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Quantification of glioblastoma progression in zebrafish xenografts: Adhesion to laminin alpha 5 promotes glioblastoma microtumor formation and inhibits cell invasion
Highlights: • Developed an embryo-larval zebrafish model to study GBM progression. • Quantitatively measured GBM BV association, invasion and microtumor formation. • Laminin alpha 5 decreases U251MG dispersal and increases microtumors. • Microenvironmental laminin alpha 5 slows U251MG cell invasion in vivo. Glioblastoma (GBM) is a deadly disease due to its ability to quickly invade and destroy brain tissue. Slowing or stopping GBM cell progression is crucial to help those inflicted with the disease. Our lab created an embryo-larval zebrafish xenograft model as a tool to study human GBM progression in an observable brain environment. The zebrafish brain is a dynamic and complex environment providing an optimal setting for studying GBM cell progression. Here we demonstrate the ability of our model to quantitate GBM proliferation, dispersal, blood vessel association, microtumor formation, and individual cell invasion by evaluating the importance of an extracellular matrix protein, laminin alpha 5 (lama5), on U251MG cell progression. Lama5 has been implicated in cancer cell survival, proliferation and invasion and is a known adhesion site for GBM cells. While lama5 is highly expressed in endothelial cells in the brain, it is unknown how lama5 affects GBM behavior. Using a lama5 morpholino, we discovered that lama5 decreased U251MG dispersal by 23% and doubles the formation of blood vessel dependent microtumors. Despite lama5 being a known attachment site for GBM, lama5 expression had no effect on U251MG association with blood vessels. Analysis of individual U251MG cells revealed lama5 significantly lowered invasion as mobile U251MG cells traveled 32.5 μm less, invaded 5.0 μm/hr slower and initiated invasion 60% few times per cell.
High temperature magnetic properties of SmCo{sub 5}/{alpha}-Fe(Co) bulk nanocomposite magnets
To find alternative high temperature magnets containing no heavy rare earths for power applications, SmCo{sub 5}/Fe bulk nanocomposite magnets with enhanced energy density and high thermal stability have been produced by using a ball-milling plus warm-compaction route. Up to 30% of the Fe soft magnetic phase has been added to the composites with grain size <20 nm distributed homogenously in the matrix of the SmCo{sub 5} hard magnetic phase. It was observed that the microstructure does not change with temperature up to 500 Degree-Sign C. It is also observed that the thermal stability of bulk nanocomposite samples is closely related to bulk density. Energy products above 11 MGOe have been obtained at 300 Degree-Sign C in fully dense bulk SmCo{sub 5}/Fe nanocomposite magnets, which is 65% higher than that of a single-phase counterpart at the same temperature.
Structure of human steroid 5[alpha]-reductase 2 with the anti-androgen drug finasteride
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A structural model of anti-anti-[sigma] inhibition by a two-component receiver domain: the PhyR stress response regulator
PhyR is a hybrid stress regulator conserved in {alpha}-proteobacteria that contains an N-terminal {sigma}-like (SL) domain and a C-terminal receiver domain. Phosphorylation of the receiver domain is known to promote binding of the SL domain to an anti-{sigma} factor. PhyR thus functions as an anti-anti-{sigma} factor in its phosphorylated state. We present genetic evidence that Caulobacter crescentus PhyR is a phosphorylation-dependent stress regulator that functions in the same pathway as {sigma}{sup T} and its anti-{sigma} factor, NepR. Additionally, we report the X-ray crystal structure of PhyR at 1.25 {angstrom} resolution, which provides insight into the mechanism of anti-anti-{sigma} regulation. Direct intramolecular contact between the PhyR receiver and SL domains spans regions {sigma}{sub 2} and {sigma}{sub 4}, likely serving to stabilize the SL domain in a closed conformation. The molecular surface of the receiver domain contacting the SL domain is the structural equivalent of {alpha}4-{beta}5-{alpha}5, which is known to undergo dynamic conformational change upon phosphorylation in a diverse range of receiver proteins. We propose a structural model of PhyR regulation in which receiver phosphorylation destabilizes the intramolecular interaction between SL and receiver domains, thereby permitting regions {sigma}{sub 2} and {sigma}{sub 4} in the SL domain to open about a flexible connector loop and bind anti-{sigma} factor.
