operation. Recently, miniaturized cathodic arcs have already been developed and considered for space propulsion. It is proposed to combine miniaturized pulsed FCA technology and robotics to create a robust, enabling space-based deposition system for the fabrication, improvement, and repair of thin films, especially of silver and aluminum, on telescope mirrors and eventually on large area flexible substrates. Using miniature power supplies with inductive storage, the typical low-voltage supply systems used in space are adequate. It is shown that high-value, small area coatings are within the reach …

To understand how non-malignant human mammary epithelial cells (HMEC) transit from a disorganized proliferating to an organized growth arrested state, and to relate this process to the changes that occur in breast cancer, we studied gene expression changes in non-malignant HMEC grown in three-dimensional cultures, and in a previously published panel of microarray data for 295 breast cancer samples. We hypothesized that the gene expression pattern of organized and growth arrested mammary acini would share similarities with breast tumors with good prognoses. Using Affymetrix HG-U133A microarrays, we analyzed the expression of 22,283 gene transcripts in two HMEC cell lines, 184 (finite life span) and HMT3522 S1 (immortal non-malignant), on successive days post-seeding in a laminin-rich extracellular matrix assay. Both HMECs underwent growth arrest in G0/G1 and differentiated into polarized acini between days 5 and 7. We identified gene expression changes with the same temporal pattern in both lines. We show that genes that are significantly lower in the organized, growth arrested HMEC than in their proliferating counterparts can be used to classify breast cancer patients into poor and good prognosis groups with high accuracy. This study represents a novel unsupervised approach to identifying breast cancer markers that may be of …

Pallavi Pharkya thinks a lot about the future. Pharkya, a Ph.D. candidate in materials science and engineering, works in the area of corrosion science, predicting how materials will perform over extended periods of time. Her particular focus is a nickel-chromium-molybdenum alloy called C-22, a highly corrosion-resistant metal. Pharkya's aim is to help determine whether containers made from C-22 can be used to store high-energy nuclear waste--for 10,000 years and longer. Pharkya's work is part of a plan by the U.S. Department of Energy to consolidate the country's nuclear waste in a single proposed repository. The proposed repository is in Yucca Mountain located in a remote Nevada desert. Currently about 70,000 metric tons of spent nuclear fuel and high-level radioactive waste are divided between approximately 100 sites around the country. The undertaking, Pharkya emphasizes, is massive. To study just the corrosion aspects of the packaging, Case is collaborating with eight other universities, five national labs and Atomic Energy of Canada Limited. Even with so many players, the study will likely take several years to complete. Heading the entire group is Joe Payer, a professor of materials science and engineering at Case and Pharkya's mentor. ''I came here to have the opportunity …

Pharkya, a Ph.D. candidate in materials science and engineering, works in the area of corrosion science, predicting how materials will perform over extended periods of time. Her particular focus is a nickel-chromium-molybdenum alloy called C-22, a highly corrosion-resistant metal. Pharkya's aim is to help determine whether containers made from C-22 can be used to store high-energy nuclear waste--for 10,000 years and longer. Pharkya's work is part of a plan by the U.S. Department of Energy to consolidate the country's nuclear waste in a single proposed repository. The proposed repository is in Yucca Mountain located in a remote Nevada desert. Currently about 70,000 metric tons of spent nuclear fuel and high-level radioactive waste are divided between approximately 100 sites around the country. The undertaking, Pharkya emphasizes, is massive. To study just the corrosion aspects of the packaging, Case is collaborating with eight other universities, five national labs and Atomic Energy of Canada Limited. Even with so many players, the study will likely take several years to complete. Heading the entire group is Joe Payer, a professor of materials science and engineering at Case and Pharkya's mentor. ''I came here to have the opportunity to work with Dr. Payer, an expert in …

