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Sample records for m-theory type iia

  1. Nonsupersymmetric brane/antibrane configurations in type IIA and M theory

    NASA Astrophysics Data System (ADS)

    Marsano, Joseph; Papadodimas, Kyriakos; Shigemori, Masaki

    2008-01-01

    We study metastable nonsupersymmetric configurations in type IIA string theory, obtained by suspending D4-branes and D4¯-branes between holomorphically curved NS5's, which are related to those of arxiv:/hep-th/0610249 by T-duality. When the numbers of branes and antibranes are the same, we are able to obtain an exact M theory lift which can be used to reliably describe the vacuum configuration as a curved NS5 with dissolved RR flux for g≪1 and as a curved M5 for g≫1. When our weakly coupled description is reliable, it is related by T-duality to the deformed IIB geometry with flux of hep-th/0610249 with moduli exactly minimizing the potential derived therein using special geometry. Moreover, we can use a direct analysis of the action to argue that this agreement must also hold for the more general brane/antibrane configurations of hep-th/0610249. On the other hand, when our strongly coupled description is reliable, the M5 wraps a nonholomorphic minimal area curve that can exhibit quite different properties, suggesting that the residual structure remaining after spontaneous breaking of supersymmetry at tree level can be further broken by the effects of string interactions. Finally, we discuss the boundary condition issues raised in hep-th/0608157 for nonsupersymmetric IIA configurations, their implications for our setup, and their realization on the type IIB side.

  2. Investigating Inflation in Type IIA

    SciTech Connect

    Hertzberg, Mark P.; Kachru, Shamit; Taylor, Washington; Tegmark, Max; /MIT, LNS

    2007-12-14

    We prove that inflation is forbidden in the most well understood class of semi-realistic type IIA string compactifications: Calabi-Yau compactifications with only standard NS-NS 3-form flux, R-R fluxes, D6-branes and O6-planes at large volume and small string coupling. With these ingredients, the first slow-roll parameter satisfies {epsilon} {ge} 27/13 whenever V > 0, ruling out both inflation (including brane/anti-brane inflation) and de Sitter vacua in this limit. Our proof is based on the dependence of the 4-dimensional potential on the volume and dilaton moduli in the presence of fluxes and branes. We also describe broader classes of IIA models which may include cosmologies with inflation and/or de Sitter vacua. The inclusion of extra ingredients, such as NS 5-branes and geometric or non-geometric NS-NS fluxes, evades the assumptions used in deriving the no-go theorem. We focus on NS 5-branes and outline how such ingredients may prove fruitful for cosmology, but we do not provide an explicit model. We contrast the results of our IIA analysis with the rather different situation in IIB.

  3. Type IIa Bragg gratings formed in microfibers.

    PubMed

    Ran, Yang; Jin, Long; Gao, Shuai; Sun, Li-Peng; Huang, Yun-Yun; Li, Jie; Guan, Bai-Ou

    2015-08-15

    In this Letter, Type IIa Bragg gratings are inscribed into microfibers. The large germanium-doped core region of the multimode fiber provides the necessary photosensitivity to form a Type IIa grating when it is drawn down to the microscale. Reducing the diameter of the microfiber due to lower saturate modulation and the amplified tension-strain transformation effect can accelerate the formation of a Type IIa grating. This provides an efficient method for the fabrication of fiber gratings with 800°C temperature resistance. PMID:26274664

  4. Phacomatosis pigmentovascularis type IIa - Case report*

    PubMed Central

    Segatto, Majoriê Mergen; Schmitt, Eloísa Unfer; Hagemann, Laura Netto; da Silva, Roberta Castilhos; Cattani, Cristiane Almeida Soares

    2013-01-01

    Phacomatosis Pigmentovascularis is a rare syndrome characterized by capillary malformation and pigmentary nevus. A case of a 2-year-old patient is reported, who presented extensive nevus flammeus and an aberrant Mongolian spot, without systemic disease, manifestations that allow us to classify this case as type IIa Phacomatosis Pigmentovascularis, according to Hasegawa's classification. PMID:24346888

  5. Thermal Conductivity Of Natural Type IIa Diamond

    NASA Technical Reports Server (NTRS)

    Vandersande, Jan; Vining, Cronin; Zoltan, Andrew

    1992-01-01

    Report describes application of flash diffusivity method to measure thermal conductivity of 8.04 x 8.84 x 2.35-mm specimen of natural, white, type-IIa diamond at temperatures between 500 and 1,250 K. Provides baseline for comparison to isotopically pure (12C) diamond. Results used as reference against which diamond films produced by chemical-vapor deposition at low pressures can be compared. High thermal conductivity of diamond exploited for wide variety of applications, and present results also used to estimate heat-conduction performances of diamond films in high-temperature applications.

  6. Accelerated universes from type IIA compactifications

    SciTech Connect

    Blåbäck, Johan; Danielsson, Ulf; Dibitetto, Giuseppe E-mail: ulf.danielsson@physics.uu.se

    2014-03-01

    We study slow-roll accelerating cosmologies arising from geometric compactifications of type IIA string theory on T{sup 6}/(Z{sub 2}  ×  Z{sub 2}). With the aid of a genetic algorithm, we are able to find quasi-de Sitter backgrounds with both slow-roll parameters of order 0.1. Furthermore, we study their evolution by numerically solving the corresponding time-dependent equations of motion, and we show that they actually display a few e-folds of accelerated expansion. Finally, we comment on their perturbative reliability.

  7. Type IIA Klebanov-Strassler: the hard way

    NASA Astrophysics Data System (ADS)

    Pasini, Giulio

    2016-03-01

    We construct the T-dual of the Klebanov-Strassler solution on a small region at the tip of the deformed conifold. The isometry coordinate we choose is the correct one to obtain an NS5 brane wrapping a holomorphic curve in Type IIA, as shown by a thorough analysis of the deformed conifold geometry. The shape of the locus wrapped by the NS5 brane matches the predictions from the Type IIA brane engineering construction dual to the SU(N + M) × SU(N) cascading gauge theory. The same isometry is then used to T-dualize the solution obtained by adding backreacted D3 branes to the Klebanov-Strassler solution. Our construction is the first step in a program to test the stability of antibranes in Type IIA backgrounds.

  8. One-phonon absorption by type IIa diamonds

    NASA Astrophysics Data System (ADS)

    Kiflawi, I.; Welbourn, C. M.; Woods, G. S.

    1993-02-01

    Brown type IIa diamonds have been found to exhibit a very weak one-phonon infrared absorption that begins near the Raman energy at 1332cm -1, and increases, with decreasing wavenumber, to a maximum at 1016cm -1 with a shoulder on the high-wavenumber side at about 1050cm -1. A colourless type IIa specimen showed an even weaker absorption beginning again near 1332cm -1 and increasing to show two maxima near 1100cm -1 and 1000cm -1. These specimen also showed birefringence patterns between crossed polars that are indicative of plastic deformation. It is suggested that the infrared absorptions are caused by dislocations.

  9. Stringy evidence for {ital D}=11 structure in a strongly coupled type-IIA superstring

    SciTech Connect

    Bars, I.

    1995-09-15

    Witten proposed that the low energy physics of a strongly coupled {ital D}=10 type-IIA superstring may be described by {ital D}=11 supergravity. To explore the stringy aspects of the underlying theory we examine the stringy massive states. We propose a systematic formula for identifying nonperturbative states in {ital D}=10 type-IIA superstring theory, such that, together with the elementary excited string states, they form {ital D}=11 supersymmetric multiplets, in SO(10) representations. This provides hints for the construction of a conjectured weakly coupled {ital D}=11 theory that is dual to the strongly coupled {ital D}=10 type-IIA superstring.

  10. Type-IIB-string-M-theory duality and longitudinal membranes in M(atrix) theory

    NASA Astrophysics Data System (ADS)

    Ho, Pei-Ming; Wu, Yong-Shi

    1998-02-01

    In this paper we study duality properties of the M(atrix) theory compactified on a circle. We present evidence for the equivalence of this theory to the strong coupling limit of type-IIB string theory compactified on a circle. In the M(atrix) theory context, our evidence for this duality consists of showing the appearance (upon compactification) of a topological term recently discovered in the D-string action, identifying the BPS states of type-IIB strings in the spectrum and finding the remnant symmetry of SL(2,Z) and the associated τ moduli. By this type-IIB-string-M-theory duality, a number of insights are gained into the physics of longitudinal membranes in the infinite momentum frame.

  11. Heterotic-type IIA duality and degenerations of K3 surfaces

    NASA Astrophysics Data System (ADS)

    Braun, A. P.; Watari, T.

    2016-08-01

    We study the duality between four-dimensional N = 2 compactifications of heterotic and type IIA string theories. Via adiabatic fibration of the duality in six dimensions, type IIA string theory compactified on a K3-fibred Calabi-Yau threefold has a potential heterotic dual compactification. This adiabatic picture fails whenever the K3 fibre degenerates into multiple components over points in the base of the fibration. Guided by monodromy, we identify such degenerate K3 fibres as solitons generalizing the NS5-brane in heterotic string theory. The theory of degenerations of K3 surfaces can then be used to find which solitons can be present on the heterotic side. Similar to small instanton transitions, these solitons escort singular transitions between different Calabi-Yau threefolds. Starting from well-known examples of heterotic-type IIA duality, such transitions can take us to type IIA compactifications with unknown heterotic duals.

  12. Type IIa Bragg grating based ultra-short DBR fiber laser with high temperature resistance.

    PubMed

    Ran, Yang; Feng, Fu-Rong; Liang, Yi-Zhi; Jin, Long; Guan, Bai-Ou

    2015-12-15

    We report on the fabrication of a thermally resistant ultra-short distributed Bragg reflector (DBR) fiber laser based on the photo inscription of two wavelength-matched type IIa gratings in a thin-core Er-doped fiber. With continuous UV exposure, each Bragg reflector initially grows as a type I grating, followed by decay in strength, and then re-grows as a type IIa grating with enhanced thermal resistance. The DBR laser, with an entire length of 13 mm, can stably operate at 600°C with single longitude mode, which provides potential applications in high temperature environments. PMID:26670491

  13. M-theory interpretation of the real topological string

    NASA Astrophysics Data System (ADS)

    Piazzalunga, Nicolò; Uranga, Angel M.

    2014-08-01

    We describe the type IIA physical realization of the unoriented topological string introduced by Walcher, describe its M-theory lift, and show that it allows to compute the open and unoriented topological amplitude in terms of one-loop diagram of BPS M2-brane states. This confirms and allows to generalize the conjectured BPS integer expansion of the topological amplitude. The M-theory lift of the orientifold is freely acting on the M-theory circle, so that integer multiplicities are a weighted version of the (equivariant subsector of the) original closed oriented Gopakumar-Vafa invariants. The M-theory lift also provides new perspective on the topological tadpole cancellation conditions. We finally comment on the M-theory version of other unoriented topological strings, and clarify certain misidentifications in earlier discussions in the literature.

  14. Type-IIA flux compactifications and Script N = 4 gauged supergravities

    NASA Astrophysics Data System (ADS)

    Dall'Agata, Gianguido; Villadoro, Giovanni; Zwirner, Fabio

    2009-08-01

    We establish the precise correspondence between Type-IIA flux compactifications preserving an exact or spontaneously broken Script N = 4 supersymmetry in four dimensions, and gaugings of their effective Script N = 4 supergravities. We exhibit the explicit map between fluxes and Bianchi identities in the higher-dimensional theory and generalized structure constants and Jacobi identities in the reduced theory, also detailing the origin of gauge groups embedded at angles in the duality group. We present AdS4 solutions of the massive Type-IIA theory with spontaneous breaking to Script N = 1, at small string coupling and large volume, and discuss their dual CFT3.

  15. PTH-induced internalization of a type IIa Na/Pi cotransporter in OK-cells.

    PubMed

    Jankowski, M; Biber, J; Murer, H

    1999-10-01

    Regulatory phenomena in brush border membrane sodium/phosphate (Na/Pi) cotransport are directly related to the type IIa Na/Pi-cotransporter and can be analyzed in opossum kidney cells (OK-cells). Parathyroid hormone (PTH) leads to a decreased expression of the type IIa Na/Pi-cotransporter protein at the apical cell surface. To provide evidence for PTH-induced membrane retrieval of the cotransporter protein we labeled OK-cell surface membrane protein NH2-groups with N-hydroxysuccinimide bound via a disulfide bond to biotin (NHS-SS-biotin) prior to or after treatment with PTH. Biotinylated transporters can be detected by streptavidin precipitation and Western blotting using type IIa Na/Pi-cotransporter specific antibodies. To detect only internalized biotinylated transporters biotin located at the cell surface was removed ("stripped") by disulfide bond splitting reagents under reducing conditions. Neither biotinylation per se, nor "stripping" interfered with PTH-induced inhibition of Na/Pi-cotransport activity. The internalization of the transporter was highly increased in response to PTH treatment. The data document that the first step in PTH regulation is internalization of the type IIa Na/Pi-cotransporter protein from the apical membrane. PMID:10555567

  16. Expression of Dihydropyridine and Ryanodine Receptors in Type IIA Fibers of Rat Skeletal Muscle

    PubMed Central

    Anttila, Katja; Mänttäri, Satu; Järvilehto, Matti

    2007-01-01

    In this study, the fiber type specificity of dihydropyridine receptors (DHPRs) and ryanodine receptors (RyRs) in different rat limb muscles was investigated. Western blot and histochemical analyses provided for the first time evidence that the expression of both receptors correlates to a specific myosin heavy chain (MHC) composition. We observed a significant (p=0.01) correlation between DHP as well as Ry receptor density and the expression of MHC IIa (correlation factor r=0.674 and r=0.645, respectively) in one slow-twitch, postural muscle (m. soleus), one mixed, fast-twitch muscle (m. gastrocnemius) and two fast-twitch muscles (m. rectus femoris, m. extensor digitorum longus). The highest DHP and Ry receptor density was found in the white part of m. rectus femoris (0.058±0.0060 and 0.057±0.0158 ODu, respectively). As expected, the highest relative percentage of MHC IIa was also found in the white part of m. rectus femoris (70.0±7.77%). Furthermore, histochemical experiments revealed that the IIA fibers stained most strongly for the fluorophore-conjugated receptor blockers. Our data clearly suggest that the expression of DHPRs and RyRs follows a fiber type-specific pattern, indicating an important role for these proteins in the maintenance of an effective Ca2+ cycle in the fast contracting fiber type IIA. PMID:17576431

  17. Coupling ATP hydrolysis to DNA strand passage in type IIA DNA topoisomerases.

    PubMed

    Maxwell, A; Costenaro, L; Mitelheiser, S; Bates, A D

    2005-12-01

    Type IIA topos (topoisomerases) catalyse topological conversions of DNA through the passage of one double strand through a transient break in another. In the case of the archetypal enzyme, DNA gyrase, it has always been apparent that the enzyme couples the free energy of ATP hydrolysis to the introduction of negative supercoiling, and the structural details of this process are now becoming clearer. The homologous type IIA enzymes such as topo IV and eukaryotic topo II also require ATP and it has more recently been shown that the energy of hydrolysis is coupled to a reduction of supercoiling or catenation (linking) beyond equilibrium. The mechanism behind this effect is less clear. We review the energy coupling process in both classes of enzyme and describe recent mechanistic and structural work on gyrase that addresses the mechanism of energy coupling. PMID:16246146

  18. Entropy function for 4-charge extremal black holes in type IIA superstring theory

    SciTech Connect

    Cai Ronggen; Pang Dawei

    2006-09-15

    We calculate the entropy of 4-charge extremal black holes in Type IIA supersting theory by using Sen's entropy function method. Using the low-energy effective actions in both 10D and 4D, we find precise agreements with the Bekenstein-Hawking entropy of the black hole. We also calculate the higher-order corrections to the entropy and find that they depend on the exact form of the higher-order corrections to the effective action.

  19. Photoconductive response of type IIa diamond in the 222-353-nm range

    NASA Astrophysics Data System (ADS)

    Krishnan, Mahadevan; Lipatov, Evgenii E. I.; Parks, D.; Panchenko, Alexei N.; Schein, Jochen; Tarasenko, Victor F.; Thompson, J.

    2004-05-01

    Diamond radiation detectors (DRDs) operate on the principle of photoconductive response of the normally insulating, Type IIa diamond when dosed by electromagnetic radiation or high energy particles. As detectors, they offer fast response (~100 ps) and can handle high radiation doses (~1 GGy) without degradation. Diamond also offers significant advantages over semiconducting materials as a compact, bi-polar, high voltage switching medium because of its high dielectric strength and thermal conductivity. However, the wide band-gap of diamond and its normally insulating state impose stringent requirements on the trigger radiation that is used to make the diamond conductive. This paper describes a simple model for conduction in diamond, and compares this model with experimental conductivity as measured in a natural diamond Type IIa radiation detector that was irradiated by laser excitation at various wavelengths from 222-353 nm. The DRD geometry consisted of a 3x1x0.5 mm3 Type IIa diamond with metallization on the 3x0.5mm2 sides. The DRD was exposed to laser light in the orthogonal 3x1 mm2 plane. Agreement with the measured data is achieved by fitting a parameter (defined here as β) at the various irradiation wavelengths. This fitting parameter is itself a function of two physical quantities: α, the absorption coefficient of the diamond and ɛo, the ionization cost to produce a hole-pair. Using published values of α, we deduce values of ɛo and compare them with published values for Type IIa diamond in the deep UV to soft x-ray regions. This model also provides a basis for design of high voltage diamond switches that are triggered by near-bandgap (220-250 nm) UV radiation.

  20. On the E{sub 10}/massive type IIA supergravity correspondence

    SciTech Connect

    Henneaux, Marc; Persson, Daniel; Jamsin, Ella; Kleinschmidt, Axel

    2009-02-15

    In this paper we investigate in detail the correspondence between E{sub 10} and Romans' massive deformation of type IIA supergravity. We analyze the dynamics of a nonlinear sigma model for a spinning particle on the coset space E{sub 10}/K(E{sub 10}) and show that it reproduces the dynamics of the bosonic as well as the fermionic sector of the massive IIA theory, within the standard truncation. The mass deformation parameter corresponds to a generator of E{sub 10} outside the realm of the generators entering the usual D=11 analysis, and is naturally included without any deformation of the coset model for E{sub 10}/K(E{sub 10}). Our analysis thus provides a dynamical unification of the massless and massive versions of type IIA supergravity inside E{sub 10}. We discuss a number of additional and general features of relevance in the analysis of any deformed supergravity in the correspondence to Kac-Moody algebras, including recently studied deformations where the trombone symmetry is gauged.

  1. Type IIA photosensitivity and formation of pores in optical fibers under intense ultraviolet irradiation

    SciTech Connect

    Kukushkin, S. A.; Shlyagin, M. G.; Swart, P. L.; Chtcherbakov, A. A.; Osipov, A. V.

    2007-09-01

    Formation of the type IIA Bragg gratings in germanosilicate optical fibers is studied. We report the observation of such a type of gratings in the standard single-mode fiber (Corning SMF-28) under different experimental conditions. A mechanism for the type IIA photosensitivity in optical fibers is proposed which is based on nucleation and evolution of pores from vacancy-type defects in fiber areas where a high level of mechanical stress is induced under intense ultraviolet (UV) light. Evolution of fiber core temperature under influence of a single 20 ns light pulse from a KrF excimer laser was measured and compared with theoretical calculations. It was shown that transient thermoinduced stress in the fiber core can achieve a level sufficient for effective nucleation of pores. A theory describing formation of pores in optical fibers has been developed and was used to estimate the pore nucleation rate, concentration, and other parameters of pore evolution for different levels of UV fluence and fiber core stress.

  2. The effective action of D6-branes in mathcal{N} = 1 type IIA orientifolds

    NASA Astrophysics Data System (ADS)

    Kerstan, Max; Weigand, Timo

    2011-06-01

    We use a Kaluza-Klein reduction to compute the low-energy effective action for the massless modes of a spacetime-filling D6-brane wrapped on a special Lagrangian 3-cycle of a type IIA Calabi-Yau orientifold. The modifications to the characteristic data of the mathcal{N} = 1 bulk orientifold theory in the presence of a D6-brane are analysed by studying the underlying Type IIA supergravity coupled to the brane world volume in the democratic formulation and performing a detailed dualisation procedure. The mathcal{N} = 1 chiralcoordinates are found to be in agreement with expectations from mirror symmetry. We work out the Kähler potential for the chiral superfields as well as the gauge kinetic functions for the bulk and the brane gauge multiplets including the kinetic mixing between the two. The scalar potential resulting from the dualisation procedure can be formally interpreted in terms of a superpotential. Finally, the gauging of the Peccei-Quinn shift symmetries of the complex structure multiplets reproduces the D-term potential enforcing the calibration condition for special Lagrangian 3-cycles.

  3. Microstates of a neutral black hole in M theory.

    PubMed

    Emparan, Roberto; Horowitz, Gary T

    2006-10-01

    We consider vacuum solutions in M theory of the form of a five-dimensional Kaluza-Klein black hole cross T6. In a certain limit, these include the five-dimensional neutral rotating black hole (cross T6). From a type-IIA standpoint, these solutions carry D0 and D6 charges. We show that there is a simple D-brane description which precisely reproduces the Hawking-Bekenstein entropy in the extremal limit, even though supersymmetry is completely broken. PMID:17155239

  4. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5.

    PubMed

    Scerri, Thomas; Riseley, Jessica R; Gillies, Greta; Pope, Kate; Burgess, Rosemary; Mandelstam, Simone A; Dibbens, Leanne; Chow, Chung W; Maixner, Wirginia; Harvey, Anthony Simon; Jackson, Graeme D; Amor, David J; Delatycki, Martin B; Crino, Peter B; Berkovic, Samuel F; Scheffer, Ingrid E; Bahlo, Melanie; Lockhart, Paul J; Leventer, Richard J

    2015-05-01

    Whole-exome sequencing of two brothers with drug-resistant, early-onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin (mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation. PMID:26000329

  5. Biological evaluation and molecular modelling study of thiosemicarbazide derivatives as bacterial type IIA topoisomerases inhibitors.

    PubMed

    Paneth, Agata; Stączek, Paweł; Plech, Tomasz; Strzelczyk, Aleksandra; Dzitko, Katarzyna; Wujec, Monika; Kuśmierz, Edyta; Kosikowska, Urszula; Grzegorczyk, Agnieszka; Paneth, Piotr

    2016-01-01

    In the present article, we describe the inhibitory potency of nine thiosemicarbazide derivatives against bacterial type IIA topoisomerases, their antibacterial profile and molecular modelling evaluation. We found that one of the tested compounds, compound 7, significantly inhibits activity of Staphylococcus aureus DNA gyrase with an IC(50) below 15 μM. Besides, this compound displays antibacterial activity on reference Staphylococuss spp. and Enterococcus faecalis strains as well as clinical S. aureus isolates at non-cytotoxic concentrations in mammalian cells with MIC values ranging from 16 to 32 μg/mL thereby indicating, in some cases, equipotent or even more effective action than standard drugs such as vancomycin, ampicillin and nitrofurantoin. The computational studies showed that both molecular geometry and the electron density distribution have a great impact on antibacterial activity of thiosemicarbazide derivatives. PMID:25792505

  6. Dualities in M-theory and Born-Infeld Theory

    SciTech Connect

    Brace, Daniel, M

    2001-08-01

    We discuss two examples of duality. The first arises in the context of toroidal compactification of the discrete light cone quantization of M-theory. In the presence of nontrivial moduli coming from the M-theory three form, it has been conjectured that the system is described by supersymmetric Yang-Mills gauge theory on a noncommutative torus. We are able to provide evidence for this conjecture, by showing that the dualities of this M-theory compactification, which correspond to T-duality in Type IIA string theory, are also dualities of the noncommutative supersymmetric Yang-Mills description. One can also consider this as evidence for the accuracy of the Matrix Theory description of M-theory in this background. The second type of duality is the self-duality of theories with U(1) gauge fields. After discussing the general theory of duality invariance for theories with complex gauge fields, we are able to find a generalization of the well known U(1) Born-Infeld theory that contains any number of gauge fields and which is invariant under the maximal duality group. We then find a supersymmetric extension of our results, and also show that our results can be extended to find Born-Infeld type actions in any even dimensional spacetime.

  7. M theory fivebrane and SQCD

    SciTech Connect

    Ooguri, H. |

    1997-09-01

    A low energy effective theory of parallel D(irichlet) branes is a gauge theory with sixteen supercharges, but one can consider a web of brane to realize situations with reduced number of supersymmetry. In this talk, the authors discusses four-dimensional theories with N = 1 and 2 supersymmetry (i.e. four and eight supercharges). In the case of theories with N = 2 supersymmetry, the exact description of the Coulomb branch is given by reinterpreting the web of branes as a configuration of a single fivebrane in the IIA theory. Recently the authors studied the case with N = 1 supersymmetry, and found that description in terms of the fivebrane in M Theory captures strong coupling dynamics of the N = 1 gauge theory in four dimensions. In particular, they found that the configuration of the fivebrane geometrically encodes information on the Affleck-Dine-Seiberg superpotential and the structure of the quantum moduli space of vacua.

  8. On the cosmology of type IIA compactifications on SU(3)-structure manifolds

    NASA Astrophysics Data System (ADS)

    Caviezel, Claudio; Koerber, Paul; Körs, Simon; Lüst, Dieter; Wrase, Timm; Zagermann, Marco

    2009-04-01

    We study cosmological properties of type IIA compactifications on orientifolds of SU(3)-structure manifolds with non-vanishing geometric flux. These compactifications give rise to effective 4D Script N = 1 supergravity theories that do not fall under some recently-proven no-go theorems against de Sitter vacua and slow-roll inflation. Focusing on a well-understood class of models based on coset spaces, however, we can use a refined no-go theorem that rules out de Sitter vacua and slow-roll inflation in all but one case. The refined no-go theorem uses the dilaton and a specific linear combination of the Kähler moduli, which is different from the overall volume modulus. It puts a lower bound on the first slow-roll parameter: epsilon >= 2. The only case not ruled out is the manifold SU(2) × SU(2), for which we indeed find critical points with epsilon numerically zero. However, all the points we could find have a tachyon corresponding to an eta-parameter η lesssim -2.4.

  9. Direct control of type IIA topoisomerase activity by a chromosomally encoded regulatory protein

    PubMed Central

    Vos, Seychelle M.; Lyubimov, Artem Y.; Hershey, David M.; Schoeffler, Allyn J.; Sengupta, Sugopa; Nagaraja, Valakunja; Berger, James M.

    2014-01-01

    Precise control of supercoiling homeostasis is critical to DNA-dependent processes such as gene expression, replication, and damage response. Topoisomerases are central regulators of DNA supercoiling commonly thought to act independently in the recognition and modulation of chromosome superstructure; however, recent evidence has indicated that cells tightly regulate topoisomerase activity to support chromosome dynamics, transcriptional response, and replicative events. How topoisomerase control is executed and linked to the internal status of a cell is poorly understood. To investigate these connections, we determined the structure of Escherichia coli gyrase, a type IIA topoisomerase bound to YacG, a recently identified chromosomally encoded inhibitor protein. Phylogenetic analyses indicate that YacG is frequently associated with coenzyme A (CoA) production enzymes, linking the protein to metabolism and stress. The structure, along with supporting solution studies, shows that YacG represses gyrase by sterically occluding the principal DNA-binding site of the enzyme. Unexpectedly, YacG acts by both engaging two spatially segregated regions associated with small-molecule inhibitor interactions (fluoroquinolone antibiotics and the newly reported antagonist GSK299423) and remodeling the gyrase holoenzyme into an inactive, ATP-trapped configuration. This study establishes a new mechanism for the protein-based control of topoisomerases, an approach that may be used to alter supercoiling levels for responding to changes in cellular state. PMID:24990966

  10. Evaluation of heat-labile enterotoxins type IIa and type IIb in the pathogenicity of enterotoxigenic Escherichia coli for neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Type II heat-labile enterotoxins (LT-II) have been reported in Escherichia coli isolates from humans, animals, food and water samples. The roles of the antigenically distinguishable LT-IIa and LT-IIb subtypes in pathogenesis and virulence of enterotoxigenic E. coli (ETEC) have not been previously re...

  11. Evaluation of heat-labile enterotoxins type IIa and type IIb in the pathogenicity of enterotoxigenic Escherichia coli for neonatal pigs.

    PubMed

    Casey, Thomas A; Connell, Terry D; Holmes, Randall K; Whipp, Shannon C

    2012-09-14

    Type II heat-labile enterotoxins (LT-II) have been reported in Escherichia coli isolates from humans, animals, food and water samples. The goal here was to determine the specific roles of the antigenically distinguishable LT-IIa and LT-IIb subtypes in pathogenesis and virulence of enterotoxigenic E. coli (ETEC) which has not been previously reported. The prevalence of genes encoding for LT-II was determined by colony blot hybridization in a collection of 1648 E. coli isolates from calves and pigs with diarrhea or other diseases and from healthy animals. Only five isolates hybridized with the LT-II probe and none of these isolates contained genes for other enterotoxins or adhesins associated with porcine or bovine ETEC. Ligated intestinal loops in calves, pigs, and rabbits were used to determine the potential of purified LT-IIa and LT-IIb to cause intestinal secretion. LT-IIa and LT-IIb caused significant secretion in the intestinal loops in calves but not in the intestinal loops of rabbits or pigs. In contrast, neonatal pigs inoculated with isogenic adherent E. coli containing the cloned genes for LT-I, LT-IIa or LT-IIb developed severe watery diarrhea with weight loss that was significantly greater than pigs inoculated with the adherent, non-toxigenic parental or vector only control strains. The results demonstrate that the incidence of LT-II appeared to be very low in porcine and bovine E. coli. However, a potential role for these enterotoxins in E. coli-mediated diarrhea in animals was confirmed because purified LT-IIa and LT-IIb caused fluid secretion in bovine intestinal loops and adherent isogenic strains containing cloned genes encoding for LT-IIa or LT-IIb caused severe diarrhea in neonatal pigs. PMID:22480773

  12. Interleukin-1beta-induced type IIA secreted phospholipase A2 gene expression and extracellular activity in rat vascular endothelial cells.

    PubMed

    Schwemmer, M; Aho, H; Michel, J B

    2001-06-01

    Two phospholipase A2 (PLA2) isoforms, secretory and cytosolic, have been implicated in inflammation. Secretory type IIA PLA2 (sPLA2-IIA), which hydrolyzes fatty acids bound at the sn-2 position of glycerophospholipids, has been detected universally in a variety of mammalian tissues and cells. The expression of the sPLA2-IIA gene and its extracellular activity were shown to be regulated by different factors such as hypoxia, cytokines and phorbol esters. In the present study, we examined the effects of interleukin-1beta (IL-1beta) on the expression of the 14kDa sPLA2-IIA, determined using reverse transcription polymerase chain reaction and radiometric Escherichia coli enzyme assay in primary cultures of rat endothelial cells and in two different rat endothelial cell lines (SVAREC and RBE4). These experiments revealed that IL-1beta induces sPLA2-IIa gene expression and secretion of the enzyme in endothelial cells in a dose- and time-dependent manner. The cAMP-elevator forskolin did not augment the cytokine-induced elevation of sPLA2-IIa enzyme activity but significantly increased the IL-1beta-stimulated sPLA2-IIa mRNA contents in endothelial cells. PMID:11469536

  13. Issues in IIA Uplifting

    SciTech Connect

    Kallosh, Renata; Soroush, Masoud

    2006-12-12

    Moduli stabilization in the type IIA massive string theory so far was achieved only in the AdS vacua. The uplifting to dS vacua has not been performed as yet: neither the analogs of type IIB anti-D3 brane at the tip of the conifold, nor the appropriate D-terms have been identified. The hope was recently expressed that the F-term uplifting may work. We investigate this possibility in the context of a simplified version of the type IIA model developed in hep-th/0505160 and find that the F-term does not uplift the AdS vacua to dS vacua with positive CC. Thus it remains a challenging task to find phenomenologically acceptable vacua in the type IIA string theory.

  14. Fermionic T-duality in massive type IIA supergravity on AdS_{10-k} × M_k

    NASA Astrophysics Data System (ADS)

    Bakhmatov, Ilya

    2016-04-01

    Fermionic T-duality transformation is studied for supersymmetric solutions of massive type IIA supergravity with the metric AdS_{10-k} × M_k for k=3 and 5. We derive the Killing spinors of these backgrounds and use them as input for the fermionic T-duality transformation. The resulting dual solutions form a large family of supersymmetric deformations of the original solutions by complex valued RR fluxes. We observe that the Romans mass parameter does not change under fermionic T-duaity, and prove its invariance in the k=3 case.

  15. Anthrax lethal toxin down-regulates type-IIA secreted phospholipase A(2) expression through MAPK/NF-kappaB inactivation.

    PubMed

    Raymond, Benoit; Ravaux, Lucas; Mémet, Sylvie; Wu, YongZheng; Sturny-Leclère, Aude; Leduc, Dominique; Denoyelle, Chantal; Goossens, Pierre L; Payá, Miguel; Raymondjean, Michel; Touqui, Lhousseine

    2010-04-15

    Bacillus anthracis, the etiological agent of anthrax, produces lethal toxin (LT) that displays a metallo-proteolytic activity toward the N-terminus of the MAPK-kinases. We have previously shown that secreted type-IIA phospholipase A(2) (sPLA(2)-IIA) exhibits potent anthracidal activity. In vitro expression of sPLA(2)-IIA in guinea pig alveolar macrophages (AMs), the major source of this enzyme in lung tissues, is inhibited by LT. Here, we examined the mechanisms involved in sPLA(2)-IIA inhibition by LT. We first showed that chemical inhibitors of p38 and ERK MAPKs reduced sPLA(2)-IIA expression in AMs indicating that these kinases play a role in sPLA(2)-IIA expression. LT inhibited IL-1beta-induced p38 phosphorylation as well as sPLA(2)-IIA promoter activity in CHO cells. Inhibition of sPLA(2)-IIA promoter activity was mimicked by co-transfection with dominant negative construct of p38 (DN-p38) and reversed by the active form of p38-MAPK (AC-p38). Both LT and DN-p38 decreased IL-1beta-induced NF-kappaB luciferase activity. This contrasted with the effect of AC-p38, which enhanced this activity. However, neither LT nor specific p-38 inhibitor interfered with LPS-induced IkappaBalpha degradation or NF-kappaB nuclear translocation in AMs. Subcutaneous administration of LT to guinea pig before LPS challenge reduced sPLA(2)-IIA levels in broncho-alveolar lavages and ears. We conclude that sPLA(2)-IIA expression is induced via a sequential MAPK-NF-kappaB activation and that LT inhibits this expression likely by interfering with the transactivation of NF-kappaB in the nucleus. This inhibition, which is operating both in vitro and in vivo, may represent a mechanism by which B. anthracis subvert host defense. PMID:19962969

  16. Little M-theory

    NASA Astrophysics Data System (ADS)

    Cheng, Hsin-Chia; Thaler, Jesse; Wang, Lian-Tao

    2006-09-01

    Using the language of theory space, i.e. moose models, we develop a unified framework for studying composite Higgs models at the LHC. This framework — denoted little M-theory — is conveniently described by a theoretically consistent three-site moose diagram which implements minimal flavor and isospin violation. By taking different limits of the couplings, one can interpolate between simple group-like and minimal moose-like models with and without T-parity. In this way, little M-theory reveals a large model space for composite Higgs theories. We argue that this framework is suitable as a starting point for a comprehensive study of composite Higgs scenarios. The rich collider phenomenology of this framework is briefly discussed.

  17. N =3 solution in dyonic ISO(7) gauged maximal supergravity and its uplift to massive type IIA supergravity

    NASA Astrophysics Data System (ADS)

    Pang, Yi; Rong, Junchen

    2015-10-01

    We consider a certain N =1 supersymmetric, SO (3 )×SO (3 ) invariant, subsector of the dyonic ISO(7)-gauged maximal supergravity in four dimensions. The theory contains two scalar fields and two pseudoscalar fields. We look for stationary points of the scalar potential, especially the one preserving N =3 supersymmetry of the original ISO(7) gauged theory. The N =3 stationary point corresponding to the AdS vacuum in the D =4 theory is lifted to a warped AdS4×X6 type solution in massive type IIA supergravity. This D =10 background should be the dual of a certain N =3 Chern-Simons matter theory in three dimensions.

  18. Soft x-ray measurements using photoconductive type-IIa and single-crystal chemical vapor deposited diamond detectors

    SciTech Connect

    Moore, A. S.; Bentley, C. D.; Foster, J. M.; Goedhart, G.; Graham, P.; Taylor, M. J.; Hellewell, E.

    2008-10-15

    Photoconductive detectors (PCDs) are routinely used alongside vacuum x-ray diodes (XRDs) to provide an alternative x-ray flux measurement at laser facilities such as HELEN at AWE Aldermaston, UK, and Omega at the Laboratory for Laser Energetics. To evaluate diamond PCDs as an alternative to XRD arrays, calibration measurements made at the National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory are used to accurately calculate the x-ray flux from a laser-heated target. This is compared to a flux measurement using the Dante XRD diagnostic. Estimates indicate that the photoinduced conductivity from measurements made at Omega are too large, and calculations using the radiometric calibrations made at the NSLS agree with this hypothesis. High-purity, single-crystal, chemical vapor deposited (CVD) diamond samples are compared to natural type-IIa PCDs and show promising high resistivity effects, the corollary of which preliminary results show is a slower response time.

  19. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor.

    PubMed Central

    Dent, J A; Berkowitz, S D; Ware, J; Kasper, C K; Ruggeri, Z M

    1990-01-01

    Proteolytic cleavage of the von Willebrand factor subunit may be important for processing and/or function of the molecule and is altered in certain subtypes of von Willebrand disease. It results in the generation of two main fragments with apparent molecular masses of 140 kDa and 176 kDa from the 225-kDa subunit. We have now obtained chemical evidence to locate the protease-sensitive bond between residues Tyr-842 and Met-843, a site that appears to reflect the specificity of calcium-dependent neutral proteases (calpains). Antibodies were raised against four synthetic peptides that represented sequences immediately preceding or following or including the cleavage site. One antibody (against the fragment from Ala-837 through Asp-851) reacted only with the intact subunit, and its epitope included the cleavage site. All others reacted specifically with either the 140-kDa or the 176-kDa fragment, demonstrating their origin from a single cleavage. In samples of purified von Willebrand factor from four of five patients with type IIA von Willebrand disease, the anti-peptide antibodies showed markedly decreased reactivity with either the 140-kDa or the 176-kDa fragment, suggesting the existence of distinct molecular abnormalities clustered around the cleavage site. Thus, in the majority of type IIA patients, a common pathogenetic mechanism may lead to the disappearance of the larger multimers as a consequence of structural changes that may expose a sensitive bond to the action of specific proteases. These studies demonstrate the use of anti-peptide antibodies directed at a relevant structural domain for the immunochemical differentiation of normal and mutant molecules. Images PMID:2385594

  20. Six-Dimensional Superconformal Theories and their Compactifications from Type IIA Supergravity

    NASA Astrophysics Data System (ADS)

    Apruzzi, Fabio; Fazzi, Marco; Passias, Achilleas; Rota, Andrea; Tomasiello, Alessandro

    2015-08-01

    We describe three analytic classes of infinitely many AdSd supersymmetric solutions of massive IIA supergravity, for d =7 ,5 ,4 . The three classes are related by simple universal maps. For example, the AdS7×M3 solutions (where M3 is topologically S3 ) are mapped to AdS5×Σ2×M3' , where Σ2 is a Riemann surface of genus g ≥2 and the metric on M3' is obtained by distorting M3 in a certain way. The solutions can have localized D6 or O6 sources, as well as an arbitrary number of D8-branes. The AdS7 case (previously known only numerically) is conjecturally dual to an NS5-D6-D8 system. The field theories in three and four dimensions are not known, but their number of degrees of freedom can be computed in the supergravity approximation. The AdS4 solutions have numerical "attractor" generalizations that might be useful for flux compactification purposes.

  1. Evidence for the holographic dual of N =3 solution in massive type IIA supergravity

    NASA Astrophysics Data System (ADS)

    Pang, Yi; Rong, Junchen

    2016-03-01

    We calculate the Kaluza-Klein spectrum of spin-2 fluctuations around the N =3 warped AdS4×M6 solution in massive IIA supergravity. This solution was conjectured to be dual to the D =3 N =3 superconformal SU (N ) Chern-Simons matter theory with level k and 2 adjoint chiral multiplets. The SO (3 )R×SO (3 )D isometry of the N =3 solution is identified with the SU (2 )F×SU (2 )R global symmetry of the dual N =3 supersymmetric conformal field theory (SCFT). We show that the SO (3 )R×SO (3 )D quantum numbers and the AdS energies carried by the BPS spin-2 modes match precisely with those of the spin-2 gauge invariant operators in the short multiplets of operators in the N =3 SCFT. We also compute the Euclidean action of the N =3 solution and the free energy of the N =3 SCFT on S3, in the limit N ≫k . Remarkably, the results show a complete agreement.