Structure of the Response Regulator PhoP from Mycobacterium tuberculosis Reveals a Dimer Through the Receiver Domain
The PhoP protein from Mycobacterium tuberculosis is a response regulator of the OmpR/PhoB subfamily, whose structure consists of an N-terminal receiver domain and a C-terminal DNA-binding domain. How the DNA-binding activities are regulated by phosphorylation of the receiver domain remains unclear due to a lack of structural information on the full-length proteins. Here we report the crystal structure of the full-length PhoP of M. tuberculosis. Unlike other known structures of full-length proteins of the same subfamily, PhoP forms a dimer through its receiver domain with the dimer interface involving {alpha}4-{beta}5-{alpha}5, a common interface for activated receiver domain dimers. However, the switch residues, Thr99 and Tyr118, are in a conformation resembling those of nonactivated receiver domains. The Tyr118 side chain is involved in the dimer interface interactions. The receiver domain is tethered to the DNA-binding domain through a flexible linker and does not impose structural constraints on the DNA-binding domain. This structure suggests that phosphorylation likely facilitates/stabilizes receiver domain dimerization, bringing the DNA-binding domains to close proximity, thereby increasing their binding affinity for direct repeat DNA sequences.
Consolidated Nuclear Security, LLC, Excess Facility Disposition Program - 17289
Consolidated Nuclear Security, LLC (CNS), the management and operating contractor for the Y-12 National Security Complex (Y-12) in Oak Ridge, Tennessee, and the Pantex Plant (Pantex) in Amarillo, Texas, has developed an integrated strategy to address badly deteriorating excess facilities presenting risks to people, the environment, and the National Nuclear Security Administration (NNSA) mission. The comprehensive, integrated Excess Facilities Disposition Program (EFDP) incorporates NNSA scope for excess facility risk reduction, preparation of facilities to be transferred to the U.S. Department of Energy (DOE) Office of Environmental Management (EM) for demolition, and demolition of non-process contaminated facilities. The Program has been developed using the NNSA Office of Safety, Infrastructure, and Operations (NA-50) Program Management Plan as a guide. The Program has undertaken actions to address the most immediate risks associated with CNS excess facilities. At Y-12, new foam roofs have been installed on Buildings 9201-5 (Alpha 5), 9204-4 (Beta 4), and 9206 to minimize further facility degradation. Tanks and dikes outside of Alpha 5 and Beta 4 are also being disconnected, drained, and filled with concrete. In addition, Beta 4 will be getting a new electrical system as its Manhattan Project-era system will be replaced by a temporary 'construction power' setup that will provide as-needed electricity to the building that is safer, more reliable, and will ease demolition activities in the future. The EFDP is also focusing on the basement of Alpha 5 and is planning to remove the water from the aging facility's flooded basement, which in some areas contains up to 54 inches of water. The EFDP is also planning several efforts to remove excess materials from Alpha 5 and Beta 4, de-inventory the Alpha 5 Mercury House System and numerous transformers, and de-inventory Beta 4 hydraulic pumps and systems. Efforts are also underway to deactivate and decommission non-process-contaminated facilities at Y-12 and at Pantex. The EFDP has prioritized the performance of work to reduce risk while at the same time supporting the preparation of process-contaminated Y-12 facilities for transfer to EM. The Program aligns with the EM goal to have the NNSA scope completed in Alpha 5 and Beta 4 by the end of FY 2020, and Building 9206 completed by the end of FY 2024. These dates and project sequencing will support the Y-12-related DOE EM cleanup initiatives. (authors)
Approximate recalculation of the {alpha}(Z{alpha}){sup 5} contribution to the self-energy effect on hydrogenic states with a multipole expansion
A contribution of virtual electron states with large wave numbers to the self-energy of an electron bound in the weak Coulomb field is analyzed in the context of the evaluation method suggested in the previous paper. The contribution is of the order {alpha}(Z{alpha}){sup 5}. The same value for this contribution is found here as the one found in the previous calculations using different evaluation methods. When we add the remaining terms of the order {alpha}(Z{alpha}){sup 5} to the calculation of the self-energy effect in hydrogen-like ions presented in the previous paper we find a very good agreement with numerical evaluations. The relative difference between present and numerical evaluations ranges from 2 parts in 10{sup 6} for Z=1 up to 6 parts in 10{sup 4} for Z=10. - Highlights: Black-Right-Pointing-Pointer The complete terms of the order {alpha}(Z{alpha}){sup 5} are identified. Black-Right-Pointing-Pointer The accuracy of the result for the ground state of the hydrogen is 2 ppm. Black-Right-Pointing-Pointer The separation into the low and high energy regions and their matching is avoided.
