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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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Synthesis of 3,5-alpha-dichloro-3,5-seco-A- norcholestane
Synthesis of alpha-dichloro-seco-A-norcholestane from diol monoacetate reaction with triphenylphosphine followed by hydrolysis and repeated chlorination
Sterols of a contemporary lacustrine sediment
Results are reported for detailed sterol analyses of several depths (corresponding to between zero and about 150 yr in age) in a contemporary lacustrine sediment from a freshwater lake of postglacial origin in England. Delta 5-, delta 22-, and delta 5,22-sterols are identified along with 5 alpha- and 5 beta-stanols as well as a C26 stanol with a C7 side chain. Solvent extraction yields carbon number distributions for the 5 alpha- and 5 beta-stanol sediment constituents that parallel the corresponding delta 5-sterol distributions. The amounts of 5 alpha-stanols are found to exceed those of 5 beta-stanols in the sediment, and variations in the ratio of 5 alpha- to 5 beta-stanol between sediment samples from similar depths are shown to suggest an inhomogeneity of the sediment. It is found that the sterol composition of sediment cores varies markedly with depth, reflecting both the effects of a sterol hydrogenation process and a changing input to the sediment. It is concluded that C29 sterols, of probable higher-plant origin, predominate at lower sediment depths while C27 sterols, possibly derived from autochthonous sources, are more abundant in the surface sediment.
Probing transmembrane mechanical coupling and cytomechanics using magnetic twisting cytometry
We recently developed a magnetic twisting cytometry technique that allows us to apply controlled mechanical stresses to specific cell surface receptors using ligand-coated ferromagnetic microbeads and to simultaneously measure the mechanical response in living cells. Using this technique, we have previously shown the following: (i) beta 1 integrin receptors mediate mechanical force transfer across the cell surface and to the cytoskeleton, whereas other transmembrane receptors (e.g., scavenger receptors) do not; (ii) cytoskeletal stiffness increases in direct proportion to the level of stress applied to integrins; and (iii) the slope of this linear stiffening response differs depending on the shape of the cell. We now show that different integrins (beta 1, alpha V beta 3, alpha V, alpha 5, alpha 2) and other transmembrane receptors (scavenger receptor, platelet endothelial cell adhesion molecule) differ in their ability to mediate force transfer across the cell surface. In addition, the linear stiffening behavior previously observed in endothelial cells was found to be shared by other cell types. Finally, we demonstrate that dynamic changes in cell shape that occur during both cell spreading and retraction are accompanied by coordinate changes in cytoskeletal stiffness. Taken together, these results suggest that the magnetic twisting cytometry technique may be a powerful and versatile tool for studies analyzing the molecular basis of transmembrane mechanical coupling to the cytoskeleton as well as dynamic relations between changes in cytoskeletal structure and alterations in cell form and function.
Interpretation of the Mariner 5 Lyman alpha measurements.
Mariner 5 Lyman alpha measurements fitted with barometric-exospheric equation using two component model atmosphere
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.
Analysis of two-dimensional incompressible flow past airfoils using unsteady Navier-Stokes equations
The conservative form of the unsteady Navier-Stokes equations in terms of vorticity and stream function in generalized curvilinear coordinates are used to analyze the flow structure of steady separation and unsteady flow with massive separation. The numerical method solves the discretized equations using an ADI-BGE method. The method is applied to a symmetric 12 percent thick Joukowski airfoil. A conformal clustered grid is generated; several 1-D stretching transformations are used to obtain a grid that attempts to resolve many of the multiple scales of the unsteady flow with massive separation, while maintaining the transformation metrics to be smooth and continuous in the entire flow field. Detailed numerical results are obtained for three flow configurations (1) Re = 1000, alpha = 5 deg, (2) Re = 1000, alpha = 15 deg, (3) Re = 10,000, alpha = 5 deg. No artificial dissipation was added; however, lack of a fine grid in the normal direction has presently led to results which are considered qualitative, especially for case (3).
Analysis of two-dimensional incompressible flow past airfoils using unsteady Navier-Stokes equations
The conservative form of the unsteady Navier-Stokes equations in terms of vorticity and stream function in generalized curvilinear coordinates are used to analyze the flow structure of steady separation and unsteady flow with massive separation. The numerical method solves the discretized equations using an ADI-BGE method. The method is applied to a symmetric 12 percent thick Joukowski airfoil. A conformal clustered grid is generated; several 1-D stretching transformations are used to obtain a grid that attempts to resolve many of the multiple scales of the unsteady flow with massive separation, while maintaining the transformation metrics to be smooth and continuous in the entire flow field. Detailed numerical results are obtained for three flow configurations (1) Re = 1000, alpha = 5 deg., (2) Re =1000, alpha = 15 deg., (3) Re = 10,000, alpha = 5 deg. No artificial dissipation was added; however, lack of a fine grid in the normal direction has presently led to results which are considered qualitative, especially for case (3).
GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls
The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation. In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (alpha 1, alpha 2, alpha 5, beta 1, beta 2, gamma 2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitometry. Three types of laminar expression pattern were observed: mRNAs for the alpha 1, beta 2, and gamma 2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the alpha 2, alpha 5, and beta 1 subunits were expressed at lower levels; alpha 2 and beta 1 were expressed predominantly by cells in layers II, III, and IV; alpha 5 was expressed predominantly in layers IV, V, and VI. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls. Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of schizophrenics, the previously reported upregulation of muscimol binding sites and downregulation of benzodiazepine binding sites in the prefrontal and adjacent cingulate cortex of schizophrenics are possibly due to posttranscriptional modifications of mRNAs and their translated polypeptides.