  2. Modeling human congenital disorder of glycosylation type IIa in the mouse: conservation of asparagine-linked glycan-dependent functions in mammalian physiology and insights into disease pathogenesis.

    PubMed

    Wang, Y; Tan, J; Sutton-Smith, M; Ditto, D; Panico, M; Campbell, R M; Varki, N M; Long, J M; Jaeken, J; Levinson, S R; Wynshaw-Boris, A; Morris, H R; Le, D; Dell, A; Schachter, H; Marth, J D

    2001-12-01

    The congenital disorders of glycosylation (CDGs) are recent additions to the repertoire of inherited human genetic diseases. Frequency of CDGs is unknown since most cases are believed to be misdiagnosed or unrecognized. With few patients identified and heterogeneity in disease signs noted, studies of animal models may provide increased understanding of pathogenic mechanisms. However, features of mammalian glycan biosynthesis and species-specific variations in glycan repertoires have cast doubt on whether animal models of human genetic defects in protein glycosylation will reproduce pathogenic events and disease signs. We have introduced a mutation into the mouse germline that recapitulates the glycan biosynthetic defect responsible for human CDG type IIa (CDG-IIa). Mice lacking the Mgat2 gene were deficient in GlcNAcT-II glycosyltransferase activity and complex N-glycans, resulting in severe gastrointestinal, hematologic, and osteogenic abnormalities. With use of a lectin-based diagnostic screen for CDG-IIa, we found that all Mgat2-null mice died in early postnatal development. However, crossing the Mgat2 mutation into a distinct genetic background resulted in a low frequency of survivors. Mice deficient in complex N-glycans exhibited most CDG-IIa disease signs; however, some signs were unique to the aged mouse or are prognostic in human CDG-IIa. Unexpectedly, analyses of N-glycan structures in Mgat2-null mice revealed a novel oligosaccharide branch on the "bisecting" N-acetylglucosamine. These genetic, biochemical, and physiologic studies indicate conserved functions for N-glycan branches produced in the Golgi apparatus among two mammalian species and suggest possible therapeutic approaches to GlcNAcT-II deficiency. Our findings indicate that human genetic disease due to aberrant protein glycosylation can be modeled in the mouse to gain insights into N-glycan-dependent physiology and the pathogenesis of CDG-IIa. PMID:11805078

  3. Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases.

    PubMed

    Miles, Timothy J; Hennessy, Alan J; Bax, Ben; Brooks, Gerald; Brown, Barry S; Brown, Pamela; Cailleau, Nathalie; Chen, Dongzhao; Dabbs, Steven; Davies, David T; Esken, Joel M; Giordano, Ilaria; Hoover, Jennifer L; Jones, Graham E; Kusalakumari Sukmar, Senthill K; Markwell, Roger E; Minthorn, Elisabeth A; Rittenhouse, Steve; Gwynn, Michael N; Pearson, Neil D

    2016-05-15

    During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties. PMID:27055939

  4. QTL Analysis of Type I and Type IIA Fibers in Soleus Muscle in a Cross between LG/J and SM/J Mouse Strains

    PubMed Central

    Carroll, Andrew M.; Palmer, Abraham A.; Lionikas, Arimantas

    2011-01-01

    Properties of muscle fibers, i.e., their type, number and size, are important determinants of functional characteristics of skeletal muscle, and of the quality of meat in livestock. Genetic factors play an important role in determining variation in fiber properties, however, specific genes remain largely elusive. We examined histological properties of soleus muscle fibers in two strains of mice exhibiting a twofold difference in muscle mass, LG/J and SM/J, and their F2 intercross. The total number of muscle fibers (555 ± 106; mean ± SD) did not differ between the strains or between males and females. A higher percentage of type I fibers was observed in the LG/J compared to the SM/J strain (P < 0.001) in both males (45 ± 3 vs. 37 ± 4%) and females (58 ± 4 vs. 41 ± 3%). Across strains, females had a higher percentage of type I fibers than males (P < 0.001), and the sex effect was greater in the LG/J strain (strain-by-sex interaction, P < 0.001). The cross-sectional area (CSA) did not differ between type I and type IIA fibers, but was greater in the LG/J than the SM/J strain (1365 ± 268 vs. 825 ± 229 μm2, P < 0.001). Three significant quantitative trait locus (QTL) affecting CSA for type I and type IIA fibers mapped to chromosomes (Chr) 1, 6, and 11 and three suggestive QTL for percentage of type I fibers mapped to Chr 2, 3, and 4. Within each significant QTL, regions of conserved synteny were also implicated in variation of similar traits in an analogous study in pigs. Our results provide the evidence that the intercross between the SM/J and LG/J strains is a promising model to search for genes affecting muscle fiber properties. PMID:22303393

  5. Chondrogenesis in the regenerating antler tip in red deer: expression of collagen types I, IIA, IIB, and X demonstrated by in situ nucleic acid hybridization and immunocytochemistry.

    PubMed

    Price, J S; Oyajobi, B O; Nalin, A M; Frazer, A; Russell, R G; Sandell, L J

    1996-03-01

    The annual regrowth of antlers in male deer is a unique example of complete bone regeneration occurring in an adult animal. Growth is initiated at the distal antler tip, which is similar to the epiphyseal growth plate in some respects. However, there is some debate as to whether this process represents "true" endochondral ossification. As part of the characterization of the developmental process in pre-osseus antler tissue, we have studied, by in situ hybridization, the spatial expression of mRNAs for types I, II, and X collagen. Viewed in a coronal plane, type I procollagen mRNA was observed in skin, the fibrous perichondrium, and the densely cellular area immediately adjacent to the perichondrium. Below this area, as cells began to assume a columnar arrangement and coincident with the appearance of a vasculature and synthesis of a cartilaginous matrix, transcripts for types I, IIA, IIB procollagen and X collagen were detected. Further down in the cartilage zone, the pattern of type I procollagen mRNA expression was altered. Here, the signal was detected only in a morphologically distinct subpopulation of small, flattened cells within the intercellular matrix at the periphery of the columns of chondrocytes. The alternative splice form of type II procollagen mRNA (IIA), characteristic of chondroprogenitor cells (Sandell et al. [1991] J. Cell Biol. 114:1307-1319), was expressed by a subset of cells in the upper region of the columns, indicating that this zone contains a population of prechondrocytic cells. Positive hybridization to type IIA was most abundant in these cells. In contrast, transcripts for the other procollagen splice form (IIB) and type X collagen were expressed by chondrocytes throughout the whole of the cartilage region studied. The translation and export of type II collagen and type X collagen were confirmed by detecting specific immunoreactivity for each. The spatial distribution of immunoreactivity for collagen types II and X was consistent with

  6. Analysis of the type II-A CRISPR-Cas system of Streptococcus agalactiae reveals distinctive features according to genetic lineages

    PubMed Central

    Lier, Clément; Baticle, Elodie; Horvath, Philippe; Haguenoer, Eve; Valentin, Anne-Sophie; Glaser, Philippe; Mereghetti, Laurent; Lanotte, Philippe

    2015-01-01

    CRISPR-Cas systems (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) are found in 90% of archaea and about 40% of bacteria. In this original system, CRISPR arrays comprise short, almost unique sequences called spacers that are interspersed with conserved palindromic repeats. These systems play a role in adaptive immunity and participate to fight non-self DNA such as integrative and conjugative elements, plasmids, and phages. In Streptococcus agalactiae, a bacterium implicated in colonization and infections in humans since the 1960s, two CRISPR-Cas systems have been described. A type II-A system, characterized by proteins Cas9, Cas1, Cas2, and Csn2, is ubiquitous, and a type I–C system, with the Cas8c signature protein, is present in about 20% of the isolates. Unlike type I–C, which appears to be non-functional, type II-A appears fully functional. Here we studied type II-A CRISPR-cas loci from 126 human isolates of S. agalactiae belonging to different clonal complexes that represent the diversity of the species and that have been implicated in colonization or infection. The CRISPR-cas locus was analyzed both at spacer and repeat levels. Major distinctive features were identified according to the phylogenetic lineages previously defined by multilocus sequence typing, especially for the sequence type (ST) 17, which is considered hypervirulent. Among other idiosyncrasies, ST-17 shows a significantly lower number of spacers in comparison with other lineages. This characteristic could reflect the peculiar virulence or colonization specificities of this lineage. PMID:26124774

  7. From superstrings to M theory

    SciTech Connect

    Schwarz, John H.

    1999-07-15

    In this talk I will survey some of the basic facts about superstring theories in 10 dimensions and the dualities that relate them to M theory in 11 dimensions. Then I will mention some important unresolved issues.

  8. Corners in M-theory

    NASA Astrophysics Data System (ADS)

    Sati, Hisham

    2011-06-01

    M-theory can be defined on closed manifolds as well as on manifolds with boundary. As an extension, we show that manifolds with corners appear naturally in M-theory. We illustrate this with four situations: the lift to bounding 12 dimensions of M-theory on anti-de Sitter spaces, ten-dimensional heterotic string theory in relation to 12 dimensions, and the two M-branes within M-theory in the presence of a boundary. The M2-brane is taken with (or as) a boundary and the worldvolume of the M5-brane is viewed as a tubular neighborhood. We then concentrate on the (variant) of the heterotic theory as a corner and explore analytical and geometric consequences. In particular, we formulate and study the phase of the partition function in this setting and identify the corrections due to the corner(s). The analysis involves considering M-theory on disconnected manifolds and makes use of the extension of the Atiyah-Patodi-Singer index theorem to manifolds with corners and the b-calculus of Melrose.

  9. Geometry of Spin and SPINc Structures in the M-Theory Partition Function

    NASA Astrophysics Data System (ADS)

    Sati, Hisham

    We study the effects of having multiple Spin structures on the partition function of the spacetime fields in M-theory. This leads to a potential anomaly which appears in the eta invariants upon variation of the Spin structure. The main sources of such spaces are manifolds with nontrivial fundamental group, which are also important in realistic models. We extend the discussion to the Spinc case and find the phase of the partition function, and revisit the quantization condition for the C-field in this case. In type IIA string theory in 10 dimensions, the (mod 2) index of the Dirac operator is the obstruction to having a well-defined partition function. We geometrically characterize manifolds with and without such an anomaly and extend to the case of nontrivial fundamental group. The lift to KO-theory gives the α-invariant, which in general depends on the Spin structure. This reveals many interesting connections to positive scalar curvature manifolds and constructions related to the Gromov-Lawson-Rosenberg conjecture. In the 12-dimensional theory bounding M-theory, we study similar geometric questions, including choices of metrics and obtaining elements of K-theory in 10 dimensions by pushforward in K-theory on the disk fiber. We interpret the latter in terms of the families index theorem for Dirac operators on the M-theory circle and disk. This involves superconnections, eta forms, and infinite-dimensional bundles, and gives elements in Deligne cohomology in lower dimensions. We illustrate our discussion with many examples throughout.

  10. Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease.

    PubMed

    Agapova, Olga A; Fang, Yifu; Sugatani, Toshifumi; Seifert, Michael E; Hruska, Keith A

    2016-06-01

    The causes of cardiovascular mortality associated with chronic kidney disease (CKD) are partly attributed to the CKD-mineral bone disorder (CKD-MBD). The causes of the early CKD-MBD are not well known. Our discovery of Wnt (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. In the search for such factors, we studied the effects of activin receptor type IIA (ActRIIA) signaling by using a ligand trap for the receptor, RAP-011 (a soluble extracellular domain of ActRIIA fused to a murine IgG-Fc fragment). In a mouse model of CKD that stimulated atherosclerotic calcification, RAP-011 significantly increased aortic ActRIIA signaling assessed by the levels of phosphorylated Smad2/3. Furthermore, RAP-011 treatment significantly reversed CKD-induced vascular smooth muscle dedifferentiation as assessed by smooth muscle 22α levels, osteoblastic transition, and neointimal plaque calcification. In the diseased kidneys, RAP-011 significantly stimulated αklotho levels and it inhibited ActRIIA signaling and decreased renal fibrosis and proteinuria. RAP-011 treatment significantly decreased both renal and circulating Dickkopf 1 levels, showing that Wnt activation was downstream of ActRIIA. Thus, ActRIIA signaling in CKD contributes to the CKD-MBD and renal fibrosis. ActRIIA signaling may be a potential therapeutic target in CKD. PMID:27165838

  11. Molecular cloning, expression and characterization of albolamin: a type P-IIa snake venom metalloproteinase from green pit viper (Cryptelytrops albolabris).

    PubMed

    Jangprasert, Panchalee; Rojnuckarin, Ponlapat

    2014-03-01

    Snake venom metalloproteinases (SVMPs) can damage vessel wall, degrade clotting factors, inhibit integrins and block platelet functions. Studying them not only gives us deeper insights in pathogenesis of snakebites, but also potentially yields novel therapeutic agents. Here, we discovered a clone of an RGD-containing SVMP from the green pit viper (Cryptelytrops albolabris) venom gland cDNA library. Sequence analysis revealed that it belonged to the P-IIa subclass of SVMP comprising signal peptide, prodomain, metalloproteinase and disintegrin. Compared with other P-II SVMPs, it contained 2 additional conserved cysteines that were predicted to prevent the release of disintegrin from the metalloproteinase domain in the mature protein. The N-terminal histidine-tagged construct of metalloproteinase and disintegrin domains of albolamin was inserted into the pPICZαA vector and expressed in Pichia pastoris. The recombinant protein molecular weight was approximately 35 kDa on Western blot probed with anti-polyhistidine antibody. The recombinant albolamin could digest human type IV collagen starting within 15 min after incubation. In addition, it dose-dependently inhibited collagen-induced platelet aggregation with the IC50 of 1.8 μM. However, there was no effect on ADP-induced platelet aggregation. Therefore, the inhibition mechanism is probably through blocking collagen receptor(s). Albolamin activities probably contributed to pathology of green pit viper bites. Its disintegrin domain deserves further studies for the potential to be a useful agent affecting platelet functions. PMID:24380672

  12. CRISPathBrick: Modular Combinatorial Assembly of Type II-A CRISPR Arrays for dCas9-Mediated Multiplex Transcriptional Repression in E. coli.

    PubMed

    Cress, Brady F; Toparlak, Ö Duhan; Guleria, Sanjay; Lebovich, Matthew; Stieglitz, Jessica T; Englaender, Jacob A; Jones, J Andrew; Linhardt, Robert J; Koffas, Mattheos A G

    2015-09-18

    Programmable control over an addressable global regulator would enable simultaneous repression of multiple genes and would have tremendous impact on the field of synthetic biology. It has recently been established that CRISPR/Cas systems can be engineered to repress gene transcription at nearly any desired location in a sequence-specific manner, but there remain only a handful of applications described to date. In this work, we report development of a vector possessing a CRISPathBrick feature, enabling rapid modular assembly of natural type II-A CRISPR arrays capable of simultaneously repressing multiple target genes in Escherichia coli. Iterative incorporation of spacers into this CRISPathBrick feature facilitates the combinatorial construction of arrays, from a small number of DNA parts, which can be utilized to generate a suite of complex phenotypes corresponding to an encoded genetic program. We show that CRISPathBrick can be used to tune expression of plasmid-based genes and repress chromosomal targets in probiotic, virulent, and commonly engineered E. coli strains. Furthermore, we describe development of pCRISPReporter, a fluorescent reporter plasmid utilized to quantify dCas9-mediated repression from endogenous promoters. Finally, we demonstrate that dCas9-mediated repression can be harnessed to assess the effect of downregulating both novel and computationally predicted metabolic engineering targets, improving the yield of a heterologous phytochemical through repression of endogenous genes. These tools provide a platform for rapid evaluation of multiplex metabolic engineering interventions. PMID:25822415

  13. Implantation of a Novel Allogeneic Mesenchymal Precursor Cell Type in Patients with Ischemic Cardiomyopathy Undergoing Coronary Artery Bypass Grafting: an Open Label Phase IIa Trial.

    PubMed

    Anastasiadis, Kyriakos; Antonitsis, Polychronis; Westaby, Stephen; Reginald, Ajan; Sultan, Sabena; Doumas, Argirios; Efthimiadis, George; Evans, Martin John

    2016-06-01

    Heart failure is a life-limiting condition affecting over 40 million patients worldwide. Ischemic cardiomyopathy (ICM) is the most common cause. This study investigates in situ cardiac regeneration utilizing precision delivery of a novel mesenchymal precursor cell type (iMP) during coronary artery bypass surgery (CABG) in patients with ischemic cardiomyopathy (LVEF < 40 %). The phase IIa safety study was designed to enroll 11 patients. Preoperative scintigraphy imaging (SPECT) was used to identify hibernating myocardium not suitable for conventional myocardial revascularization for iMP implantation. iMP cells were implanted intramyocardially in predefined viable peri-infarct areas that showed poor perfusion, which could not be grafted due to poor target vessel quality. Postoperatively, SPECT was then used to identify changes in scar area. Intramyocardial implantation of iMP cells with CABG was safe with preliminary evidence of efficacy of improved myocardial contractility and perfusion of nonrevascularized territories resulting in a significant reduction in left ventricular scar area at 12 months after treatment. Clinical improvement was associated with a significant improvement in quality of life at 6 months posttreatment in all patients. The results suggest the potential for in situ myocardial regeneration in ischemic heart failure by delivery of iMP cells. PMID:27037806

  14. U-duality and M-theory

    NASA Astrophysics Data System (ADS)

    Obers, N. A.; Pioline, B.

    1999-09-01

    This work is intended as a pedagogical introduction to M-theory and to its maximally supersymmetric toroidal compactifications, in the frameworks of 11D supergravity, type II string theory and M(atrix) theory. U-duality is used as the main tool and guideline in uncovering the spectrum of BPS states. We review the 11D supergravity algebra and elementary 1/2-BPS solutions, discuss T-duality in the perturbative and non-perturbative sectors from an algebraic point of view, and apply the same tools to the analysis of U-duality at the level of the effective action and of the BPS spectrum, with a particular emphasis on Weyl and Borel generators. We derive the U-duality multiplets of BPS particles and strings, U-duality invariant mass formulae for 1/2- and 1/4-BPS states for general toroidal compactifications on skew tori with gauge backgrounds, and U-duality multiplets of constraints for states to preserve a given fraction of supersymmetry. A number of mysterious states are encountered in D≤3, whose existence is implied by T-duality and 11D Lorentz invariance. We then move to the M(atrix) theory point of view, give an introduction to Discrete Light-Cone Quantization (DLCQ) in general and DLCQ of M-theory in particular. We discuss the realization of U-duality as electric-magnetic dualities of the Matrix gauge theory, display the Matrix gauge theory BPS spectrum in detail, and discuss the conjectured extended U-duality group in this scheme.

  15. Interaction of the human T-cell lymphotropic virus type 1 tax transactivator with transcription factor IIA.

    PubMed Central

    Clemens, K E; Piras, G; Radonovich, M F; Choi, K S; Duvall, J F; DeJong, J; Roeder, R; Brady, J N

    1996-01-01

    The Tax protein of human T-cell lymphotropic virus type 1 (HTLV-1) is a 40-kDa transcriptional activator which is critical for HTLV-1 gene regulation and virus-induced cellular transformation. Tax is localized to the DNA through its interaction with the site-specific activators cyclic AMP-responsive element-binding protein, NF-kappaB, and serum response factor. It has been suggested that the recruitment of Tax to the DNA positions Tax for interaction with the basal transcriptional machinery. On the basis of several independent assays, we now report a physical and functional interaction between Tax and the transcription factor, TFIIA. First, Tax was found to interact with the 35-kDa (alpha) subunit of TFIIA in the yeast two-hybrid interaction system. Importantly, two previously characterized mutants with point mutations in Tax, M32 (Y196A, K197S) and M41 (H287A, P288S), which were shown to be defective in Tax-activated transcription were unable to interact with TFIIA in this assay. Second, a glutathione-S-transferase (GST) affinity-binding assay showed that the interaction of holo-TFIIA with GST-Tax was 20-fold higher than that observed with either the GST-Tax M32 activation mutant or the GST control. Third, a coimmunoprecipitation assay showed that in HTLV-1-infected human T lymphocytes, Tax and TFIIA were associated. Finally, TFIIA facilitates Tax transactivation in vitro and in vivo. In vitro transcription studies showed reduced levels of Tax-activated transcription in cell extracts depleted of TFIIA. In addition, transfection of human T lymphocytes with TFIIA expression vectors enhanced Tax-activated transcription of an HTLV-1 long terminal repeat-chloramphenicol acetyltransferase reporter construct. Our study suggests that the interaction of Tax with the transcription factor TFIIA may play a role in Tax-mediated transcriptional activation. PMID:8756622

  16. Role of Na+/H+ exchanger regulatory factor 1 in forward trafficking of the type IIa Na+-Pi cotransporter

    PubMed Central

    Ketchem, Corey J.; Khundmiri, Syed J.; Gaweda, Adam E.; Murray, Rebecca; Clark, Barbara J.; Weinman, Edward J.

    2015-01-01

    Na+/H+ exchanger regulatory factor (NHERF1) plays a critical role in the renal transport of phosphate by binding to Na+-Pi cotransporter (NpT2a) in the proximal tubule. While the association between NpT2a and NHERF1 in the apical membrane is known, the role of NHERF1 to regulate the trafficking of NpT2a has not been studied. To address this question, we performed cell fractionation by sucrose gradient centrifugation in opossum kidney (OK) cells placed in low-Pi medium to stimulate forward trafficking of NpT2a. Immunoblot analysis demonstrated expression of NpT2a and NHERF1 in the endoplasmic reticulum (ER)/Golgi. Coimmunoprecipitation demonstrated a NpT2a-NHERF1 interaction in the ER/Golgi. Low-Pi medium for 4 and 8 h triggered a decrease in NHERF1 in the plasma membrane with a corresponding increase in the ER/Golgi. Time-lapse total internal reflection fluorescence imaging of OK cells placed in low-Pi medium, paired with particle tracking and mean square displacement analysis, indicated active directed movement of NHERF1 at early and late time points, whereas NpT2a showed active movement only at later times. Silence of NHERF1 in OK cells expressing green fluorescent protein (GFP)-NpT2a resulted in an intracellular accumulation of GFP-NpT2a. Transfection with GFP-labeled COOH-terminal (TRL) PDZ-binding motif deleted or wild-type NpT2a in OK cells followed by cell fractionation and immunoprecipitation confirmed that the interaction between NpT2a and NHERF1 was dependent on the TRL motif of NpT2a. We conclude that appropriate trafficking of NpT2a to the plasma membrane is dependent on the initial association between NpT2a and NHERF1 through the COOH-terminal TRL motif of NpT2a in the ER/Golgi and requires redistribution of NHERF1 to the ER/Golgi. PMID:25995109

  17. Role of Na+/H+ exchanger regulatory factor 1 in forward trafficking of the type IIa Na+-Pi cotransporter.

    PubMed

    Ketchem, Corey J; Khundmiri, Syed J; Gaweda, Adam E; Murray, Rebecca; Clark, Barbara J; Weinman, Edward J; Lederer, Eleanor D

    2015-07-15

    Na+/H+ exchanger regulatory factor (NHERF1) plays a critical role in the renal transport of phosphate by binding to Na+-Pi cotransporter (NpT2a) in the proximal tubule. While the association between NpT2a and NHERF1 in the apical membrane is known, the role of NHERF1 to regulate the trafficking of NpT2a has not been studied. To address this question, we performed cell fractionation by sucrose gradient centrifugation in opossum kidney (OK) cells placed in low-Pi medium to stimulate forward trafficking of NpT2a. Immunoblot analysis demonstrated expression of NpT2a and NHERF1 in the endoplasmic reticulum (ER)/Golgi. Coimmunoprecipitation demonstrated a NpT2a-NHERF1 interaction in the ER/Golgi. Low-Pi medium for 4 and 8 h triggered a decrease in NHERF1 in the plasma membrane with a corresponding increase in the ER/Golgi. Time-lapse total internal reflection fluorescence imaging of OK cells placed in low-Pi medium, paired with particle tracking and mean square displacement analysis, indicated active directed movement of NHERF1 at early and late time points, whereas NpT2a showed active movement only at later times. Silence of NHERF1 in OK cells expressing green fluorescent protein (GFP)-NpT2a resulted in an intracellular accumulation of GFP-NpT2a. Transfection with GFP-labeled COOH-terminal (TRL) PDZ-binding motif deleted or wild-type NpT2a in OK cells followed by cell fractionation and immunoprecipitation confirmed that the interaction between NpT2a and NHERF1 was dependent on the TRL motif of NpT2a. We conclude that appropriate trafficking of NpT2a to the plasma membrane is dependent on the initial association between NpT2a and NHERF1 through the COOH-terminal TRL motif of NpT2a in the ER/Golgi and requires redistribution of NHERF1 to the ER/Golgi. PMID:25995109

  18. Borcherds symmetries in M-theory

    NASA Astrophysics Data System (ADS)

    Henry-Labordère, Pierre; Julia, Bernard; Paulot, Louis

    2002-04-01

    It is well known but rather mysterious that root spaces of the Ek Lie groups appear in the second integral cohomology of regular, complex, compact, del Pezzo surfaces. The corresponding groups act on the scalar fields (0-forms) of toroidal compactifications of M theory. Their Borel subgroups are actually subgroups of supergroups of finite dimension over the Grassmann algebra of differential forms on spacetime that have been shown to preserve the self-duality equation obeyed by all bosonic form-fields of the theory. We show here that the corresponding duality superalgebras are nothing but Borcherds superalgebras truncated by the above choice of Grassmann coefficients. The full Borcherds' root lattices are the second integral cohomology of the del Pezzo surfaces. Our choice of simple roots uses the anti-canonical form and its known orthogonal complement. Another result is the determination of del Pezzo surfaces associated to other string and field theory models. Dimensional reduction on Tk corresponds to blow-up of k points in general position with respect to each other. All theories of the Magic triangle that reduce to the En sigma model in three dimensions correspond to singular del Pezzo surfaces with A8-n (normal) singularity at a point. The case of type-I and heterotic theories if one drops their gauge sector corresponds to non-normal (singular along a curve) del Pezzo's. We comment on previous encounters with Borcherds algebras at the end of the paper.

  19. Sasakian manifolds and M-theory

    NASA Astrophysics Data System (ADS)

    Figueroa-O'Farrill, José; Santi, Andrea

    2016-05-01

    We extend the link between Einstein Sasakian manifolds and Killing spinors to a class of η-Einstein Sasakian manifolds, both in Riemannian and Lorentzian settings, characterizing them in terms of generalized Killing spinors. We propose a definition of supersymmetric M-theory backgrounds on such a geometry and find a new class of such backgrounds, extending previous work of Haupt, Lukas and Stelle.

  20. M Theory Solution to the Hierarchy Problem

    SciTech Connect

    Acharya, Bobby; Bobkov, Konstantin; Kane, Gordon; Kumar, Piyush; Vaman, Diana

    2006-11-10

    An old idea for explaining the hierarchy is strong gauge dynamics. We show that such dynamics also stabilizes the moduli in M theory compactifications on manifolds of G{sub 2} holonomy without fluxes. This gives stable vacua with softly broken supersymmetry, grand unification, and a distinctive spectrum of TeV and sub-TeV sparticle masses.

  1. Tanshinone IIA Inhibits Proliferation and Induces Apoptosis Through the Downregulation of Survivin in Keloid Fibroblasts.

    PubMed

    Chen, Gang; Liang, Yimin; Liang, Xiao; Li, Qingfeng; Liu, Dalie

    2016-02-01

    Keloids are considered benign dermal fibroproliferative tumors. Keloid fibroblasts (KFs) persistently proliferate and fail to undergo apoptosis, and no treatment is completely effective against these lesions. Tanshinone IIA induces apoptosis and inhibits the proliferation of various tumor cell types. In this study, we investigated the effect of tanshinone IIA on the regulation of proliferation, cell cycle, and apoptosis in KFs, and investigated potential mechanisms involved in the effects. First, KFs and normal skin fibroblasts (NSFs) were treated with various concentrations of tanshinone IIA. Cell counting kit-8 (CCK-8) was used to assess the proliferative activity of KFs and NSFs, and flow cytometry was used to investigate the cell cycle and apoptosis in KFs. We found that the proliferation of all tanshinone IIA-treated KFs was significantly decreased after treatment for 72 hours (P < 0.001). Also, NSFs treated with tanshinone IIA did not exhibit noticeable effects compared with KFs. In addition, the percentages of G0/G1 cells in all tanshinone IIA-treated KFs were significantly increased after treatment for 72 hours (P < 0.001). And the percentages of cells undergoing early apoptosis in all tanshinone IIA-treated KFs were significantly increased after treatment for 120 hours (P < 0.001). Furthermore, the apoptosis antibody array kit and Western blot analysis revealed that tanshinone IIA decreased survivin expression in KFs (P < 0.001). In conclusion, tanshinone IIA downregulates survivin and deactivates KFs, thus suggesting that tanshinone IIA could serve as a potential clinical keloid treatment. PMID:26101974

  2. M-theory and G2 manifolds

    NASA Astrophysics Data System (ADS)

    Becker, Katrin; Becker, Melanie; Robbins, Daniel

    2015-11-01

    In this talk we report on recent progress in describing compactifications of string theory and M-theory on G2 and Spin(7) manifolds. We include the infinite set of α’-corrections and describe the entire tower of massless and massive Kaluza-Klein modes resulting from such compactifications. Contribution to the ‘Focus Issue on Gravity, Supergravity and Fundamental Physics: the Richard Arnowitt Symposium’, to be published in Physica Scripta. Based on a talk delivered by Becker at the workshop ‘Superstring Perturbation Theory’ at the Perimeter Institute, 22-24 April 2015.

  3. M-theory, the signature theorem, and geometric invariants

    NASA Astrophysics Data System (ADS)

    Sati, Hisham

    2011-06-01

    The equations of motion and the Bianchi identity of the C-field in M-theory are encoded in terms of the signature operator. We then reformulate the topological part of the action in M-theory using the signature, which leads to connections to the geometry of the underlying manifold, including positive scalar curvature. This results in a variation on the miraculous cancellation formula of Alvarez-Gaumé and Witten in 12 dimensions and leads naturally to the Kreck-Stolz s-invariant in 11 dimensions. Hence M-theory detects the diffeomorphism type of 11-dimensional (and seven-dimensional) manifolds and in the restriction to parallelizable manifolds classifies topological 11 spheres. Furthermore, requiring the phase of the partition function to be anomaly-free imposes restrictions on allowed values of the s-invariant. Relating to string theory in ten dimensions amounts to viewing the bounding theory as a disk bundle, for which we study the corresponding phase in this formulation.

  4. [Biological and clinical safety of nomegestrol acetate administered alone then associated in inverse sequence with transdermal 17 beta estradiol, in women at risk of dyslipoproteinemia type IIa].

    PubMed

    Zartarian, M; Chevallier, T; Micheletti, M C; Leber, C; Jamin, C

    1998-12-01

    In this study including 26 patients with dyslipoproteinemia classified IIa, we evaluated biochemical and clinical safety of Nomegestrol acetate (Lutenyl) used for its antigonadotrophin property. It was administered alone, during 3 cycles at the dose of 5 mg/d for 21 days by cycle and then it was associated (at the same sequence and dose), without any wash out, for the next 6 cycles, with a 17 beta estradiol patch (Estraderm TTS 50), 50 micrograms/d from the 11th to the 21st day of each cycle. Nomegestrol acetate, alone, had no significant effect on glycemia, antithrombin III, triglycerides, total cholesterol, apoprotein A1, and LpA1 values compared to those at baseline but apoprotein B and Lp (a) values tended to decrease slightly. Serum progesterone levels were collapsed, and FSH values were low. Weight and blood pressure remained constant. Adding 17 beta estradiol enabled to significantly decrease and normalize the apoprotein B values after the first 3 cycles compared to the baseline values, then these values remained constant during the next 3 cycles. There was no effect on the other parameters (except for a significant increase in plasmatic estradiol values) on the antigonadotrophin property of Nomegestrol acetate, nor on weight and blood pressure which remained constant. Moreover, we observed an important decrease in the rate of amenorrheic cycles compared to those with Nomegestrol acetate alone. PMID:9949893

  5. String Theory and M-Theory

    NASA Astrophysics Data System (ADS)

    Becker, Katrin; Becker, Melanie; Schwarz, John H.

    String theory is one of the most exciting and challenging areas of modern theoretical physics. This book guides the reader from the basics of string theory to recent developments. It introduces the basics of perturbative string theory, world-sheet supersymmetry, space-time supersymmetry, conformal field theory and the heterotic string, before describing modern developments, including D-branes, string dualities and M-theory. It then covers string geometry and flux compactifications, applications to cosmology and particle physics, black holes in string theory and M-theory, and the microscopic origin of black-hole entropy. It concludes with Matrix theory, the AdS/CFT duality and its generalizations. This book is ideal for graduate students and researchers in modern string theory, and will make an excellent textbook for a one-year course on string theory. It contains over 120 exercises with solutions, and over 200 homework problems with solutions available on a password protected website for lecturers at www.cambridge.org/9780521860697. Comprehensive coverage of topics from basics of string theory to recent developments Ideal textbook for a one-year course in string theory Includes over 100 exercises with solutions Contains over 200 homework problems with solutions available to lecturers on-line

  6. Regulation of myosin IIA and filamentous actin during insulin-stimulated glucose uptake in 3T3-L1 adipocytes

    SciTech Connect

    Stall, Richard; Ramos, Joseph; Kent Fulcher, F.; Patel, Yashomati M.

    2014-03-10

    Insulin stimulated glucose uptake requires the colocalization of myosin IIA (MyoIIA) and the insulin-responsive glucose transporter 4 (GLUT4) at the plasma membrane for proper GLUT4 fusion. MyoIIA facilitates filamentous actin (F-actin) reorganization in various cell types. In adipocytes F-actin reorganization is required for insulin-stimulated glucose uptake. What is not known is whether MyoIIA interacts with F-actin to regulate insulin-induced GLUT4 fusion at the plasma membrane. To elucidate the relationship between MyoIIA and F-actin, we examined the colocalization of MyoIIA and F-actin at the plasma membrane upon insulin stimulation as well as the regulation of this interaction. Our findings demonstrated that MyoIIA and F-actin colocalized at the site of GLUT4 fusion with the plasma membrane upon insulin stimulation. Furthermore, inhibition of MyoII with blebbistatin impaired F-actin localization at the plasma membrane. Next we examined the regulatory role of calcium in MyoIIA-F-actin colocalization. Reduced calcium or calmodulin levels decreased colocalization of MyoIIA and F-actin at the plasma membrane. While calcium alone can translocate MyoIIA it did not stimulate F-actin accumulation at the plasma membrane. Taken together, we established that while MyoIIA activity is required for F-actin localization at the plasma membrane, it alone is insufficient to localize F-actin to the plasma membrane. - Highlights: • Insulin induces colocalization of MyoIIA and F-actin at the cortex in adipocytes. • MyoIIA is necessary but not sufficient to localize F-actin at the cell cortex. • MyoIIA-F-actin colocalization is regulated by calcium and calmodulin.

  7. MYBPH inhibits NM IIA assembly via direct interaction with NMHC IIA and reduces cell motility

    SciTech Connect

    Hosono, Yasuyuki; Usukura, Jiro; Yamaguchi, Tomoya; Yanagisawa, Kiyoshi; Suzuki, Motoshi; Takahashi, Takashi

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer MYBPH inhibits NMHC IIA assembly and cell motility. Black-Right-Pointing-Pointer MYBPH interacts to assembly-competent NM IIA. Black-Right-Pointing-Pointer MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA. -- Abstract: Actomyosin filament assembly is a critical step in tumor cell migration. We previously found that myosin binding protein H (MYBPH) is directly transactivated by the TTF-1 lineage-survival oncogene in lung adenocarcinomas and inhibits phosphorylation of the myosin regulatory light chain (RLC) of non-muscle myosin IIA (NM IIA) via direct interaction with Rho kinase 1 (ROCK1). Here, we report that MYBPH also directly interacts with an additional molecule, non-muscle myosin heavy chain IIA (NMHC IIA), which was found to occur between MYBPH and the rod portion of NMHC IIA. MYBPH inhibited NMHC IIA assembly and reduced cell motility. Conversely, siMYBPH-induced increased motility was partially, yet significantly, suppressed by blebbistatin, a non-muscle myosin II inhibitor, while more profound effects were attained by combined treatment with siROCK1 and blebbistatin. Electron microscopy observations showed well-ordered paracrystals of NMHC IIA reflecting an assembled state, which were significantly less frequently observed in the presence of MYBPH. Furthermore, an in vitro sedimentation assay showed that a greater amount of NMHC IIA was in an unassembled state in the presence of MYBPH. Interestingly, treatment with a ROCK inhibitor that impairs transition of NM IIA from an assembly-incompetent to assembly-competent state reduced the interaction between MYBPH and NMHC IIA, suggesting that MYBPH has higher affinity to assembly-competent NM IIA. These results suggest that MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA, and negatively regulates actomyosin organization at 2 distinct steps, resulting in firm inhibition of NM IIA assembly.

  8. Efficacy and mechanism of tanshinone IIA liquid nanoparticles in preventing experimental postoperative peritoneal adhesions in vivo and in vitro

    PubMed Central

    Qin, Fei; Ma, Yun; Li, Xiao; Wang, Xian; Wei, Yuanyi; Hou, Chuqi; Lin, Si; Hou, Lianbing; Wang, Chengxi

    2015-01-01

    Up to 90% of patients develop adhesion following laparotomy. Upregulating fibrinolysis within the peritoneum reduces adhesions. Tanshinone IIA (Tan IIA) promotes fibrinolysis in hepatic fibrosis and the cardiovascular system and may play a role in preventing adhesions. We report preparation and characterization of liquid nanoparticles of Tan IIA for intravenous administration and investigate its feasibility in clinical practice. Tan IIA liquid nanoparticles (Tan IIA-NPs) were prepared using the emulsion/solvent evaporation method. Adhesions were induced in Sprague–Dawley rats by injuring the parietal peritoneum and cecum, followed by intravenous administration of various Tan IIA-NP dosages. The adhesion scores for each group were collected 7 days after the initial laparotomy. The activity of tissue-type plasminogen activator (tPA) was measured from the peritoneal lavage fluid. The messenger RNA and protein expression levels of plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. TGF-β1 and collagen I expressions were measured immunohistochemically in the ischemic tissues. The effects of Tan IIA-NPs and free-Tan IIA on tPA and PAI-1 were measured in vitro in TGF-β1-induced HMrSV5 cells. Tan IIA-NPs exhibited small particle size, high encapsulation efficiency, good stability for storage, and safety for intravenous administration. Tan IIA-NPs were effective in preventing adhesion. Tan IIA-NPs increased tPA activity in peritoneal lavage fluid, and tPA mRNA and protein expression, and decreased PAI-1 mRNA and protein expression in the ischemic tissues. Moreover, Tan IIA-NPs decreased TGF-β1 and collagen I expressions in the ischemic tissues. Tan IIA-NPs administered via tail veins upregulated fibrinolysis in the peritoneum. In vitro studies showed that these effects may be mediated by the TGF-β signal pathway. PMID:26056449

  9. Tanshinone IIA ameliorates dextran sulfate sodium-induced inflammatory bowel disease via the pregnane X receptor

    PubMed Central

    Zhang, Xianxie; Wang, Yuguang; Ma, Zengchun; Liang, Qiande; Tang, Xianglin; Hu, Donghua; Tan, Hongling; Xiao, Chengrong; Gao, Yue

    2015-01-01

    Tanshinone IIA (Tan IIA) (C19H18O3) is one of the major active lipophilic components in a conventional Chinese medicine called danshen, and it has long been used in the People’s Republic of China and other neighboring countries to treat patients suffering from inflammatory bowel disease (IBD). Previous experiments by many teams determined which mechanism of Tan IIA is relevant to the treatment of IBD associated with inflammation and the pregnane X receptor (PXR). The current study demonstrated that Tan IIA is an efficacious PXR agonist and its ability to induce CYP3A4 mRNA and protein expression was mediated by the transactivation of PXR, a known target of abrogating inflammation in IBD. Clinical symptoms in mice and histological assessment data suggested that administration of Tan IIA in mice demonstrated significant protection and showed that in DSS-induced IBD it acts in a concentration-dependent manner. PXR-silenced mice treated with Tan IIA demonstrated low protection against DSS-induced mouse IBD and exacerbated the severity of IBD compared with wild-type mice; PXR-silenced mice demonstrated the necessity for PXR in Tan IIA-mediated upregulation of xenobiotic metabolism genes. The IBD treatment effects of Tan IIA are partially due to PXR-mediated upregulation of xenobiotic metabolism and downregulation of inflammatory mediators. The novel findings reported here may contribute to the effective utilization of Tan IIA and its derivatives as a PXR ligand in the treatment of human IBD. This suggests that Tan IIA may have considerable clinical utility. PMID:26674743

  10. BPS amplitudes, helicity supertraces and membranes in M-theory

    NASA Astrophysics Data System (ADS)

    Wit, B. d.; Lüst, D.