Numerical Study of Vortex Core in Turbulent Swirling Flow
Swirling flow has attracted a great deal of research interest. An application of swirling flow can be found in many engineering areas; such as gas cyclone and heat transfer enhancement. In nuclear engineering, swirling flow is used as heat transfer enhancement in rod bundle by installing grid spacer and mixing vane. Because of its extensive applications, there has been a great number of experimental and numerical investigations of swirling flow. McClusky et al., experimentally studied mapping of the lateral velocity in rod bundle using Laser Doppler Velocimetry (LDV) and Conner et al. predicted the flow field in rod bundle by CFD. To understand the characteristics of swirling flow such as tangential velocity and vortex core swirling flow, some researchers investigated swirling flow in a pipe instead of in rod bundle. This is due to the similarity between swirling flow in a pipe and rod bundle. In recent study, flow mapping of 2D velocity field of single-phase swirling flow had been conducted experimentally by Particle Image Velocimetry (PIV). However, this method needs calibration and complicated. The new measurement technique for flow mapping in swirling flow was done by phased array Ultrasonic Velocity Profiler (PAUVP). Hamdani et al., successfully plotted velocity field and determined the swirling core region (vortex core). This technique is nonintrusive and no need calibration. However, there was a limitation of the measurement because phased array UVP cannot capture 360 deg. velocity field inside the pipe. In addition, tangential velocity in CFD results was not agree well with experiment data due asymmetric problem. To evaluate this limitation of experimental method, the numerical simulations using Computational Fluid Dynamics (CFD) needs to be performed. The objective of this study is to use the commercial CFD code Fluent to model the developing turbulent swirling flow induced by twisted tape inside a straight pipe, and to gain an understanding of such a flow and the turbulence models involved in the simulation. Straight pipe is used instead of rod bundle for a simplification. In this work, the Renormalized Group (RNG) k-{epsilon} turbulence model and Reynolds Stress Model (RSM) turbulence model, are performed to study the phenomena of vortex core in a pipe with twisted tape inserts. Effects of the Reynolds number and asymmetric of twisted tape (inclination, {alpha} = 5 deg. and {alpha} = 20 deg.) on swirling core position are examined using water as the testing fluid. Furthermore, the Navier-Stokes equations will be solved to obtain results that can be validated with the previous experimental results. (authors)
Successful Characterization Strategies for the Active High Risk Y-12 National Security Complex 9201-5 (Alpha-5) Facility, Oak Ridge, TN - 12164
Building 9201-5 (Alpha 5) was completed in May 1944 and served as a production facility for National Nuclear Security Administration (NNSA) Y-12 Weapons Plant. During the Manhattan Project, it functioned as a uranium enrichment facility. The facility was renovated and altered over the years, converting the calutrons to support other missions. Alpha 5 consists of 4 floors and a basement measuring approximately 600,000 square feet. The facility contains various pieces of equipment remaining from legacy operations. A significant amount (approximately 200,000 kgs) of mercury (Hg) has been spilled in the facility over the operational history of the building. To further complicate matters, beryllium (Be) contamination in 9201-5 is found throughout approximately sixty percent of the facility. Concentrations varying from very low (< 0.2 micrograms (μg)/100 cm{sup 2}) to areas where concentrations are relatively high, approximately 600 μg/100 cm{sup 2}, in regulated beryllium areas. The primary site related contaminants (SRCs) for the waste in this facility are enriched uranium, depleted uranium, beryllium and mercury. This facility represents the highest environmental risk for DOE-ORO EM and NNSA at Y-12 