466 research outputs found
Screening for candidate hepatic growth factors by selective portal infusion after canine Eck's fistula.
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Role of PINCH and Its Partner Tumor Suppressor Rsu-1 in Regulating Liver Size and Tumorigenesis
No full textParticularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH-Parvin-α) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1) protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests) but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype. © 2013 Donthamsetty et al
The onset of large-scale turbulence in the interstellar medium of spiral galaxies
No full textDFG thanks the European Research Council (ADG-2011 ECOGAL), and Brazilian agencies CAPES (3400-13-1) and FAPESP (no.2011/12909-8) for financial support. IB acknowledges the European Research Council (ADG-2011 ECOGAL) for financial support. GK acknowledges support from FAPESP (grants no. 2013/04073-2 and 2013/18815-0).Turbulence is ubiquitous in the interstellar medium (ISM) of the Milky Way and other spiral galaxies. The energy source for this turbulence has been much debated with many possible origins proposed. The universality of turbulence, its reported large-scale driving, and that it occurs also in starless molecular clouds, challenges models invoking any stellar source. A more general process is needed to explain the observations. In this work, we study the role of galactic spiral arms. This is accomplished by means of three-dimensional hydrodynamical simulations which follow the dynamical evolution of interstellar diffuse clouds (similar to 100 cm-3) interacting with the gravitational potential field of the spiral pattern. We find that the tidal effects of the arm's potential on the cloud result in internal vorticity, fragmentation and hydrodynamical instabilities. The triggered turbulence results in large-scale driving, on sizes of the ISM inhomogeneities, i.e. as large as similar to 100 pc, and efficiencies in converting potential energy into turbulence in the range similar to 10-25 per cent per arm crossing. This efficiency is much higher than those found in previous models. The statistics of the turbulence in our simulations are strikingly similar to the observed power spectrum and Larson scaling relations of molecular clouds and the general ISM. The dependence found from different models indicate that the ISM turbulence is mainly related to local spiral arm properties, such as its mass density and width. This correlation seems in agreement with recent high angular resolution observations of spiral galaxies, e.g. M51 and M33.Peer reviewe
Experimental studies on isolated supersonic air-intake models of a typical air-breathing launch vehicle
No full textThe performance of two supersonic air-intake configurations, S1 and S2, has been extensively analyzed through qualitative and quantitative measurements at Mach numbers in the range 1.8 to 3.0. The exit area of the intake was varied during the tests using a butterfly valve, which was controlled using a PC. The performance of S2 was found to be comparable with that of a standard supersonic intake, with characteristic features of supercritical and subcritical behavior, whereas S1 configuration did not indicate any critical condition. The critical condition for S2 was found to occur when the exit area was about 1.24 times the throat area at M = 3.0. The measured total pressure recovery with S2 was found to be marginally higher than that for S1, whereas the mass flow rate through the intake showed considerable improvement (e.g., 11 percent at M = 3.0 and 19 percent at M = 2.0 at maximum pressure recovery condition). Similar improvements were found with the S2 configuration at other Mach numbers also. It is proposed that an Intake Performance Index (product of the pressure recovery and mass flow efficiencies), as a function of the back-pressure, may be used to compare the efficiencies of different intake configurations. (Author
PRECISION MEASUREMENT OF THE IONIZATION ENERGY OF THE STATE OF MOLECULAR HYDROGEN.
No full textAuthor Institution: ETH Zurich, Laboratorium fur Physikalische Chemie, Wolfgang-Pauli-Strasse 10, 8093 Zurich, SwitzerlandThe ionization energy of the state of ortho H has been determined at a precision of 1.2~MHz by near-infrared laser spectroscopy. The measurement was performed by first exciting molecular hydrogen from the state to the state in a resonant two-photon process via the state and then measuring the frequency of the transition between the state and the 56p~ Rydberg state belonging to the series converging on the ground state of ortho H. The ionization energy of the state was obtained by adding this frequency to the binding energy of the 56p~ Rydberg state which has been determined previously by millimeter-wave spectroscopy and multichannel quantum-defect theory \textbf{121} (23), 11810 (2004).} \textbf{150}, 51 (2011).}. For the measurement we used a homebuilt pulsed NIR laser with Fourier-transform-limited linewidth and adjustable pulse duration. To reach the desired accuracy, systematic errors originating from ac and dc Stark shifts, from pressure shifts, and from the frequency shifts and chirps accompanying the generation of the NIR laser pulses were quantified. The ionization energy of the state will be compared with earlier results \textbf{93} (4), 2289 (1990).} \textbf{108} (7-9), 827 (2010).}. New attempts of measuring the binding energy of the state will also be mentioned
Identification and Visualization of Functionally Important Domains and Residues in Herpes Simplex Virus Glycoprotein K(gK) Using a Combination of Phylogenetics and Protein Modeling
No full text© 2019, The Author(s). Alphaherpesviruses are a subfamily of herpesviruses that include the significant human pathogens herpes simplex viruses (HSV) and varicella zoster virus (VZV). Glycoprotein K (gK), conserved in all alphaherpesviruses, is a multi-membrane spanning virion glycoprotein essential for virus entry into neuronal axons, virion assembly, and pathogenesis. Despite these critical functions, little is known about which gK domains and residues are most important for maintaining these functions across all alphaherpesviruses. Herein, we employed phylogenetic and structural analyses including the use of a novel model for evolutionary rate variation across residues to predict conserved gK functional domains. We found marked heterogeneity in the evolutionary rate at the level of both individual residues and domains, presumably as a result of varying selective constraints. To clarify the potential role of conserved sequence features, we predicted the structures of several gK orthologs. Congruent with our phylogenetic analysis, slowly evolving residues were identified at potentially structurally significant positions across domains. We found that using a quantitative measure of amino acid rate variation combined with molecular modeling we were able to identify amino acids predicted to be critical for gK protein structure/function. This analysis yields targets for the design of anti-herpesvirus therapeutic strategies across all alphaherpesvirus species that would be absent from more traditional analyses of conservation
On Type IIA AdS3 solutions and massive GK geometries
No full textWe give necessary and sufficient conditions for warped AdS3 (and Mink3) solutions of Type II supergravities to preserve N= (2, 0) supersymmetry, in terms of geometric conditions on their internal space M7. Such solutions possess a canonical ten-dimensional Killing vector that can be either time-like or null. In this work we classify the null case in massive Type IIA supergravity which necessitates that M7 decomposes as a circle fibration over a six-dimensional base with orthogonal SU(2)-structure containing a complex four-manifold. We narrow our focus to solutions for which M7 becomes T2 fibred over a foliation of a Kähler manifold over an interval. We find a class of solutions which are the massive Type IIA version of GK geometries and present an extremal problem which computes the central charge of the solution using just topology. Finally, we present geometric conditions for AdS3 solutions to preserve arbitrary extended chiral supersymmetry. © 2022, The Author(s)
Benefit-risk analysis for decision-making: An approach
No full textThe analysis of benefit and risk is an important aspect of decision-making throughout the drug lifecycle. In this work, the use of a benefit-risk analysis approach to support decision-making was explored. The proposed approach builds on the qualitative US Food and Drug Administration (FDA) approach to include a more explicit analysis based on international standards and guidance that enables aggregation and comparison of benefit and risk on a common basis and a lifecycle focus. The approach is demonstrated on six decisions over the lifecycle (e.g., accelerated approval, withdrawal, and traditional approval) using two case studies: natalizumab for multiple sclerosis (MS) and bedaquiline for multidrug-resistant tuberculosis (MDR-TB)
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