    2000-03-01

    We study BPS dominated loop amplitudes in M-theory on T2. For this purpose we generalize the concept of helicity supertraces to nine spacetime dimensions. These traces distinguish between various massive supermultiplets and appear as coefficients in their one-loop contributions to n-graviton scattering amplitudes. This can be used to show that only ultrashort BPS multiplets contribute to the R4 term in the effective action, which was first computed by Green, Gutperle and Vanhove. There are two inequivalent ultrashort BPS multiplets which describe the Kaluza-Klein states and the wrapped membranes that cover the torus a number of times. From the perspective of the type-II strings they correspond to momentum and winding states and D0 or D1 branes.

  11. Consistent N=8 truncation of massive IIA on S 6

    NASA Astrophysics Data System (ADS)

    Guarino, Adolfo; Varela, Oscar

    2015-12-01

    Massive type IIA supergravity is shown to admit a consistent truncation on the six-sphere to maximal supergravity in four dimensions with a dyonic ISO(7) gauging. We obtain the complete, non-linear embedding of all the D = 4 fields into the IIA metric and form potentials, and show its consistency. We first rewrite the IIA theory in an SO(1 , 3) × SL(7)-covariant way. Then, we employ an N=8 SL(7)-covariant restriction of the D = 4 tensor hierarchy in order to find the full embedding. The redundant D = 4 degrees of freedom introduced by the tensor hierarchy can be eliminated by writing the embedding in terms of the field strengths and exploiting the restricted duality hierarchy. In particular, closed expressions for the Freund-Rubin term are found using this technique which reveal a pattern valid for other truncations. Finally, we show that the present N=8 truncation of massive IIA on S 6 and the N=2 truncation obtained when S 6 is equipped with its nearly-Kähler structure, overlap in the N=1 , G2-invariant sector of the former.

  12. Cholera toxin, LT-I, LT-IIa, and LT-IIb: the critical role of ganglioside-binding in immunomodulation by Type I and Type II heat-labile enterotoxins

    PubMed Central

    Connell, Terry D.

    2010-01-01

    The heat-labile enterotoxins (HLT) expressed by Vibrio cholerae (cholera toxin) and Escherichia coli (LT-I, LT-IIa, and LT-IIb) are potent systemic and mucosal adjuvants. Co-administration of the enterotoxins with a foreign antigen (Ag) produces an augmented immune response to that antigen. Although each enterotoxin has potent adjuvant properties, the means by which the enterotoxins induce various immune responses are distinctive for each adjuvant. Various mutants have been engineered to dissect the functions of the enterotoxins required for their adjuvanticity. The capacity to strongly bind to one or more specific ganglioside receptors appears to drive the distinctive immunomodulatory properties associated with each enterotoxin. Mutant enterotoxins with ablated or altered ganglioside binding affinities have been employed to investigate the role of gangliosides in enterotoxin-dependent immunomodulation. PMID:17931161

  13. M-theory Calabi-Yau Quantum Mechanics

    NASA Astrophysics Data System (ADS)

    Haupt, Alexander S.

    2009-11-01

    This thesis explores an exotic class of M-theory compactifications in which the compact manifold is taken to be a Calabi-Yau five-fold. The resulting effective theory is a one-dimensional N=2 super-mechanics model that exhibits peculiar features of one-dimensional supersymmetry, such as the appearance of fermion-only super-multiplets. The latter necessitates reducing also the fermionic sector of M-theory, which is not normally included in the compactification literature and is thus presented, together with the required technology, in detail. The one-dimensional effective theory is most elegantly described in superspace and therefore, a detailed account of one-dimensional flat and curved N=2 superspace is provided. This includes developing the theory of fermionic multiplets and the study of cross-couplings between 2a and 2b multiplets. Another important aspect is the inclusion of flux. We study its consistency conditions, its relation to supersymmetry and the way it gives rise to a potential in the one-dimensional effective action. It is also explained how the supersymmetry-preserving part of the potential can be obtained from a Gukov-type superpotential. The main motivation of this compactification scenario is rooted in the realm of cosmology. Its virtue is a democratic treatment of spatial dimensions. As opposed to the artificial 3+7 split in most string compactifications, the early universe starts out with all spatial dimensions compact and small in our approach. One then seeks for dynamical ways in which three dimensions grow large at late times. Possible realisations of this idea are discussed both at the classical and at the quantum level. Finally, preliminary work on Calabi-Yau five-fold compactifications of F-theory and the resulting two-dimensional string-like actions is presented.

  14. Noncommutative Geometry in M-Theory and Conformal Field Theory

    SciTech Connect

    Morariu, Bogdan

    1999-05-01

    In the first part of the thesis I will investigate in the Matrix theory framework, the subgroup of dualities of the Discrete Light Cone Quantization of M-theory compactified on tori, which corresponds to T-duality in the auxiliary Type II string theory. After a review of matrix theory compactification leading to noncommutative supersymmetric Yang-Mills gauge theory, I will present solutions for the fundamental and adjoint sections on a two-dimensional twisted quantum torus and generalize to three-dimensional twisted quantum tori. After showing how M-theory T-duality is realized in supersymmetric Yang-Mills gauge theories on dual noncommutative tori I will relate this to the mathematical concept of Morita equivalence of C*-algebras. As a further generalization, I consider arbitrary Ramond-Ramond backgrounds. I will also discuss the spectrum of the toroidally compactified Matrix theory corresponding to quantized electric fluxes on two and three tori. In the second part of the thesis I will present an application to conformal field theory involving quantum groups, another important example of a noncommutative space. First, I will give an introduction to Poisson-Lie groups and arrive at quantum groups using the Feynman path integral. I will quantize the symplectic leaves of the Poisson-Lie group SU(2)*. In this way we obtain the unitary representations of U{sub q}(SU(2)). I discuss the X-structure of SU(2)* and give a detailed description of its leaves using various parametrizations. Then, I will introduce a new reality structure on the Heisenberg double of Fun{sub q} (SL(N,C)) for q phase, which can be interpreted as the quantum phase space of a particle on the q-deformed mass-hyperboloid. I also present evidence that the above real form describes zero modes of certain non-compact WZNW-models.

  15. Using the Fe/Mn Ratio of FeO-Rich Olivine In WILD 2, Chondrite Matrix, and Type IIA Chondrules to Disentangle Their Histories

    NASA Technical Reports Server (NTRS)

    Frank, David R.; Le, L.; Zolensky, M. E.

    2012-01-01

    The Stardust Mission returned a large abundance of impactors from Comet 81P/Wild2 in the 5-30 m range. The preliminary examination of just a limited number of these particles showed that the collection captured abundant crystalline grains with a diverse mineralogy [1,2]. Many of these grains resemble those found in chondrite matrix and even contain fragments of chondrules and CAIs [1-3]. In particular, the olivine found in Wild 2 exhibits a wide compositional range (Fa0-97) with minor element abundances similar to the matrix olivine found in many carbonaceous chondrites (CCs) and unequilibrated ordinary chondrites (UOCs). Despite the wide distribution of Fa content, the olivine found in the matrices of CCs, UOCs, and Wild 2 can be roughly lumped into two types based solely on fayalite content. In fact, in some cases, a distinct bi-modal distribution is observed.

  16. Gene mapping of Usher syndrome type IIa: Localization of the gene to a 2.1-cM segment on chromosome 1q41

    SciTech Connect

    Kimberling, W.J.; Weston, M.D.; Ing, P.S.; Connolly, C.; Sumegi, J.; Moeller, C.; Aarem, A. van; Cremers, C.W.R.J.; Martini, A.; Milani, M.

    1995-01-01

    Usher syndrome type II is associated with hearing loss and retinitis pigmentosa but not with any vestibular problems. It is known to be genetically heterogeneous, and one locus (termed USH2A) has been linked to chromosome 1q41. In an effort to refine the localization of USH2A, the genetic map of the region between and adjacent to the marker loci previously recognized as flanking USH2A (D1S70 and PPOL) is updated. Analysis of marker data on 68 Usher II families places the USH2A gene into a 2.1-cM region between the markers D1S237 and D1S229. The gene for transforming growth factor {beta}2 (TGFB2) and the gene for the homeodomain box (HLX1) are both eliminated as candidates for USH2A, by virtue of their localization outside these flanking markers. The earlier finding of genetic heterogeneity was confirmed in six new families, and the proportion of unlinked Usher II families is estimated at 12.5%. The placement of the USH2A gene into this region will aid in the physical mapping and isolation of the gene itself. 30 refs., 4 figs., 2 tabs.

  17. The Continuing Story of Class IIa Bacteriocins

    PubMed Central

    Drider, Djamel; Fimland, Gunnar; Héchard, Yann; McMullen, Lynn M.; Prévost, Hervé

    2006-01-01

    Many bacteria produce antimicrobial peptides, which are also referred to as peptide bacteriocins. The class IIa bacteriocins, often designated pediocin-like bacteriocins, constitute the most dominant group of antimicrobial peptides produced by lactic acid bacteria. The bacteriocins that belong to this class are structurally related and kill target cells by membrane permeabilization. Despite their structural similarity, class IIa bacteriocins display different target cell specificities. In the search for new antibiotic substances, the class IIa bacteriocins have been identified as promising new candidates and have thus received much attention. They kill some pathogenic bacteria (e.g., Listeria) with high efficiency, and they constitute a good model system for structure-function analyses of antimicrobial peptides in general. This review focuses on class IIa bacteriocins, especially on their structure, function, mode of action, biosynthesis, bacteriocin immunity, and current food applications. The genetics and biosynthesis of class IIa bacteriocins are well understood. The bacteriocins are ribosomally synthesized with an N-terminal leader sequence, which is cleaved off upon secretion. After externalization, the class IIa bacteriocins attach to potential target cells and, through electrostatic and hydrophobic interactions, subsequently permeabilize the cell membrane of sensitive cells. Recent observations suggest that a chiral interaction and possibly the presence of a mannose permease protein on the target cell surface are required for a bacteria to be sensitive to class IIa bacteriocins. There is also substantial evidence that the C-terminal half penetrates into the target cell membrane, and it plays an important role in determining the target cell specificity of these bacteriocins. Immunity proteins protect the bacteriocin producer from the bacteriocin it secretes. The three-dimensional structures of two class IIa immunity proteins have been determined, and it has

  18. Crystal structure of MboIIA methyltransferase.

    SciTech Connect

    Osipiuk, J.; Walsh, M. A.; Joachimiak, A.; Biosciences Division; Univ. of Gdansk; Medical Research Council France

    2003-09-15

    DNA methyltransferases (MTases) are sequence-specific enzymes which transfer a methyl group from S-adenosyl-L-methionine (AdoMet) to the amino group of either cytosine or adenine within a recognized DNA sequence. Methylation of a base in a specific DNA sequence protects DNA from nucleolytic cleavage by restriction enzymes recognizing the same DNA sequence. We have determined at 1.74 {angstrom} resolution the crystal structure of a {beta}-class DNA MTase MboIIA (M {center_dot} MboIIA) from the bacterium Moraxella bovis, the smallest DNA MTase determined to date. M {center_dot} MboIIA methylates the 3' adenine of the pentanucleotide sequence 5'-GAAGA-3'. The protein crystallizes with two molecules in the asymmetric unit which we propose to resemble the dimer when M {center_dot} MboIIA is not bound to DNA. The overall structure of the enzyme closely resembles that of M {center_dot} RsrI. However, the cofactor-binding pocket in M {center_dot} MboIIA forms a closed structure which is in contrast to the open-form structures of other known MTases.

  19. What lattice theorists can do for superstring/M-theory

    NASA Astrophysics Data System (ADS)

    Hanada, Masanori

    2016-08-01

    The gauge/gravity duality provides us with nonperturbative formulation of superstring/M-theory. Although inputs from gauge theory side are crucial for answering many deep questions associated with quantum gravitational aspects of superstring/M-theory, many of the important problems have evaded analytic approaches. For them, lattice gauge theory is the only hope at this moment. In this review I give a list of such problems, putting emphasis on problems within reach in a five-year span, including both Euclidean and real-time simulations.

  20. (M-theory-)Killing spinors on symmetric spaces

    SciTech Connect

    Hustler, Noel; Lischewski, Andree

    2015-08-15

    We show how the theory of invariant principal bundle connections for reductive homogeneous spaces can be applied to determine the holonomy of generalised Killing spinor covariant derivatives of the form D = ∇ + Ω in a purely algebraic and algorithmic way, where Ω : TM → Λ{sup ∗}(TM) is a left-invariant homomorphism. Specialising this to the case of symmetric M-theory backgrounds (i.e., (M, g, F) with (M, g) an eleven-dimensional Lorentzian (locally) symmetric space and F an invariant closed 4-form), we derive several criteria for such a background to preserve some supersymmetry and consequently find all supersymmetric symmetric M-theory backgrounds.

  1. All AdS7 solutions of type II supergravity

    NASA Astrophysics Data System (ADS)

    Apruzzi, Fabio; Fazzi, Marco; Rosa, Dario; Tomasiello, Alessandro

    2014-04-01

    In M-theory, the only AdS7 supersymmetric solutions are AdS7 × S 4 and its orbifolds. In this paper, we find and classify new supersymmetric solutions of the type AdS7 × M 3 in type II supergravity. While in IIB none exist, in IIA with Romans mass (which does not lift to M-theory) there are many new ones. We use a pure spinor approach reminiscent of generalized complex geometry. Without the need for any Ansatz, the system determines uniquely the form of the metric and fluxes, up to solving a system of ODEs. Namely, the metric on M 3 is that of an S 2 fibered over an interval; this is consistent with the Sp(1) R-symmetry of the holographically dual (1,0) theory. By including D8 brane sources, one can numerically obtain regular solutions, where topologically M 3 ≅ S 3.

  2. Class IIa Bacteriocins: Current Knowledge and Perspectives

    NASA Astrophysics Data System (ADS)

    Belguesmia, Yanath; Naghmouchi, Karim; Chihib, Nour-Eddine; Drider, Djamel

    Lactic acid bacteria (LAB) are known to produce antibacterial peptides and small proteins called bacteriocins, which enable them to compete against other bacteria in the environment. Bacteriocins fall structurally and chemically into three different classes, I, II, and III. Bacteriocins are ribosomally synthesized peptides with antagonism against closely related bacteria. This late observation has evolved because bacteriocins active against Gram-negative bacteria have recently been reported. Members of class IIa bacteriocins, referred to as pediocin-like bacteriocins, are among the most studied bacteriocins. This chapter is aimed at providing an updated review on the biology of class IIa bacteriocins.

  3. Class IIa Bacteriocins: Diversity and New Developments

    PubMed Central

    Cui, Yanhua; Zhang, Chao; Wang, Yunfeng; Shi, John; Zhang, Lanwei; Ding, Zhongqing; Qu, Xiaojun; Cui, Hongyu

    2012-01-01

    Class IIa bacteriocins are heat-stable, unmodified peptides with a conserved amino acids sequence YGNGV on their N-terminal domains, and have received much attention due to their generally recognized as safe (GRAS) status, their high biological activity, and their excellent heat stability. They are promising and attractive agents that could function as biopreservatives in the food industry. This review summarizes the new developments in the area of class IIa bacteriocins and aims to provide uptodate information that can be used in designing future research. PMID:23222636

  4. Pre-big bang in M-theory

    NASA Astrophysics Data System (ADS)

    Cavaglià, Marco

    2001-04-01

    We discuss a simple cosmological model derived from M-theory. Three assumptions lead naturally to a pre-big bang scenario: (a) 11-dimensional supergravity describes the low-energy world; (b) non-gravitational fields live on a three-dimensional brane; and (c) asymptotically past triviality.

  5. The Sodium-Dependent Inorganic Phosphate Transporter SLC34A1 (NaPi-IIa) Is Not Localized in the Mouse Brain

    PubMed Central

    Larsson, Max; Morland, Cecilie; Poblete-Naredo, Irais; Biber, Jürg; Danbolt, Niels Christian; Gundersen, Vidar

    2011-01-01

    The sodium-dependent inorganic phosphate transporter NaPi-IIa is expressed in the kidney. Here, the authors used a polyclonal antiserum raised against NaPi-IIa- and NaPi-IIa-deficient mice to characterize its expression in nervous tissue. Western blots showed that a NaPi-IIa immunoreactive band (~90 kDa) was only present in wild-type kidney membranes and not in kidney knockout or wild-type brain membranes. In the water-soluble fraction of wild-type and knockout brains, another band (~50 kDa) was observed; this band was not detected in the kidney. Light and electron microscopic immunohistochemistry using the NaPi-IIa antibodies showed immunolabeling of kidney tubules in wild-type but not knockout mice. In the brain, labeling of presynaptic nerve terminals was present also in NaPi-IIa-deficient mice. This labeling pattern was also produced by the NaPi-IIa preimmune serum. The authors conclude that the polyclonal antiserum is specific toward NaPi-IIa in the kidney, but in the brain, immunolabeling is caused by a cross-reaction of the antiserum with an unknown cytosolic protein that is not present in the kidney. This tissue-specific cross-reactivity highlights a potential pitfall when validating antibody specificity using knockout mouse-derived tissue other than the specific tissue of interest and underlines the utility of specificity testing using preimmune sera. PMID:21606201

  6. Class IIa Histone Deacetylases are Hormone-activated regulators of FOXO and Mammalian Glucose Homeostasis

    PubMed Central

    Mihaylova, Maria M.; Vasquez, Debbie S.; Ravnskjaer, Kim; Denechaud, Pierre-Damien; Yu, Ruth T.; Alvarez, Jacqueline G.; Downes, Michael; Evans, Ronald M.; Montminy, Marc; Shaw, Reuben J.

    2011-01-01

    SUMMARY Class IIa histone deacetylases (HDACs) are signal-dependent modulators of transcription with established roles in muscle differentiation and neuronal survival. We show here that in liver, Class IIa HDACs (HDAC4, 5, and 7) are phosphorylated and excluded from the nucleus by AMPK family kinases. In response to the fasting hormone glucagon, Class IIa HDACs are rapidly dephosphorylated and translocated to the nucleus where they associate with the promoters of gluconeogenic enzymes such as G6Pase. In turn, HDAC4/5 recruit HDAC3, which results in the acute transcriptional induction of these genes via deacetylation and activation of Foxo family transcription factors. Loss of Class IIa HDACs in murine liver results in inhibition of FOXO target genes and lowers blood glucose, resulting in increased glycogen storage. Finally, suppression of Class IIa HDACs in mouse models of Type 2 Diabetes ameliorates hyperglycemia, suggesting that inhibitors of Class I/II HDACs may be potential therapeutics for metabolic syndrome. PMID:21565617

  7. Supersymmetric geometries of IIA supergravity III

    NASA Astrophysics Data System (ADS)

    Gran, Ulf; Papadopoulos, George; von Schultz, Christian

    2016-06-01

    We find that (massive) IIA backgrounds that admit a {G}_2ltimes {mathbb{R}}^8 invariant Killing spinor must exhibit a null Killing vector field which leaves the Killing spinor invariant and that the rotation of the Killing vector field satisfies a certain g2 instanton condition. This result together with those in [4] and [5] complete the classification of geometries of all (massive) IIA backgrounds that preserve one supersymmetry. We also explore the geometry of a class of backgrounds which admit a {G}_2ltimes {mathbb{R}}^8 invariant Killing spinor and where in addition an appropriate 1-form bilinear vanishes. In all cases, we express the fluxes of the theory in terms of the geometry.

  8. Supersymmetric geometries of IIA supergravity III

    NASA Astrophysics Data System (ADS)

    Gran, Ulf; Papadopoulos, George; von Schultz, Christian

    2016-06-01

    We find that (massive) IIA backgrounds that admit a {G}_2ltimes {{R}}^8 invariant Killing spinor must exhibit a null Killing vector field which leaves the Killing spinor invariant and that the rotation of the Killing vector field satisfies a certain g2 instanton condition. This result together with those in [4] and [5] complete the classification of geometries of all (massive) IIA backgrounds that preserve one supersymmetry. We also explore the geometry of a class of backgrounds which admit a {G}_2ltimes {{R}}^8 invariant Killing spinor and where in addition an appropriate 1-form bilinear vanishes. In all cases, we express the fluxes of the theory in terms of the geometry.

  9. Supersymmetric geometries of IIA supergravity II

    NASA Astrophysics Data System (ADS)

    Gran, Ulf; Papadopoulos, George; von Schultz, Christian

    2015-12-01

    We solve the Killing spinor equations of standard and massive IIA supergravities for a Killing spinor whose isotropy subgroup in Spin(9, 1) is SU(4) and identify the geometry of the spacetime. We demonstrate that the Killing spinor equations impose some mild constraints on the geometry of the spacetime which include the existence of a time-like Killing vector field which leaves the fields and the Killing spinor invariant.

  10. Inflation from superstring and M-theory compactification with higher order corrections

    SciTech Connect

    Maeda, Kei-ichi; Ohta, Nobuyoshi

    2005-03-15

    We study time-dependent solutions in M and superstring theories with higher-order corrections. We first present general field equations for theories of Lovelock type with stringy corrections in arbitrary dimensions. We then exhaust all exact and asymptotic solutions of exponential and power-law expansions in the theory with Gauss-Bonnet terms relevant to heterotic strings and in the theories with quartic corrections corresponding to the M theory and type II superstrings. We discuss interesting inflationary solutions that can generate enough e foldings in the early universe.

  11. Duality and cohomology in M-theory with boundary

    NASA Astrophysics Data System (ADS)

    Sati, Hisham

    2012-05-01

    We consider geometric and analytical aspects of M-theory on a manifold with boundary Y11. The partition function of the C-field requires summing over harmonic forms. When Y11 is closed, Hodge theory gives a unique harmonic form in each de Rham cohomology class, while in the presence of a boundary the Hodge-Morrey-Friedrichs decomposition should be used. This leads us to study the boundary conditions for the C-field. The dynamics and the presence of the dual to the C-field gives rise to a mixing of boundary conditions with one being Dirichlet and the other being Neumann. We describe the mixing between the corresponding absolute and relative cohomology classes via Poincaré duality angles, which we also illustrate for the M5-brane as a tubular neighborhood. Several global aspects are then considered. We provide a systematic study of the extension of the E8 bundle and characterize obstructions. Considering Y11 as a fiber bundle, we describe how the phase looks like on the base, hence providing dimensional reduction in the boundary case via the adiabatic limit of the eta invariant. The general use of the index theorem leads to a new effect given by a gravitational Chern-Simons term CS11 on Y11 whose restriction to the boundary would be a generalized WZW model. This suggests that holographic models of M-theory can be viewed as a sector within this index-theoretic approach.

  12. Anabolic effect of the traditional Chinese medicine compound tanshinone IIA on myotube hypertrophy is mediated by estrogen receptor.

    PubMed

    Zhao, Piwen; Soukup, Sebastian Tobias; Hegevoss, Jonas; Ngueu, Sandrine; Kulling, Sabine Emma; Diel, Patrick

    2015-05-01

    Skeletal muscle loss during menopause is associated with a higher risk of developing diabetes type II and the general development of the metabolic syndrome. Therefore, strategies combining nutritional and training interventions to prevent muscle loss are necessary. Danshen Si Wu is a traditional Chinese medicine used for menopausal complains. One of the main compounds of Danshen Si Wu is tanshinone IIA. Physiological effects of tanshinone IIA have been described as being mediated via the estrogen receptor. Therefore, it was the aim of this study to determine its tissue specific ERα- and ERβ-mediated estrogenic activity, to investigate its antiestrogenic properties, and, particularly, to study estrogen receptor-mediated biological responses to tanshinone IIA on skeletal muscle cells. The purity of tanshinone IIA was analyzed by LC-DAD-MS/MS analysis. ERα/ERβ-mediated activity was dose-dependently analyzed in HEK 239 cells transfected with ERα or ERβ expression vectors and respective reporter genes. Androgenic, antiandrogenic, and antiestrogenic properties of tanshinone IIA were analyzed in a yeast reporter gene assay. The effects of tanshinone IIA on proliferation and cell cycle distribution were investigated in ERα positive T47D breast cancer cells. The ability of tanshinone IIA to stimulate estrogen receptor-mediated myotube hypertrophy was studied in C2C12 myoblastoma cells. Our data show that tanshinone IIA is quite potent at stimulating ERα and ERβ reporter genes with comparable efficacy. Tanshinone IIA displayed antiestrogenic and also antiandrogenic properties in a yeast reporter gene assay. It inhibited the growth of T47D breast cancer cells by suppressing proliferation and arresting the cells in G0/G1. Tanshinone IIA also stimulated the hypertrophy of C2C12 myotubes via an estrogen receptor-mediated mechanism. Summarizing our results, tanshinone IIA can be characterized as an estrogen receptor partial agonist with antiandrogenic properties. It

  13. Large superconformal near-horizons from M-theory

    NASA Astrophysics Data System (ADS)

    Kelekci, Ö.; Lozano, Y.; Montero, J.; O'Colgáin, E.; Park, M.

    2016-04-01

    We report on a classification of supersymmetric solutions to 11D supergravity with S O (2 ,2 )×S O (3 ) isometry, which are AdS /CFT dual to 2D CFTs with N =(0 ,4 ) supersymmetry. We recover the Maldacena, Strominger, Witten near-horizon with small superconformal symmetry and identify a class of AdS3×S2×S2×C Y2 geometries with emergent large superconformal symmetry. This exhausts known compact geometries. Compactification of M-theory on C Y2 results in a vacuum of 7D supergravity with large superconformal symmetry, providing a candidate near-horizon for an extremal black hole and a potential new setting to address microstates.

  14. Anomaly cancellation in M-theory on orbifolds

    NASA Astrophysics Data System (ADS)

    Meissner, Krzysztof A.; Olechowski, Marek

    2000-12-01

    We present calculation of the anomaly cancellation in M-theory on orbifolds S 1/ Z2 and T 5/ Z2 in the upstairs approach. The main requirement that allows one to uniquely define solutions to the modified Bianchi identities in this case is that the field strength G be globally defined on S 1 or T 5 and properly transforming under Z2. We solve for general G that satisfies these requirements and explicitly construct anomaly-free theories in the upstairs approach. We also obtain the solutions in the presence of five-branes. All these constructions show equivalence of the downstairs and upstairs approaches. For example in the S 1/ Z2 case the ten-dimensional gauge coupling and the anomaly cancellation at each wall are the same as in the downstairs approach.

  15. Constraints on heterotic M-theory from s-cobordism

    NASA Astrophysics Data System (ADS)

    Sati, Hisham

    2011-12-01

    We interpret heterotic M-theory in terms of h-cobordism, that is the eleven-manifold is a product of the ten-manifold times an interval is translated into a statement that the former is a cobordism of the latter which is a homotopy equivalence. In the non-simply connected case, which is important for model building, the interpretation is then in terms of s-cobordism, so that the cobordism is a simple-homotopy equivalence. This gives constraints on the possible cobordisms depending on the fundamental groups and hence provides a characterization of possible compactification manifolds using the Whitehead group - a quotient of algebraic K-theory of the integral group ring of the fundamental group - and a distinguished element, the Whitehead torsion. We also consider the effect on the dynamics via diffeomorphisms and general dimensional reduction, and comment on the effect on F-theory compactifications.

  16. Foliated backgrounds for M-theory compactifications (I)

    SciTech Connect

    Babalic, Elena Mirela; Lazaroiu, Calin Iuliu

    2015-12-07

    Using the theory of foliations, we give a geometric and topological description of compact eight-manifolds which arise as internal spaces in N = 1 flux compactifications of M-theory down to AdS{sub 3}. We prove that specifying such a supersymmetric background is equivalent with giving a codimension one foliation defined by a closed one-form and which carries a leafwise G{sub 2} structure, whose geometry we characterize explicitly. It can be shown that the leaves of this foliation acquire singularities on the chiral locus, which is a set with empty interior when the equations of motion for the supregravity four-form field strength are imposed, but here we concentrate only on the case of an everywhere non-chiral spinor.

  17. High altitude balloon experiments at IIA

    NASA Astrophysics Data System (ADS)

    Nayak, Akshata; Sreejith, A. G.; Safonova, Margarita; Murthy, Jayant

    Recent advances in balloon experiments as well as in electronics have made it possible to fly scientific payloads at costs accessible to university departments. We have begun a program of high altitude ballooning at the Indian Institute of Astrophysics, Bengaluru. The primary purpose of this activity is to test low-cost ultraviolet (UV) payloads for eventual space flight, but we will also try scientific exploration of the phenomena occurring in the upper atmosphere, including sprites and meteorite impacts. We present the results of the initial experiments carried out at the CREST campus of IIA, Hosakote, and describe our plans for the future.

  18. Dualising consistent IIA/IIB truncations

    NASA Astrophysics Data System (ADS)

    Malek, Emanuel; Samtleben, Henning

    2015-12-01

    We use exceptional field theory to establish a duality between certain consistent 7-dimensional truncations with maximal SUSY from IIA to IIB. We use this technique to obtain new consistent truncations of IIB on S 3 and H p,q and work out the explicit reduction formulas in the internal sector. We also present uplifts for other gaugings of 7-d maximal SUGRA, including theories with a trombone gauging. Some of the latter can only be obtained by a non-geometric compactification.

  19. Effects of starch synthase IIa gene dosage on grain, protein and starch in endosperm of wheat.

    PubMed

    Konik-Rose, Christine; Thistleton, Jenny; Chanvrier, Helene; Tan, Ihwa; Halley, Peter; Gidley, Michael; Kosar-Hashemi, Behjat; Wang, Hong; Larroque, Oscar; Ikea, Joseph; McMaugh, Steve; Regina, Ahmed; Rahman, Sadequr; Morell, Matthew; Li, Zhongyi

    2007-11-01

    Starch synthases (SS) are responsible for elongating the alpha-1,4 glucan chains of starch. A doubled haploid population was generated by crossing a line of wheat, which lacks functional ssIIa genes on each genome (abd), and an Australian wheat cultivar, Sunco, with wild type ssIIa alleles on each genome (ABD). Evidence has been presented previously indicating that the SGP-1 (starch granule protein-1) proteins present in the starch granule in wheat are products of the ssIIa genes. Analysis of 100 progeny lines demonstrated co-segregation of the ssIIa alleles from the three genomes with the SGP-1 proteins, providing further evidence that the SGP-1 proteins are the products of the ssIIa genes. From the progeny lines, 40 doubled haploid lines representing the eight possible genotypes for SSIIa (ABD, aBD, AbD, ABd, abD, aBd, Abd, abd) were characterized for their grain weight, protein content, total starch content and starch properties. For some properties (chain length distribution, pasting properties, swelling power, and gelatinization properties), a progressive change was observed across the four classes of genotypes (wild type, single nulls, double nulls and triple nulls). However, for other grain properties (seed weight and protein content) and starch properties (total starch content, granule morphology and crystallinity, granule size distribution, amylose content, amylose-lipid dissociation properties), a statistically significant change only occurred for the triple nulls, indicating that all three genes had to be missing or inactive for a change to occur. These results illustrate the importance of SSIIa in controlling grain and starch properties and the importance of amylopectin fine structure in controlling starch granule properties in wheat. PMID:17721773

  20. Synapsin IIa accelerates functional development of neuromuscular synapses.

    PubMed Central

    Schaeffer, E; Alder, J; Greengard, P; Poo, M M

    1994-01-01

    We have investigated the possible involvement of the synaptic vesicle protein synapsin IIa in synapse development. Synapsin IIa was introduced into Xenopus embryonic spinal neurons by early blastomere injection, and nerve-muscle cultures were prepared. Synaptic currents were measured by comparing synapses in which the presynaptic neuron either contained [syn IIa (+)] or lacked (control) exogenous synapsin IIa. Syn IIa (+) synapses had a 3.6-fold increase in the frequency and a 2.1-fold increase in the amplitude of spontaneous synaptic currents, compared to controls, after 2 days in culture. Synapsin IIa also increased the amplitude of evoked synaptic currents by 2.3-fold in 2-day cultures. The evoked synaptic current amplitudes of syn IIa (+) synapses had a lower coefficient of variation indicating a more stable evoked response. These enhanced synaptic activities were independent of the presence or absence of the protein in the postsynaptic muscle cell. The findings indicate a role for synapsin IIa in synapse maturation. Images PMID:8171006

  1. Explaining the electroweak scale and stabilizing moduli in M theory

    SciTech Connect

    Acharya, Bobby S.; Bobkov, Konstantin; Kane, Gordon L.; Kumar, Piyush; Shao Jing

    2007-12-15

    In a recent paper [B. Acharya, K. Bobkov, G. Kane, P. Kumar, and D. Vaman, Phys. Rev. Lett. 97, 191601 (2006).] it was shown that in fluxless M theory vacua with at least two hidden sectors undergoing strong gauge dynamics and a particular form of the Kaehler potential, all moduli are stabilized by the effective potential and a stable hierarchy is generated, consistent with standard gauge unification. This paper explains the results of [B. Acharya, K. Bobkov, G. Kane, P. Kumar, and D. Vaman, Phys. Rev. Lett. 97, 191601 (2006).] in more detail and generalizes them, finding an essentially unique de Sitter vacuum under reasonable conditions. One of the main phenomenological consequences is a prediction which emerges from this entire class of vacua: namely, gaugino masses are significantly suppressed relative to the gravitino mass. We also present evidence that, for those vacua in which the vacuum energy is small, the gravitino mass, which sets all the superpartner masses, is automatically in the TeV-100 TeV range.

  2. AdS4 solutions of massive IIA from dyonic ISO(7) supergravity

    NASA Astrophysics Data System (ADS)

    Varela, Oscar

    2016-03-01

    Explicit formulae are given for the consistent truncation of massive type IIA supergravity on the six-sphere to the SU(3)-invariant sector of D = 4 {N}=8 supergravity with dyonic ISO(7) gauging. These formulae are then used to construct AdS4 solutions of massive type IIA via uplift on S 6 of the critical points of the D = 4 supergravity with at least SU(3) symmetry. We find a new {N}=1 solution with SU(3) symmetry, a new non-supersymmetric solution with SO(6) symmetry, and recover previously known solutions. We quantise the fluxes, calculate the gravitational free energies of the solutions and discuss the stability of the non-supersymmetric ones. Among these, a (previously known) G2-invariant solution is found to be stable.

  3. Strings on AdS2 and the high-energy limit of noncritical M-theory

    SciTech Connect

    Horava, Petr; Horava, Petr; Keeler, Cynthia A.

    2007-04-16

    Abstract. Noncritical M-theory in 2+1 dimensions has been defined as a double-scaling limit of a nonrelativistic Fermi liquid on a flat two-dimensional plane. Here we study this noncritical M-theory in the limit of high energies, analogous to the alpha' --> infinity limit of string theory. In the related case of two-dimensional Type 0A strings, it has been argued that the conformal alpha' --> infinity limit leads to AdS_2 with a propagating fermion whose mass is set by the value of the RR flux. Here we provide evidence that in the high-energy limit, the natural ground state of noncritical M-theory similarly describes the AdS_2 x S1 spacetime, with a massless propagating fermion. We argue that the spacetime effective theory in this background is captured by a topological higher-spin extension of conformal Chern-Simons gravity in 2+1 dimensions, consistently coupled to a massless Dirac field. Intriguingly, the two-dimensional plane populated by the original nonrelativistic fermions is essentially the twistor space associated with the symmetry group of the AdS_2 x S1 spacetime; thus, at least in the high-energy limit, noncritical M-theory can be nonperturbatively described as a"Fermi liquid on twistor space.''

  4. N=3 supersymmetric effective action of D2-branes in massive IIA string theory

    NASA Astrophysics Data System (ADS)

    Go, Gyungchoon; Kwon, O.-Kab; Tolla, D. D.

    2012-01-01

    We obtain a new type of N=3 Yang-Mills Chern-Simons theory from the Mukhi-Papageorgakis Higgs mechanism of the N=3 Gaiotto-Tomasiello theory. This theory has N=1 BPS fuzzy funnel solution, which is expressed in terms of the seven generators of SU(3), excluding T8. We propose that this is an effective theory of multiple D2-branes with D6- and D8-branes background in massive IIA string theory.

  5. Counting the microstates of a Kerr black hole in M theory.

    PubMed

    Horowitz, Gary T; Roberts, Matthew M

    2007-11-30

    We show that an extremal Kerr black hole, appropriately lifted to M theory, can be transformed to a Kaluza-Klein black hole in M theory, or a D0-D6 charged black hole in string theory. Since all the microstates of the latter have recently been identified, one can exactly reproduce the entropy of an extremal Kerr black hole. We also show that the topology of the event horizon is not well defined in M theory. PMID:18233277

  6. Monopole Condensation and Confining Phase of N=1 Gauge Theories Via M Theory Fivebrane

    SciTech Connect

    de Boer, Jan; Oz, Yaron

    1997-08-07

    The fivebrane of M theory is used in order to study the moduli space of vacua of confining phase N=1 supersymmetric gauge theories in four dimensions. The supersymmetric vacua correspond to the condensation of massless monopoles and confinement of photons. The monopole and meson vacuum expectation values are computed using the fivebrane configuration. The comparison of the fivebrane computation and the field theory analysis shows that at vacua with a classically enhanced gauge group SU(r) the effective superpotential obtained by the"integrating in" method is exact for r=2 but is not exact for r> 2. The fivebrane configuration corresponding to N=1 gauge theories with Landau-Ginzburg type superpotentials is studied. N=1 non-trivial fixed points are analyzed using the brane geometry.

  7. Fixing All Moduli for M-Theory on K3xK3

    SciTech Connect

    Aspinwall, Paul S.; Kallosh, Renata; /Stanford U., Phys. Dept.

    2005-06-15

    We analyze M-theory compactified on K3 x K3 with fluxes preserving half the supersymmetry and its F-theory limit, which is dual to an orientifold of the type IIB string on K3 x (T{sup 2}/Z{sub 2}). The geometry of attractive K3 surfaces plays a significant role in the analysis. We prove that the number of choices for the K3 surfaces is finite and we show how they can be completely classified. We list the possibilities in one case. We then study the instanton effects and see that they will generically fix all of the moduli. We also discuss situations where the instanton effects might not fix all the moduli.

  8. Nonmuscle Myosin Heavy Chain IIA Is a Critical Factor Contributing to the Efficiency of Early Infection of Severe Fever with Thrombocytopenia Syndrome Virus

    PubMed Central

    Qi, Yonghe; Liu, Chenxuan; Gao, Wenqing; Chen, Pan; Fu, Liran; Peng, Bo; Wang, Haimin; Jing, Zhiyi; Zhong, Guocai

    2014-01-01

    Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus in the Bunyaviridae family. Most patients infected by SFTSV present with fever and thrombocytopenia, and up to 30% die due to multiple-organ dysfunction. The mechanisms by which SFTSV enters multiple cell types are unknown. SFTSV contains two species of envelope glycoproteins, Gn (44.2 kDa) and Gc (56 kDa), both of which are encoded by the M segment and are cleaved from a precursor polypeptide (about 116 kDa) in the endoplasmic reticulum (ER). Gn fused with an immunoglobulin Fc tag at its C terminus (Gn-Fc) bound to multiple cells susceptible to the infection of SFTSV and blocked viral infection of human umbilical vein endothelial cells (HUVECs). Immunoprecipitation assays following mass spectrometry analysis showed that Gn binds to nonmuscle myosin heavy chain IIA (NMMHC-IIA), a cellular protein with surface expression in multiple cell types. Small interfering RNA (siRNA) knockdown of NMMHC-IIA, but not the closely related NMMHC-IIB or NMMHC-IIC, reduced SFTSV infection, and NMMHC-IIA specific antibody blocked infection by SFTSV but not other control viruses. Overexpression of NMMHC-IIA in HeLa cells, which show limited susceptivity to SFTSV, markedly enhanced SFTSV infection of the cells. These results show that NMMHC-IIA is critical for the cellular entry of SFTSV. As NMMHC-IIA is essential for the normal functions of platelets and human vascular endothelial cells, it is conceivable that NMMHC-IIA directly contributes to the pathogenesis of SFTSV and may be a useful target for antiviral interventions against the viral infection. PMID:24155382

  9. Formation of nanostructured Group IIA metal activated sensors: The transformation of Group IIA metal compound sites

    NASA Astrophysics Data System (ADS)

    Tune, Travis C.; Baker, Caitlin; Hardy, Neil; Lin, Arthur; Widing, Timothy J.; Gole, James L.