and must be quickly addressed to minimize impacts to future Y-12 missions, as well as human health and the environment. As part of the American Recovery and Reinvestment Act (ARRA), approximately 700,000 cubic feet of legacy material was removed in 2010 and 2011. In addition, characterization of the 9201-5 facility was scheduled in the winter and spring of 2011. This activity was initiated in January 2011 and was completed in July 2011. Heavy schedule pressure was further complicated by the fact that this building has active utility, security and process systems. Given these complex variables, a unique, out of the box characterization strategy was forged in an effort to bound radiological and chemical contaminants, as well as providing the appropriate level of quality to ensure that this data could be used to develop waste profiles when deactivation, decontamination and demolition (D and D) activities are authorized at a future date. The characterization strategy involved a hybrid model of statistically-based and biased sampling events. To achieve the desired results, traditional intrusive sampling and laboratory analysis, as well as a number of field-based characterization methodologies (e.g., X-ray Fluorescence [XRF], Lumex and Non-Destructive Assay [NDA]) were utilized. Results were captured and synthesized into meaningful, usable conclusions in a facility characterization report that will more accurately aid D and D cost estimates for future remedial actions. This massive characterization campaign involved over 1,200 separate sample locations using 4 separate characterization methods and was successfully completed to meet a performance-based milestone within 8 months of initiation. (authors)
Synthesis, crystal structure and magnetic characterization of metal(II) coordination polymers based on 2-carboxyethylphosphonic acid and 1,10-phenanthroline (metal=Cu, Co, Cd)
Three non-isostructural metal(II) coordination polymers (metal=copper, cobalt, cadmium) were synthesized under the same mild hydrothermal conditions (T=408 K) by mixture of the corresponding metal acetate with 2-carboxyethylphosphonic acid and 1,10-phenanthroline (1:1:1 M ratio) and their structures were determined by single-crystal X-ray diffraction. Cu{sub 2}(HO{sub 3}PCH{sub 2}CH{sub 2}COO){sub 2}(C{sub 12}H{sub 8}N{sub 2}){sub 2}(H{sub 2}O){sub 2} and Cd{sub 2}(HO{sub 3}PCH{sub 2}CH{sub 2}COO){sub 2}(C{sub 12}H{sub 8}N{sub 2}){sub 2} are triclinic (space group P-1) with a=7.908(5) A, b=10.373(5) A, c=11.515(5) A, {alpha}=111.683(5) Degree-Sign , {beta}=95.801(5) Degree-Sign , {gamma}=110.212(5) Degree-Sign (T=120 K), and a=8.162(5) A, b=9.500(5) A, c=11.148(5) A, {alpha}=102.623(5) Degree-Sign , {beta}=98.607(5) Degree-Sign , {gamma}=113.004(5) Degree-Sign (T=293 K), respectively. In contrast, [Co{sub 2}(HO{sub 3}PCH{sub 2}CH{sub 2}COO){sub 2}(C{sub 12}H{sub 8}N{sub 2}){sub 2}({mu}-OH{sub 2})](H{sub 2}O) is orthorhombic (space group Pbcn) with a=21.1057(2) A, b=9.8231(1) A, c=15.4251(1) A (T=120 K). For these three compounds, structural features, including H-bond network and the {pi}-{pi} stacking interactions, and thermal stability are reported and discussed. None of the materials present a long-range magnetic order in the range of temperatures investigated from 300 K down to 1.8 K. - Graphical abstract: In same synthetic conditions, both the chemical and structural features of three transition metal(II) coordination polymers based on 2-carboxyethylphosphonate and 1-10 Prime -phenanthroline are influenced by the metal cation characteristics, leading to non-homologous materials with different properties, which show the high chemical versatility of this interesting system. Highlights: Black-Right-Pointing-Pointer Non-isostructural metal coordination polymers were synthesized under mild hydrothermal conditions. Black-Right-Pointing-Pointer Ligand's flexibility provides the opportunity to design compounds with tailored properties. Black-Right-Pointing-Pointer Structural changes in the secondary building units are induced by metal features.