Akt1 is frequently upregulated in human tumors, and has been shown to accelerate cell proliferation and to suppress programmed cell death; consequently, inhibiting the activity of Akt1 has been seen as an attractive target for therapeutic intervention. Paradoxically, hyperactivation of the Akt1 oncogene can also prevent the invasive behavior that underlies progression to metastasis. Here we show that overexpression of activated myr-Akt1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation, leading to reduced Rho-GTPase activity, decreased actin stress fibers and focal adhesions, and reduced motility and invasion. Overexpression of TSC2 rescues the migration phenotype of myr-Akt1-expressing tumor cells, and high levels of TSC2 in breast cancer patients correlate with increased metastasis and reduced survival. These data indicate that the functional properties of genes designated as oncogenes or tumor suppressor genes depends on the context of the cell type and the tissues studied, and suggest the need for caution in designing therapies targeting the function of individual genes in epithelial tissues.

Since the end of the cold war, the need for operating weapons production facilities has faded. Criticality Safety Limits and controls supporting production modes in these facilities became outdated and furthermore lacked the procedure based rigor dictated by present day requirements. In the past, in many instances, the formalism of present day criticality safety evaluations was not applied. Some of the safety evaluations amounted to a paragraph in a notebook with no safety basis and questionable arguments with respect to double contingency criteria. When material stabilization, clean out, and deactivation activities commenced, large numbers of these older criticality safety evaluations were uncovered with limits and controls backed up by tenuous arguments. A dilemma developed: on the one hand, cleanup activities were placed on very aggressive schedules; on the other hand, a highly structured approach to limits development was required and applied to the cleanup operations. Some creative approaches were needed to cope with the limits development process.

An important aspect of plasma wake field accelerators (PWFA) is stable propagation of the drive beam. In the under dense plasma regime, the drive beam creates an ion channel which acts on the beam as a strong thick focusing lens. The ion channel causes the beam to undergo multiple betatron oscillations along the length of the plasma. There are several advantages if the beam size can be matched to a constant radius. First, simulations have shown that instabilities such as hosing are reduced when the beam is matched [1]. Second, synchrotron radiation losses are minimized when the beam is matched. Third, an initially matched beam will propagate with no significant change in beam size in spite of large energy loss or gain. Coupling to the plasma with a matched radius can be difficult in some cases. This paper shows how an appropriate density ramp at the plasma entrance can be useful for achieving a matched beam. Additionally, the density ramp is helpful in bringing a misaligned trailing beam onto the drive beam axis. A plasma source with boundary profiles useful for matching has been created for the E-164X PWFA experiments at SLAC.

Despite substantial clinical interest in the fracture resistance of human dentin, there is little mechanistic information in archival literature that can be usefully used to model such fracture. In fact, although the fracture event indent in, akin to other mineralized tissues like bone, is widely believed to be locally strain-controlled, there has never been any scientific proof to support this belief. The present study seeks to address this issue through the use of a novel set of in vitro experiments in Hanks' balanced salt solution involving a double-notched bend test geometry, which is designed to discern whether the critical failure events involved in the onset of fracture are locally stress- or strain-controlled. Such experiments are further used to characterize the notion of ''plasticity'' in dentin and the interaction of cracks with the salient microstructural features. It is observed that fracture in dentin is indeed locally strain-controlled and that the presence of dentinal tubules does not substantially affect this process of crack initiation and growth. The results presented are believed to be critical steps in the development of a micromechanical model for the fracture of human dentin that takes into consideration the influence of both the microstructure and the local failure …

A compact source of monoenergetic X-rays, generated via Compton backscattering, has been developed in a collaboration between U.C Davis and SLAC. The source consists of a 5.5 cell X-band photoinjector, a 1.05 m long high gradient accelerator structure and an interaction chamber where a high power (TW), short pulse (sub-ps) infrared laser beam is brought into a nearly head-on collision with a high quality focused electron beam. Successful completion of this project will result in the capability of generating a monoenergetic X-ray beam, continuously tunable from 20 - 85 keV. We have completed a series of measurements leading up to the generation of monoenergetic X-rays. Measurements of essential electron beam parameters and the techniques used in establishing electron/photon collisions will be presented. We discuss the design of an improved interaction chamber, future electro-optic experiments using this chamber and plans for expanding the overall program to the generation of Terahertz radiation.