    2015-05-01

    Trends in the Group IIA metal oxides and hydroxides of magnesium, calcium, and barium are unique in the periodic table. In this study we find that they display novel trends as decorating nanostructures for extrinsic semiconductor interfaces. The Group IIA metal ions are strong Lewis acids. We form these M2+ ions in aqueous solution and bring these solutions in contact with a porous silicon interface to form interfaces for conductometric measurements. Observed responses are consistent with the formation of MgO whereas the heavier elements display behaviors which suggest the effect of their more basic nature. Mg(OH)2, when formed, represents a weak base whereas the heavier metal hydroxides of Ca, Sr, and Ba are strong bases. However, the hydroxides tend to give up hydrogen and act as Brönsted acids. For the latter elements, the reversible interaction response of nanostructures deposited to the porous silicon (PS) interface is modified, as the formation of more basic sites appears to compete with M2+ Lewis acidity and hydroxide Brönsted acidity. Mg2+ forms an interface whose response to the analytes NH3 and NO is consistent with MgO and well explained by the recently developing Inverse Hard/Soft Acid/Base model. The behavior of the Ca2+ and Ba2+ decorated interfaces as they interact with the hard base NH3 follows a reversal of the model, indicating a decrease in acidic character as the observed conductometric response suggests the interaction with hydroxyl groups. A change from oxide-like to hydroxide-like constituents is supported by XPS studies. The changes in conductometric response is easily monitored in contrast to changes associated with the Group IIA oxides and hydroxides observed in XPS, EDAX, IR, and NMR measurements.

  10. High-level resistance to class IIa bacteriocins is associated with one general mechanism in Listeria monocytogenes.

    PubMed

    Gravesen, Anne; Ramnath, Manilduth; Rechinger, K Björn; Andersen, Natalie; Jänsch, Lothar; Héchard, Yann; Hastings, John W; Knøchel, Susanne

    2002-08-01

    Class IIa bacteriocins may be used as natural food preservatives, yet resistance development in the target organisms is still poorly understood. In this study, the understanding of class IIa resistance development in Listeria monocytogenes is extended, linking the seemingly diverging results previously reported. Eight resistant mutants having a high resistance level (at least a 10(3)-fold increase in MIC), originating from five wild-type listerial strains, were independently isolated following exposure to four different class IIa bacteriocin-producing lactic acid bacteria (including pediocin PA-1 and leucocin A producers). Two of the mutants were isolated from food model systems (a saveloy-type sausage at 10 degrees C, and salmon juice at 5 degrees C). Northern blot analysis showed that the eight mutants all had increased expression of EII(Bgl) and a phospho-beta-glucosidase homologue, both originating from putative beta-glucoside-specific phosphoenolpyruvate-dependent phosphotransferase systems (PTSs). However, disruption of these genes in a resistant mutant did not confer pediocin sensitivity. Comparative two-dimensional gel analysis of proteins isolated from mutant and wild-type strains showed that one spot was consistently missing in the gels from mutant strains. This spot corresponded to the MptA subunit of the mannose-specific PTS, found only in the gels of wild-type strains. The mptACD operon was recently shown to be regulated by the sigma(54) transcription factor in conjunction with the activator ManR. Class IIa bacteriocin-resistant mutants having defined mutations in mpt or manR also exhibited the two diverging PTS expression changes. It is suggested here that high-level class IIa resistance in L. monocytogenes and at least some other Gram-positive bacteria is developed by one prevalent mechanism, irrespective of wild-type strain, class IIa bacteriocin, or the tested environmental conditions. The changes in expression of the beta-glucoside-specific and

  11. Physiological implications of class IIa bacteriocin resistance in Listeria monocytogenes strains.

    PubMed

    Vadyvaloo, Viveka; Snoep, Jacky L; Hastings, John W; Rautenbach, Marina

    2004-02-01

    High-level resistance to class IIa bacteriocins has been directly associated with the absent EIIAB(Man) (MptA) subunit of the mannose-specific phosphoenolpyruvate-dependent phosphotransferase system (PTS) (EIIt(MAN)) in Listeria monocytogenes strains. Class IIa bacteriocin-resistant strains used in this study were a spontaneous resistant, L. monocytogenes B73-MR1, and a defined mutant, L. monocytogenes EGDe-mptA. Both strains were previously reported to have the EIIAB(Man) PTS component missing. This study shows that these class IIa bacteriocin-resistant strains have significantly decreased specific growth and glucose consumption rates, but they also have a significantly higher growth yield than their corresponding wild-type strains, L. monocytogenes B73 and L. monocytogenes EGDe, respectively. In the presence of glucose, the strains showed a shift from a predominantly lactic-acid to a mixed-acid fermentation. It is here proposed that elimination of the EIIAB(Man) in the resistant strains has caused a reduced glucose consumption rate and a reduced specific growth rate. The lower glucose consumption rate can be correlated to a shift in metabolism to a more efficient pathway with respect to ATP production per glucose, leading to a higher biomass yield. Thus, the cost involved in obtaining bacteriocin resistance, i.e. losing substrate transport capacity leading to a lower growth rate, is compensated for by a higher biomass yield. PMID:14766911

  12. The activity of the lactose transporter from Streptococcus thermophilus is increased by phosphorylated IIA and the action of beta-galactosidase.

    PubMed

    Geertsma, Eric R; Duurkens, Ria H; Poolman, Bert

    2005-12-01

    The metabolism of lactose by Streptococcus thermophilus is highly regulated, allowing the bacterium to prefer lactose over glucose as main source of carbon and energy. In vitro analysis of the enzymes involved in transport and hydrolysis of lactose showed that the transport reaction benefits from the hydrolysis of lactose at the trans side of the membrane. Furthermore, the activity of LacS is modulated by PEP-dependent phosphorylation of the IIA domain via the general energy coupling proteins of the PTS, Enzyme I and HPr. To determine whether unphosphorylated LacS-IIA inhibited, or the phosphorylated form stimulated lactose counterflow, a LacS-IIA truncation mutant of LacS was constructed. Detailed analyses of transport in whole cells and in proteoliposomes indicated that unphosphorylated LacS-IIA does not functionally interact with the carrier domain. Instead, interaction of the phosphorylated form of LacS-IIA with the carrier stimulates lactose counterflow transport. The proposed mode of regulation thus proceeds via a mechanism opposite to the inducer exclusion type of regulation in gram-negative bacteria, where transporters are inhibited by binding of the unphosphorylated form of IIA(Glc). PMID:16313191

  13. Transcriptional activation in yeast cells lacking transcription factor IIA.

    PubMed Central

    Chou, S; Chatterjee, S; Lee, M; Struhl, K

    1999-01-01

    The general transcription factor IIA (TFIIA) forms a complex with TFIID at the TATA promoter element, and it inhibits the function of several negative regulators of the TATA-binding protein (TBP) subunit of TFIID. Biochemical experiments suggest that TFIIA is important in the response to transcriptional activators because activation domains can interact with TFIIA, increase recruitment of TFIID and TFIIA to the promoter, and promote isomerization of the TFIID-TFIIA-TATA complex. Here, we describe a double-shut-off approach to deplete yeast cells of Toa1, the large subunit of TFIIA, to <1% of the wild-type level. Interestingly, such TFIIA-depleted cells are essentially unaffected for activation by heat shock factor, Ace1, and Gal4-VP16. However, depletion of TFIIA causes a general two- to threefold decrease of transcription from most yeast promoters and a specific cell-cycle arrest at the G2-M boundary. These results indicate that transcriptional activation in vivo can occur in the absence of TFIIA. PMID:10581267

  14. The D0 experiment's integrated luminosity for Tevatron Run IIa

    SciTech Connect

    Andeen, T.; Casey, B.C.K.; DeVaughan, K.; Enari, Y.; Gallas, E.; Krop, D.; Partridge, R.; Schellman, H.; Snow, G.R.; Yacoob, S.; Yoo, H.D.; /Brown U. /Fermilab /Indiana U. /Northwestern U. /Nebraska U.

    2007-04-01

    An essential ingredient in all cross section measurements is the luminosity used to normalize the data sample. In this note, we present the final assessment of the integrated luminosity recorded by the D0 experiment during Tevatron Run IIa. The luminosity measurement is derived from hit rates from the products of inelastic proton-antiproton collisions registered in two arrays of scintillation counters called the luminosity monitor (LM) detectors. Measured LM rates are converted to absolute luminosity using a normalization procedure that is based on previously measured inelastic cross sections and the geometric acceptance and efficiency of the LM detectors for registering inelastic events. During Run IIa, the LM detector performance was improved by a sequence of upgrades to the electronic readout system and other factors summarized in this note. The effects of these changes on the reported luminosity were tracked carefully during the run. Due to the changes, we partition the run into periods for which different conversions from measured LM rates to absolute luminosity apply. The primary upgrade to the readout system late in Run IIa facilitated a reevaluation of the overall normalization of the luminosity measurement for the full data sample. In this note, we first review the luminosity measurement technique employed by D0. We then summarize the changes to the LM system during Run IIa and the corresponding normalization adjustments. The effect of the adjustments is to increase D0's assessment of its recorded integrated luminosity compared to what was initially reported during Run IIa. The overall increase is 13.4% for data collected between April 20, 2002 (the beginning of Run IIa data used for physics analysis) and February 22, 2006 (the end of Run IIa).

  15. Epidemiology and genetic characterization of hepatitis A virus genotype IIA.

    PubMed

    Desbois, Delphine; Couturier, Elisabeth; Mackiewicz, Vincent; Graube, Arielle; Letort, Marie-José; Dussaix, Elisabeth; Roque-Afonso, Anne-Marie

    2010-09-01

    Three hepatitis A virus (HAV) genotypes, I, II, and III, divided into subtypes A and B, infect humans. Genotype I is the most frequently reported, while genotype II is hardly ever isolated, and its genetic diversity is unknown. From 2002 to 2007, a French epidemiological survey of HAV identified 6 IIA isolates, mostly from patients who did not travel abroad. The possible African origin of IIA strains was investigated by screening the 2008 mandatory notification records of HAV infection: 171 HAV strains from travelers to West Africa and Morocco were identified. Genotyping was performed by sequencing of the VP1/2A junction in 68 available sera. Entire P1 and 5' untranslated regions of IIA strains were compared to reference sequences of other genotypes. The screening retrieved 5 imported IIA isolates. An additional autochthonous case and 2 more African cases were identified in 2008 and 2009, respectively. A total of 14 IIA isolates (8 African and 6 autochthonous) were analyzed. IIA sequences presented lower nucleotide and amino acid variability than other genotypes. The highest variability was observed in the N-terminal region of VP1, while for other genotypes the highest variability was observed at the VP1/2A junction. Phylogenetic analysis identified 2 clusters, one gathering all African and two autochthonous cases and a second including only autochthonous isolates. In conclusion, most IIA strains isolated in France are imported by travelers returning from West Africa. However, the unexplained contamination mode of autochthonous cases suggests another, still to be discovered geographical origin or a French reservoir to be explored. PMID:20592136

  16. Transcriptional regulation of the rat type IIA phospholipase A2 gene by cAMP and interleukin-1beta in vascular smooth muscle cells: interplay of the CCAAT/enhancer binding protein (C/EBP), nuclear factor-kappaB and Ets transcription factors.

    PubMed Central

    Antonio, Valérie; Brouillet, Arthur; Janvier, Brigitte; Monne, Claire; Bereziat, Gilbert; Andreani, Marise; Raymondjean, Michel

    2002-01-01

    The abundant secretion of type IIA secreted phospholipase A(2) (sPLA(2)) is a major feature of the inflammatory process of atherosclerosis. sPLA(2) is crucial for the development of inflammation, as it catalyses the production of lipid mediators and induces the proliferation of smooth muscle cells. We have analysed the activation of sPLA(2) transcription by cAMP and interleukin-1beta (IL-1beta), and shown that the 500 bp region upstream of the transcription start site of the rat sPLA(2) gene is implicated in activation by synergistically acting cAMP and IL-1beta. We transiently transfected and stimulated rat smooth muscle cells in primary culture and measured the promoter activities of serial and site-directed deletion mutants of sPLA(2)-luciferase constructs. A distal region, between -488 and -157 bp, bearing a CAAT/enhancer binding protein (C/EBP)-responsive element (-242 to -223) was sufficient for cAMP/protein kinase A-mediated sPLA(2) promoter activation. We find evidence for the first time that activation of the sPLA(2) promoter by IL-1beta requires activation of an Ets-responsive element in the -184 to -180 region of the distal promoter via the Ras pathway and a nuclear factor-kappaB site at positions -141 to -131 of the proximal promoter. We also used electrophoretic mobility shift assays to identify five binding sites for the Sp1 factor; a specific inhibitor of Sp1, mithramycin A, showed that this factor is crucial for the basal activity of the sPLA(2) promoter. PMID:12188923

  17. H-IIA: Concept, missions, program status, and future prospects

    SciTech Connect

    Watanabe, A.

    1997-01-01

    In addition to earth orbiting satellite missions, cargo supply to the International Space Station/Japanese Experiment Module (ISS/JEM), lunar and planetary probes, technology verifications for the H-II Orbiting Plane (HOPE), and other missions are under study for early in the new century. The National Space Development Agency of Japan (NASDA) is developing the H-IIA rocket to meet these diversifying missions and to conduct them efficiently and economically. This paper presents the purposes, concept, and philosophy of system planning of the H-IIA rocket, the combinations of the H-IIA and a transfer vehicle to the ISS/JEM and an experimental winged re-entry vehicle, HOPE-X. {copyright} {ital 1997 American Institute of Physics.}

  18. Covariant Action for the Super-Five-Brane of {ital M} Theory

    SciTech Connect

    Bandos, I.; Nurmagambetov, A.; Sorokin, D.; Lechner, K.; Pasti, P.; Tonin, M.

    1997-06-01

    We propose a complete, d=6 covariant and kappa-symmetric, action for the M theory five-brane propagating in D=11 supergravity background. This opens a direct way of relating a wide class of super-p -brane solutions of string theory with the five-brane of M theory, which should be useful for studying corresponding dualities and nonperturbative aspects of these theories. {copyright} {ital 1997} {ital The American Physical Society}

  19. Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA

    PubMed Central

    Duchez, Anne-Claire; Boudreau, Luc H.; Naika, Gajendra S.; Bollinger, James; Belleannée, Clémence; Cloutier, Nathalie; Laffont, Benoit; Mendoza-Villarroel, Raifish E.; Lévesque, Tania; Rollet-Labelle, Emmanuelle; Rousseau, Matthieu; Allaeys, Isabelle; Tremblay, Jacques J.; Poubelle, Patrice E.; Lambeau, Gérard; Pouliot, Marc; Provost, Patrick; Soulet, Denis; Gelb, Michael H.; Boilard, Eric

    2015-01-01

    Platelets are anucleated blood elements highly potent at generating extracellular vesicles (EVs) called microparticles (MPs). Whereas EVs are accepted as an important means of intercellular communication, the mechanisms underlying platelet MP internalization in recipient cells are poorly understood. Our lipidomic analyses identified 12(S)-hydroxyeicosatetranoic acid [12(S)-HETE] as the predominant eicosanoid generated by MPs. Mechanistically, 12(S)-HETE is produced through the concerted activity of secreted phospholipase A2 IIA (sPLA2-IIA), present in inflammatory fluids, and platelet-type 12-lipoxygenase (12-LO), expressed by platelet MPs. Platelet MPs convey an elaborate set of transcription factors and nucleic acids, and contain mitochondria. We observed that MPs and their cargo are internalized by activated neutrophils in the endomembrane system via 12(S)-HETE. Platelet MPs are found inside neutrophils isolated from the joints of arthritic patients, and are found in neutrophils only in the presence of sPLA2-IIA and 12-LO in an in vivo model of autoimmune inflammatory arthritis. Using a combination of genetically modified mice, we show that the coordinated action of sPLA2-IIA and 12-LO promotes inflammatory arthritis. These findings identify 12(S)-HETE as a trigger of platelet MP internalization by neutrophils, a mechanism highly relevant to inflammatory processes. Because sPLA2-IIA is induced during inflammation, and 12-LO expression is restricted mainly to platelets, these observations demonstrate that platelet MPs promote their internalization in recipient cells through highly regulated mechanisms. PMID:26106157

  20. Higher-order M-theory corrections and the Kac Moody algebra E10

    NASA Astrophysics Data System (ADS)

    Damour, Thibault; Nicolai, Hermann

    2005-07-01

    It has been conjectured that the classical dynamics of M-theory is equivalent to a null geodesic motion in the infinite-dimensional coset space E10/K(E10), where K(E10) is the maximal compact subgroup of the hyperbolic Kac Moody group E10. We here provide further evidence for this conjecture by showing that the leading higher-order corrections, quartic in the curvature and related 3-form-dependent terms, correspond to negative imaginary roots of E10. The conjecture entails certain predictions for which higher-order corrections are allowed: in particular corrections of type RM(DF)N are compatible with E10 only for M + N = 3k + 1. Furthermore, the leading parts of the R4, R7, ... terms are predicted to be associated with singlets under the {\\mathfrak{sl}}_{10} decomposition of E10. Although singlets are extremely rare among the 4400 752 653 representations of {\\mathfrak{sl}}_{10} appearing in E10 up to level ell <= 28, there are indeed singlets at levels ell = 10 and ell = 20 which do match with the R4 and the expected R7 corrections. Our analysis indicates a far more complicated behaviour of the theory near the cosmological singularity than suggested by the standard homogeneous ansätze.

  1. M Theory on AdSp x 511-p and superconformal field theories

    SciTech Connect

    Aharony, Ofer; Yaron, Oz; Zheng, Yin

    1998-04-01

    We study the large N limit of the interacting superconformal field theories associated with N M5 branes or M2 branes using the recently proposed relation between these theories and M theory on AdS spaces. We first analyze the spectrum of chiral operators of the 6d (0, 2) theory associated with M5 branes in flat space, and find full agreement with earlier results obtained using its DLCQ description as quantum mechanics on a moduli space of instantons. We then perform a similar analysis for the D{sub N} type 6d (0, 2) theories associated with M5 branes at an R{sup 5}/Z{sub 2} singularity, and for the 3d N = 8 superconformal field theories associated with M2 branes in flat space and at an R{sup 8}/Z{sub 2} singularity respectively. Little is known about these three theories, and our study yields for the first time their spectrum of chiral operators (in the large N limit).

  2. Hermitian versus holomorphic complex and quaternionic generalized supersymmetries of the M-theory. A classification

    NASA Astrophysics Data System (ADS)

    Toppan, Francesco

    2004-09-01

    Relying upon the division-algebra classification of Clifford algebras and spinors, a classification of generalized supersymmetries (or, with a slight abuse of language,``generalized supertranslations") is provided. In each given space-time the maximal, saturated, generalized supersymmetry, compatible with the division-algebra constraint that can be consistently imposed on spinors and on superalgebra generators, is furnished. Constraining the superalgebra generators in both the complex and the quaternionic cases gives rise to the two classes of constrained hermitean and holomorphic generalized supersymmetries. In the complex case these two classes of generalized supersymmetries can be regarded as complementary. The quaternionic holomorphic supersymmetry only exists in certain space-time dimensions and can admit at most a single bosonic scalar central charge. The results here presented pave the way for a better understanding of the various M algebra-type of structures which can be introduced in different space-time signatures and in association with different division algebras, as well as their mutual relations. In a previous work, e.g., the introduction of a complex holomorphic generalized supersymmetry was shown to be necessary in order to perform the analytic continuation of the standard M-theory to the 11-dimensional euclidean space. As an application of the present results, it is shown that the above algebra also admits a 12-dimensional, euclidean, F-algebra presentation.

  3. Class IIa Histone Deacetylases Are Conserved Regulators of Circadian Function*

    PubMed Central

    Fogg, Paul C. M.; O'Neill, John S.; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C.; McIntosh, Rebecca L. L.; Elliott, Christopher J. H.; Sweeney, Sean T.; Hastings, Michael H.; Chawla, Sangeeta

    2014-01-01

    Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca2+ and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID:25271152

  4. Secretory Phospholipase A2-IIA and Cardiovascular Disease

    PubMed Central

    Holmes, Michael V.; Simon, Tabassome; Exeter, Holly J.; Folkersen, Lasse; Asselbergs, Folkert W.; Guardiola, Montse; Cooper, Jackie A.; Palmen, Jutta; Hubacek, Jaroslav A.; Carruthers, Kathryn F.; Horne, Benjamin D.; Brunisholz, Kimberly D.; Mega, Jessica L.; van Iperen, Erik P.A.; Li, Mingyao; Leusink, Maarten; Trompet, Stella; Verschuren, Jeffrey J.W.; Hovingh, G. Kees; Dehghan, Abbas; Nelson, Christopher P.; Kotti, Salma; Danchin, Nicolas; Scholz, Markus; Haase, Christiane L.; Rothenbacher, Dietrich; Swerdlow, Daniel I.; Kuchenbaecker, Karoline B.; Staines-Urias, Eleonora; Goel, Anuj; van 't Hooft, Ferdinand; Gertow, Karl; de Faire, Ulf; Panayiotou, Andrie G.; Tremoli, Elena; Baldassarre, Damiano; Veglia, Fabrizio; Holdt, Lesca M.; Beutner, Frank; Gansevoort, Ron T.; Navis, Gerjan J.; Mateo Leach, Irene; Breitling, Lutz P.; Brenner, Hermann; Thiery, Joachim; Dallmeier, Dhayana; Franco-Cereceda, Anders; Boer, Jolanda M.A.; Stephens, Jeffrey W.; Hofker, Marten H.; Tedgui, Alain; Hofman, Albert; Uitterlinden, André G.; Adamkova, Vera; Pitha, Jan; Onland-Moret, N. Charlotte; Cramer, Maarten J.; Nathoe, Hendrik M.; Spiering, Wilko; Klungel, Olaf H.; Kumari, Meena; Whincup, Peter H.; Morrow, David A.; Braund, Peter S.; Hall, Alistair S.; Olsson, Anders G.; Doevendans, Pieter A.; Trip, Mieke D.; Tobin, Martin D.; Hamsten, Anders; Watkins, Hugh; Koenig, Wolfgang; Nicolaides, Andrew N.; Teupser, Daniel; Day, Ian N.M.; Carlquist, John F.; Gaunt, Tom R.; Ford, Ian; Sattar, Naveed; Tsimikas, Sotirios; Schwartz, Gregory G.; Lawlor, Debbie A.; Morris, Richard W.; Sandhu, Manjinder S.; Poledne, Rudolf; Maitland-van der Zee, Anke H.; Khaw, Kay-Tee; Keating, Brendan J.; van der Harst, Pim; Price, Jackie F.; Mehta, Shamir R.; Yusuf, Salim; Witteman, Jaqueline C.M.; Franco, Oscar H.; Jukema, J. Wouter; de Knijff, Peter; Tybjaerg-Hansen, Anne; Rader, Daniel J.; Farrall, Martin; Samani, Nilesh J.; Kivimaki, Mika; Fox, Keith A.A.; Humphries, Steve E.; Anderson, Jeffrey L.; Boekholdt, S. Matthijs; Palmer, Tom M.; Eriksson, Per; Paré, Guillaume; Hingorani, Aroon D.; Sabatine, Marc S.; Mallat, Ziad; Casas, Juan P.; Talmud, Philippa J.

    2013-01-01

    Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. PMID:23916927

  5. M-theory compactification, fluxes, and AdS{sub 4}

    SciTech Connect

    Lukas, Andre; Saffin, P.M.

    2005-02-15

    We analyze supersymmetric solutions of M-theory based an a seven-dimensional internal space with SU(3) structure and a four-dimensional maximally symmetric space. The most general supersymmetry conditions are derived and we show that a nonvanishing cosmological constant requires the norms of the two internal spinors to differ. We find explicit local solutions with singlet flux and the space being a warped product of a circle, a nearly Kaehler manifold and AdS{sub 4}. The embedding of solutions into heterotic M-theory is also discussed.

  6. Composite diholes and intersecting brane-antibrane configurations in string/M-theory

    NASA Astrophysics Data System (ADS)

    Chattaraputi, Auttakit; Emparan, Roberto; Taormina, Anne

    2000-05-01

    We construct new configurations of oppositely charged, static black hole pairs (diholes) in four dimensions which are solutions of low energy string/M-theory. The black holes are extremal and have four different charges. We also consider diholes in other theories with an arbitrary number of abelian gauge fields and scalars, where the black holes can be regarded as composite objects. We uplift the four-charge solutions to higher dimensions in order to describe intersecting brane-antibrane systems in string and M-theory. The properties of the strings and membranes stretched in between these branes and antibranes are studied. Several other generic features of these solutions are discussed.

  7. AMPK Signaling Involvement for the Repression of the IL-1β-Induced Group IIA Secretory Phospholipase A2 Expression in VSMCs

    PubMed Central

    El Hadri, Khadija; Denoyelle, Chantal; Ravaux, Lucas; Viollet, Benoit; Foretz, Marc; Friguet, Bertrand; Rouis, Mustapha; Raymondjean, Michel

    2015-01-01

    Secretory Phospholipase A2 of type IIA (sPLA2 IIA) plays a crucial role in the production of lipid mediators by amplifying the neointimal inflammatory context of the vascular smooth muscle cells (VSMCs), especially during atherogenesis. Phenformin, a biguanide family member, by its anti-inflammatory properties presents potential for promoting beneficial effects upon vascular cells, however its impact upon the IL-1β-induced sPLA2 gene expression has not been deeply investigated so far. The present study was designed to determine the relationship between phenformin coupling AMP-activated protein kinase (AMPK) function and the molecular mechanism by which the sPLA2 IIA expression was modulated in VSMCs. Here we find that 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleotide (AICAR) treatment strongly repressed IL-1β-induced sPLA2 expression at least at the transcriptional level. Our study reveals that phenformin elicited a dose-dependent inhibition of the sPLA2 IIA expression and transient overexpression experiments of constitutively active AMPK demonstrate clearly that AMPK signaling is involved in the transcriptional inhibition of sPLA2-IIA gene expression. Furthermore, although the expression of the transcriptional repressor B-cell lymphoma-6 protein (BCL-6) was markedly enhanced by phenformin and AICAR, the repression of sPLA2 gene occurs through a mechanism independent of BCL-6 DNA binding site. In addition we show that activation of AMPK limits IL-1β-induced NF-κB pathway activation. Our results indicate that BCL-6, once activated by AMPK, functions as a competitor of the IL-1β induced NF-κB transcription complex. Our findings provide insights on a new anti-inflammatory pathway linking phenformin, AMPK and molecular control of sPLA2 IIA gene expression in VSMCs. PMID:26162096

  8. Effects of Tanshinone IIA on the modulation of miR‑33a and the SREBP‑2/Pcsk9 signaling pathway in hyperlipidemic rats.

    PubMed

    Jia, Lianqun; Song, Nan; Yang, Guanlin; Ma, Yixin; Li, Xuetao; Lu, Ren; Cao, Huimin; Zhang, Ni; Zhu, Meilin; Wang, Junyan; Leng, Xue; Cao, Yuan; Du, Ying; Xu, Yue

    2016-06-01

    Tanshinone IIA is the active compound isolated from Salvia miltiorrhiza bunge, which is a traditional Chinese medicine known as Danshen. The aim of the present study was to assess the effect of Tanshinone IIA on the regulation of lipid metabolism in the livers of hyperlipidemic rats and the underlying molecular events. An in vivo model of hyperlipidemia was established in rats, with the animals receiving a daily dose of Tanshinone IIA. The serum lipid profiles were analyzed using an automatic biochemical analyzer, and the histopathological alterations and lipid deposition in liver tissue were assessed using hematoxylin and eosin staining, and oil red O staining, respectively. The mRNA expression levels of microRNA (miR)‑33a, ATP‑binding cassette transporter (ABC)A1, ABCG1, sterol regulatory element‑binding protein 2 (SREBP‑2), proprotein convertase subtilisin/kexin type 9 (Pcsk9) and low‑density lipoprotein receptor (LDL‑R) in liver tissues were measured using reverse transcription‑quantitative polymerase chain reaction, and the protein expression levels of ABCA1, ABCG1, SREBP‑2, Pcsk9, and LDL‑R were analyzed using western blotting. Tanshinone IIA reduced lipid deposition and improved histopathology in the rat liver tissue, however, did not alter the lipid profile in rat serum. In addition, Tanshinone IIA treatment suppressed the expression of miR‑33a, whereas the protein expression levels of ABCA1, SREBP‑2, Pcsk9 in addition to LDL‑R mRNA and protein were upregulated. In conclusion, the present study indicated that Tanshinone IIA attenuated lipid deposition in the livers of hyperlipidemic rats and modulated the expression of miR‑33a and SREBP‑2/Pcsk9 signaling pathway proteins. PMID:27082100

  9. Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-α-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney.

    PubMed

    Webster, Rose; Sheriff, Sulaiman; Faroqui, Rashma; Siddiqui, Faraaz; Hawse, John R; Amlal, Hassane

    2016-08-01

    Estrogen treatment causes renal phosphate (Pi) wasting and hypophosphatemia in rats and humans; however, the signaling mechanisms mediating this effect are still poorly understood. To determine the specific roles of estrogen receptor isoforms (ERα and ERβ) and the Klotho pathway in mediating these effects, we studied the effects of estrogen on renal Pi handling in female mice with null mutations of ERα or ERβ or Klotho and their wild type (WT) using balance studies in metabolic cages. Estrogen treatment of WT and ERβ knockout (KO) mice caused a significant reduction in food intake along with increased renal phosphate wasting. The latter resulted from a significant downregulation of NaPi-IIa and NaPi-IIc protein abundance. The mRNA expression levels of both transporters were unchanged in estrogen-treated mice. These effects on both food intake and renal Pi handling were absent in ERα KO mice. Estrogen treatment of Klotho KO mice or parathyroid hormone (PTH)-depleted thyroparathyroidectomized mice exhibited a significant downregulation of NaPi-IIa with no change in the abundance of NaPi-IIc. Estrogen treatment of a cell line (U20S) stably coexpressing both ERα and ERβ caused a significant downregulation of NaPi-IIa protein when transiently transfected with a plasmid containing full-length or open-reading frame (ORF) 3'-untranslated region (UTR) but not 5'-UTR ORF of mouse NaPi-IIa transcript. In conclusion, estrogen causes phosphaturia and hypophosphatemia in mice. These effects result from downregulation of NaPi-IIa and NaPi-IIc proteins in the proximal tubule through the activation of ERα. The downregulation of NaPi-IIa by estrogen involves 3'-UTR of its mRNA and is independent of Klotho/fibroblast growth factor 23 and PTH signaling pathways. PMID:27194721

  10. Effects of Tanshinone IIA on the modulation of miR-33a and the SREBP-2/Pcsk9 signaling pathway in hyperlipidemic rats

    PubMed Central

    JIA, LIANQUN; SONG, NAN; YANG, GUANLIN; MA, YIXIN; LI, XUETAO; LU, REN; CAO, HUIMIN; ZHANG, NI; ZHU, MEILIN; WANG, JUNYAN; LENG, XUE; CAO, YUAN; DU, YING; XU, YUE

    2016-01-01

    Tanshinone IIA is the active compound isolated from Salvia miltiorrhiza bunge, which is a traditional Chinese medicine known as Danshen. The aim of the present study was to assess the effect of Tanshinone IIA on the regulation of lipid metabolism in the livers of hyperlipidemic rats and the underlying molecular events. An in vivo model of hyperlipidemia was established in rats, with the animals receiving a daily dose of Tanshinone IIA. The serum lipid profiles were analyzed using an automatic biochemical analyzer, and the histopathological alterations and lipid deposition in liver tissue were assessed using hematoxylin and eosin staining, and oil red O staining, respectively. The mRNA expression levels of microRNA (miR)-33a, ATP-binding cassette transporter (ABC)A1, ABCG1, sterol regulatory element-binding protein 2 (SREBP-2), proprotein convertase subtilisin/kexin type 9 (Pcsk9) and low-density lipoprotein receptor (LDL-R) in liver tissues were measured using reverse transcription-quantitative polymerase chain reaction, and the protein expression levels of ABCA1, ABCG1, SREBP-2, Pcsk9, and LDL-R were analyzed using western blotting. Tanshinone IIA reduced lipid deposition and improved histopathology in the rat liver tissue, however, did not alter the lipid profile in rat serum. In addition, Tanshinone IIA treatment suppressed the expression of miR-33a, whereas the protein expression levels of ABCA1, SREBP-2, Pcsk9 in addition to LDL-R mRNA and protein were upregulated. In conclusion, the present study indicated that Tanshinone IIA attenuated lipid deposition in the livers of hyperlipidemic rats and modulated the expression of miR-33a and SREBP-2/Pcsk9 signaling pathway proteins. PMID:27082100

  11. Inflation from superstring and M-theory compactification with higher order corrections. - II. - Case of quartic Weyl terms

    SciTech Connect

    Akune, Kenta; Maeda, Kei-ichi; Ohta, Nobuyoshi

    2006-05-15

    We present a detailed study of inflationary solutions in M theory with higher order quantum corrections. We first exhaust all exact and asymptotic solutions of exponential and power-law expansions in this theory with quartic curvature corrections, and then perform a linear perturbation analysis around fixed points for the exact solutions in order to see which solutions are more generic and give interesting cosmological models. We find an interesting solution in which the external space expands exponentially and the internal space is static both in the original and Einstein frames. Furthermore, we perform a numerical calculation around this solution and find numerical solutions which give enough e-foldings. We also briefly summarize similar solutions in type II superstrings.

  12. Gravitational wave solutions in string and M-theory AdS backgrounds

    SciTech Connect

    Kumar, Alok; Kunduri, Hari K.

    2004-11-15

    In this paper, we present several gravitational wave solutions in AdS{sub 5}xS{sup 5} string backgrounds, as well as in AdS{sub 7}xS{sup 4} and AdS{sub 4}xS{sup 7} backgrounds in M theory, generalizing the results of Phys. Lett. B 594, 368 (2004).. In each case, we present the general form of such solutions and give explicit examples, preserving certain amount of supersymmetry, by taking limits on known Bogomol'nyi-Prasad-Sommerfield D3 and M2, M5-brane solutions in pp-wave backgrounds. A key feature of our examples is the possibility of a wider variety of wave profiles, than in pure gravity and string/M-theory examples known earlier, coming from the presence of various p-form field strengths appearing in the gravitational wave structure.

  13. M-theory on non-Kähler eight-manifolds

    NASA Astrophysics Data System (ADS)

    Shahbazi, C. S.

    2015-09-01

    We show that M-theory admits a class of supersymmetric eight-dimensional compactification background solutions, equipped with an internal complex pure spinor, more general than the Calabi-Yau one. Building-up on this result, we obtain a a particular class of supersymmetric M-theory eight-dimensional non-geometric compactification backgrounds with external three-dimensional Minkowski space-time, proving that the global space of the non-geometric compactification is again a differentiable manifold, although with very different geometric and topological properties respect to the corresponding standard M-theory compactification background: it is a compact complex manifold admitting a Kähler covering with deck transformations acting by holomorphic homotheties with respect to the Kähler metric. We show that this class of non-geometric compactifications evade the Maldacena-Nuñez no-go theorem by means of a mechanism originally developed by Mario García-Fernández and the author for Heterotic Supergravity, and thus do not require l P -corrections to allow for a nontrivial warp factor or four-form flux. We obtain an explicit compactification background on a complex Hopf four-fold that solves all the equations of motion of the theory, including the warp factor equation of motion. We also show that this class of non-geometric compactifications are equipped with a holomorphic principal torus fibration over a projective Kähler base as well as a codimension-one foliation with nearly-parallel G 2-leaves, making thus contact with the work of M. Babalic and C. Lazaroiu on the foliation structure of the most general M-theory supersymmetric compactifications.

  14. Atlas II and IIA analyses and environments validation

    NASA Astrophysics Data System (ADS)

    Martin, Richard E.

    1995-06-01

    General Dynamics has now flown all four versions of the Atlas commercial launch vehicle, which cover a payload weight capability to geosynchronous transfer orbit (GTO) in the range of 5000-8000 lb. The key analyses to set design and environmental test parameters for the vehicle modifications and the ground and flight test data that validated them were prepared in paper IAF-91-170 for the first version, Atlas I. This paper presents similar data for the next two versions, Atlas II and IIA. The Atlas II has propellant tanks lengthened by 12 ft and is boosted by MA-5A rocket engines uprated to 474,000 lb liftoff thrust. GTO payload capability is 6225 lb with the 11-ft fairing. The Atlas IIA is an Atlas II with uprated RL10A-4 engines on the lengthened Centaur II upper stage. The two 20,800 lb thrust, 449 s specific impulse engines with an optional extendible nozzle increase payload capability to GTO to 6635 lb. The paper describes design parameters and validated test results for many other improvements that have generally provided greater capability at less cost, weight and complexity and better reliability. Those described include: moving the MA-5A start system to the ground, replacing the vernier engines with a simple 50 lb thrust on-off hydrazine roll control system, addition of a POGO suppressor, replacement of Centaur jettisonable insulation panels with fixed foam, a new inertial navigation unit (INU) that combines in one package a ring-laser gyro based strapdown guidance system with two MIL-STD-1750A processors, redundant MIL-STD-1553 data bus interfaces, robust Ada-based software and a new Al-Li payload adapter. Payload environment is shown to be essentially unchanged from previous Atlas vehicles. Validation of load, stability, control and pressurization requirements for the larger vehicle is discussed. All flights to date (five Atlas II, one Atlas IIA) have been successful in launching satellites for EUTELSAT, the U.S. Air Force and INTELSAT. Significant design

  15. Atlas IIA/Centaur rocket arrives at CCAFS

    NASA Technical Reports Server (NTRS)

    2000-01-01

    At Cape Canaveral Air Force skid strip, the Centaur upper stage is placed aboard a transporter after arriving aboard a Russian cargo plane, the Antenov 124. The Centaur will be coupled with an Atlas IIA to launch the latest Tracking and Data Relay Satellite (TDRS) June 29 from Cape Canaveral Air Force Station. The Centaur, manufactured and operated by Lockheed Martin, is 3.05 m (10 ft) in diameter and 10.0 m (33-ft) long. It uses liquid hydrogen (LH2) and liquid oxygen (LO2) propellants.

  16. Atlas IIA/Centaur rocket arrives at CCAFS

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Workers at Cape Canaveral Air Force skid strip oversee the offloading of the Centaur upper stage from a Russian cargo plane, the Antenov 124. The Centaur will be coupled with an Atlas IIA to launch the latest Tracking and Data Relay Satellite (TDRS) June 29 from Cape Canaveral Air Force Station. The Centaur, manufactured and operated by Lockheed Martin, is 3.05 m (10 ft) in diameter and 10.0 m (33-ft) long. It uses liquid hydrogen (LH2) and liquid oxygen (LO2) propellants.

  17. Atlas IIA/Centaur rocket arrives at CCAFS

    NASA Technical Reports Server (NTRS)

    2000-01-01

    - A Russian cargo plane, the Antenov 124, arrives at Cape Canaveral Air Force skid strip to deliver the Atlas IIA/Centaur rocket scheduled to launch the latest Tracking and Data Relay Satellite (TDRS) June 29 from Cape Canaveral Air Force Station. Visible is the Centaur upper stage, manufactured and operated by Lockheed Martin. The Centaur vehicle is 3.05 m (10 ft) in diameter and 10.0 m (33-ft) long. It uses liquid hydrogen (LH2) and liquid oxygen (LO2) propellants.

  18. Assessing a candidate IIA dual to metastable supersymmetry-breaking

    NASA Astrophysics Data System (ADS)

    Giecold, Gregory; Goi, Enrico; Orsi, Francesco

    2012-02-01

    We analyze the space of linearized non-supersymmetric deformations around a IIA solution found by Cvetič, Gibbons, Lü and Pope (CGLP) in hep-th/0101096. We impose boundary conditions aimed at singling out among those perturbations the ones describing the backreaction of anti-D2 branes on the CGLP background. The corresponding supergravity solution is a would-be dual to a metastable supersymmetry-breaking state. However, it turns out that this candidate bulk solution is inevitably riddled with IR divergences of its flux densities and action, whose physical meaning and implications for models of string cosmology call for further investigation.