Metal ion and ligand binding of integrin [alpha subscript 5 beta subscript 1]
Abstract not provided
A novel adipocytokine, chemerin exerts anti-inflammatory roles in human vascular endothelial cells
Highlights: Black-Right-Pointing-Pointer Chemerin is a novel adipocytokine with almost unknown function in vasculature. Black-Right-Pointing-Pointer Chemerin activates Akt/eNOS/NO pathways in endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-{alpha}-induced monocyte adhesion to endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-induced VCAM-1 via suppressing NF-{kappa}B and p38 signal. Black-Right-Pointing-Pointer Chemerin is anti-inflammatory through producing NO in vascular endothelium. -- Abstract: Chemerin is a recently identified adipocytokine which plays a role on inflammation and adipocytes metabolism. However, its function in vasculature is largely unknown. We examined the effects of chemerin on vascular endothelial inflammatory states. Treatment of human umbilical vein endothelial cells with chemerin (300 ng/ml, 20 min) induced phosphorylation of Akt (Ser473) and endothelial nitric oxide (NO) synthase (eNOS) (Ser1177). Consistently, chemerin increased intracellular cyclic GMP content. Pretreatment with chemerin (1-300 ng/ml, 24 h) significantly inhibited phosphorylation of nuclear factor (NF)-{kappa}B p65 (Ser536) and p38 as well as vascular cell adhesion molecule (VCAM)-1 expression induced by tumor necrosis factor (TNF)-{alpha} (5 ng/ml, 20 min-6 h). Inhibitor of NF-{kappa}B or p38 significantly inhibited the TNF-{alpha}-induced VCAM-1 expression. Chemerin also inhibited TNF-{alpha}-induced VCAM-1 expression in rat isolated aorta. Moreover, chemerin significantly inhibited monocytes adhesion to TNF-{alpha}-stimulated endothelial cells. The inhibitory effect of chemerin on TNF-{alpha}-induced VCAM-1 was reversed by a NOS inhibitor. Conversely, an NO donor, sodium nitroprusside significantly inhibited TNF-{alpha}-induced VCAM-1. The present results for the first time demonstrate that chemerin plays anti-inflammatory roles by preventing TNF-{alpha}-induced VCAM-1 expression and monocytes adhesion in vascular endothelial cells. The effect is mediated via inhibiting activation of NF-{kappa}B and p38 through stimulation of Akt/eNOS signaling and NO production.
DUST EXTINCTION FROM BALMER DECREMENTS OF STAR-FORMING GALAXIES AT 0.75 {<=} z {<=} 1.5 WITH HUBBLE SPACE TELESCOPE/WIDE-FIELD-CAMERA 3 SPECTROSCOPY FROM THE WFC3 INFRARED SPECTROSCOPIC PARALLEL SURVEY
Spectroscopic observations of H{alpha} and H{beta} emission lines of 128 star-forming galaxies in the redshift range 0.75 {<=} z {<=} 1.5 are presented. These data were taken with slitless spectroscopy using the G102 and G141 grisms of the Wide-Field-Camera 3 (WFC3) on board the Hubble Space Telescope as part of the WFC3 Infrared Spectroscopic Parallel survey. Interstellar dust extinction is measured from stacked spectra that cover the Balmer decrement (H{alpha}/H{beta}). We present dust extinction as a function of H{alpha} luminosity (down to 3 Multiplication-Sign 10{sup 41} erg s{sup -1}), galaxy stellar mass (reaching 4 Multiplication-Sign 10{sup 8} M {sub Sun }), and rest-frame H{alpha} equivalent width. The faintest galaxies are two times fainter in H{alpha} luminosity than galaxies previously studied at z {approx} 1.5. An evolution is observed where galaxies of the same H{alpha} luminosity have lower extinction at higher redshifts, whereas no evolution is found within our error bars with stellar mass. The lower H{alpha} luminosity galaxies in our sample are found to be consistent with no dust extinction. We find an anti-correlation of the [O III] {lambda}5007/H{alpha} flux ratio as a function of luminosity where galaxies with L {sub H{alpha}} < 5 Multiplication-Sign 10{sup 41} erg s{sup -1} are brighter in [O III] {lambda}5007 than H{alpha}. This trend is evident even after extinction correction, suggesting that the increased [O III] {lambda}5007/H{alpha} ratio in low-luminosity galaxies is likely due to lower metallicity and/or higher ionization parameters.
Conversion of Human Steroid 5[beta]-Reductase (AKR1D1) into 3[beta]-Hydroxysteroid Dehydrogenase by Single Point Mutation E120H: Example of Perfect Enzyme Engineering
Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5{beta}-reduction of {Delta}{sup 4}-3-ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His120 (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5{beta}-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5{alpha}-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3{beta}-HSD as opposed to a 3{alpha}-HSD. The catalytic efficiency achieved for 3{beta}-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5{beta}-dihydrotestosterone, and {Delta}{sup 4}-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the {Delta}{sup 4}-double bond and confers 3{beta}-HSD activity on the 5{beta}-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its {alpha}-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.