We show that light ({approx_equal} 1-30 MeV) dark matter particles can play a significant role in core-collapse supernovae, if they have relatively large annihilation and scattering cross sections, as compared to neutrinos. We find that if such particles are lighter than {approx_equal} 10 MeV and reproduce the observed dark matter relic density, supernovae would cool on a much longer time scale and would emit neutrinos with significantly smaller energies than in the standard scenario, in disagreement with observations. This constraint may be avoided, however, in certain situations for which the neutrino-dark matter scattering cross sections remain comparatively small.

Experimental measurements of the properties of the top quark have improved and will continue to improve significantly, with the excellent operation of the CDF and D0 experiments and the Tevatron p{bar p} collider at the Fermi National Accelerator Laboratory. All of the final state experimental signatures from top quark production and decay are being analyzed to test if this most massive quark is sensitive to new physics beyond the standard model. So far, observations are consistent with the standard model. New techniques have dramatically improved the precision of the top quark mass measurement to 1.7% and set the stage for a sub-1% measurement by 2008. This improved knowledge of the top quark mass sharpens the standard model prediction for the mass of the undiscovered Higgs boson, with implications for Higgs studies at the future LHC and ILC.

Large amounts of CO2 would need to be injected underground to achieve a significant reduction of atmospheric emissions. The large areal extent expected for CO2 plumes makes it likely that caprock imperfections will be encountered, such as fault zones or fractures, which may allow some CO2 to escape from the primary storage reservoir. Leakage of CO2 could also occur along wellbores. Concerns with escape of CO2 from a primary geologic storage reservoir include (1) acidification of groundwater resources, (2) asphyxiation hazard when leaking CO2 is discharged at the land surface, (3) increase in atmospheric concentrations of CO2, and (4) damage from a high-energy, eruptive discharge (if such discharge is physically possible). In order to gain public acceptance for geologic storage as a viable technology for reducing atmospheric emissions of CO2, it is necessary to address these issues and demonstrate that CO2 can be injected and stored safely in geologic formations.

We have studied the spin relaxation in diluted spin ice Ho{sub 2-x} Y{sub x} Ti{sub 2}O{sub 7} by means of neutron spin echo spectroscopy. Remarkably, the geometrical frustration is not relieved by doping with non-magnetic Y, and the dynamics of the freezing is unaltered in the spin echo time window up to x {approx_equal} 1.6. At higher doping with non-magnetic Y (x {ge} 1.6) a new relaxation process at relatively high temperature (up to at least T {approx_equal} 55 K) appears which is more than 10 times faster than the thermally activated main relaxation process. We find evidence that over the whole range of composition all Ho spins participate in the dynamics. These results are compared to a.c. susceptibility measurements of the diluted Ho and Dy spin ice systems. X-ray absorption fine structure (EXAFS) spectra and x-ray diffraction show that the samples are structurally well ordered.

Resonance enhancement of the quantum efficiency of new polarized electron photocathodes based on a short-period strain-compensated AlInGaAs/GaAsP superlattice structure is reported. The superlattice is a part of an integrated Fabry-Perot optical cavity. We demonstrate that the Fabry-Perot resonator enhances the quantum efficiency by up to a factor 10 in the wavelength region of the main polarization maximum. The high structural quality implied by these results points to the very promising application of these photocathodes for spin-polarized electron sources.