  19. IIaO ultraviolet and nuclear emulsion films responses to orbital flights on STS-3, STS-7, STS-8, and STS-40

    NASA Technical Reports Server (NTRS)

    Hammond, E. C., Jr.; Peters, K. A.; Blake, S. M.; Bailey, Y.; Johnson, D.; Robancho, S.; Stober, A.

    1992-01-01

    Two types of film were flown on STS-40 space shuttle mission in June 1991. The IIaO special purpose ultraviolet film showed continued desensitization because of various thermal and cosmic ray interactions. The films were exposed to the space orbital environment for 9 days. There were several built-in launch pad delays of the shuttle mission. However, there was adequate monitoring of the temperature variations on board the shuttle that allowed for adequate knowledge of the thermal film history. This IIaO film was flown on the ASTRO I mission and is currently slated for use with the ASTRO II mission. A 50 micron thick IIIford Nuclear emulsion film was also placed on a 175 micron polyester base. The exposure to space produced several cosmic ray interactions that were analyzed and measured using Digital Image Processing techniques. This same nuclear emulsion film was flown on STS-8 and produced a similar number of cosmic ray and thermal interactions. From previous experiments of film using various laboratory electromagnetic radiation sources (e.g., alpha, beta, and neutron particles), we have been able to infer the possible oribtal interactions of both IIaO and nuclear emulsion films. The characteristic responses of IIaO on STS-40 compared favorably to the results obtained from previous STS-7 and STS-8 gas can experiments. The results indicate sufficient evidence correlating increased density on the film with possible cosmic ray, thermal and shuttle out gassing interactions.

  20. Identification of the First Sodium Binding Site of the Phosphate Cotransporter NaPi-IIa (SLC34A1)

    PubMed Central

    Fenollar-Ferrer, Cristina; Forster, Ian C.; Patti, Monica; Knoepfel, Thomas; Werner, Andreas; Forrest, Lucy R.

    2015-01-01

    Transporters of the SLC34 family (NaPi-IIa,b,c) catalyze uptake of inorganic phosphate (Pi) in renal and intestinal epithelia. The transport cycle requires three Na+ ions and one divalent Pi to bind before a conformational change enables translocation, intracellular release of the substrates, and reorientation of the empty carrier. The electrogenic interaction of the first Na+ ion with NaPi-IIa/b at a postulated Na1 site is accompanied by charge displacement, and Na1 occupancy subsequently facilitates binding of a second Na+ ion at Na2. The voltage dependence of cotransport and presteady-state charge displacements (in the absence of a complete transport cycle) are directly related to the molecular architecture of the Na1 site. The fact that Li+ ions substitute for Na+ at Na1, but not at the other sites (Na2 and Na3), provides an additional tool for investigating Na1 site-specific events. We recently proposed a three-dimensional model of human SLC34a1 (NaPi-IIa) including the binding sites Na2, Na3, and Pi based on the crystal structure of the dicarboxylate transporter VcINDY. Here, we propose nine residues in transmembrane helices (TM2, TM3, and TM5) that potentially contribute to Na1. To verify their roles experimentally, we made single alanine substitutions in the human NaPi-IIa isoform and investigated the kinetic properties of the mutants by voltage clamp and 32P uptake. Substitutions at five positions in TM2 and one in TM5 resulted in relatively small changes in the substrate apparent affinities, yet at several of these positions, we observed significant hyperpolarizing shifts in the voltage dependence. Importantly, the ability of Li+ ions to substitute for Na+ ions was increased compared with the wild-type. Based on these findings, we adjusted the regions containing Na1 and Na3, resulting in a refined NaPi-IIa model in which five positions (T200, Q206, D209, N227, and S447) contribute directly to cation coordination at Na1. PMID:25992725

  1. Identification of the first sodium binding site of the phosphate cotransporter NaPi-IIa (SLC34A1).

    PubMed

    Fenollar-Ferrer, Cristina; Forster, Ian C; Patti, Monica; Knoepfel, Thomas; Werner, Andreas; Forrest, Lucy R

    2015-05-19

    Transporters of the SLC34 family (NaPi-IIa,b,c) catalyze uptake of inorganic phosphate (Pi) in renal and intestinal epithelia. The transport cycle requires three Na(+) ions and one divalent Pi to bind before a conformational change enables translocation, intracellular release of the substrates, and reorientation of the empty carrier. The electrogenic interaction of the first Na(+) ion with NaPi-IIa/b at a postulated Na1 site is accompanied by charge displacement, and Na1 occupancy subsequently facilitates binding of a second Na(+) ion at Na2. The voltage dependence of cotransport and presteady-state charge displacements (in the absence of a complete transport cycle) are directly related to the molecular architecture of the Na1 site. The fact that Li(+) ions substitute for Na(+) at Na1, but not at the other sites (Na2 and Na3), provides an additional tool for investigating Na1 site-specific events. We recently proposed a three-dimensional model of human SLC34a1 (NaPi-IIa) including the binding sites Na2, Na3, and Pi based on the crystal structure of the dicarboxylate transporter VcINDY. Here, we propose nine residues in transmembrane helices (TM2, TM3, and TM5) that potentially contribute to Na1. To verify their roles experimentally, we made single alanine substitutions in the human NaPi-IIa isoform and investigated the kinetic properties of the mutants by voltage clamp and (32)P uptake. Substitutions at five positions in TM2 and one in TM5 resulted in relatively small changes in the substrate apparent affinities, yet at several of these positions, we observed significant hyperpolarizing shifts in the voltage dependence. Importantly, the ability of Li(+) ions to substitute for Na(+) ions was increased compared with the wild-type. Based on these findings, we adjusted the regions containing Na1 and Na3, resulting in a refined NaPi-IIa model in which five positions (T200, Q206, D209, N227, and S447) contribute directly to cation coordination at Na1. PMID:25992725

  2. Structure of hepatitis C virus IRES subdomain IIa

    SciTech Connect

    Zhao, Q.; Han, Q.; Kissinger, C.R.; Hermann, T.; Thompson, P.A.

    2008-07-03

    The hepatitis C (HCV) internal ribosome entry site (IRES) element plays a central role in cap-independent translation of the viral genomic RNA. The unique conformation of IRES domain II is critical for 80S ribosomal assembly and initiation of viral translation. Here, the crystal structure of subdomain IIa of the HCV IRES has been determined at 2.3 {angstrom} resolution, revealing the positions of divalent metal ions and complex inter-strand interactions that stabilize the L-shaped conformation of the RNA. The presence of divalent metal ions was necessary for crystal formation. Magnesium ions occupy specific sites that appear to be critical for the formation of the folded conformation. Subdomain IIa also was crystallized in the presence of strontium, which improved the diffraction quality of the crystals and the ability to identify interactions of the RNA with metal ions and tightly bound water molecules. The hinge region and noncanonical G-U base-pair motifs are stabilized by divalent metal ions and provide unique structural features that are potential interaction sites for small-molecule ligands. The information obtained from the crystal structure provides a basis for structure-guided design of HCV translation inhibitors targeting disruption of ribosomal assembly.

  3. Eccentric contraction-induced injury to type I, IIa, and IIa/IIx muscle fibers of elderly adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Muscles of old laboratory rodents experience exaggerated force losses after eccentric contractile activity. We extended this line of inquiry to humans and investigated the influence of fiber myosin heavy chain (MHC) isoform content on the injury process. Skinned muscle fiber segments, prepared from ...

  4. 49 CFR 107.803 - Approval of an independent inspection agency (IIA).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 2 2011-10-01 2011-10-01 false Approval of an independent inspection agency (IIA... TRANSPORTATION HAZARDOUS MATERIALS PROGRAM PROCEDURES Approval of Independent Inspection Agencies, Cylinder... an independent inspection agency (IIA). (a) General. Prior to performing cylinder inspections...

  5. 49 CFR 107.803 - Approval of an independent inspection agency (IIA).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Approval of an independent inspection agency (IIA... TRANSPORTATION HAZARDOUS MATERIALS PROGRAM PROCEDURES Approval of Independent Inspection Agencies, Cylinder... an independent inspection agency (IIA). (a) General. Prior to performing cylinder inspections...

  6. 49 CFR 107.803 - Approval of an independent inspection agency (IIA).

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 2 2014-10-01 2014-10-01 false Approval of an independent inspection agency (IIA... TRANSPORTATION HAZARDOUS MATERIALS PROGRAM PROCEDURES Approval of Independent Inspection Agencies, Cylinder... an independent inspection agency (IIA). (a) General. Prior to performing cylinder inspections...

  7. 49 CFR 107.803 - Approval of an independent inspection agency (IIA).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 2 2013-10-01 2013-10-01 false Approval of an independent inspection agency (IIA... TRANSPORTATION HAZARDOUS MATERIALS PROGRAM PROCEDURES Approval of Independent Inspection Agencies, Cylinder... an independent inspection agency (IIA). (a) General. Prior to performing cylinder inspections...

  8. 49 CFR 107.803 - Approval of an independent inspection agency (IIA).

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Approval of an independent inspection agency (IIA... TRANSPORTATION HAZARDOUS MATERIALS PROGRAM PROCEDURES Approval of Independent Inspection Agencies, Cylinder... an independent inspection agency (IIA). (a) General. Prior to performing cylinder inspections...

  9. Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors.

    PubMed

    Luckhurst, Christopher A; Breccia, Perla; Stott, Andrew J; Aziz, Omar; Birch, Helen L; Bürli, Roland W; Hughes, Samantha J; Jarvis, Rebecca E; Lamers, Marieke; Leonard, Philip M; Matthews, Kim L; McAllister, George; Pollack, Scott; Saville-Stones, Elizabeth; Wishart, Grant; Yates, Dawn; Dominguez, Celia

    2016-01-14

    Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models. PMID:26819662

  10. 30 CFR 57.22219 - Seals and stoppings (II-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Seals and stoppings (II-A mines). 57.22219... Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22219 Seals and stoppings (II-A mines... fire resistance. (b) Seals shall be of substantial construction. Exposed surfaces on the fresh air...

  11. 30 CFR 57.22219 - Seals and stoppings (II-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Seals and stoppings (II-A mines). 57.22219... Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22219 Seals and stoppings (II-A mines... fire resistance. (b) Seals shall be of substantial construction. Exposed surfaces on the fresh air...

  12. 30 CFR 57.22219 - Seals and stoppings (II-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Seals and stoppings (II-A mines). 57.22219... Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22219 Seals and stoppings (II-A mines... fire resistance. (b) Seals shall be of substantial construction. Exposed surfaces on the fresh air...

  13. 30 CFR 57.22219 - Seals and stoppings (II-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Seals and stoppings (II-A mines). 57.22219... Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22219 Seals and stoppings (II-A mines... fire resistance. (b) Seals shall be of substantial construction. Exposed surfaces on the fresh air...

  14. 30 CFR 57.22219 - Seals and stoppings (II-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Seals and stoppings (II-A mines). 57.22219... Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22219 Seals and stoppings (II-A mines... fire resistance. (b) Seals shall be of substantial construction. Exposed surfaces on the fresh air...

  15. Anti-Inflammatory and Immunomodulatory Mechanism of Tanshinone IIA for Atherosclerosis

    PubMed Central

    Chen, Zhuo

    2014-01-01

    Tanshinone IIA (Tan II A) is widely used in the treatment of cardiovascular diseases as an active component of Salvia miltiorrhiza Bunge. It has been demonstrated to have pleiotropic effects for atherosclerosis. From the anti-inflammatory and immunomodulatory mechanism perspective, this paper reviewed major progresses of Tan IIA in antiatherosclerosis research, including immune cells, antigens, cytokines, and cell signaling pathways. PMID:25525444

  16. Cryptosporidium parvum genotype IIa and Giardia duodenalis assemblage A in Mytilus galloprovincialis on sale at local food markets.

    PubMed

    Giangaspero, Annunziata; Papini, Roberto; Marangi, Marianna; Koehler, Anson V; Gasser, Robin B

    2014-02-01

    To date, there has been no study to establish the genotypic or subgenotypic identities of Cryptosporidium and Giardia in edible shellfish. Here, we explored the genetic composition of these protists in Mytilus galloprovincialis (Mediterranean mussel) purchased from three markets in the city of Foggia, Italy, from May to December 2012. Samples from the digestive glands, gills and haemolymph were tested by nested PCR, targeting DNA regions within the 60 kDa glycoprotein (gp60) gene of Cryptosporidium, and the triose-phosphate isomerase (tpi) and β-giardin genes of Giardia. In total, Cryptosporidium and Giardia were detected in 66.7% of mussels (M. galloprovincialis) tested. Cryptosporidium was detected mostly between May and September 2012. Sequencing of amplicons showed that 60% of mussels contained Cryptosporidium parvum genotype IIa (including subgenotypes A15G2R1, IIaA15G2 and IIaA14G3R1), 23.3% Giardia duodenalis assemblage A, and 6.6% had both genetic types. This is the first report of these types in fresh, edible shellfish, particularly the very commonly consumed M. galloprovincialis from highly frequented fish markets. These genetic types of Cryptosporidium and Giardia are known to infect humans and thus likely to represent a significant public health risk. The poor observance of hygiene rules by vendors, coupled to the large numbers of M. galloprovincialis sold and the eating habits of consumers in Italy, call for more effective sanitary measures pertaining to the selling of fresh shellfish in street markets. PMID:24334090

  17. Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.

    PubMed

    Gaur, Vidhi; Connor, Timothy; Sanigorski, Andrew; Martin, Sheree D; Bruce, Clinton R; Henstridge, Darren C; Bond, Simon T; McEwen, Kevin A; Kerr-Bayles, Lyndal; Ashton, Trent D; Fleming, Cassandra; Wu, Min; Pike Winer, Lisa S; Chen, Denise; Hudson, Gregg M; Schwabe, John W R; Baar, Keith; Febbraio, Mark A; Gregorevic, Paul; Pfeffer, Frederick M; Walder, Ken R; Hargreaves, Mark; McGee, Sean L

    2016-09-13

    Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity. PMID:27626651

  18. The M-theory origin of global properties of gauge theories

    NASA Astrophysics Data System (ADS)

    Amariti, Antonio; Klare, Claudius; Orlando, Domenico; Reffert, Susanne

    2015-12-01

    We show that global properties of gauge groups can be understood as geometric properties in M-theory. Different wrappings of a system of N M5-branes on a torus reduce to four-dimensional theories with AN-1 gauge algebra and different unitary groups. The classical properties of the wrappings determine the global properties of the gauge theories without the need to impose any quantum conditions. We count the inequivalent wrappings as they fall into orbits of the modular group of the torus, which correspond to the S-duality orbits of the gauge theories.

  19. Probing non-perturbative effects in M-theory on orientifolds

    NASA Astrophysics Data System (ADS)

    Okuyama, Kazumi

    2016-01-01

    Using holography, we study non-perturbative effects in M-theory on orientifolds from the analysis of the S 3 partition functions of dual field theories. We consider the S 3 partition functions of N=4 Yang-Mills theory with O( n) gauge symmetry coupled to one (anti)symmetric and N f fundamental hypermultiplets from the Fermi gas approach. In addition to the worldsheet instanton and membrane instanton corrections to the grand potential, which are also present in the U( n) Yang-Mills case, we find that there exist "half instanton" corrections coming from the effect of orientifold plane.

  20. S O (10 ) grand unification in M theory on a G2 manifold

    NASA Astrophysics Data System (ADS)

    Acharya, Bobby S.; BoŻek, Krzysztof; Crispim Romão, Miguel; King, Stephen F.; Pongkitivanichkul, Chakrit

    2015-09-01

    We consider grand unified theories based on S O (10 ) which originate from string/M theory on G2 manifolds or Calabi-Yau spaces with discrete symmetries. In this framework we are naturally led to a novel solution of the doublet-triplet splitting problem previously considered by Dvali which involves an extra vectorlike Standard Model family and light but weakly coupled color triplets. These additional states are predicted to be accessible at the LHC and also induce R-parity violation. Gauge coupling unification occurs with a larger GUT coupling.

  1. Purification and biochemical characterization of a secreted group IIA chicken intestinal phospholipase A2

    PubMed Central

    2011-01-01

    Background Secretory phospholipase A2 group IIA (IIA PLA2) is a protein shown to be highly expressed in the intestine of mammals. However, no study was reported in birds. Results Chicken intestinal group IIA phospholipase A2 (ChPLA2-IIA) was obtained after an acidic treatment (pH.3.0), precipitation by ammonium sulphate, followed by sequential column chromatographies on Sephadex G-50 and mono-S ion exchanger. The enzyme was found to be a monomeric protein with a molecular mass of around 14 kDa. The purified enzyme showed a substrate preference for phosphatidylethanolamine and phosphatidylglycerol, and didn't hydrolyse phosphatidylcholine. Under optimal assay conditions, in the presence of 10 mM NaTDC and 10 mM CaCl2, a specific activity of 160 U.mg-1 for purified ChPLA2-IIA was measured using egg yolk as substrate. The fifteen NH2-terminal amino acid residues of ChPLA2-IIA were sequenced and showed a close homology with known intestinal secreted phospholipases A2. The gene encoding the mature ChPLA2-IIA was cloned and sequenced. To further investigate structure-activity relationship, a 3D model of ChPLA2-IIA was built using the human intestinal phospholipase A2 structure as template. Conclusion ChPLA2-IIA was purified to homogeneity using only two chromatographic colomns. Sequence analysis of the cloned cDNA indicates that the enzyme is highly basic with a pI of 9.0 and has a high degree of homology with mammalian intestinal PLA2-IIA. PMID:21284884

  2. A densitometric analysis of IIaO film flown aboard the space shuttle transportation system STS #3, 7, and 8

    NASA Technical Reports Server (NTRS)

    Hammond, Ernest C., Jr.

    1989-01-01

    Since the United States of America is moving into an age of reusable space vehicles, both electronic and photographic materials will continue to be an integral part of the recording techniques available. Film as a scientifically viable recording technique in astronomy is well documented. There is a real need to expose various types of films to the Shuttle environment. Thus, the main objective was to look at the subtle densitometric changes of canisters of IIaO film that was placed aboard the Space Shuttle 3 (STS-3).

  3. Characterizing GPS Block IIA Shadow and Post-Shadow Maneuvers

    NASA Astrophysics Data System (ADS)

    Weiss, J.; Bar-Sever, Y.; Bertiger, W.; Desai, S.; Haines, B.; Harvey, N.; Sibthorpe, A.

    2012-04-01

    We characterize GPS Block IIA shadow and post-shadow maneuvers by way of "reverse" precise point positioning (PPP). This technique takes advantage of the non-zero antenna phase center offset, representing the vector from the satellites' center of gravity (CG) to the antenna phase center, to estimate the spacecraft yaw attitude. We begin with a standard GIPSY-based precise orbit determination (POD) solution for the GPS constellation, and use the ground station troposphere, clock, and position estimates, as well as the reduced-dynamic GPS orbit solution as input to a follow-up estimation where the spacecraft body-fixed x, y, and z antenna phase center offsets relative the CG are estimated as unconstrained stochastic white noise parameters every 30 seconds. These estimates directly provide yaw attitude because the spacecraft attitude in the follow-up estimation is set to follow the "velocity frame," where the body-fixed z points towards the Earth, x points along the velocity vector, and y completes the right-handed coordinate system. The estimated antenna offsets absorb errors in the velocity frame attitude model, which does not perform noon and shadow maneuvers, and in turn directly measure spacecraft yaw attitude. In this presentation we utilize the outlined approach to characterize both shadow and post-shadow maneuvers of the GPS Block IIA spacecraft over a period of three years. We fit linear models to the yaw angle estimates during shadow (when the spacecraft traverses umbra) and compare the resulting yaw rate to estimates from standard POD solutions. We particularly focus on changes in yaw rate over time, and on using estimates from reverse PPP to improve nominal yaw rate values. We additionally characterize post-shadow maneuvers for which data are typically removed in POD solutions because the direction and duration of the yaw maneuver to recover nominal attitude are not straightforward to model. We analyze post-shadow maneuvers in terms of yaw angle versus

  4. Brane cosmology in string/M-theory and cosmological parameters estimation

    NASA Astrophysics Data System (ADS)

    Wu, Qiang

    In this dissertation, I mainly focus on two subjects: (I) highly effective and efficient parameter estimation algorithms and their applications to cosmology; and (II) the late cosmic acceleration of the universe in string/M theory. In Part I, after developing two highly successful numerical codes, I apply them to study the holographical dark energy model and ΛCMD model with curvature. By fitting these models with the most recent observations, I find various tight constraints on the parameters involved in the models. In part II, I develop the general formulas to describe orbifold branes in both string and M theories, and then systematical study the two most important issues: (1) the radion stability and radion mass; and (2) the localization of gravity, the effective 4D Newtonian potential. I find that the radion is stable and its mass is in the order of GeV, which is well above the current observational constraints. The gravity is localized on the TeV brane, and the spectra of the gravitational Kluza-Klein towers are discrete and have a mass gap of TeV. The contributions of high order Yukawa corrections to the Newtonian potential are negligible. Using the large extra dimensions, I also show that the cosmological constant can be lowered to its current observational value. Applying the formulas to cosmology, I study several models in the two theories, and find that a late transient acceleration of the universe is a generic feature of our setups.

  5. M-theory through the looking glass: Tachyon condensation in the E8 heterotic string

    SciTech Connect

    Horava, Petr; Horava, Petr; Keeler, Cynthia A.

    2007-09-20

    We study the spacetime decay to nothing in string theory and M-theory. First we recall a nonsupersymmetric version of heterotic M-theory, in which bubbles of nothing -- connecting the two E_8 boundaries by a throat -- are expected to be nucleated. We argue that the fate of this system should be addressed at weak string coupling, where the nonperturbative instanton instability is expected to turn into a perturbative tachyonic one. We identify the unique string theory that could describe this process: The heterotic model with one E_8 gauge group and a singlet tachyon. We then use worldsheet methods to study the tachyon condensation in the NSR formulation of this model, and show that it induces a worldsheet super-Higgs effect. The main theme of our analysis is the possibility of making meaningful alternative gauge choices for worldsheet supersymmetry, in place of the conventional superconformal gauge. We show in a version of unitary gauge how the worldsheet gravitino assimilates the goldstino and becomes dynamical. This picture clarifies recent results of Hellerman and Swanson. We also present analogs of R_\\xi gauges, and note the importance of logarithmic CFT in the context of tachyon condensation.

  6. M-theory on S1/Z2: new facts from a careful analysis1

    NASA Astrophysics Data System (ADS)

    Bilal, Adel; Derendinger, Jean-Pierre; Sauser, Roger

    2000-06-01

    We carefully reexamine the issues of solving the modified Bianchi identity, anomaly cancellations and flux quantization in the S 1/ Z2 orbifold of M-theory using the boundary-free "upstairs" formalism, avoiding several misconceptions present in earlier literature. While the solution for the four-form G to the modified Bianchi identity appears to depend on an arbitrary parameter b, we show that requiring G to be globally well-defined, i.e., invariant under small and large gauge and local Lorentz transformations, fixes b=1. This value also is necessary for a consistent reduction to the heterotic string in the small-radius limit. Insisting on properly defining all fields on the circle, we find that there is a previously unnoticed additional contribution to the anomaly inflow from the eleven-dimensional topological term. Anomaly cancellation then requires a quadratic relation between b and the combination λ 6/κ 4 of the gauge and gravitational coupling constants λ and κ. This contrasts with previous beliefs that anomaly cancellation would give a cubic equation for b. We observe that our solution for G automatically satisfies integer or half-integer flux quantization for the appropriate cycles. We explicitly write out the anomaly cancelling terms of the heterotic string as inherited from the M-theory approach. They differ from the usual ones by the addition of a well-defined local counterterm. We also show how five-branes enter our analysis.

  7. M-theory and E10: Billiards, Branes, and Imaginary Roots

    SciTech Connect

    Brown, Jeffrey; Ganor, Ori J.; Helfgott, Craig

    2004-01-09

    Eleven dimensional supergravity compactified on $T^10$ admits classical solutions describing what is known as billiard cosmology - a dynamics expressible as an abstract (billiard) ball moving in the 10-dimensional root space of the infinite dimensional Lie algebra E10, occasionally bouncing off walls in that space. Unlike finite dimensional Lie algebras, E10 has negative and zero norm roots, in addition to the positive norm roots. The walls above are related to physical fluxes that, in turn, are related to positive norm roots (called real roots) of E10. We propose that zero and negative norm roots, called imaginary roots, are related to physical branes. Adding 'matter' to the billiard cosmology corresponds to adding potential terms associated to imaginary roots. The, as yet, mysterious relation between E10 and M-theory on $T^10$ can now be expanded as follows: real roots correspond to fluxes or instantons, and imaginary roots correspond to particles and branes (in the cases we checked). Interactions between fluxes and branes and between branes and branes are classified according to the inner product of the corresponding roots (again in the cases we checked). We conclude with a discussion of an effective Hamiltonian description that captures some features of M-theory on $T^10.$

  8. Nonmuscle myosin heavy chain IIA mediates Epstein–Barr virus infection of nasopharyngeal epithelial cells

    PubMed Central

    Xiong, Dan; Du, Yong; Wang, Hong-Bo; Zhao, Bo; Zhang, Hua; Li, Yan; Hu, Li-Juan; Cao, Jing-Yan; Zhong, Qian; Liu, Wan-Li; Li, Man-Zhi; Zhu, Xiao-Feng; Tsao, Sai Wah; Hutt-Fletcher, Lindsey M.; Song, Erwei; Zeng, Yi-Xin; Kieff, Elliott; Zeng, Mu-Sheng

    2015-01-01

    EBV causes B lymphomas and undifferentiated nasopharyngeal carcinoma (NPC). Although the mechanisms by which EBV infects B lymphocytes have been extensively studied, investigation of the mechanisms by which EBV infects nasopharyngeal epithelial cells (NPECs) has only recently been enabled by the successful growth of B lymphoma Mo-MLV insertion region 1 homolog (BMI1)-immortalized NPECs in vitro and the discovery that neuropilin 1 expression positively affects EBV glycoprotein B (gB)-mediated infection and tyrosine kinase activations in enhancing EBV infection of BMI1-immortalized NPECs. We have now found that even though EBV infected NPECs grown as a monolayer at extremely low efficiency (<3%), close to 30% of NPECs grown as sphere-like cells (SLCs) were infected by EBV. We also identified nonmuscle myosin heavy chain IIA (NMHC-IIA) as another NPEC protein important for efficient EBV infection. EBV gH/gL specifically interacted with NMHC-IIA both in vitro and in vivo. NMHC-IIA densely aggregated on the surface of NPEC SLCs and colocalized with EBV. EBV infection of NPEC SLCs was significantly reduced by NMHC-IIA siRNA knock-down. NMHC-IIA antisera also efficiently blocked EBV infection. These data indicate that NMHC-IIA is an important factor for EBV NPEC infection. PMID:26290577

  9. Protective effects of tanshinone IIA on endothelial progenitor cells injured by tumor necrosis factor-α

    PubMed Central

    WANG, XING-XIANG; YANG, JIN-XIU; PAN, YAN-YUN; ZHANG, YE-FEI

    2015-01-01

    Tanshinone IIA (Tan IIA) is a Traditional Chinese Medicine commonly used in Asian and Western countries for the prevention and treatment of cardiovascular disorders, such as atherosclerosis. Endothelial dysfunction and associated inflammatory processes have a critical role in the development of atherosclerosis. Endothelial progenitor cells (EPCs) have been demonstrated to be involved in certain aspects of the endothelial repair process. The present study aimed to investigate the putative protective effects of Tan IIA on EPCs injured by tumor necrosis factor-α (TNF-α). The potential effects of Tan IIA on TNF-α-stimulated EPC proliferation, migration, adhesion, in vitro tube formation ability and paracrine activity were investigated in the current study. The results indicated that TNF-α impaired EPC proliferation, migration, adhesion capacity and vasculogenesis ability in vitro as well as promoted EPC secretion of inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and soluble CD40 ligand (sCD40L). However, Tan IIA was able to reverse these effects. In conclusion, these findings demonstrated that Tan IIA may have the potential to protect EPCs against damage induced by TNF-α. Therefore, these results may provide evidence for the pharmacological basis of Tan IIA and its potential use in the prevention and treatment of early atherosclerosis associated with EPC and endothelial damage. PMID:26095681

  10. Phytoestrogen, tanshinone IIA diminishes collagen deposition and stimulates new elastogenesis in cultures of human cardiac fibroblasts.

    PubMed

    Mao, Shuai; Wang, Yanting; Zhang, Minzhou; Hinek, Aleksander

    2014-04-15

    It has been previously reported that oral or intra-peritoneal administration of tanshinone IIA can alleviate the ventricular hypertrophy and fibrosis that develops in rats after experimental cardiac infarction. Our present studies, performed on cultures of human cardiac fibroblasts, investigated the mechanism by which tanshinone IIA produces these beneficial effects. We found that treatment of cardiac fibroblasts with 0.1-10µM tanshinone IIA significantly inhibited their deposition of collagen I, while enhancing production of new elastic fibers. Moreover, both anti-collagenogenic and pro-elastogenic effects of tanshinone IIA occurred only after selective activation of the G protein-coupled estrogen receptor (GPER). This subsequently leads to initiation of the PKA/CREB phosphorylation pathway that inversely modulated transcription of collagen I and elastin genes. Interestingly, treatment of human cardiac fibroblasts with tanshinone IIA additionally up-regulated the production of the 67-kDa elastin binding protein, which facilitates tropoelastin secretion, and increased synthesis of lysyl oxidase, catalyzing cross-linkings of tropoelastin. Moreover, tanshinone IIA also caused up-regulation in the synthesis of collagenolytic MMP-1, but down-regulated levels of elastolytic MMP-2 and MMP-9. In summary, our data validate a novel mechanism in which tanshinone IIA, interacting with a non-classic estrogen receptor, maintains the proper balance between the net deposition of collagen and elastin, allowing for optimal durability and resiliency of the newly deposited matrix. PMID:24525372

  11. Value of urinary topoisomerase-IIA cell-free DNA for diagnosis of bladder cancer

    PubMed Central

    Kim, Ye-Hwan; Yan, Chunri; Lee, Il-Seok; Piao, Xuan-Mei; Byun, Young Joon; Jeong, Pildu; Kim, Won Tae; Yun, Seok-Joong

    2016-01-01

    Purpose Topoisomerase-II alpha (TopoIIA ), a DNA gyrase isoform that plays an important role in the cell cycle, is present in normal tissues and various human cancers, and can show altered expression in both. The aim of the current study was to examine the value of urinary TopoIIA cell-free DNA as a noninvasive diagnosis of bladder cancer (BC). Materials and Methods Two patient cohorts were examined. Cohort 1 (73 BC patients and seven controls) provided bladder tissue samples, whereas cohort 2 (83 BC patients, 54 nonmalignant hematuric patients, and 61 normal controls) provided urine samples. Real-time quantitative polymerase chain reaction was used to measure expression of TopoIIA mRNA in tissues and TopoIIA cell-free DNA in urine samples. Results The results showed that expression of TopoIIA mRNA in BC tissues was significantly higher than that in noncancer control tissues (p<0.001). The expression of urinary TopoIIA cell-free DNA in BC patients was also significantly higher than that in noncancer patient controls and hematuria patients (p < 0.001 and p < 0.001, respectively). High expression of urinary TopoIIA cell-free DNA was also detected in muscle invasive bladder cancer (MIBC) when compared with nonmuscle invasive bladder cancer (NMIBC) (p=0.002). Receiver operating characteristics (ROC) curve analysis was performed to examine the sensitivity/specificity of urinary TopoIIA cell-free DNA for diagnosing BC, NMIBC, and MIBC. The areas under the ROC curve for BC, NMIBC, and MIBC were 0.741, 0.701, and 0.838, respectively. Conclusions In summary, the results of this study provide evidence that cell-free TopoIIA DNA may be a potential biomarker for BC. PMID:26981592

  12. Complex phenotypic and genotypic responses of Listeria monocytogenes strains exposed to the class IIa bacteriocin sakacin P.

    PubMed

    Tessema, Girum Tadesse; Møretrø, Trond; Kohler, Achim; Axelsson, Lars; Naterstad, Kristine

    2009-11-01

    Sakacin P is a class IIa bacteriocin that is active against the food-borne pathogen Listeria monocytogenes, and use of this compound as a biopreservative in foods has been suggested. In the present study, we characterized 30 spontaneous sakacin P-resistant mutants of L. monocytogenes obtained after single exposure to sakacin P. The frequency of development of sakacin P resistance for all strains was in the range from 10(-8) to 10(-9). Using the 50% inhibitory concentration (IC(50)) of sakacin P, the strains could be grouped into strains with high levels of resistance (IC(50), > or =10(4) ng ml(-1)) and strains with low levels of resistance (IC(50), <10(4) ng ml(-1)). Resistant strains belonging to the same IC(50) group also had similar physiological and genetic characteristics. Generally, the resistant strains showed substantial variations in many parameters, such as differences in the stability of the acquired resistance to sakacin P, growth fitness, food-related stress tolerance, and biofilm-forming ability. Fourier transform infrared spectroscopy revealed differences between wild-type and resistant strains in polysaccharide, fatty acid, and, protein regions. A mannose-specific phosphotransferase (PTS) operon has been described for class IIa bacteriocin resistance, and the sakacin P-resistant strains displayed both up- and downregulation of the expression of the mptA gene encoding the PTS system. This is the first comprehensive study of the diversity of a large number of spontaneous resistant mutants obtained after one exposure to a class IIa bacteriocin, particularly to sakacin P. The great diversity among the resistant strains exposed to the same stress conditions suggests that there are different resistance mechanisms. PMID:19767478

  13. Numerical solution of first order initial value problem using 4-stage sixth order Gauss-Kronrod-Radau IIA method

    NASA Astrophysics Data System (ADS)

    Ying, Teh Yuan; Yaacob, Nazeeruddin

    2013-04-01

    In this paper, a new implicit Runge-Kutta method which based on a 4-point Gauss-Kronrod-Radau II quadrature formula is developed. The resulting implicit method is a 4-stage sixth order Gauss-Kronrod-Radau IIA method, or in brief as GKRM(4,6)-IIA. GKRM(4,6)-IIA requires four function of evaluations at each integration step and it gives accuracy of order six. In addition, GKRM(4,6)-IIA has stage order four and being L-stable. Numerical experiments compare the accuracy between GKRM(4,6)-IIA and the classical 3-stage sixth order Gauss-Legendre method in solving some test problems. Numerical results reveal that GKRM(4,6)-IIA is more accurate than the 3-stage sixth order Gauss-Legendre method because GKRM(4,6)-IIA has higher stage order.

  14. World-volume effective action of exotic five-brane in M-theory

    NASA Astrophysics Data System (ADS)

    Kimura, Tetsuji; Sasaki, Shin; Yata, Masaya

    2016-02-01

    We study the world-volume effective action of an exotic five-brane, known as the M-theory 53-brane (M53-brane) in eleven dimensions. The supermultiplet of the world-volume theory is the {N}=(2, 0) tensor multiplet in six dimensions. The world-volume action contains three Killing vectors {widehat{k}}_{widehat{I}}^M ( Ȋ = 1 , 2 , 3) associated with the U(1)3 isometry. We find the effective T-duality rule for the eleven-dimensional backgrounds that transforms the M5-brane effective action to that of the M53-brane. We also show that our action provides the source term for the M53-brane geometry in eleven-dimensional supergravity.

  15. On the stability of (M theory) stars against collapse: Role of anisotropic pressures

    NASA Astrophysics Data System (ADS)

    Kalyana Rama, S.

    2015-09-01

    Unitarity of evolution in gravitational collapses implies existence of macroscopic stable horizonless objects. With such objects in mind, we study the effects of anisotropy of pressures on the stability of stars. We consider stars in four or higher dimensions and also stars in M theory made up of (intersecting) branes. Taking the stars to be static, spherically symmetric and the equations of state to be linear, we study “singular solutions” and the asymptotic perturbations around them. Oscillatory perturbations are likely to imply instability. We find that nonoscillatory perturbations, which may imply stability, are possible if an appropriate amount of anisotropy is present. This result suggests that it may be possible to have stable horizonless objects in four or any higher dimensions, and that anisotropic pressures may play a crucial role in ensuring their stability.

  16. Superpartners at LHC and future colliders: predictions from constrained compactified M-theory

    NASA Astrophysics Data System (ADS)

    Ellis, Sebastian A. R.; Kane, Gordon L.; Zheng, Bob

    2015-07-01

    We study a realistic top-down M-theory compactification with low-scale effective Supersymmetry, consistent with phenomenological constraints. A combination of top-down and generic phenomenological constraints fix the spectrum. Three and only three superpartner channels, , χ {2/0} χ {1/±} and χ {1/+} χ {1/-} (where χ {2/0} , χ {1/±} are Wino-like), are expected to be observable at LHC-14. We also investigate the prospects of finding heavy squarks and Higgsinos at future colliders. Gluino-stop-top, gluino-sbottom-bottom associated production and first generation squark associated production should be observable at a 100 TeV collider, along with direct production of heavy Higgsinos. Within this framework the discovery of a single sparticle is sufficient to determine uniquely the SUSY spectrum, yielding a number of concrete testable predictions for LHC-14 and future colliders, and determination of M 3/2 and thereby other fundamental quantities.

  17. Supernatural supersymmetry and its classic example: M-theory inspired NMSSM

    NASA Astrophysics Data System (ADS)

    Li, Tianjun; Raza, Shabbar; Wang, Xiao-Chuan

    2016-06-01

    We briefly review the supernatural supersymmetry (SUSY), which provides a most promising solution to the SUSY electroweak fine-tuning problem. In particular, we address its subtle issues as well. Unlike the minimal supersymmetric standard model (MSSM), the next to MSSM (NMSSM) can be scale invariant and has no mass parameter in its Lagrangian before SUSY and gauge symmetry breakings. Therefore, the NMSSM is a perfect framework for supernatural SUSY. To give the SUSY breaking soft mass to the singlet, we consider the moduli and dilaton dominant SUSY breaking scenarios in M-theory on S1/Z2. In these scenarios, SUSY is broken by one and only one F term of moduli or dilaton, and the SUSY breaking soft terms can be determined via the Kähler potential and superpotential from Calabi-Yau compactification of M-theory on S1/Z2. Thus, as predicted by supernatural SUSY, the SUSY electroweak fine-tuning measure is of unity order. In the moduli dominant SUSY breaking scenario, the right-handed sleptons are relatively light around 1 TeV, stau can even be as light as 580 GeV and degenerate with the lightest neutralino, chargino masses are larger than 1 TeV, the light stop masses are around 2 TeV or larger, the first two-generation squark masses are about 3 TeV or larger, and gluinos are heavier tha.n squarks. In the dilaton dominant SUSY breaking scenario, the qualitative picture remains the same but we have heavier spectra as compared to the moduli dominant SUSY breaking scenario. In addition to it, we have Higgs H2/A1-resonance solutions for dark matter (DM). In both scenarios, the minimal value of DM relic density is about 0.2. To obtain the observed DM relic density, we can consider the dilution effect from supercritical string cosmology or introduce the axino as the lightest supersymmetric particle.

  18. [Research progress in the study of protective effect of tanshinone IIA on cerebral ischemic stroke].

    PubMed

    Li, De-chuan; Bao, Xiu-qi; Sun, Hua; Zhang, Dan

    2015-06-01

    Danshen is one of the traditional Chinese herbal medicines and nas a long history or being used clinically in the treatment of cardiovascular and cerebrovascular conditions such as coronary heart disease and angina pectoris. Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen. It has been reported to be the major bioactive compound of Danshen and has diverse biological effects. Recent studies demonstrated that tanshinone IIA had neuroprotective effects on experimental ischemic stroke through its antiinflammatory, anti-oxidant, anti-apoptosis effects and its inhibitory effect on excitatory amino acid toxicity. In this review, we summarized all the recent progresses on the protective effect of tanshinone IIA on cerebral ischemic stroke. Hopefully, this article will throw some light on further study and application of tanshinone IIA. PMID:26521431

  19. Point of care testing of phospholipase A2 group IIA for serological diagnosis of rheumatoid arthritis

    NASA Astrophysics Data System (ADS)

    Liu, Nathan J.; Chapman, Robert; Lin, Yiyang; Mmesi, Jonas; Bentham, Andrew; Tyreman, Matthew; Abraham, Sonya; Stevens, Molly M.

    2016-02-01

    Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08423g

  20. Low frequency solar radio astronomy at the Indian Institute of Astrophysics (IIA)

    NASA Astrophysics Data System (ADS)

    Ramesh, R.

    IIA is presently involved in the expansion of its existing radioheliograph operating in the frequency 120-40 MHz at the Gauribidanur radio observatory located about 80 km north of Bangalore. Once completed, the expanded array will have an angular resolution of ≈ 1' at a typical frequency of 100 MHz. This paper describes the development of solar radio astronomy activities at IIA since 1952 when the first observations were carried out.

  1. Tanshinon IIA Injection Accelerates Tissue Expansion by Reducing the Formation of the Fibrous Capsule

    PubMed Central

    Yang, Mei; Zhu, Ming; Huang, Xiaolu; Li, Qingfeng

    2014-01-01

    The tissue expansion technique has been applied to obtain new skin tissue to repair large defects in clinical practice. The implantation of tissue expander could initiate a host response to foreign body (FBR), which leads to fibrotic encapsulation around the expander and prolongs the period of tissue expansion. Tanshinon IIA (Tan IIA) has been shown to have anti-inflammation and immunoregulation effect. The rat tissue expansion model was used in this study to observe whether Tan IIA injection systematically could inhibit the FBR to reduce fibrous capsule formation and accelerate the process of tissue expansion. Forty-eight rats were randomly divided into the Tan IIA group and control group with 24 rats in each group. The expansion was conducted twice a week to maintain a capsule pressure of 60 mmHg. The expansion volume and expanded area were measured. The expanded tissue in the two groups was harvested, and histological staining was performed; proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and transforming growth factor-β (TGF-β) were examined. The expansion volume and the expanded area in the Tan IIA group were greater than that of the control group. The thickness of the fibrous capsule in the Tan IIA group was reduced with no influence on the normal skin regeneration. Decreased infiltration of macrophages, lower level of TNF-α, IL-6, IL-1β and TGF-β, less proliferating myofibroblasts and enhanced neovascularization were observed in the Tan IIA group. Our findings indicated that the Tan IIA injection reduced the formation of the fibrous capsule and accelerated the process of tissue expansion by inhibiting the FBR. PMID:25157742

  2. ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares

    PubMed Central

    Lee, Chi-Pin; Chiang, Shang-Lun; Ko, Albert Min-Shan; Liu, Yu-Fan; Ma, Che; Lu, Chi-Yu; Huang, Chung-Ming; Chang, Jan-Gowth; Kuo, Tzer-Min; Chen, Chia-Lin; Tsai, Eing-Mei; Ko, Ying-Chin

    2016-01-01

    Gout is characterized by the monosodium urate monohydrate (MSU)-induced arthritis. Alpha kinase-1 (ALPK1) has shown to be associated with MSU-induced inflammation and gout. Here, we used bioinformatics, proteomics, cell models, and twenty in vitro human assays to clarify some of its role in the inflammatory response to MSU. We found myosin IIA to be a frequent interacting protein partner of ALPK1, binding to its N-terminal and forming a protein complex with calmodulin and F-actin, and that MSU-induced ALPK1 phosphorylated the myosin IIA. A knockdown of endogenous ALPK1 or myosin IIA significantly reduced the MSU-induced secretion of tumour necrosis factor (TNF)-α. Furthermore, all gouty patients expressed higher basal protein levels of ALPK1, myosin IIA, and plasma TNF-α, however those medicated with colchicine has shown reduced myosin IIA and TNF-α but not ALPK1. The findings suggest ALPK1 is a kinase that participates in the regulation of Golgi-derived TNF-α trafficking through myosin IIA phosphorylation in the inflammation of gout. This novel pathway could be blocked at the level of myosin by colchicine in gout treatment. PMID:27169898

  3. ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares.

    PubMed

    Lee, Chi-Pin; Chiang, Shang-Lun; Ko, Albert Min-Shan; Liu, Yu-Fan; Ma, Che; Lu, Chi-Yu; Huang, Chung-Ming; Chang, Jan-Gowth; Kuo, Tzer-Min; Chen, Chia-Lin; Tsai, Eing-Mei; Ko, Ying-Chin

    2016-01-01

    Gout is characterized by the monosodium urate monohydrate (MSU)-induced arthritis. Alpha kinase-1 (ALPK1) has shown to be associated with MSU-induced inflammation and gout. Here, we used bioinformatics, proteomics, cell models, and twenty in vitro human assays to clarify some of its role in the inflammatory response to MSU. We found myosin IIA to be a frequent interacting protein partner of ALPK1, binding to its N-terminal and forming a protein complex with calmodulin and F-actin, and that MSU-induced ALPK1 phosphorylated the myosin IIA. A knockdown of endogenous ALPK1 or myosin IIA significantly reduced the MSU-induced secretion of tumour necrosis factor (TNF)-α. Furthermore, all gouty patients expressed higher basal protein levels of ALPK1, myosin IIA, and plasma TNF-α, however those medicated with colchicine has shown reduced myosin IIA and TNF-α but not ALPK1. The findings suggest ALPK1 is a kinase that participates in the regulation of Golgi-derived TNF-α trafficking through myosin IIA phosphorylation in the inflammation of gout. This novel pathway could be blocked at the level of myosin by colchicine in gout treatment. PMID:27169898

  4. Influence of Tanshinone IIA on the Apoptosis of Human Esophageal Ec-109 Cells.

    PubMed

    Zhu, Yan-Qin; Wang, Bai-Yan; Wu, Fang; An, Yong-Kang; Zhou, Xin-Qiang

    2016-01-01

    The induced-apoptosis effect and mechanism of human esophageal cancer Ec-109 cells via tanshinone IIA was investigated. The Ec-109 cells were cultured in vitro with different concentrations of tanshinone IIA (2 µg/mL, 4 µg/mL, or 8 µg/mL) for 12, 24, 36, and 48 hours. MTT assay was used to evaluate the proliferative inhibition rate of tanshinone IIA on esophageal Ec-109 cells. After 24 hours of culturing in vitro, a control group was assigned. The apoptosis rate was detected by the AO/EB and annexin V-FITC/propidium iodide assay, and the protein levels of Caspase-4 and CHOP were determined by the Western blot technique. MTT data showed that tanshinone IIA could significantly inhibit the proliferation of Ec-109 cells with a dose- and time-dependent mode. Compared with the control group, tanshinone IIA could apparently induce apoptosis of Ec-109 cells, and the level of Caspase-4 and CHOP (p < 0.01) obviously increased. Tanshinone IIA can significantly induce the apoptosis of Ec-109 cells, which may take effect by the stress pathway of the endoplasmic reticulum. PMID:26996008

  5. Cucurbitacin IIa induces caspase-3-dependent apoptosis and enhances autophagy in lipopolysaccharide-stimulated RAW 264.7 macrophages.

    PubMed

    He, Jian; Wang, Yao; Xu, Li-hui; Qiao, Jing; Ouyang, Dong-yun; He, Xian-hui

    2013-05-01

    Cucurbitacin IIa (CuIIa), a member of cucurbitacin family, is isolated from the root of Hemsleya amabilis which has been used as an ancient remedy for bacillary dysentery and gastroenteritis. The anti-inflammatory properties of CuIIa have long been recognized but the underlying mechanism is largely unknown. In this study, we investigated the anti-inflammatory effect of CuIIa on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The results showed that CuIIa inhibited the proliferation and migration of RAW 264.7 cells in a dose-dependent manner. Whereas CuIIa did not cause apoptosis in unstimulated RAW 264.7 cells, it did induce a significant apoptosis in LPS-stimulated cells, which was caspase-3-dependent and associated with downregulation of survivin. Furthermore, LPS induced autophagy in RAW 264.7 cells and this effect was further enhanced by CuIIa as evidenced by increased levels of LC3-II conjugates and formation of LC3 puncta. In addition, CuIIa disrupted actin cytoskeleton via inducing actin aggregation. However, neither the synthesis of tumor necrosis factor-α, nor the activation of the mitogen-activated protein kinases and NF-κB pathways in LPS-stimulated cells was suppressed by CuIIa treatment. Collectively, these results suggested that induction of apoptosis and enhancement of autophagy contributed to the anti-inflammatory activity of CuIIa against inflammation-related diseases. PMID:23541744

  6. Development of intravenous lipid emulsion of tanshinone IIA and evaluation of its anti-hepatoma activity in vitro.

    PubMed

    Chu, Ting; Zhang, Qing; Li, Hui; Ma, Wei-cong; Zhang, Na; Jin, Hui; Mao, Sheng-jun

    2012-03-15

    The purpose of this study was to develop a lipid emulsion of tanshinone IIA (Tan IIA-LE) for intravenous administration and to investigate its feasibility for future clinical practice. The formulation was optimized using central composite design-response surface methodology (CCD-RSM), and the homogenization process was investigated systematically. The Tan IIA-LE was evaluated in terms of stability, safety and in vitro anti-hepatoma activity. The formulation of Tan IIA-LE is composed of 0.05% (w/v) Tan IIA, 20% (w/v) soybean oil-MCT mixture (1:1, w/w), 1.2% (w/v) soybean lecithin, 0.3% (w/v) F68 and 2.2% (w/v) glycerol, a high pressure homogenization at 100 MPa for 3 cycles was selected as the optimal homogenization process. The Tan IIA-LE was light-sensitive but stable for at least 12 months at room temperature in dark. The safety study demonstrated that the Tan IIA-LE did not cause venous irritation or obvious acute toxicity. Furthermore, the Tan IIA-LE displayed significant anti-tumor activity against human hepatoma cell lines in vitro. Overall, the Tan IIA-LE developed in this study was suggested to be a suitable and safe dosage form of Tan IIA for intravenous administration and has potential in liver cancer therapy in future. PMID:22226873

  7. Shank2 contributes to the apical retention and intracellular redistribution of NaPiIIa in OK cells.

    PubMed

    Dobrinskikh, Evgenia; Lanzano, Luca; Rachelson, Joanna; Cranston, DeeAnn; Moldovan, Radu; Lei, Tim; Gratton, Enrico; Doctor, R Brian

    2013-03-01

    In renal proximal tubule (PT) cells, sodium-phosphate cotransporter IIa (NaPiIIa) is normally concentrated within the apical membrane where it reabsorbs ∼70% of luminal phosphate (Pi). NaPiIIa activity is acutely regulated by moderating its abundance within the apical membrane. Under low-Pi conditions, NaPiIIa is retained within the apical membrane. Under high-Pi conditions, NaPiIIa is retrieved from the apical membrane and trafficked to the lysosomes for degradation. The present study investigates the role of Shank2 in regulating the distribution of NaPiIIa. In opossum kidney cells, a PT cell model, knockdown of Shank2 in cells maintained in low-Pi media resulted in a marked decrease in NaPiIIa abundance. After being transferred into high-Pi media, live-cell imaging showed that mRFP-Shank2E and GFP-NaPiIIa underwent endocytosis and trafficked together through the subapical domain. Fluorescence cross-correlation spectroscopy demonstrated that GFP-NaPiIIa and mRFP-Shank2 have indistinguishable diffusion coefficients and migrated through the subapical domain in temporal synchrony. Raster image cross-correlation spectroscopy demonstrated these two proteins course through the subapical domain in temporal-spatial synchrony. In the microvilli of cells under low-Pi conditions and in the subapical domain of cells under high-Pi conditions, fluorescence lifetime imaging microscopy-Forster resonance energy transfer analysis of Cer-NaPiIIa and EYFP-Shank2E found these fluors reside within 10 nm of each other. Demonstrating a complexity of functions, in cells maintained under low-Pi conditions, Shank2 plays an essential role in the apical retention of NaPiIIa while under high-Pi conditions Shank2 remains associated with NaPiIIa and escorts NaPiIIa through the cell interior. PMID:23325414

  8. Tanshinone IIA attenuates experimental autoimmune encephalomyelitis in rats

    PubMed Central

    Yan, Jun; Yang, Xue; Han, Dong; Feng, Juan

    2016-01-01

    Multiple sclerosis (MS) is an inflammatory autoimmune neurodegenerative disease, which features focal demyelination and inflammatory cell infiltration of the brain and the spinal cord. Tanshinone IIA (TSIIA), one of the major fat-soluble components of Salvia miltiorrhiza (Danshen), has anti-inflammatory, immunoregulatory and neuroprotective activity; however, its efficacy in MS remains unknown. The current study was designed to investigate the potential therapeutic function of TSIIA on MS in the experimental autoimmune encephalomyelitis (EAE) rat model. In comparison to the vehicle control group, the TSIIA-treated groups showed notably improved clinical symptoms and pathological changes, including central nervous system inflammatory cell infiltration and demyelination. Following administration of TSIIA, the quantity of CD4+ T cells, CD8+ T cells and macrophages/microglia in the spinal cord were reduced to different extents. Furthermore, TSIIA was also shown to downregulate interleukin (IL)-17 and IL-23 levels in the brain and serum of EAE rats. The results collectively provide evidence that TSIIA alleviates EAE and support its utility as a novel therapy for MS. PMID:27357729

  9. Tanshinone IIA attenuates experimental autoimmune encephalomyelitis in rats.

    PubMed

    Yan, Jun; Yang, Xue; Han, Dong; Feng, Juan

    2016-08-01

    Multiple sclerosis (MS) is an inflammatory autoimmune neurodegenerative disease, which features focal demyelination and inflammatory cell infiltration of the brain and the spinal cord. Tanshinone IIA (TSIIA), one of the major fat‑soluble components of Salvia miltiorrhiza (Danshen), has anti‑inflammatory, immunoregulatory and neuroprotective activity; however, its efficacy in MS remains unknown. The current study was designed to investigate the potential therapeutic function of TSIIA on MS in the experimental autoimmune encephalomyelitis (EAE) rat model. In comparison to the vehicle control group, the TSIIA‑treated groups showed notably improved clinical symptoms and pathological changes, including central nervous system inflammatory cell infiltration and demyelination. Following administration of TSIIA, the quantity of CD4+ T cells, CD8+ T cells and macrophages/microglia in the spinal cord were reduced to different extents. Furthermore, TSIIA was also shown to downregulate interleukin (IL)‑17 and IL‑23 levels in the brain and serum of EAE rats. The results collectively provide evidence that TSIIA alleviates EAE and support its utility as a novel therapy for MS. PMID:27357729

  10. Modeling the Electron Transport in Nanostructures by Using the Concept of BIons in M-theory

    NASA Astrophysics Data System (ADS)

    Sepehri, Alireza; Pincak, Richard

    2016-06-01

    In this paper, using the similarity between quantum tunnels in nanostructures and BIon in M-theory, we propose a new model which considers the process of formation of superconductors in nanostructures. We show that by decreasing the size of nanostructures, emitted photons by electrons connect to each other and form a wormhole-like tunnel. This tunnel is a channel for transporting electron inside the nanostructure. If different wormhole-like tunnels join to each other, one big tunnel is constructed that can be an origin for superconductivity in matter. The superconductor order parameter depends on the size of nanostructure and temperature. Increasing temperature, it is shown that the model matches with quantum theory prescriptions. Also, by applying external electromagnetism, external photons interact with exchanging photons between electrons, exchanging photons deviate from original route and the formation of wormhole-like tunnels inside a nanostructure is prevented. Finally, it is shown that the origin of electrodynamics and gravity are the same and thus, the phrase of wormhole can be applied for appeared tunnels in nanostructures.

  11. {N} =2 supersymmetric Janus solutions and flows: from gauged supergravity to M theory

    NASA Astrophysics Data System (ADS)

    Pilch, Krzysztof; Tyukov, Alexander; Warner, Nicholas P.

    2016-05-01

    We investigate a family of SU(3)×U(1)×U(1)-invariant holographic flows and Janus solutions obtained from gauged {N} = 8 supergravity in four dimensions. We give complete details of how to use the uplift formulae to obtain the corresponding solutions in M theory. While the flow solutions appear to be singular from the four-dimensional perspective, we find that the eleven-dimensional solutions are much better behaved and give rise to interesting new classes of compactification geometries that are smooth, up to orbifolds, in the infra-red limit. Our solutions involve new phases in which M2 branes polarize partially or even completely into M5 branes. We derive the eleven-dimensional supersymmetries and show that the eleven-dimensional equations of motion and BPS equations are indeed satisfied as a consequence of their four-dimensional counterparts. Apart from elucidating a whole new class of eleven-dimensional Janus and flow solutions, our work provides extensive and highly non-trivial tests of the recently-derived uplift formulae.

  12. On gauge enhancement and singular limits in G 2 compactifications of M-theory

    NASA Astrophysics Data System (ADS)

    Halverson, James; Morrison, David R.

    2016-04-01

    We study the physics of singular limits of G 2 compactifications of M-theory, which are necessary to obtain a compactification with non-abelian gauge symmetry or massless charged particles. This is more difficult than for Calabi-Yau compactifications, due to the absence of calibrated two-cycles that would have allowed for direct control of W-boson masses as a function of moduli. Instead, we study the relationship between gauge enhancement and singular limits in G 2 moduli space where an associative or coassociative submanifold shrinks to zero size; this involves the physics of topological defects and sometimes gives indirect control over particle masses, even though they are not BPS. We show how a lemma of Joyce associates the class of a three-cycle to any U(1) gauge theory in a smooth G 2 compactification. If there is an appropriate associative submanifold in this class then in the limit of nonabelian gauge symmetry it may be interpreted as a gauge theory worldvolume and provides the location of the singularities associated with non-abelian gauge or matter fields. We identify a number of gauge enhancement scenarios related to calibrated submanifolds, including Coulomb branches and non-isolated conifolds, and also study examples that realize them.

  13. G{sub 2}-MSSM: An M theory motivated model of particle physics

    SciTech Connect

    Acharya, Bobby S.; Bobkov, Konstantin; Kane, Gordon L.; Shao Jing; Kumar, Piyush

    2008-09-15

    We continue our study of the low energy implications of M theory vacua on G{sub 2}-manifolds, undertaken in B. S. Acharya, K. Bobkov, G. L. Kane, P. Kumar, and J. Shao, Phys. Rev. D 76, 126010 (2007); B. Acharya, K. Bobkov, G. Kane, P. Kumar, and D. Vaman, Phys. Rev. Lett. 97, 191601 (2006), where it was shown that the moduli can be stabilized and a TeV scale generated, with the Planck scale as the only dimensionful input. A well-motivated phenomenological model, the G{sub 2}-MSSM, can be naturally defined within the above framework. In this paper, we study some of the important phenomenological features of the G{sub 2}-MSSM. In particular, the soft supersymmetry breaking parameters and the superpartner spectrum are computed. The G{sub 2}-MSSM generically gives rise to light gauginos and heavy scalars with wino lightest supersymmetric particles when one tunes the cosmological constant. Electroweak symmetry breaking is present but fine-tuned. The G{sub 2}-MSSM is also naturally consistent with precision gauge coupling unification. The phenomenological consequences for cosmology and collider physics of the G{sub 2}-MSSM will be reported in more detail soon.

  14. Cell-surface alterations in class IIa bacteriocin-resistant Listeria monocytogenes strains.

    PubMed

    Vadyvaloo, Viveka; Arous, Safia; Gravesen, Anne; Héchard, Yann; Chauhan-Haubrock, Ramola; Hastings, John W; Rautenbach, Marina

    2004-09-01

    Strains of the food-borne pathogen Listeria monocytogenes, showing either intermediate or high-level resistance to class IIa bacteriocins, were investigated to determine characteristics that correlated with their sensitivity levels. Two intermediate and one highly resistant spontaneous mutant of L. monocytogenes B73, a highly resistant mutant of L. monocytogenes 412, and a highly resistant, defined (mptA) mutant of L. monocytogenes EGDe were compared with their respective wild-type strains in order to investigate the contribution of different factors to resistance. Decreased mannose-specific phosphotransferase system gene expression (mptA, EIIAB(Man) component) was implicated in all levels of resistance, confirming previous studies by the authors' group. However, a clear correlation between d-alanine content in teichoic acid (TA), in particular the alanine : phosphorus ratio, and a more positive cell surface, as determined by cytochrome c binding, were found for the highly resistant strains. Furthermore, two of the three highly resistant strains showed a significant increase in sensitivity towards d-cycloserine (DCS). However, real-time PCR of the dltA (d-alanine esterification), and dal and ddlA genes (peptidoglycan biosynthesis) showed no change in transcriptional levels. The link between DCS sensitivity and increased d-alanine esterification of TA may be that DCS competes with alanine for transport via the alanine transporter. A possible tendency towards increased lysinylation of membrane phospholipid in the highly resistant strains was also found. A previous study reported that cell membranes of all the resistant strains, including the intermediate resistant strains, contained more unsaturated phosphatidylglycerol, which is an indication of a more fluid cell membrane. The results of that study correlate with the possible lysinylation, decreased mptA expression, d-alanine esterification of TA and more positive cell surface charge found in this study for

  15. ART CCIM Phase II-A Off-Gas System Evaluation Test Plan

    SciTech Connect

    Nick Soelberg; Jay Roach

    2009-01-01

    This test plan defines testing to be performed using the Idaho National Laboratory (INL) engineering-scale cold crucible induction melter (CCIM) test system for Phase II-A of the Advanced Remediation Technologies (ART) CCIM Project. The multi-phase ART-CCIM Project is developing a conceptual design for replacing the joule-heated melter (JHM) used to treat high level waste (HLW) in the Defense Waste Processing Facility (DWPF) at the Savannah River Site (SRS) with a cold crucible induction melter. The INL CCIM test system includes all feed, melter off-gas control, and process control subsystems needed for fully integrated operation and testing. Testing will include operation of the melter system while feeding a non-radioactive slurry mixture prepared to simulate the same type of waste feed presently being processed in the DWPF. Process monitoring and sample collection and analysis will be used to characterize the off-gas composition and properties, and to show the fate of feed constituents, to provide data that shows how the CCIM retrofit conceptual design can operate with the existing DWPF off-gas control system.

  16. Effect of Tanshinone IIA intrathecal injections on pain and spinal inflammation in mice with bone tumors.

    PubMed

    Ren, B X; Ji, Y; Tang, J C; Sun, D P; Hui, X; Yang, D Q; Zhu, X L

    2015-01-01

    The study aimed to investigate the effect of intrathecal injections of Tanshinone IIA on thermal hyperalgesia in a mouse model of bone cancer-pain. Spinal IL-1β, IL-6, TNF-α expression levels were analyzed. C3H/HeNCrlVr male mice were assigned to groups that either received dose-dependent injections of Tanshinone IIA, or the DMSO + Sham, Tanshinone IIA + Sham, DMSO + Tumor, and Control groups. Paw withdrawal thermal latency (PWTL) was measured with a radiant heat stimulus and mRNA expression levels were determined using real-time PCR. Fourteen days post-injection, PWTL in the DMSO + Tumor group was lower than that in the controls (P < 0.05). Twenty-one days post-injection, compared with the Control group, there was no significant difference in PWTL and IL-1β, IL-6, and TNF-α expression levels between the Tanshinone IIA + Sham and DMSO + Sham groups (P > 0.05). PWTL in the DMSO + Tumor group was significantly lower than the Control group (P < 0.05), while the expression levels of IL-1β, IL-6, and TNF-α were significantly higher than controls. Compared with the DMSO + Tumor group, PWTLs were higher in the Tanshinone IIA - 20-μg and 40-μg groups, while expression levels of IL-1β, IL-6, and TNF-α were significantly lower (P < 0.05). These measures were not significantly different between the Tanshinone IIA 10 μg and the DMSO + Tumor groups (P > 0.05). In conclusion, Tanshinone IIA may inhibit the release of inflammatory cytokines, such as, IL-1 β, IL-6 α, TNF-α. PMID:25867360

  17. M theory model of a big crunch/big bang transition

    SciTech Connect

    Turok, Neil; Perry, Malcolm; Steinhardt, Paul J.

    2004-11-15

    We consider a picture in which the transition from a big crunch to a big bang corresponds to the collision of two empty orbifold planes approaching each other at a constant nonrelativistic speed in a locally flat background space-time, a situation relevant to recently proposed cosmological models. We show that p-brane states which wind around the extra dimension propagate smoothly and unambiguously across the orbifold plane collision. In particular we calculate the quantum mechanical production of winding M2-branes extending from one orbifold to the other. We find that the resulting density is finite and that the resulting gravitational backreaction is small. These winding states, which include the string theory graviton, can be propagated smoothly across the transition using a perturbative expansion in the membrane tension, an expansion which from the point of view of string theory is an expansion in inverse powers of {alpha}{sup '}. The conventional description of a crunch based on Einstein general relativity, involving Kasner or mixmaster behavior is misleading, we argue, because general relativity is only the leading order approximation to string theory in an expansion in positive powers of {alpha}{sup '}. In contrast, in the M theory setup we argue that interactions should be well behaved because of the smooth evolution of the fields combined with the fact that the string coupling tends to zero at the crunch. The production of massive Kaluza-Klein states should also be exponentially suppressed for small collision speeds. We contrast this good behavior with that found in previous studies of strings in Lorentzian orbifolds.

  18. M theory model of a big crunch/big bang transition

    NASA Astrophysics Data System (ADS)

    Turok, Neil; Perry, Malcolm; Steinhardt, Paul J.

    2004-11-01

    We consider a picture in which the transition from a big crunch to a big bang corresponds to the collision of two empty orbifold planes approaching each other at a constant nonrelativistic speed in a locally flat background space-time, a situation relevant to recently proposed cosmological models. We show that p-brane states which wind around the extra dimension propagate smoothly and unambiguously across the orbifold plane collision. In particular we calculate the quantum mechanical production of winding M2-branes extending from one orbifold to the other. We find that the resulting density is finite and that the resulting gravitational backreaction is small. These winding states, which include the string theory graviton, can be propagated smoothly across the transition using a perturbative expansion in the membrane tension, an expansion which from the point of view of string theory is an expansion in inverse powers of α'. The conventional description of a crunch based on Einstein general relativity, involving Kasner or mixmaster behavior is misleading, we argue, because general relativity is only the leading order approximation to string theory in an expansion in positive powers of α'. In contrast, in the M theory setup we argue that interactions should be well behaved because of the smooth evolution of the fields combined with the fact that the string coupling tends to zero at the crunch. The production of massive Kaluza-Klein states should also be exponentially suppressed for small collision speeds. We contrast this good behavior with that found in previous studies of strings in Lorentzian orbifolds.

  19. Tanshinone IIA Induces Heme Oxygenase 1 Expression and Inhibits Cyclic Strain-Induced Interleukin 8 Expression in Vascular Endothelial Cells.

    PubMed

    Zhuang, Shaowei; Cheng, Tzu-Hurng; Shih, Nang-Lang; Liu, Ju-Chi; Chen, Jin-Jer; Hong, Hong-Jye; Chan, Paul

    2016-04-01

    Tanshinone IIA is the main effective component of Salvia miltiorrhiza, known as "Danshen," which has been used in many therapeutic remedies in traditional Chinese medicine. However, the direct effects of tanshinone IIA on vascular endothelial cells have not yet been fully described. In the present study, we demonstrated that tanshinone IIA increased heme oxygenase-1 (HO-1) expression in human umbilical vein endothelial cells. Western blot analyses and experiments with specific inhibitors indicated tanshinone IIA enhanced HO-1 expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt and the subsequent induction of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. In addition, tanshinone IIA inhibited cyclic strain induced interleukin-8 (IL-8) expression. HO-1 silencing significantly abrogated the repressive effects of tanshinone IIA on strain-induced IL-8 expression, which suggests HO-1 has a role in mediating the effects of tanshinone IIA. This study reports for the first time that tanshinone IIA inhibits cyclic strain-induced IL-8 expression via the induction of HO-1 in endothelial cells, providing valuable new insight into the molecular pathways that may contribute to the effects of tanshinone IIA. PMID:27080946

  20. Tanshinone IIA exerts antitumor activity against vestibular schwannoma cells by inhibiting the expression of hypoxia-inducible factor-1α.

    PubMed

    Kim, Ju Yeon; Song, Jae-Jun; Kwon, Byoung-Mog; Lee, Jong Dae

    2015-09-01

    The aim of the present study was to evaluate the effect of the herbal medicine, tanshinone IIA (Tan IIA), on vestibular schwannoma (VS) cells and assess the functional targets of Tan IIA. HEI‑193 cells and Nf2‑/‑mouse Schwann (SC4) cells were used to investigate the inhibitory effects of Tan IIA on VS. Cell viability was measured using an MTT assay and apoptosis was assessed by flow cytometry. Western blot analysis and reverse transcription quantitative polymerase chain reaction (RT‑qPCR) were performed to assess the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and its signaling pathways. In addition, the effect of Tan IIA on HIF‑1α transcription was determined using a luciferase reporter assay. Schwannoma cell proliferation was observed to be inhibited as the Tan IIA concentration increased under normoxic and hypoxic conditions. Furthermore, Tan IIA induced apoptosis in the HEI‑193 cells and inhibited the protein expression of HIF‑1α in the HEI‑193 cells under hypoxia, thus repressing the transcriptional activity of HIF‑1α. The present study demonstrated that HIF‑1α is expressed in hypoxic VS cells and Tan IIA inhibits VS cells by suppressing the activity of HIF‑1α. In conclusion, these results indicate that Tan IIA is a potential chemotherapeutic agent for the treatment of VS. PMID:26080622

  1. Phenomenology of stabilizing moduli in a framework of gx meson compactification of M-theory

    NASA Astrophysics Data System (ADS)

    Shao, Jing

    This thesis explores an interesting class of fluxless G 2 compactifications of M-theory, where all the moduli are stabilized and a TeV scale is generated with the Planck scale as the only dimensionful input. A well-motivated phenomenological model---the G 2-MSSM, can be naturally defined within this framework. In this thesis, important phenomenological aspects of the G2-MSSM are carefully studied. First, the soft supersymmetry breaking parameters and the superpartner mass spectrum are computed. The spectrum is found to contain light gauginos and heavy scalars with a wino LSP when the vacuum energy is tuned to be small. The prospects for discovery at the Large Hadron Collider (LHC) are promising. The model predicts a spectacular four-top signature, which can be easily identified at the LHC. In addition, the charginos are meta-stable and could be detected directly at the LHC providing additional information about the nature of the LSP. Second, in the G 2-MSSM CP-violating phases occur in the quark and lepton Yukawas but are not generated from the supersymmetry breaking. However, in such models additional CP violation can be generated because the soft trilinear matrices are not proportional to the Yukawa matrices. The estimated upper bounds for the electric dipole moments of the electron, neutron and mercury are all within the current experimental limits and could be probed in the near future. Finally, the cosmological moduli/gravitino problems and the issue of too little thermal but excessive non-thermal dark matter from the decays of moduli are studied. It is shown that the late decaying moduli not only satisfy the Big Bang Nucleosynthesis constraints but also avoid the gravitino problem. The non-thermal production of wino LSPs gives a right amount of relic density. The phenomenological results obtained in this thesis can be tested by coming experiments, particularly the LHC experiments, and therefore provide a means to connect the experimental data to a high scale

  2. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa.

    PubMed

    Harenberg, Job; Wehling, Martin

    2008-02-01

    Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed. PMID:18393142

  3. Thrombin time and anti-IIa dabigatran's activity: hypothesis of thrombin time's predictive value.

    PubMed

    Le Guyader, Maïlys; Kaabar, Mohammed; Lemaire, Pierre; Pineau Vincent, Fabienne

    2015-01-01

    Dabigatran etexilate (Pradaxa®) is a new oral anticoagulant, competitive inhibitor, selective, fast, direct and reversible of thrombin. Dabigatran has an impact on a large panel of used coagulation tests. There is no relationship between thrombin time's lengthening and anti-IIa activity. This study defines thrombin time's predictive value, when its time is normal. The result of negative value is 97,6%. 255 patients were studied between January 2013 and July 2014. Thrombin time and anti-IIa activity were dosed for each patient. This study can be an assistant for therapeutic decision for laboratories without specialized test. PMID:26489812

  4. Tanshinone IIA Protects against Dextran Sulfate Sodium- (DSS-) Induced Colitis in Mice by Modulation of Neutrophil Infiltration and Activation

    PubMed Central

    Liu, Xiaowei; He, Haiyue; Huang, Tingting; Lei, Zhen; Liu, Fuquan; An, Guangyu; Wen, Tao

    2016-01-01

    Neutrophils play a critical role in the initiation and maintenance of intestinal inflammation. However, conventional neutrophil-targeted therapies can impair normal host defense. Tanshinone IIA has been recently revealed to act directly on neutrophils. Hence, we aimed at investigating whether Tanshinone IIA can protect against experimental colitis through modulation of neutrophils. We induced colitis in C57BL/6 mice by giving 3% dextran sulfate sodium (DSS) orally, and meanwhile, we treated mice daily with Tanshinone IIA intraperitoneally. The severity of colitis was evaluated by calculating disease activity index (DAI) and histological parameters. Neutrophil infiltration and activation in the colons of mice were measured. Moreover, whether Tanshinone IIA has direct effects on neutrophil migration and activation was determined in vitro. Our data showed that Tanshinone IIA significantly ameliorated the severity of DSS-induced colitis in mice, evidenced by the reduced DAI and improved colonic inflammation. In addition, Tanshinone IIA decreased neutrophil infiltration of intestinal mucosa and activation and reduced colonic inflammatory cytokines in DSS-treated mice. Furthermore, Tanshinone IIA was demonstrated to significantly suppress neutrophil migration and activation. These results provide compelling evidence that Tanshinone IIA has a therapeutic potential for alleviating inflammatory colitis in mice, which is possibly mediated by the immunomodulation of neutrophils. PMID:26881040

  5. Tanshinone IIA Prevents Leu27IGF-II-Induced Cardiomyocyte Hypertrophy Mediated by Estrogen Receptor and Subsequent Akt Activation.

    PubMed

    Weng, Yueh-Shan; Wang, Hsueh-Fang; Pai, Pei-Ying; Jong, Gwo-Ping; Lai, Chao-Hung; Chung, Li-Chin; Hsieh, Dennis Jine-Yuan; HsuanDay, Cecilia; Kuo, Wei-Wen; Huang, Chih-Yang

    2015-01-01

    IGF-IIR plays important roles as a key regulator in myocardial pathological hypertrophy and apoptosis, which subsequently lead to heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat cardiovascular diseases. Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-estradiol (E[Formula: see text]. However, whether tanshinone IIA improves cardiomyocyte survival in pathological hypertrophy through estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of tanshinone IIA on IGF-IIR-induced myocardial hypertrophy. Leu27IGF-II (IGF-II analog) was shown in this study to specifically activate IGF-IIR expression and ICI 182,780 (ICI), an ER antagonist used to investigate tanshinone IIA estrogenic activity. We demonstrated that tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced calcineurin expression and subsequent NFATc3 nuclear translocation to suppress myocardial hypertrophy. Tanshinone IIA reduced the cell size and suppressed ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of tanshinone IIA that inhibit Leu27IGF-II-induced cell hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt, Ly294002 (PI3K inhibitor), and PI3K siRNA significantly reduced the tanshinone IIA-induced protective effect. The above results suggest that tanshinone IIA inhibited cardiomyocyte hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced calcineurin and NFATC3. Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block cardiac hypertrophy. PMID:26621443

  6. Structural Basis for Catalysis of a Tetrameric Class IIa Fructose 1,6-Bisphosphate Aldolase from Mycobacterium tuberculosis

    SciTech Connect

    Pegan, Scott D.; Ruskseree, Kamolchanok; Franzblau, Scott G.; Mesecar, Andrew D. ); )

    2009-03-04

    Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), currently infects one-third of the world's population in its latent form. The emergence of multidrug-resistant and extensive drug-resistant strains has highlighted the need for new pharmacological targets within M. tuberculosis. The class IIa fructose 1,6-bisphosphate aldolase (FBA) enzyme from M. tuberculosis (MtFBA) has been proposed as one such target since it is upregulated in latent TB. Since the structure of MtFBA has not been determined and there is little information available on its reaction mechanism, we sought to determine the X-ray structure of MtFBA in complex with its substrates. By lowering the pH of the enzyme in the crystalline state, we were able to determine a series of high-resolution X-ray structures of MtFBA bound to dihydroxyacetone phosphate, glyceraldehyde 3-phosphate, and fructose 1,6-bisphosphate at 1.5, 2.1, and 1.3 {angstrom}, respectively. Through these structures, it was discovered that MtFBA belongs to a novel tetrameric class of type IIa FBAs. The molecular details at the interface of the tetramer revealed important information for better predictability of the quaternary structures among the FBAs based on their primary sequences. These X-ray structures also provide interesting and new details on the reaction mechanism of class II FBAs. Substrates and products were observed in geometries poised for catalysis; in addition, unexpectedly, the hydroxyl-enolate intermediate of dihydroxyacetone phosphate was also captured and resolved structurally. These concise new details offer a better understanding of the reaction mechanisms for FBAs in general and provide a structural basis for inhibitor design efforts aimed at this class of enzymes.

  7. Structural basis for catalysis of a tetrameric, class IIa fructose 1,6-bisphosphate aldolase from M. tuberculosis

    PubMed Central

    Pegan, Scott D.; Rukseree, Kamolchanok; Franzblau, Scott G.; Mesecar, Andrew D.

    2009-01-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), currently infects one third of the world’s population in its latent form. The emergence of multidrug resistant strains, MDR-TB and XDR-TB has highlighted the need for new pharmacological targets within M. tuberculosis. The Class IIa fructose 1,6-bisphosphate aldolase (FBA) enzyme from M. tuberculosis (MtFBA) has been proposed as one such target since its upregulated in latent TB. Since the structure of MtFBA had not been determined and since there was little information available on its reaction mechanism, we sought to determine the X-ray structure of MtFBA in complex with its substrates. By lowering the pH of the enzyme in the crystalline state, we were able to determine a series of high-resolution X-ray structures of MtFBA bound to dihydroxyacetonephosphate (DHAP), glyceraldehyde-3-phosphate (G3P), and fructose 1,6-bisphosphate (FBP) at 1.5 Å, 2.1 Å, and 1.3 Å respectively. Through these structures it was discovered that MtFBA belongs to a novel tetrameric class of the type IIa FBAs. The molecular details at the interface of the tetramer revealed important information for being able to better predict the quaternary structures among the FBAs based on their primary sequences. These X-ray structures also provide interesting and new details on the reaction mechanism of class II FBAs. Not only were the substrates and products observed in geometries poised for catalysis, but unexpectedly the hydroxyl enolate intermediate of DHAP was also captured and resolved structurally. These concise new details provide a better understanding of the reaction mechanisms for FBAs in general and provide a structural basis for inhibitor design efforts aimed at this class of enzymes. PMID:19167403

  8. Sodium Tanshinone IIA Sulfonate Attenuates Scopolamine-Induced Cognitive Dysfunctions via Improving Cholinergic System

    PubMed Central

    Xu, Yi-Jun; Yang, Cong; Li, Lin; Hou, Bo-Nan; Chen, Hui-Fang; Wang, Qi

    2016-01-01

    Sodium Tanshinone IIA sulfonate (STS) is a derivative of Tanshinone IIA (Tan IIA). Tan IIA has been reported to possess neuroprotective effects against Alzheimer's disease (AD). However, whether STS possesses effect on AD remains unclear. This study aims to estimate whether STS could protect against scopolamine- (SCOP-) induced learning and memory deficit in Kunming mice. Morris water maze results showed that oral administration of STS (10 mg/kg and 20 mg/kg) and Donepezil shortened escape latency, increased crossing times of the original position of the platform, and increased the time spent in the target quadrant. STS decreased the activity of acetylcholinesterase (AChE) and increased the activity of choline acetyltransferase (ChAT) in the hippocampus and cortex of SCOP-treated mice. Oxidative stress results showed that STS increased the activity of superoxide dismutase (SOD) and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in hippocampus and cortex. In addition, western blot was carried out to detect the expression of apoptosis related proteins (Bcl-2, Bax, and Caspase-3). STS upregulated the protein expression of Bcl-2 and downregulated the proteins expression of Bax and Caspase-3. These results indicated that STS might become a promising therapeutic candidate for attenuating AD-like pathological dysfunction. PMID:27556046

  9. Genomic analysis of Ovis aries (Ovar)MHC Class IIa loci

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Determining the genomic organization of the Ovis aries (Ovar) major histocompatibility complex class IIa region is essential for future functional studies related to antigen presentation. In this study, a bacterial artificial chromosome (BAC) library of genomic DNA from peripheral blood leukocytes ...