The laser system for the Fermilab-NIU photoinjector [1] has been recently upgraded in order to improve reliability and to reduce amplitude fluctuations. Major modifications included the replacement of the oscillator by a diode-pumped passively mode locked Nd:YLF commercial laser [2]. The oscillator delivers 5 ps long pulses at 81.25 MHz at an average power of 450 mW. The number of round trips in the multi-pass amplifier was reduced by half and image relaying was introduced throughout the optical system. The frequency of the IR ({lambda} = 1053 nm) pulse was quadrupled to UV ({lambda} = 263.5 nm) by two BBO crystals. The overall efficiency for frequency quadrupling was of order 20%. The shot to shot fluctuations in the UV are {approx} 5%. The UV energy on the cathode is 5 {micro}J/pulse (10{micro}J/pulse without the pulse stacker), yielding charge of 10 nC/pulse.

Denitrification can effectively mitigate the problem of high nitrate concentrations in groundwater under dairy operations by reducing nitrate to N{sub 2} gas, at sites where biogeochemical conditions are favorable. We present results from field studies at central California dairies that document the occurrence of saturated-zone denitrification in shallow groundwater using biomolecular indicators, stable isotope compositions of nitrate, and measurements of dissolved excess N{sub 2} gas. Excess N{sub 2} concentrations provide a measure of the extent to which nitrate in groundwater has been partially or completely denitrified. Abundant excess N{sub 2} and young {sup 3}H/{sup 3}He apparent groundwater ages indicate high denitrification rates near manure lagoons where multiple lines of evidence indicate seepage of lagoon water into the groundwater system. Natural tracers of lagoon water include high chloride and dissolved organic carbon concentrations, distinctive trace organic compounds, and high groundwater {delta}{sup 18}O values (relative to other recharge sources). Proximal to the lagoons, NH{sub 4}{sup +} may be present in groundwater, but is strongly adsorbed on to sediment particles. Bubble formation in the lagoons causes the exsolution of other gases (N{sub 2}, Ar, Ne, He, etc.), which partition into the gas phase and strip the lagoon water of its dissolved gas load, …

A geophysical characterization project was conducted at the BC Cribs and Trenches Area, located south of 200 East at the Hanford Site. The area consists of 26 waste disposal trenches and cribs, which received approximately 30 million gallons of liquid waste from the uranium recovery process and the ferrocyanide processes associated with wastes generated by reprocessing nuclear fuel. Waste discharges to BC Cribs contributed perhaps the largest liquid fraction of contaminants to the ground in the 200 Areas. The site also includes possibly the largest inventory of Tc-99 ever disposed to the soil at Hanford with an estimated quantity of 400 Ci. Other waste constituents included high volumes of nitrate and U-238. The geophysical characterization at the 50 acre site primarily included high resolution resistivity (HRR). The resistivity technique is a non-invasive method by which electrical resistivity data are collected along linear transects, and data are presented as continuous profiles of subsurface electrical properties. The transects ranged in size from about 400-700 meters and provided information down to depths of 60 meters. The site was characterized by a network of 51 HRR lines with a total of approximately 19.7 line kilometers of data collected parallel and perpendicular to the trenches …

Characterization of the epistemic uncertainty and aleatory variability of ground motion, as part of the Yucca Mountain nuclear waste repository PSHA (Stepp et al., 2001), results in ground motion values that increase without bound as lower and lower annual probabilities of exceedance are considered. For probabilities of exceedance less than about 10{sup -6} (yr{sup -1}), use of these results as input to the site response model leads to ground motion values for the repository that most engineering seismologists feel are not credible. To provide a defensible technical basis to develop credible emplacement level motions for extreme events, the undeformed nature of the 12.8 million year old lithophysal tuff units at Yucca Mountain provide strong constraints on the level of strain (stress) not experienced by the site since deposition of the tuff. Uniaxial unconfined compressive tests (the only tests available to the project) of the lithophysal tuff indicate axial strains of about 0.3% at fracture, which converts to approximately 0.2% shear-strain. This shear-strain limit (fracture strain), which has not occurred, is used with standard equivalent-linear (and nonlinear) point-source site response analyses to develop corresponding response spectra assuming a controlling earthquake of M 6.5 at a distance of 5 km, based on …