  10. Tanshinone IIA exhibits anticonvulsant activity in zebrafish and mouse seizure models.

    PubMed

    Buenafe, Olivia Erin; Orellana-Paucar, Adriana; Maes, Jan; Huang, Hao; Ying, Xuhui; De Borggraeve, Wim; Crawford, Alexander D; Luyten, Walter; Esguerra, Camila V; de Witte, Peter

    2013-11-20

    Danshen or Chinese red sage (Salvia miltiorrhiza, Bunge) is used by traditional Chinese medicine (TCM) practitioners to treat neurological, cardiovascular, and cerebrovascular disorders and is included in some TCM formulations to control epileptic seizures. In this study, acetonic crude extracts of danshen inhibited pentylenetetrazol (PTZ)-induced seizure activity in zebrafish larvae. Subsequent zebrafish bioassay-guided fractionation of the extract resulted in the isolation of four major tanshinones, which suppressed PTZ-induced activity to varying degrees. One of the active tanshinones, tanshinone IIA, also reduced c-fos expression in the brains of PTZ-exposed zebrafish larvae. In rodent seizure models, tanshinone IIA showed anticonvulsive activity in the mouse 6-Hz psychomotor seizure test in a biphasic manner and modified seizure thresholds in a complex manner for the mouse i.v. PTZ seizure assay. Interestingly, tanshinone IIA is used as a prescription drug in China to address cerebral ischemia in patients. Here, we provide the first in vivo evidence demonstrating that tanshinone IIA has anticonvulsant properties as well. PMID:23937066

  11. Sodium Tanshinone IIA Sulfonate Attenuates Scopolamine-Induced Cognitive Dysfunctions via Improving Cholinergic System.

    PubMed

    Xu, Qing-Qing; Xu, Yi-Jun; Yang, Cong; Tang, Ying; Li, Lin; Cai, Hao-Bin; Hou, Bo-Nan; Chen, Hui-Fang; Wang, Qi; Shi, Xu-Guang; Zhang, Shi-Jie

    2016-01-01

    Sodium Tanshinone IIA sulfonate (STS) is a derivative of Tanshinone IIA (Tan IIA). Tan IIA has been reported to possess neuroprotective effects against Alzheimer's disease (AD). However, whether STS possesses effect on AD remains unclear. This study aims to estimate whether STS could protect against scopolamine- (SCOP-) induced learning and memory deficit in Kunming mice. Morris water maze results showed that oral administration of STS (10 mg/kg and 20 mg/kg) and Donepezil shortened escape latency, increased crossing times of the original position of the platform, and increased the time spent in the target quadrant. STS decreased the activity of acetylcholinesterase (AChE) and increased the activity of choline acetyltransferase (ChAT) in the hippocampus and cortex of SCOP-treated mice. Oxidative stress results showed that STS increased the activity of superoxide dismutase (SOD) and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in hippocampus and cortex. In addition, western blot was carried out to detect the expression of apoptosis related proteins (Bcl-2, Bax, and Caspase-3). STS upregulated the protein expression of Bcl-2 and downregulated the proteins expression of Bax and Caspase-3. These results indicated that STS might become a promising therapeutic candidate for attenuating AD-like pathological dysfunction. PMID:27556046

  12. 30 CFR 57.22603 - Blasting from the surface (II-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... shall be approved by MSHA under the applicable requirements of 30 CFR parts 18 through 36. Vehicles... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Blasting from the surface (II-A mines). 57... MINES Safety Standards for Methane in Metal and Nonmetal Mines Explosives § 57.22603 Blasting from...

  13. 30 CFR 57.22311 - Electrical cables (II-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Electrical cables (II-A mines). 57.22311 Section 57.22311 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  14. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Weekly testing (II-A mines). 57.22230 Section 57.22230 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  15. 30 CFR 57.22311 - Electrical cables (II-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Electrical cables (II-A mines). 57.22311 Section 57.22311 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  16. 30 CFR 57.22307 - Methane monitors (II-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18, and prevent starting... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Methane monitors (II-A mines). 57.22307 Section 57.22307 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL...

  17. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Weekly testing (II-A mines). 57.22230 Section 57.22230 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  18. 30 CFR 57.22311 - Electrical cables (II-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Electrical cables (II-A mines). 57.22311 Section 57.22311 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  19. 30 CFR 57.22307 - Methane monitors (II-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18, and prevent starting... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Methane monitors (II-A mines). 57.22307 Section 57.22307 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL...

  20. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Weekly testing (II-A mines). 57.22230 Section 57.22230 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  1. 30 CFR 57.22307 - Methane monitors (II-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18, and prevent starting... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Methane monitors (II-A mines). 57.22307 Section 57.22307 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL...

  2. 30 CFR 57.22311 - Electrical cables (II-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Electrical cables (II-A mines). 57.22311 Section 57.22311 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  3. 30 CFR 57.22307 - Methane monitors (II-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18, and prevent starting... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Methane monitors (II-A mines). 57.22307 Section 57.22307 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL...

  4. 30 CFR 57.22311 - Electrical cables (II-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Electrical cables (II-A mines). 57.22311 Section 57.22311 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  5. 30 CFR 57.22307 - Methane monitors (II-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... monitoring equipment determined by MSHA to be intrinsically safe under 30 CFR part 18, and prevent starting... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Methane monitors (II-A mines). 57.22307 Section 57.22307 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL...

  6. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Weekly testing (II-A mines). 57.22230 Section 57.22230 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  7. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Weekly testing (II-A mines). 57.22230 Section 57.22230 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES...

  8. Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke.

    PubMed

    Kassis, Haifa; Shehadah, Amjad; Li, Chao; Zhang, Yi; Cui, Yisheng; Roberts, Cynthia; Sadry, Neema; Liu, Xianshuang; Chopp, Michael; Zhang, Zheng Gang

    2016-06-01

    We have previously demonstrated that stroke induces nuclear shuttling of class IIa histone deacetylase 4 (HDAC4). Stroke-induced nuclear shuttling of HDAC4 is positively and significantly correlated with improved indices of neuronal remodeling in the peri-infarct cortex. In this study, using a rat model for middle cerebral artery occlusion (MCAO), we tested the effects of selective inhibition of class IIa HDACs on functional recovery and neuronal remodeling when administered 24hr after stroke. Adult male Wistar rats (n = 15-17/group) were subjected to 2 h MCAO and orally gavaged with MC1568 (a selective class IIa HDAC inhibitor), SAHA (a non-selective HDAC inhibitor), or vehicle-control for 7 days starting 24 h after MCAO. A battery of behavioral tests was performed. Lesion volume measurement and immunohistochemistry were performed 28 days after MCAO. We found that stroke increased total HDAC activity in the ipsilateral hemisphere compared to the contralateral hemisphere. Stroke-increased HDAC activity was significantly decreased by the administration of SAHA as well as by MC1568. However, SAHA significantly improved functional outcome compared to vehicle control, whereas selective class IIa inhibition with MC1568 increased mortality and lesion volume and did not improve functional outcome. In addition, MC1568 decreased microtubule associated protein 2 (MAP2, dendrites), phosphorylated neurofilament heavy chain (pNFH, axons) and myelin basic protein (MBP, myelination) immunoreactivity in the peri-infarct cortex. Quantitative RT-PCR of cortical neurons isolated by laser capture microdissection revealed that MC1568, but not SAHA, downregulated CREB and c-fos expression. Additionally, MC1568 decreased the expression of phosphorylated CREB (active) in neurons. Taken together, these findings demonstrate that selective inhibition of class IIa HDACs impairs neuronal remodeling and neurological outcome. Inactivation of CREB and c-fos by MC1568 likely contributes to

  9. Involvement of aph(3')-IIa in the formation of mosaic aminoglycoside resistance genes in natural environments.

    PubMed

    Woegerbauer, Markus; Kuffner, Melanie; Domingues, Sara; Nielsen, Kaare M

    2015-01-01

    Intragenic recombination leading to mosaic gene formation is known to alter resistance profiles for particular genes and bacterial species. Few studies have examined to what extent aminoglycoside resistance genes undergo intragenic recombination. We screened the GenBank database for mosaic gene formation in homologs of the aph(3')-IIa (nptII) gene. APH(3')-IIa inactivates important aminoglycoside antibiotics. The gene is widely used as a selectable marker in biotechnology and enters the environment via laboratory discharges and the release of transgenic organisms. Such releases may provide opportunities for recombination in competent environmental bacteria. The retrieved GenBank sequences were grouped in three datasets comprising river water samples, duck pathogens and full-length variants from various bacterial genomes and plasmids. Analysis for recombination in these datasets was performed with the Recombination Detection Program (RDP4), and the Genetic Algorithm for Recombination Detection (GARD). From a total of 89 homologous sequences, 83% showed 99-100% sequence identity with aph(3')-IIa originally described as part of transposon Tn5. Fifty one were unique sequence variants eligible for recombination analysis. Only a single recombination event was identified with high confidence and indicated the involvement of aph(3')-IIa in the formation of a mosaic gene located on a plasmid of environmental origin in the multi-resistant isolate Pseudomonas aeruginosa PA96. The available data suggest that aph(3')-IIa is not an archetypical mosaic gene as the divergence between the described sequence variants and the number of detectable recombination events is low. This is in contrast to the numerous mosaic alleles reported for certain penicillin or tetracycline resistance determinants. PMID:26042098

  10. [Liquisolid technique for enhancement of dissolution prosperities of tanshinone II(A)].

    PubMed

    Liu, Xiao-qian; Meng, Qing-ju; Xu, Xue-lin; Zhao, Jie; Yang, Hua; Yi, Hong

    2015-12-01

    The technique of liquisolid compress is a new technique developed in 1990s, which was considered to be the most promising technique to improve the dissolution of water-insoluble drugs. In this article, tanshinone II(A) and the extracts of the ester-solubility fractions were chosen as the model drugs to evaluate the effects of the liquisolid technique for enhancement of dissolution properties of tanshinone II(A). Several liquisolid tablets (LS) formulations containing different dosage of drugs and various liquid vehicle were pre-pared and for all the formulations, microcrystalline cellulose and silica were chosen as the carrier and coating materials to evaluate their flow properties, such as angle of repose, Carr's compressibility index and Hausner's ratio. The interaction between drug and excipients in prepared LS compacts were studied by differential scanning calorimetry(DSC) and X-ray powder diffraction (XRPD). The dissolution curves of tanshinone II(A) from liquisolid compacts were investigated to determine the technique's effect in improving the dissolution of tanshinone II(A) and its impacting factors. According to the results, the dissolution increased with the rise in the dissolution of the liquid-phase solvent. The R-value and drug dosage can significantly affect the drug release, but with less impact on active fractions. This indicated that liquisolid technique is a promising alternative for improvement of dissolution property of water-soluble drugs, and can make a synergistic effect with other ester-soluble constituents and bettern improve the release of tanshinone II(A). Therefore, the technique of liquisolid compress will have a better development prospect in traditional Chinese medicines. PMID:27245032

  11. Promiscuous Actions of Small Molecule Inhibitors of the Protein Kinase D-Class IIa HDAC Axis in Striated Muscle

    PubMed Central

    Lemon, Douglas D.; Harrison, Brooke C.; Horn, Todd R.; Stratton, Matthew S.; Ferguson, Bradley S.; Wempe, Michael F.; McKinsey, Timothy A.

    2015-01-01

    PKD-mediated phosphorylation of class IIa HDACs frees the MEF2 transcription factor to activate genes that govern muscle differentiation and growth. Studies of the regulation and function of this signaling axis have involved MC1568 and Gö-6976, which are small molecule inhibitors of class IIa HDAC and PKD catalytic activity, respectively. We describe unanticipated effects of these compounds. MC1568 failed to inhibit class IIa HDAC catalytic activity in vitro, and exerted divergent effects on skeletal muscle differentiation compared to a bona fide inhibitor of these HDACs. In cardiomyocytes, Gö-6976 triggered calcium signaling and activated stress-inducible kinases. Based on these findings, caution is warranted when employing MC1568 and Gö-6976 as pharmacological tool compounds to assess functions of class IIa HDACs and PKD. PMID:25816750

  12. Morphology of a fossil elephant calf (Archidiskodon, Elephantidae) from the Oldowan Muhkai IIa site.

    PubMed

    Mashchenko, E N; Amirkhanov, Kh A; Ozherelyev, D V

    2015-11-01

    The skull and lower jaw morphology of a calf of Archidiskodon sp. from the Oldowan (Early Paleolithic) Muhkai IIa site (Akushinskii raion, Dagestan) is described. The Muhkai IIa site is dated more than 1.5 Ma. This is the first record of the skull and lower jaw of calf of this species from the northern Caucasus. A skull fragment and lower jaw with functioning teeth of the DP2/DP3 generation are preserved. The calf is at most 8-10 months of individual age. The finely plicate enamel and formation of a complete enamel loop on DP3 are evidence that the calf belongs to Archidiskodon rather than to the European Elephas lineage. PMID:26725233

  13. Parameters of tensile strength, elongation, and tenacity of 70mm IIaO spectroscopic film

    NASA Technical Reports Server (NTRS)

    Hammond, Ernest C., Jr.; Peters, Kevin A.

    1989-01-01

    The 70mm IIaO spectroscopic film was tested to determine its tensile strength, elongation, and breaking strength, using an Instron (strength and compression) 4201 Test Instrument. These data provide information leading to the upper and lower limits of the above parameters for 70mm IIaO spectroscopic film. This film will be developed by a commercial developing machine after the Ultraviolet Telescope Space Shuttle Mission returns to the Earth in the early 1990's; thus, it is necessary to understand these force parameters. Several test strips of approximately 200mm in length were used. The results indicate that when a stress load of 100 kg was applied, the film elongated approximately 1.06mm and the break strength was 19.45 kilograms.

  14. 30 CFR 57.22212 - Air flow (I-C, II-A, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Air flow (I-C, II-A, and V-A mines). 57.22212... Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22212 Air flow (I-C, II-A, and V-A mines). Air flow across each working face shall be sufficient to carry away any accumulation of methane,...

  15. 30 CFR 57.22101 - Smoking (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Smoking (I-A, II-A, III, and V-A mines). 57.22101 Section 57.22101 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... Smoking (I-A, II-A, III, and V-A mines). Persons shall not smoke or carry smoking materials, matches,...

  16. 30 CFR 57.22101 - Smoking (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Smoking (I-A, II-A, III, and V-A mines). 57.22101 Section 57.22101 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... Smoking (I-A, II-A, III, and V-A mines). Persons shall not smoke or carry smoking materials, matches,...

  17. 30 CFR 57.22101 - Smoking (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Smoking (I-A, II-A, III, and V-A mines). 57.22101 Section 57.22101 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... Smoking (I-A, II-A, III, and V-A mines). Persons shall not smoke or carry smoking materials, matches,...

  18. 30 CFR 57.22101 - Smoking (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Smoking (I-A, II-A, III, and V-A mines). 57.22101 Section 57.22101 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... Smoking (I-A, II-A, III, and V-A mines). Persons shall not smoke or carry smoking materials, matches,...

  19. 30 CFR 57.22101 - Smoking (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Smoking (I-A, II-A, III, and V-A mines). 57.22101 Section 57.22101 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR... Smoking (I-A, II-A, III, and V-A mines). Persons shall not smoke or carry smoking materials, matches,...

  20. 30 CFR 57.22608 - Secondary blasting (I-A, II-A, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Secondary blasting (I-A, II-A, and V-A mines... blasting (I-A, II-A, and V-A mines). Prior to secondary blasting, tests for methane shall be made in the mine atmosphere at blast sites by a competent person. Secondary blasting shall not be done when...

  1. Holographic Wilson Loops and Fermions in Consistent Truncations of String Theory and M-Theory

    NASA Astrophysics Data System (ADS)

    Faraggi, Alberto T.

    In the holographic framework, a half-BPS Wilson loop in N = 4 supersymmetric Yang-Mills theory in the fundamental, symmetric or antisymmetric representation of SU(N), is best described by a fundamental string, a D3-brane or a D5-brane with fluxes in their worldvolumes, respectively. In this thesis, we derive the spectra of excitations of such D3 and D5-branes in AdS5 × S5 explicitly, considering both the bosonic and the fermionic sectors, and demonstrate that they organize according to short multiplets of the supergroup OSp(4*|4). We also show that the modes of the fundamental string form an ultra-short multiplet of this supergroup. This way we provide a step towards a unifying picture for the description of holographic excitations of supersymmetric Wilson loops in arbitrary representations. In the case of the D5-brane, we compute the effective action due to the brane fluctuations using heat kernel techniques, thus providing the first correction to the expectation value of the circular Wilson loop in the antisymmetric representation of SU( N). We also discuss the dimensional reduction of fermionic modes in a recently found class of consistent truncations of type IIB and eleven-dimensional supergravity compactified on squashed Sasaki-Einstein manifolds. Such reductions are of interest, for example, in that they have 3 + 1 and (2 + 1)-dimensional holographic duals, and the fermionic content and their interactions with charged scalars are an important aspect of their applications. We derive the lower-dimensional equations of motion for the fermions and exhibit their couplings to the various bosonic modes present in the truncations under consideration, which most notably include charged scalar and form fields. We demonstrate that our results are consistent with the expected supersymmetric structure of the lower dimensional theory, and apply them to a

  2. Roles and post-translational regulation of cardiac class IIa histone deacetylase isoforms.

    PubMed

    Weeks, Kate L; Avkiran, Metin

    2015-04-15

    Cardiomyocyte hypertrophy is an integral component of pathological cardiac remodelling in response to mechanical and chemical stresses in settings such as chronic hypertension or myocardial infarction. For hypertrophy to ensue, the pertinent mechanical and chemical signals need to be transmitted from membrane sensors (such as receptors for neurohormonal mediators) to the cardiomyocyte nucleus, leading to altered transcription of the genes that regulate cell growth. In recent years, nuclear histone deacetylases (HDACs) have attracted considerable attention as signal-responsive, distal regulators of the transcriptional reprogramming that in turn precipitates cardiomyocyte hypertrophy, with particular focus on the role of members of the class IIa family, such as HDAC4 and HDAC5. These histone deacetylase isoforms appear to repress cardiomyocyte hypertrophy through mechanisms that involve protein interactions in the cardiomyocyte nucleus, particularly with pro-hypertrophic transcription factors, rather than via histone deacetylation. In contrast, evidence indicates that class I HDACs promote cardiomyocyte hypertrophy through mechanisms that are dependent on their enzymatic activity and thus sensitive to pharmacological HDAC inhibitors. Although considerable progress has been made in understanding the roles of post-translational modifications (PTMs) such as phosphorylation, oxidation and proteolytic cleavage in regulating class IIa HDAC localisation and function, more work is required to explore the contributions of other PTMs, such as ubiquitination and sumoylation, as well as potential cross-regulatory interactions between distinct PTMs and between class IIa and class I HDAC isoforms. PMID:25362149

  3. Roles and post-translational regulation of cardiac class IIa histone deacetylase isoforms

    PubMed Central

    Weeks, Kate L; Avkiran, Metin

    2015-01-01

    Cardiomyocyte hypertrophy is an integral component of pathological cardiac remodelling in response to mechanical and chemical stresses in settings such as chronic hypertension or myocardial infarction. For hypertrophy to ensue, the pertinent mechanical and chemical signals need to be transmitted from membrane sensors (such as receptors for neurohormonal mediators) to the cardiomyocyte nucleus, leading to altered transcription of the genes that regulate cell growth. In recent years, nuclear histone deacetylases (HDACs) have attracted considerable attention as signal-responsive, distal regulators of the transcriptional reprogramming that in turn precipitates cardiomyocyte hypertrophy, with particular focus on the role of members of the class IIa family, such as HDAC4 and HDAC5. These histone deacetylase isoforms appear to repress cardiomyocyte hypertrophy through mechanisms that involve protein interactions in the cardiomyocyte nucleus, particularly with pro-hypertrophic transcription factors, rather than via histone deacetylation. In contrast, evidence indicates that class I HDACs promote cardiomyocyte hypertrophy through mechanisms that are dependent on their enzymatic activity and thus sensitive to pharmacological HDAC inhibitors. Although considerable progress has been made in understanding the roles of post-translational modifications (PTMs) such as phosphorylation, oxidation and proteolytic cleavage in regulating class IIa HDAC localisation and function, more work is required to explore the contributions of other PTMs, such as ubiquitination and sumoylation, as well as potential cross-regulatory interactions between distinct PTMs and between class IIa and class I HDAC isoforms. PMID:25362149

  4. Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma.

    PubMed

    Kikuchi, S; Suzuki, R; Ohguchi, H; Yoshida, Y; Lu, D; Cottini, F; Jakubikova, J; Bianchi, G; Harada, T; Gorgun, G; Tai, Y-T; Richardson, P G; Hideshima, T; Anderson, K C

    2015-09-01

    Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM. PMID:25801913

  5. Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain

    PubMed Central

    Bonomi, Robin; Mukhopadhyay, Uday; Shavrin, Aleksandr; Yeh, Hsien-Hsien; Majhi, Anjoy; Dewage, Sajeewa W.; Najjar, Amer; Lu, Xin; Cisneros, G. Andrés; Tong, William P.; Alauddin, Mian M.; Liu, Ren-Shuan; Mangner, Thomas J.; Turkman, Nashaat; Gelovani, Juri G.

    2015-01-01

    Histone deacetylases (HDAC’s) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa–specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA). The selectivity of these radiotracer substrates to HDAC class IIa enzymes was assessed in vitro, in a panel of recombinant HDACs, and in vivo using PET/CT imaging in rats. [18F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [18F]DFAHA and previously reported [18F]FAHA. PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo. Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases. PMID:26244761

  6. Isolation and characterization of a subgroup IIa WRKY transcription factor PtrWRKY40 from Populus trichocarpa.

    PubMed

    Karim, Abdul; Jiang, Yuanzhong; Guo, Li; Ling, Zhengyi; Ye, Shenglong; Duan, Yanjiao; Li, Chaofeng; Luo, Keming

    2015-10-01

    Salicylic acid (SA) is a defense-related key signaling molecule involved in plant immunity. In this study, a subgroup IIa WRKY gene PtrWRKY40 was isolated from Populus trichocarpa, which displayed amino acid sequence similar to Arabidopsis AtWRKY40, AtWRKY18 and AtWRKY60. PtrWRKY40 transcripts accumulated significantly in response to SA, methyl jasmonate and hemibiotrophic fungus Dothiorella gregaria Sacc. Overexpression of PtrWRKY40 in transgenic poplar conferred higher susceptibility to D. gregaria infection. This susceptibility was coupled with reduced expression of SA-associated genes (PR1.1, PR2.1, PR5.9, CPR5 and SID2) and jasmonic acid (JA)-related gene JAZ8. Decreased accumulation of endogenous SA was observed in transgenic lines overexpressing PtrWRKY40 when compared with wild-type plants. However, constitutive expression of PtrWRKY40 in Arabidopsis thaliana displayed resistance to necrotrophic fungus Botrytis cinerea, and the expression of JA-defense-related genes such as PDF1.2, VSP2 and PR3 was remarkably increased in transgenic plants upon infection with fugal pathogens. Together, our findings indicate that PtrWRKY40 plays a negative role in resistance to hemibiotrophic fungi in poplar but functions as a positive regulator of resistance toward the necrotrophic fungi in Arabidopsis. PMID:26423133

  7. Myosin IIA Modulates T Cell Receptor Transport and CasL Phosphorylation during Early Immunological Synapse Formation

    PubMed Central

    Yu, Yan; Fay, Nicole C.; Smoligovets, Alexander A.; Wu, Hung-Jen; Groves, Jay T.

    2012-01-01

    Activation of T cell receptor (TCR) by antigens occurs in concert with an elaborate multi-scale spatial reorganization of proteins at the immunological synapse, the junction between a T cell and an antigen-presenting cell (APC). The directed movement of molecules, which intrinsically requires physical forces, is known to modulate biochemical signaling. It remains unclear, however, if mechanical forces exert any direct influence on the signaling cascades. We use T cells from AND transgenic mice expressing TCRs specific to the moth cytochrome c 88–103 peptide, and replace the APC with a synthetic supported lipid membrane. Through a series of high spatiotemporal molecular tracking studies in live T cells, we demonstrate that the molecular motor, non-muscle myosin IIA, transiently drives TCR transport during the first one to two minutes of immunological synapse formation. Myosin inhibition reduces calcium influx and colocalization of active ZAP-70 (zeta-chain associated protein kinase 70) with TCR, revealing an influence on signaling activity. More tellingly, its inhibition also significantly reduces phosphorylation of the mechanosensing protein CasL (Crk-associated substrate the lymphocyte type), raising the possibility of a direct mechanical mechanism of signal modulation involving CasL. PMID:22347397

  8. Active site mutants of human secreted Group IIA Phospholipase A2 lacking hydrolytic activity retain their bactericidal effect.

    PubMed

    Chioato, Lucimara; Aragão, Elisangela Aparecida; Ferreira, Tatiana Lopes; Ward, Richard J

    2012-01-01

    The Human Secreted Group IIA Phospholipase A(2) (hsPLA2GIIA) presents potent bactericidal activity, and is considered to contribute to the acute-phase immune response. Hydrolysis of inner membrane phospholipids is suggested to underlie the bactericidal activity, and we have evaluated this proposal by comparing catalytic activity with bactericidal and liposome membrane damaging effects of the G30S, H48Q and D49K hsPLA2GIIA mutants. All mutants showed severely impaired hydrolytic activities against mixed DOPC:DOPG liposome membranes, however the bactericidal effect against Micrococcus luteus was less affected, with 50% killing at concentrations of 1, 3, 7 and 9 μg/mL for the wild-type, D49K, H48Q and G30S mutants respectively. Furthermore, all proteins showed Ca(2+)-independent damaging activity against liposome membranes demonstrating that in addition to the hydrolysis-dependent membrane damage, the hsPLA2GIIA presents a mechanism for permeabilization of phospholipid bilayers that is independent of catalytic activity, which may play a role in the bactericidal function of the protein. PMID:21986368

  9. Improving human skeletal muscle myosin heavy chain fiber typing efficiency.

    PubMed

    Murach, Kevin A; Bagley, James R; McLeland, Kathryn A; Arevalo, Jose A; Ciccone, Anthony B; Malyszek, Kylie K; Wen, Yuan; Galpin, Andrew J

    2016-04-01

    Single muscle fiber sodium dodecyl sulfate polyacrylamide gel-electrophoresis (SDS-PAGE) is a sensitive technique for determining skeletal muscle myosin heavy chain (MHC) composition of human biopsy samples. However, the number of fibers suitable to represent fiber type distribution via this method is undefined. Muscle biopsies were obtained from the vastus lateralis (VL) of nine resistance-trained males (25 ± 1 year, height = 179 ± 5 cm, mass = 82 ± 8 kg). Single fiber MHC composition was determined via SDS-PAGE. VL fiber type distribution [percent MHC I, I/IIa, IIa, IIa/IIx, and total "hybrids" (i.e. I/IIa + IIa/IIx)] was evaluated according to number of fibers analyzed per person (25 vs. 125). VL fiber type distribution did not differ according to number of fibers analyzed (P > 0.05). VL biopsy fiber type distribution of nine subjects is represented by analyzing 25 fibers per person. These data may help minimize cost, personnel-time, and materials associated with this technique, thereby improving fiber typing efficiency in humans. PMID:26842420

  10. Nonmuscle Myosin IIA Regulates Intestinal Epithelial Barrier in vivo and Plays a Protective Role During Experimental Colitis

    PubMed Central

    Naydenov, Nayden G.; Feygin, Alex; Wang, Dongdong; Kuemmerle, John F.; Harris, Gianni; Conti, Mary Anne; Adelstein, Robert S.; Ivanov, Andrei I.

    2016-01-01

    The actin cytoskeleton is a critical regulator of intestinal mucosal barrier permeability, and the integrity of epithelial adherens junctions (AJ) and tight junctions (TJ). Non muscle myosin II (NM II) is a key cytoskeletal motor that controls actin filament architecture and dynamics. While NM II has been implicated in the regulation of epithelial junctions in vitro, little is known about its roles in the intestinal mucosa in vivo. In this study, we generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. NM IIA cKO animals were characterized by a more severe disruption of the gut barrier and exaggerated mucosal injury during experimentally-induced colitis. Our study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo. PMID:27063635

  11. TanshinoneIIA ameliorates inflammatory microenvironment of colon cancer cells via repression of microRNA-155.

    PubMed

    Tu, Jiajie; Xing, Yingying; Guo, Yongjian; Tang, Feng; Guo, Le; Xi, Tao

    2012-12-01

    TanshinoneIIA, an active component derived from a traditional Chinese medicine, has anti-inflammatory and anti-cancer effect. However, the mechanisms underlying the interaction between anti-inflammation and anti-cancer of TanshinoneIIA remain elusive. In the present study, a cell model of inflammation between macrophages and colon cancer cells was used. The results showed that TanshinoneIIA inhibited the proliferation of inflammation-related colon cancer cells HCT116 and HT-29 by decreasing the production of inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), which generated by macrophage RAW264.7 cell line. We identified Phosphatidylinositol-3, 4, 5-trisphosphate 5-phosphatase 1 (SHIP1) was a bona fide target of miR-155. TanshinoneIIA restored the down-regulated level of SHIP1 protein after lipopolysaccharide (LPS)-stimulation in RAW264.7 cells. MicroRNA-155 (miR-155) was up-regulated in macrophages, possibly due to the concomitant increase of PU.1, a transcriptional activator of miR-155, accounting for decreased SHIP1. Treatment with TanshinoneIIA prevented increased PU.1 and hence increased miR-155, whereas aspirin could not. These findings support that the interruption of signal conduction between activated macrophages and colon cancer cells could be considered as a new therapeutic strategy and miR-155 could be a potential target for the prevention of inflammation-related cancer. PMID:22982040

  12. Tanshinone IIA Attenuates Renal Fibrosis after Acute Kidney Injury in a Mouse Model through Inhibition of Fibrocytes Recruitment

    PubMed Central

    Jiang, Chunming; Shao, Qiuyuan; Jin, Bo; Zhang, Miao

    2015-01-01

    Acute kidney injury (AKI) is associated with an increased risk of developing advanced chronic kidney disease (CKD). Yet, effective interventions to prevent this conversion are unavailable for clinical practice. In this study, we examined the beneficial effects of Tanshinone IIA on renal fibrosis in a mouse model of folic acid induced AKI. We found that Tanshinone IIA treatment significantly attenuated the folic acid elicited kidney dysfunction on days 3, 14, and 28. This effect was concomitant with a much lessened accumulation of fibronectin and collagen in tubulointerstitium 28 days after folic acid injury, denoting an ameliorated renal fibrosis. The kidney protective and antifibrotic effect of Tanshinone IIA was likely attributable to an early inhibition of renal recruitment of fibrocytes positive for both CD45 and collagen I. Mechanistically, Tanshinone IIA treatment not only markedly diminished renal expression of chemoattractants for fibrocytes such as TGFβ1 and MCP-1, but also significantly reduced circulating fibrocytes at the acute phase of kidney injury. These data suggested that Tanshinone IIA might be a novel therapy for preventing progression of CKD after AKI. PMID:26885500

  13. Sodium tanshinone IIA sulfonate increased intestinal hemodynamics without systemic circulatory changes in healthy newborn piglets.

    PubMed

    Liu, Jiangqin; Morton, Jude; Miedzyblocki, Margaret; Lee, Tze Fun; Bigam, David L; Fok, Tai Fai; Chen, Chao; Lee, Shoo K; Davidge, Sandra T; Cheung, Po-Yin

    2009-10-01

    In traditional Chinese medicine, tanshinone IIA is a lipid-soluble component of Danshen that has been widely used for various cardiovascular and cerebrovascular disorders, including neonatal asphyxia. Despite promising effects, little is known regarding the hemodynamic effects of tanshinone IIA in newborn subjects. To examine the dose-response effects of sodium tanshinone IIA sulfonate (STS) on systemic and regional hemodynamics and oxygen transport, 12 newborn piglets were anesthetized and acutely instrumented for the placement of femoral arterial and venous, pulmonary arterial catheters to measure mean arterial, central venous, and pulmonary arterial pressures, respectively. The blood flow at the common carotid, renal, pulmonary, and superior mesenteric (SMA) arteries were continuously monitored after treating the piglets with either STS (0.1-30 mg/kg iv) or saline treatment (n = 6/group). To further delineate the underlying mechanisms for vasorelaxant effects of STS, in vitro vascular myography was carried out to compare its effect on rat mesenteric and carotid arteries (n = 4-5/group). STS dose-dependently increased the SMA blood flow and the corresponding oxygen delivery with no significant effect on systemic and pulmonary, carotid and renal hemodynamic parameters. In vitro studies also demonstrated that STS selectively dilated rat mesenteric but not carotid arteries. Vasodilation in mesenteric arteries was inhibited by apamin and TRAM-34 (calcium-activated potassium channel inhibitors) but not by meclofenamate (cyclooxygenase inhibitor) or N-nitro-l-arginine methyl ester hydrochloride (nitric oxide synthase inhibitor). In summary, without significant hemodynamic effects on newborn piglets, intravenous infusion of STS selectively increased mesenteric perfusion in a dose-dependent manner, possibly via an endothelium-derived hyperpolarizing factor vasodilating pathway. PMID:19617411

  14. New industrial heat pump applications to a synthetic rubber plant. Final report, Phase IIA

    SciTech Connect

    1993-12-31

    This report summarizes the results of the Phase IIA of the DOE sponsored study titled, Advanced Industrial Heat Pump Application and Evaluation. The scope of this phase of the study was to finalize the process design of the heat pump scheme, develop a process and instrumentation diagram, and a detailed cost estimate for the project. This information is essential for the site management to evaluate the economic viability and operability of the proposed heat pump design, prior to the next phase of installation and testing.

  15. Post-translational Modifications Regulate Class IIa Histone Deacetylase (HDAC) Function in Health and Disease*

    PubMed Central

    Mathias, Rommel A.; Guise, Amanda J.; Cristea, Ileana M.

    2015-01-01

    Class IIa histone deacetylases (HDACs4, -5, -7, and -9) modulate the physiology of the human cardiovascular, musculoskeletal, nervous, and immune systems. The regulatory capacity of this family of enzymes stems from their ability to shuttle between nuclear and cytoplasmic compartments in response to signal-driven post-translational modification. Here, we review the current knowledge of modifications that control spatial and temporal histone deacetylase functions by regulating subcellular localization, transcriptional functions, and cell cycle-dependent activity, ultimately impacting on human disease. We discuss the contribution of these modifications to cardiac and vascular hypertrophy, myoblast differentiation, neuronal cell survival, and neurodegenerative disorders. PMID:25616866

  16. Comments on the symmetry of AdS6 solutions in string/M-theory and Killing spinor equations

    NASA Astrophysics Data System (ADS)

    Kim, Hyojoong; Kim, Nakwoo

    2016-09-01

    It was recently pointed out in [1] that AdS6 solutions in IIB theory enjoy an extended symmetry structure and the consistent truncation to D = 4 internal space leads to a nonlinear sigma model with target SL (3 , R) / SO (2 , 1). We continue to study the purely bosonic D = 4 effective action, and elucidate how the addition of scalar potential term still allows Killing spinor equations in the absence of gauge fields. In particular, the potential turns out to be a single diagonal component of the coset representative. Furthermore, we perform a general analysis of the integrability conditions of Killing spinor equations and establish that the effective action can be in fact generalized to arbitrary sizes and signatures, e.g. with target SL (n , R) / SO (p , n - p) and the scalar potential expressible by a single diagonal component of the coset representative. We also comment on a similar construction and its generalizations of effective D = 5 purely bosonic non-linear sigma model action related to AdS6 in M-theory.

  17. Inhibitor-induced structural change in the HCV IRES domain IIa RNA

    PubMed Central

    Paulsen, Ryan B.; Seth, Punit P.; Swayze, Eric E.; Griffey, Richard H.; Skalicky, Jack J.; Cheatham, Thomas E.; Davis, Darrell R.

    2010-01-01

    Translation of the hepatitis C virus (HCV) RNA is initiated from a highly structured internal ribosomal entry site (IRES) in the 5′ untranslated region (5′ UTR) of the RNA genome. An important structural feature of the native RNA is an approximately 90° helical bend localized to domain IIa that positions the apical loop of domain IIb of the IRES near the 40S ribosomal E-site to promote eIF2-GDP release, facilitating 80S ribosome assembly. We report here the NMR structure of a domain IIa construct in complex with a potent small-molecule inhibitor of HCV replication. Molecular dynamics refinement in explicit solvent and subsequent energetic analysis indicated that each inhibitor stereoisomer bound with comparable affinity and in an equivalent binding mode. The in silico analysis was substantiated by fluorescence-based assays showing that the relative binding free energies differed by only 0.7 kcal/mol. Binding of the inhibitor displaces key nucleotide residues within the bulge region, effecting a major conformational change that eliminates the bent RNA helical trajectory, providing a mechanism for the antiviral activity of this inhibitor class. PMID:20360559

  18. Tactile responses in the granule cell layer of cerebellar folium crus IIa of freely behaving rats

    NASA Technical Reports Server (NTRS)

    Hartmann, M. J.; Bower, J. M.

    2001-01-01

    We recorded activity from the granule cell layer (GCL) of cerebellar folium Crus IIa as freely moving rats engaged in a variety of natural behaviors, including grooming, eating, and free tactile exploration. Multiunit responses in the 1000-4500 Hz range were found to be strongly correlated with tactile stimulation of lip and whisker (perioral) regions. These responses occurred regardless of whether the stimulus was externally or self-generated and during both active and passive touch. In contrast, perioral movements that did not tactually stimulate this region of the face (e.g., chewing) produced no detectable increases in GCL activity. In addition, GCL responses were not correlated with movement extremes. When rats used their lips actively for palpation and exploration, the tactile responses in the GCL were not detectably modulated by ongoing jaw movements. However, active palpation and exploratory behaviors did result in the largest and most continuous bursts of GCL activity: responses were on average 10% larger and 50% longer during palpation and exploration than during grooming or passive stimulation. Although activity levels differed between behaviors, the position and spatial extent of the peripheral receptive field was similar over all behaviors that resulted in tactile input. Overall, our data suggest that the 1000-4500 Hz multiunit responses in the Crus IIa GCL of awake rats are correlated with tactile input rather than with movement or any movement parameter and that these responses are likely to be of particular importance during the acquisition of sensory information by perioral structures.

  19. Force Dependent Biotinylation of Myosin IIA by α-Catenin Tagged with a Promiscuous Biotin Ligase

    PubMed Central

    Ueda, Shuji; Blee, Alexandra M.; Macway, Katherine G.; Renner, Derrick J.; Yamada, Soichiro

    2015-01-01

    Tissues and organs undergo constant physical perturbations and individual cells must respond to mechanical forces to maintain tissue integrity. However, molecular interactions underlying mechano-transduction are not fully defined at cell-cell junctions. This is in part due to weak and transient interactions that are likely prevalent in force-induced protein complexes. Using in situ proximal biotinylation by the promiscuous biotin ligase BirA tagged to α-catenin and a substrate stretch cell chamber, we sought to identify force-dependent molecular interactions surrounding α-catenin, an actin regulator at the sites of cadherin mediated cell-cell adhesion. While E-cadherin, β-catenin, vinculin and actin localize with α-catenin at cell-cell contacts in immuno-fluorescent staining, only β-catenin and plakoglobin were biotinylated, suggesting that this proximal biotinylation is limited to the molecules that are in the immediate vicinity of α-catenin. In mechanically stretched samples, increased biotinylation of non-muscle myosin IIA, but not myosin IIB, suggests close spatial proximity between α-catenin and myosin IIA during substrate stretching. This force-induced biotinylation diminished as myosin II activity was inhibited by blebbistatin. Taken together, this promising technique enables us to identify force sensitive complexes that may be essential for mechano-responses in force bearing cell adhesion. PMID:25806963

  20. Force dependent biotinylation of myosin IIA by α-catenin tagged with a promiscuous biotin ligase.

    PubMed

    Ueda, Shuji; Blee, Alexandra M; Macway, Katherine G; Renner, Derrick J; Yamada, Soichiro

    2015-01-01

    Tissues and organs undergo constant physical perturbations and individual cells must respond to mechanical forces to maintain tissue integrity. However, molecular interactions underlying mechano-transduction are not fully defined at cell-cell junctions. This is in part due to weak and transient interactions that are likely prevalent in force-induced protein complexes. Using in situ proximal biotinylation by the promiscuous biotin ligase BirA tagged to α-catenin and a substrate stretch cell chamber, we sought to identify force-dependent molecular interactions surrounding α-catenin, an actin regulator at the sites of cadherin mediated cell-cell adhesion. While E-cadherin, β-catenin, vinculin and actin localize with α-catenin at cell-cell contacts in immuno-fluorescent staining, only β-catenin and plakoglobin were biotinylated, suggesting that this proximal biotinylation is limited to the molecules that are in the immediate vicinity of α-catenin. In mechanically stretched samples, increased biotinylation of non-muscle myosin IIA, but not myosin IIB, suggests close spatial proximity between α-catenin and myosin IIA during substrate stretching. This force-induced biotinylation diminished as myosin II activity was inhibited by blebbistatin. Taken together, this promising technique enables us to identify force sensitive complexes that may be essential for mechano-responses in force bearing cell adhesion. PMID:25806963

  1. Prevention and Therapeutic Effects and Mechanisms of Tanshinone IIA Sodium Sulfonate on Acute Liver Injury Mice Model

    PubMed Central

    Lu, Lunjie; Zhou, Jun; Zhang, Jingying; Che, Jun; Jiao, Yang; Zhang, Yusong

    2016-01-01

    Tanshinone IIA sodium sulfonate (TSS) is a water-soluble derivative of tanshinone IIA, which is the main pharmacologically active component of Salvia miltiorrhiza. This study aimed to verify the preventive and therapeutic effects of TSS and its combined therapeutic effects with magnesium isoglycyrrhizinate (MI) in D-galactosamine- (D-Gal-) induced acute liver injury (ALI) in mice. The potential regulatory mechanisms of TSS on ALI were also examined. Our results may provide a basis for the development of novel therapeutics for ALI. PMID:27274751

  2. 30 CFR 57.22221 - Overcast and undercast construction (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Overcast and undercast construction (I-A, II-A..., DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL... Overcast and undercast construction (I-A, II-A, III, and V-A mines). Overcasts and undercasts shall be—...

  3. 30 CFR 57.22221 - Overcast and undercast construction (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Overcast and undercast construction (I-A, II-A..., DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL... Overcast and undercast construction (I-A, II-A, III, and V-A mines). Overcasts and undercasts shall be—...

  4. Secretory Phospholipase A2-IIa is a Target Gene of the HER/HER2-Elicited Pathway and a Potential Plasma Biomarker for Poor Prognosis of Prostate Cancer

    PubMed Central

    Oleksowicz, Leslie; Liu, Yin; Bracken, R. Bruce; Gaitonde, Krishnanath; Burke, Barbara; Succop, Paul; Levin, Linda; Dong, Zhongyun; Lu, Shan

    2012-01-01

    BACKGROUND Our previous study showed that prostate cancer cells overexpress and secrete secretory phospholipases A2 group IIa (sPLA2-IIa) and plasma sPLA2-IIa was elevated in prostate cancer patients. The current study further explored the underlying mechanism of sPLA2-IIa overexpression and the potential role of sPLA2-IIa as a prostate cancer biomarker. METHODS Plasma and tissue specimens from prostate cancer patients were analyzed for sPLA2-IIa levels. Regulation of sPLA2-IIa expression by Heregulin-α was determined by western blot and reporter assay. RESULTS We found that Heregulin-α enhanced expression of the sPLA2-IIa gene via the HER2/HER3-elicited pathway. The EGFR/HER2 dual inhibitor Lapatinib and the NF-kB inhibitor Bortezomib inhibited sPLA2-IIa expression induced by Heregulin-α. Heregulin-α upregulated expression of the sPLA2-IIa gene at the transcriptional level. We further confirmed that plasma sPLA2-IIa secreted by mouse bearing human prostate cancer xenografts reached detectable plasma concentrations. A Receiver Operating Characteristic (ROC) analysis of patient plasma specimens revealed that high levels of plasma sPLA2-IIa, with the optimum cutoff value of 2.0 ng/ml, were significantly associated with high Gleason score (8~10) relative to intermediate Gleason score (6~7) prostate cancers and advanced relative to indolent cancers. The area under the ROC curve (AUC) was 0.73 and 0.74, respectively. CONCLUSION We found that Heregulin-α, in addition to EGF, contributes to sPLA2-IIa overexpression in prostate cancer cells. Our findings support the notion that high levels of plasma sPLA2-IIa may serve as a poor prognostic biomarker capable of distinguishing aggressive from indolent prostate cancers, which may improve decision making and optimize patient management. PMID:22127954

  5. New molecular interaction of IIA(Ntr) and HPr from Burkholderia pseudomallei identified by X-ray crystallography and docking studies.

    PubMed

    Kim, Mi-Sun; Lee, Hasup; Heo, Lim; Lim, Areum; Seok, Chaok; Shin, Dong Hae

    2013-09-01

    The nitrogen-related phosphoenolpyruvate phosphotransferase system (PTS(Ntr) ) is involved in controlling ammonia assimilation and nitrogen fixation. The additional role of PTS(Ntr) as a regulatory link between nitrogen and carbon utilization in Escherichia coli is assumed to be closely related to molecular functions of IIA(Ntr) in potassium homeostasis. We have determined the crystal structure of IIA(Ntr) from Burkholderia pseudomallei (BpIIA(Ntr) ), which is a causative agent of melioidosis. The crystal structure of dimeric BpIIA(Ntr) determined at 3.0 Å revealed that its active sites are mutually blocked. This dimeric state is stabilized by charge and weak hydrophobic interactions. Overall monomeric structure and the active site residues, Arg51 and His67, of BpIIA(Ntr) are well conserved with those of IIA(Ntr) enzymes from E. coli and Neisseria meningitides. Interestingly, His113 of BpIIA(Ntr) , which corresponds to a key residue in another phosphoryl group relay in the mannitol-specific enzyme EIIA family (EIIA(Mtl) ), is located away from the active site due to the loop connecting β5 and α3. Combined with other differences in molecular surface properties, these structural signatures distinguish the IIA(Ntr) family from the EIIA(Mtl) family. Since, there is no gene for NPr in the chromosome of B. pseudomallei, modeling and docking studies of the BpIIA(Ntr) -BpHPr complex has been performed to support the proposal on the NPr-like activity of BpHPr. A potential dual role of BpHPr as a nonspecific phosphocarrier protein interacting with both sugar EIIAs and IIA(Ntr) in B. pseudomallei has been discussed. PMID:23483653

  6. Effect of rosuvastatin on diabetic polyneuropathy: a randomized, double-blind, placebo-controlled Phase IIa study

    PubMed Central

    Hernández-Ojeda, Jaime; Román-Pintos, Luis Miguel; Rodríguez-Carrízalez, Adolfo Daniel; Troyo-Sanromán, Rogelio; Cardona-Muñoz, Ernesto Germán; Alatorre-Carranza, María del Pilar; Miranda-Díaz, Alejandra Guillermina

    2014-01-01

    Background Diabetic neuropathy affects 50%–66% of patients with diabetes mellitus. Oxidative stress generates nerve dysfunction by causing segmental demyelinization and axonal degeneration. Antioxidants are considered to be the only etiologic management for diabetic polyneuropathy, and statins such as rosuvastatin increase nitric oxide bioavailability and reduce lipid peroxidation. The aim of this study was to evaluate the antioxidant effect of rosuvastatin in diabetic polyneuropathy. Methods We conducted a randomized, double-blind, placebo-controlled Phase IIa clinical trial in patients with type 2 diabetes and diabetic polyneuropathy (DPN) stage ≥1b. We allocated subjects to two parallel groups (1:1) that received rosuvastatin 20 mg or placebo for 12 weeks. Primary outcomes were neuropathic symptom score, disability score, and nerve conduction studies, and secondary outcomes were glycemic control, lipid and hepatic profile, lipid peroxidation, and nerve growth factor beta (NGF-β) levels. Results Both groups were of similar age and duration since diagnosis of diabetes and DPN. We observed improvement of DPN in the rosuvastatin group from stage 2a (88.2%) to stage 1b (41.2%), improvement of neuropathic symptom score from 4.5±2 to 2.4±1.8, and significant (P=0.001) reductions of peroneal nerve conduction velocity (from 40.8±2.2 to 42.1±1.6 seconds) and lipid peroxidation (from 25.4±2 to 12.2±4.0 nmol/mL), with no significant change in glycemic control or β-NGF. Conclusion The severity, symptoms, and nerve conduction parameters of DPN improved after 12 weeks of treatment with rosuvastatin. These beneficial effects appear to be attributable to reductions in lipid peroxidation and oxidative stress. PMID:25214797

  7. How could (should) we make contact between string/M-theory and our four-dimensional world, and associated LHC predictions?

    NASA Astrophysics Data System (ADS)

    Kane, Gordon

    2015-12-01

    String/M-theory is an exciting framework within which we try to understand our universe and its properties. Compactified string/M-theories address and offer solutions to almost every important question and issue in particle physics and particle cosmology. But earlier goals of finding a top-down “vacuum selection” principle and deriving the 4D theory have not yet been realized. Does that mean we should stop trying, as nearly all string theorists have? Or can we proceed in the historical way to make a few generic, robust assumptions not closely related to observables, and follow where they lead to testable predictions and explanations? Making only very generic assumptions is a significant issue. I discuss how to try to proceed with this approach, particularly in M-theory compactified on a 7D manifold of G2 holonomy. One goal is to understand our universe as a string/M-theory vacuum for its own sake, in the long tradition of trying to understand our world, and what that implies. In addition, understanding our vacuum may be a prelude to understanding its connection to the multiverse.

  8. Radiation therapy for stage IIA and IIB testicular seminoma: peripheral dose calculations and risk assessments

    NASA Astrophysics Data System (ADS)

    Mazonakis, Michalis; Berris, Theocharris; Lyraraki, Efrossyni; Damilakis, John

    2015-03-01

    This study was conducted to calculate the peripheral dose to critical structures and assess the radiation risks from modern radiotherapy for stage IIA/IIB testicular seminoma. A Monte Carlo code was used for treatment simulation on a computational phantom representing an average adult. The initial treatment phase involved anteroposterior and posteroanaterior modified dog-leg fields exposing para-aortic and ipsilateral iliac lymph nodes followed by a cone-down phase for nodal mass irradiation. Peripheral doses were calculated using different modified dog-leg field dimensions and an extended conventional dog-leg portal. The risk models of the BEIR-VII report and ICRP-103 were combined with dosimetric calculations to estimate the probability of developing stochastic effects. Radiotherapy for stage IIA seminoma with a target dose of 30 Gy resulted in a range of 23.0-603.7 mGy to non-targeted peripheral tissues and organs. The corresponding range for treatment of stage IIB disease to a cumulative dose of 36 Gy was 24.2-633.9 mGy. A dose variation of less than 13% was found by altering the field dimensions. Radiotherapy with the conventional instead of the modern modified dog-leg field increased the peripheral dose up to 8.2 times. The calculated heart doses of 589.0-632.9 mGy may increase the risk for developing cardiovascular diseases whereas the testicular dose of more than 231.9 mGy may lead to a temporary infertility. The probability of birth abnormalities in the offspring of cancer survivors was below 0.13% which is much lower than the spontaneous mutation rate. Abdominoplevic irradiation may increase the lifetime intrinsic risk for the induction of secondary malignancies by 0.6-3.9% depending upon the site of interest, patient’s age and tumor dose. Radiotherapy for stage IIA/IIB seminoma with restricted fields and low doses is associated with an increased morbidity. These data may allow the definition of a risk-adapted follow-up scheme for long

  9. Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial

    PubMed Central

    van Noort, Johannes M.; Bsibsi, Malika; Nacken, Peter J.; Verbeek, Richard; Venneker, Edna H.G.

    2015-01-01

    As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5. Trial Registration: ClinicalTrials.gov Phase I: NCT02442557; Phase IIa: NCT02442570 PMID

  10. Silicon Phthalocyanine 4 and Photodynamic Therapy in Stage IA-IIA Cutaneous T-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2015-12-03

    Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome

  11. Experimental infection with Cryptosporidium parvum IIaA21G1R1 subtype in immunosuppressed mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cryptosporidium parvum subtype IIaA21G1R1 oocysts were used to infect dexamethasone immunosuppressed N: NIH Swiss mice. Histology showed developmental stages in the duodenum, proximal and distal jejunum, ileum, cecum and colon, with the small intestine remaining infected until day 35 post infection....

  12. Conditional deletion of nonmuscle myosin II-A in mouse tongue epithelium results in squamous cell carcinoma

    PubMed Central

    Anne Conti, Mary; Saleh, Anthony D.; Brinster, Lauren R.; Cheng, Hui; Chen, Zhong; Cornelius, Shaleeka; Liu, Chengyu; Ma, Xuefei; Van Waes, Carter; Adelstein, Robert S.

    2015-01-01

    To investigate the contribution of nonmuscle myosin II-A (NM II-A) to early cardiac development we crossed Myh9 floxed mice and Nkx2.5 cre-recombinase mice. Nkx2.5 is expressed in the early heart (E7.5) and later in the tongue epithelium. Mice homozygous for deletion of NM II-A (ANkx/ANkx) are born at the expected ratio with normal hearts, but consistently develop an invasive squamous cell carcinoma (SCC) of the tongue (32/32 ANkx/ANkx) as early as E17.5. To assess reproducibility a second, independent line of Myh9 floxed mice derived from a different embryonic stem cell clone was tested. This second line also develops SCC indistinguishable from the first (15/15). In ANkx/ANkx mouse tongue epithelium, genetic deletion of NM II-A does not affect stabilization of TP53, unlike a previous report for SCC. We attribute the consistent, early formation of SCC with high penetrance to the role of NM II in maintaining mitotic stability during karyokinesis. PMID:26369831

  13. Investigation of the effect of tanshinone IIA on nitric oxide production in human vascular endothelial cells by fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Huang, Ke-Jing; Wang, Hong; Xie, Wan-Zhen; Zhang, Hua-Shan

    2007-12-01

    Nitric oxide (NO) has been proved to be a potent vasodilator that played an important role in regulating vascular tones. Tanshinone, one of the active components of Radix Salvia miltiorrhiza, was used widely in clinics in China for treating cardiovascular diseases. The objective of this study was to sensitively and specifically investigate the effects of tanshinone IIA, one important pharmacological constituent of tanshinone, on the release of NO from human vascular endothelial cells (HVECs) by fluorescence imaging with an excellent fluorescent probe 1,3,5,7-tetramethyl-2,6-dicarbethoxy-8-(3',4'-diaminophenyl)-difluoroboradiaza- s-indacence (TMDCDABODIPY). After cells were incubated with tanshinone IIA, TMDCDABODIPY was employed to label NO. Following the tagging, real-time imaging of NO release from the cells was performed with inverted fluorescence microscope. The results of the experiments showed that tanshinone IIA could induce NO production significantly enhanced in HVECs. The activation of NO by tanshinone IIA may be employed therapeutically in modulating NO production in HVECs.

  14. UNITED PRESBYTERIAN NATIONAL EDUCATION SURVEY, AN INTERDISCIPLINARY RESEARCH PROJECT. VOLUMES IIA AND IIB, COMMUNICATIONS VARIABLES IN THE CHURCH.

    ERIC Educational Resources Information Center

    WHITMAN, LAURIS B.; AND OTHERS

    THE DEPARTMENT OF RESEARCH OF THE NATIONAL COUNCIL OF CHURCHES CONDUCTED A SURVEY FOR THE UNITED PRESBYTERIAN CHURCH OF ITS MEMBERSHIP AND RELIGIOUS BELIEFS. THE AIM WAS TO COMPARE VARIOUS POPULATIONS (CLERGY, COMMUNICANTS, CHURCH SCHOOL TEACHERS, AND YOUTH), CONCERNING THE EXTENT OF THEIR ORTHODOXY. VOLUMES IIA AND IIB OF THE REPORT RELATE TO THE…

  15. Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer

    PubMed Central

    Dong, Zhongyun; Liu, Yin; Scott, Kieran F.; Levin, Linda; Gaitonde, Krishnanath; Bracken, R. Bruce; Burke, Barbara; Zhai, Qihui Jim; Wang, Jiang; Oleksowicz, Leslie; Lu, Shan

    2010-01-01

    The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises androgen-independent cell growth. Inhibition of the ligand-induced signaling output of the HER network, by blocking PI3K-Akt signaling and the nuclear factor-kappaB (NF-κB)-mediated pathway, compromises both sPLA2-IIa protein expression and secretion, as a result of downregulation of sPLA2-IIa promoter activity. More importantly, we demonstrated elevated serum sPLA2-IIa levels in prostate cancer patients. High serum sPLA2-IIa levels are associated significantly with high Gleason score and advanced disease stage. Increased sPLA2-IIa expression was confirmed in prostate cancer cells, but not in normal epithelium and stroma by immunohistochemistry analysis. We showed that elevated signaling of the HER/HER2-PI3K-Akt-NF-κB pathway contributes to sPLA2-IIa overexpression and secretion by prostate cancer cells. Given that sPLA2-IIa overexpression is associated with prostate development and progression, serum sPLA2-IIa may serve as a prognostic biomarker for prostate cancer and a potential surrogate prostate biomarker indicative of tumor burden. PMID:20837598

  16. Effect of oral treatment with pantethine on platelet and plasma phospholipids in IIa hyperlipoproteinemia.

    PubMed

    Prisco, D; Rogasi, P G; Matucci, M; Paniccia, R; Abbate, R; Gensini, G F; Neri Serneri, G G

    1987-03-01

    In a single-blind, crossover, completely randomized study, the effects of oral treatment with pantethine or placebo on fatty acid composition of plasma and platelet phospholipids were investigated in 10 IIa hyperlipoproteinemic patients. A significant decrease of total cholesterol and total phospholipids was observed both in plasma and in platelets after a twenty-eight-day treatment. In plasma, pantethine induced a decrease of the ratio sphingomyelin/phosphatidylcholine. Moreover, a relative increase of n3-polyunsaturated fatty acids both in plasma and in platelet phospholipids and a decrease of arachidonic acid in plasma phospholipids were observed. These results indicate that pantethine can affect plasma and platelet lipid composition with possibly favorable influences on the determinants of cell membrane fluidity. PMID:3551695

  17. Characterization of thin HPHT IIa diamond by transmission and reflection measurements

    NASA Astrophysics Data System (ADS)

    Goto, Shunji; Yamazaki, Hiroshi; Miura, Ayumi; Doi, Kenji; Inubushi, Yuichi; Ohashi, Haruhiko; Yabashi, Makina

    2014-09-01

    X-ray transmission properties of a thin HPHT IIa diamond crystal were characterized around Bragg diffraction, using a pseudo plane-wave setup at the 1-km beamline of SPring-8. Monochromatic x-rays of 19.75 keV were used for diamond 400 reflection from 120-μm-thick (001) diamond crystals, and 9.44-keV x-rays were used for diamond 111 reflection from 180-μm-thick (111) crystals. These thin crystals were mounted on the aluminum plate using an ultraviolet-cured resin. Several thin crystals showed rocking curve broadening due to bend. However, by limiting a small area of the crystal, transmittance curves agreed well with those of calculation. We can select a practically usable region for various applications: phase retarder, beam splitter, and also self-seeding of x-ray free electron laser.

  18. Involvement of aph(3′)-IIa in the formation of mosaic aminoglycoside resistance genes in natural environments

    PubMed Central

    Woegerbauer, Markus; Kuffner, Melanie; Domingues, Sara; Nielsen, Kaare M.

    2015-01-01

    Intragenic recombination leading to mosaic gene formation is known to alter resistance profiles for particular genes and bacterial species. Few studies have examined to what extent aminoglycoside resistance genes undergo intragenic recombination. We screened the GenBank database for mosaic gene formation in homologs of the aph(3′)-IIa (nptII) gene. APH(3′)-IIa inactivates important aminoglycoside antibiotics. The gene is widely used as a selectable marker in biotechnology and enters the environment via laboratory discharges and the release of transgenic organisms. Such releases may provide opportunities for recombination in competent environmental bacteria. The retrieved GenBank sequences were grouped in three datasets comprising river water samples, duck pathogens and full-length variants from various bacterial genomes and plasmids. Analysis for recombination in these datasets was performed with the Recombination Detection Program (RDP4), and the Genetic Algorithm for Recombination Detection (GARD). From a total of 89 homologous sequences, 83% showed 99–100% sequence identity with aph(3′)-IIa originally described as part of transposon Tn5. Fifty one were unique sequence variants eligible for recombination analysis. Only a single recombination event was identified with high confidence and indicated the involvement of aph(3′)-IIa in the formation of a mosaic gene located on a plasmid of environmental origin in the multi-resistant isolate Pseudomonas aeruginosa PA96. The available data suggest that aph(3′)-IIa is not an archetypical mosaic gene as the divergence between the described sequence variants and the number of detectable recombination events is low. This is in contrast to the numerous mosaic alleles reported for certain penicillin or tetracycline resistance determinants. PMID:26042098

  19. New type IIB backgrounds and aspects of their field theory duals

    NASA Astrophysics Data System (ADS)

    Caceres, Elena; Macpherson, Niall T.; Núñez, Carlos

    2014-08-01

    In this paper we study aspects of geometries in Type IIA and Type IIB String theory and elaborate on their field theory dual pairs. The backgrounds are associated with reductions to Type IIA of solutions with G 2 holonomy in eleven dimensions. We classify these backgrounds according to their G-structure, perform a non-Abelian T-duality on them and find new Type IIB configurations presenting dynamical SU(2)-structure. We study some aspects of the associated field theories defined by these new backgrounds. Various technical details are clearly spelled out.

  20. Six-dimensional (1,0) effective action of F-theory via M-theory on Calabi-Yau threefolds

    NASA Astrophysics Data System (ADS)

    Bonetti, Federico; Grimm, Thomas W.

    2012-05-01

    The 6d effective action of F-theory compactified on an elliptically fibred CalabiYau threefold is determined using an M-theory lift. The non-Abelian gauge theory arises on a stack of seven-branes located on the singularities of the threefold. The gauge theory is analysed in the 5d Coulomb branch by resolving the Calabi-Yau threefold. The reduction includes an arbitrary number of 6d tensor multiplets for which the self- and anti-self duality constraints can be imposed in the 5d M-theory set-up. Higher curvature terms are crucial for anomaly cancellation in six dimensions, and are obtained from corrections to the 11d supergravity action. The chiral spectrum in a 6d supergravity theory is linked to the form of the Green-Schwarz couplings via anomalies. We find that these data are encoded in the 5d effective action via one loop corrections.

  1. Quarter-BPS AdS 5 solutions in M-theory with a T 2 bundle over a Riemann surface

    NASA Astrophysics Data System (ADS)

    Bah, Ibrahima

    2013-08-01

    We study and classify quarter-BPS AdS 5 systems in M-theory, whose internal six-dimensional geometry is a T 2 bundle over a Riemann surface and two interval directions. The general system presented, provides a unified description of all known AdS 5 solutions in M-theory. These systems are governed by two functions, one that corresponds to the conformal factor of the Riemann surface and another that describes the T 2 fibration. We find a special set of solutions that can be organized into two classes. In the first one, solutions are specified by the conformal factor of the Riemann surface which satisfies a warped generalization of the SU(∞) Toda equation. The system in the second class requires the Riemann surface to be S 2, H 2 or T 2. Class one contains the M-theory AdS 5 solutions of Lin, Lunin and Maldacena; the solutions of Maldacena and Núñez; the solutions of Gauntlett, Martelli, Sparks and Waldram; and the eleven-dimensional uplift of the Y p, q metrics. The second includes the recently found solutions of Beem, Bobev, Wecht and the author. Within each class there are new solutions that will be studied in a companion paper.

  2. Presence of Cryptosporidium scrofarum, C. suis and C. parvum subtypes IIaA16G2R1 and IIaA13G1R1 in Eurasian wild boars (Sus scrofa).

    PubMed

    García-Presedo, Ignacio; Pedraza-Díaz, Susana; González-Warleta, Marta; Mezo, Mercedes; Gómez-Bautista, Mercedes; Ortega-Mora, Luis Miguel; Castro-Hermida, José Antonio

    2013-09-23

    The aim of the present study was to identify the species of Cryptosporidium infecting Eurasian wild boars (Sus scrofa) in Galicia (NW, Spain). A sampling of 209 wild boars shot in different game preserves was carried out during the hunting season in 2009-2010. All samples were examined for Cryptosporidium infection, using both immunological and molecular tools. Cryptosporidium oocysts in faecal samples were identified using a direct immunofluorescence technique with monoclonal antibodies (DFA). The presence of Cryptosporidium DNA was determined using nested PCR involving amplification of a fragment of the small-subunit (SSU) ribosomal RNA gene (SSU rRNA). A total of 35 (16.7%) samples tested positive with both techniques. However, sequencing was only possible in 27 samples. Cryptosporidium scrofarum, Cryptosporidium suis and Cryptosporidium parvum oocysts were identified in 19, 5 and 3 of the samples, respectively. Moreover, C. scrofarum was detected as a dominant species infecting all age groups (juveniles, sub adults and adults). Sequence analyses of the glycoprotein (GP60) gene revealed the presence of C. parvum subtypes IIaA16G2R1 in 2 juveniles and IIaA13G1R1 in 1 sub adult wild boar. These species and subtypes have previously been described in human patients, indicating that isolates from asymptomatic wild boars might have zoonotic potential. This is the first report of the presence of C. scrofarum, C. suis and C. parvum subtypes IIaA16G2R1 and IIaA13G1R1 in wild boars (S. scrofa) in Spain. PMID:23643454

  3. Geology and mineral resources of central Antioquia Department (Zone IIA), Colombia

    USGS Publications Warehouse

    Hall, R.B.; Alvarez A., Jairo; Rico H., Hector

    1973-01-01

    Antioquian batholith. Displacement along the great Romeral wrench fault may have begun in the Cretaceous. Plutonism continued into the Cenozoic, exemplified by the hornblende-diorite Sabanalarga pluton. Intermontane basins were filled with molasse derived from the erosion of adjacent highlands; Tertiary sedimentation in marshy areas included organic carboniferous matter subsequently converted to lignite or subbituminous coal. The Sabanalarga fault system originated in the Late Tertiary; intermittent displacement continued on the older wrench faults such as the Romeral. Epeirogenic uplift, which probably began in the Pliocene and continued through the Pleistocene and Holocene, brought on renewed erosion which has sculptured the mountains into their present form. Mineral resources in subzone IIA are varied but not of outstanding importance. Gold and silver mining, significant in past centuries, is minor today. Ferruginous laterite on serpentinite once considered as a potential source of iron ore is not economically exploitable. IMN has explored nickeliferous laterite at the extreme northwest corner of subzone IIA; this is a potential resource, exploitable only after exhaustion of the larger and richer nickel laterite deposit at Cerro Matoso, farther to the north and outside the boundaries of Zone If. Known deposits of mercury, chromium, manganese, and copper are small, with limited economic potential. Nonmetallic resources include raw materials for cement, including portland cement. Saprolite clay is widely used in making common red brick and tile, still a dominant construction material in all but the most modern multistory buildings. Aggregate materials are varied and abundant. Kaolin of good quality near La Union is important as a ceramic raw mineral filler. Tertiary subbituminous coal beds are an important energy resource in western subzone IIA, and have a good potential for greater development. Deposits of sodic feldspar, talc, decorative stone, and silica a

  4. Proteomic analysis reveals tanshinone IIA enhances apoptosis of advanced cervix carcinoma CaSki cells through mitochondria intrinsic and endoplasmic reticulum stress pathways.

    PubMed

    Pan, Tai-Long; Wang, Pei-Wen; Hung, Yu-Chiang; Huang, Chun-Hsun; Rau, Kun-Ming

    2013-12-01

    Cervix cancer is the second most common cancer among women worldwide, whereas paclitaxel, the first line chemotherapeutic drug used to treat cervical cancer, shows low chemosensitivity on the advanced cervical cancer cell line. Tanshinone IIA (Tan IIA) exhibited strong growth inhibitory effect on CaSki cells (IC50 = 5.51 μM) through promoting caspase cascades with concomitant upregulating the phosphorylation of p38 and JNK signaling. Comprehensive proteomics revealed the global protein changes and the network analysis implied that Tan IIA treatment would activate ER stress pathways that finally lead to apoptotic cell death. Moreover, ER stress inhibitor could alleviate Tan IIA caused cell growth inhibition and ameliorate C/EBP-homologous protein as well as apoptosis signal-regulating kinase 1 mediated cell death. The therapeutic interventions targeting the mitochondrial-related apoptosis and ER stress responses might be promising strategies to conquer paclitaxel resistance. PMID:24167031

  5. A unique tool to selectively detect the chondrogenic IIB form of human type II procollagen protein.

    PubMed

    Aubert-Foucher, Elisabeth; Mayer, Nathalie; Pasdeloup, Marielle; Pagnon, Aurélie; Hartmann, Daniel; Mallein-Gerin, Frédéric

    2014-02-01

    Type II collagen, the major fibrillar collagen of cartilage, is synthesized as precursor forms (procollagens) containing N- and C-terminal propeptides. Three splice variants are thought to be translated to produce procollagen II isoforms (IIA/D and IIB) which differ in their amino propeptide parts. The IIA and IID are transient embryonic isoforms that include an additional cysteine-rich domain encoded by exon 2. The IIA and IID transcripts are co-expressed during chondrogenesis then decline and the IIB isoform is the only one expressed and synthesized in fully differentiated chondrocytes. Additionally, procollagens IIA/D can be re-expressed by dedifferentiating chondrocytes and in osteoarthritic cartilage. Therefore, it is an important point to determine which isoform(s) is (are) synthesized in vivo in normal and pathological situations and in vitro, to fully assess the phenotype of cells producing type II collagen protein. Antibodies directed against the cysteine-rich extra domain found in procollagens IIA and IID are already available but antibodies detecting only the chondrogenic IIB form of type II procollagen were missing so far. A synthetic peptide encompassing the junction between exon 1 and exon 3 of the human sequence was used as immunogen to produce rabbit polyclonal antibodies to procollagen IIB. After affinity purification on immobilized peptide their absence of crossreaction with procollagens IIA/D and with the fibrillar procollagens I, III and V was demonstrated by Western blotting. These antibodies were used to reveal at the protein level that the treatment of dedifferentiated human chondrocytes by bone morphogenic protein (BMP)-2 induces the synthesis of the IIB (chondrocytic) isoform of procollagen II. In addition, immunohistochemical staining of bovine cartilage demonstrates the potential of these antibodies in the analysis of the differential spatiotemporal distribution of N-propeptides of procollagens IIA/D and IIB during normal development and

  6. Tanshinone IIA protects H9c2 cells from oxidative stress-induced cell death via microRNA-133 upregulation and Akt activation

    PubMed Central

    Gu, Yunfei; Liang, Zhuo; Wang, Haijun; Jin, Jun; Zhang, Shouyan; Xue, Shufeng; Chen, Jianfeng; He, Huijuan; Duan, Kadan; Wang, Jing; Chang, Xuewei; Qiu, Chunguang

    2016-01-01

    The aim of the present study was to investigate the cardioprotective effect of tanshinone IIA and the underlying molecular mechanisms. An in vitro model of oxidative stress injury was established in cardiac H9c2 cells, and the effects of tanshinone IIa were investigated using cell viability, reverse transcription-quantitative polymerase chain reaction and western blotting assays. The results demonstrated that tanshinone IIA protects H9c2 cells from H2O2-induced cell death in a concentration-dependent manner, via a mechanism involving microRNA-133 (miR-133), and that treatment with TIIA alone exerted no cytotoxic effects on H9c2. In order to further elucidate the mechanisms underlying the actions of TIIA, reverse transcription-quantitative polymease chain reaction and western blot analysis were performed. Reductions in miR-133 expression levels induced by increasing concentrations of H2O2 were reversed by treatment with tanshinone IIA. In addition, the inhibition of miR-133 by transfection with an miR-133 inhibitor abolished the cardioprotective effects of tanshinone IIA against H2O2-induced cell death. Furthermore, western blot analysis demonstrated that tanshinone IIA activated Akt kinase via the phosphorylation of serine 473. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway by pretreatment with the PI3K specific inhibitors wortmannin and LY294002 also eliminated the cardioprotective effects of tanshinone IIA against H2O2-induced cell death. Western blot analysis demonstrated that H2O2-induced reductions in B cell lymphoma 2 (Bcl-2) expression levels were reversed by tanshinone IIA. In addition, the effect of tanshinone IIA on Bcl-2 protein expression level in an oxidative environment was suppressed by a PI3K inhibitor, wortmannin, indicating that tanshinone IIA exerts cardioprotective effects against H2O2-induced cell death via the activation of the PI3K/Akt signal transduction pathway and the consequent upregulation of Bcl-2. In

  7. 30 CFR 57.22222 - Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ....22222 Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). Brattice cloth and ventilation tubing shall be approved by MSHA in accordance with 30 CFR part 7, or shall bear a BC or VT... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Ventilation materials (I-A, I-B, I-C, II-A,...

  8. Tanshinone IIA inhibits breast cancer stem cells growth in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways.

    PubMed

    Lin, Caiyu; Wang, Li; Wang, Hong; Yang, Liuqi; Guo, Huijie; Wang, Xiujie

    2013-09-01

    Cancer stem cells (CSCs) are maintained by inflammatory cytokines and signaling pathways. Tanshinone IIA (Tan-IIA) possesses anti-cancer and anti-inflammatory activities. The purpose of this study is to confirm the growth inhibition effect of Tan-IIA on human breast CSCs growth in vitro and in vivo and to explore the possible mechanism of its activity. Human breast CSCs were enriched and expanded under serum-free mammosphere culture condition, and identified through mammosphere formation, toluidine blue staining, immunofluorescence staining, and flow cytometry analysis of stemness markers of CD44/CD24 and ALDH, and tumorigenecity in vivo; the growth inhibition effect of Tan-IIA on human breast CSCs in vitro were tested by cell proliferation and mammosphere formation assays; inflammatory signaling pathway related protein expression in response to Tan-IIA, IL-6, STAT3, phospho-STAT3 (Tyr705), NF-κBp65 in cytoplasm and nucleus and cyclin D1 were evaluated with Western blotting; the growth inhibition effect of Tan-IIA on human breast CSCs growth were tested in vivo. A useful model of human breast CSCs for researching and developing the agents targeting CSCs was established. After Tan-IIA treatment, cell proliferation and mammosphere formation of CSCs were decreased significantly; the expression levels of IL-6, STAT3, phospho-STAT3 (Tyr705), NF-κBp65 in nucleus and cyclin D1 proteins were decreased significantly; the tumor growth and mean tumor weight were reduced significantly. Tan-IIA has the potential to target and kill CSCs, and can inhibit human breast CSCs growth both in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways. PMID:23553622

  9. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... reverse airstream shall be approved by MSHA under the appliable requirements of 30 CFR part 18; (2) Drive... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on...

  10. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... reverse airstream shall be approved by MSHA under the appliable requirements of 30 CFR part 18; (2) Drive... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on...

  11. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... reverse airstream shall be approved by MSHA under the appliable requirements of 30 CFR part 18; (2) Drive... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V... Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). (a) Main fans shall be— (1) Installed on...

  12. Purification and Characterization of a Novel Class IIa Bacteriocin, Piscicocin CS526, from Surimi-Associated Carnobacterium piscicola CS526

    PubMed Central

    Yamazaki, Koji; Suzuki, Minako; Kawai, Yuji; Inoue, Norio; Montville, Thomas J.

    2005-01-01

    The bacteriocin piscicocin CS526 was inactivated by proteolytic enzymes, was stable at 100°C for 30 min, had a pH range of 2 to 8, and was active against Enterococcus, Listeria, Pediococcus, and Leuconostoc. The N-terminal sequence was YGNGL, not the YGNGV consensus motif common in class IIa bacteriocins (alternate residues underlined). The molecular mass of piscicocin CS526, which had a bactericidal mode of action, was ∼4,430 Da. PMID:15640235

  13. Radioactive waste disposal implications of extending Part IIA of the Environmental Protection Act to cover radioactively contaminated land.

    PubMed

    Nancarrow, D J; White, M M

    2004-03-01

    A short study has been carried out of the potential radioactive waste disposal issues associated with the proposed extension of Part IIA of the Environmental Protection Act 1990 to include radioactively contaminated land, where there is no other suitable existing legislation. It was found that there is likely to be an availability problem with respect to disposal at landfills of the radioactive wastes arising from remediation. This is expected to be principally wastes of high volume and low activity (categorised as low level waste (LLW) and very low level waste (VLLW)). The availability problem results from a lack of applications by landfill operators for authorisation to accept LLW wastes for disposal. This is apparently due to perceived adverse publicity associated with the consultation process for authorisation coupled with uncertainty over future liabilities. Disposal of waste as VLLW is limited both by questions over volumes that may be acceptable and, more fundamentally, by the likely alpha activity of wastes (originating from radium and thorium operations). Authorised on-site disposal has had little attention in policy and guidance in recent years, but may have a part to play, especially if considered commercially attractive. Disposal at BNFL's near surface disposal facility for LLW at Drigg is limited to wastes for which there are no practical alternative disposal options (and preference has been given to operational type wastes). Therefore, wastes from the radioactively contaminated land (RCL) regime are not obviously attractive for disposal to Drigg. Illustrative calculations have been performed based on possible volumes and activities of RCL arisings (and assuming Drigg's future volumetric disposal capacity is 950,000 m3). These suggest that wastes arising from implementing the RCL regime, if all disposed to Drigg, would not represent a significant fraction of the volumetric capacity of Drigg, but could have a significant impact on the radiological

  14. Histone II-A stimulates glucose-6-phosphatase and reveals mannose-6-phosphatase activities without permeabilization of liver microsomes.

    PubMed Central

    St-Denis, J F; Annabi, B; Khoury, H; van de Werve, G

    1995-01-01

    The effect of histone II-A on glucose-6-phosphatase and mannose-6-phosphatase activities was investigated in relation to microsomal membrane permeability. It was found that glucose-6-phosphatase activity in histone II-A-pretreated liver microsomes was stimulated to the same extent as in detergent-permeabilized microsomes, and that the substrate specificity of the enzyme for glucose 6-phosphate was lost in histone II-A-pretreated microsomes, as [U-14C]glucose-6-phosphate hydrolysis was inhibited by mannose 6-phosphate and [U-14C]mannose 6-phosphate hydrolysis was increased. The accumulation of [U-14C]glucose from [U-14C]glucose 6-phosphate into untreated microsomes was completely abolished in detergent-treated vesicles, but was increased in histone II-A-treated microsomes, accounting for the increased glucose-6-phosphatase activity, and demonstrating that the microsomal membrane was still intact. The stimulation of glucose-6-phosphatase and mannose-6-phosphatase activities by histone II-A was found to be reversed by EGTA. It is concluded that the effects of histone II-A on glucose-6-phosphatase and mannose-6-phosphatase are not caused by the permeabilization of the microsomal membrane. The measurement of mannose-6-phosphatase latency to evaluate the intactness of the vesicles is therefore inappropriate. PMID:7646448

  15. Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity

    SciTech Connect

    Schuetz, Anja; Min, Jinrong; Allali-Hassani, Abdellah; Schapira, Matthieu; Shuen, Michael; Loppnau, Peter; Mazitschek, Ralph; Kwiatkowski, Nick P.; Lewis, Timothy A.; Maglathin, Rebecca L.; McLean, Thomas H.; Bochkarev, Alexey; Plotnikov, Alexander N.; Vedadi, Masoud; Arrowsmith, Cheryl H.

    2010-10-18

    Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators.

  16. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation.

    PubMed

    Boudreau, Luc H; Duchez, Anne-Claire; Cloutier, Nathalie; Soulet, Denis; Martin, Nicolas; Bollinger, James; Paré, Alexandre; Rousseau, Matthieu; Naika, Gajendra S; Lévesque, Tania; Laflamme, Cynthia; Marcoux, Geneviève; Lambeau, Gérard; Farndale, Richard W; Pouliot, Marc; Hamzeh-Cognasse, Hind; Cognasse, Fabrice; Garraud, Olivier; Nigrovic, Peter A; Guderley, Helga; Lacroix, Steve; Thibault, Louis; Semple, John W; Gelb, Michael H; Boilard, Eric

    2014-10-01

    Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses. PMID:25082876

  17. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation

    PubMed Central

    Boudreau, Luc H.; Duchez, Anne-Claire; Cloutier, Nathalie; Soulet, Denis; Martin, Nicolas; Bollinger, James; Paré, Alexandre; Rousseau, Matthieu; Naika, Gajendra S.; Lévesque, Tania; Laflamme, Cynthia; Marcoux, Geneviève; Lambeau, Gérard; Farndale, Richard W.; Pouliot, Marc; Hamzeh-Cognasse, Hind; Cognasse, Fabrice; Garraud, Olivier; Nigrovic, Peter A.; Guderley, Helga; Lacroix, Steve; Thibault, Louis; Semple, John W.; Gelb, Michael H.

    2014-01-01

    Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses. PMID:25082876

  18. Myosin IIA participates in docking of Glut4 storage vesicles with the plasma membrane in 3T3-L1 adipocytes

    SciTech Connect

    Chung, Le Thi Kim; Hosaka, Toshio; Harada, Nagakatsu; Jambaldorj, Bayasgalan; Fukunaga, Keiko; Nishiwaki, Yuka; Teshigawara, Kiyoshi; Sakai, Tohru; Nakaya, Yutaka; Funaki, Makoto

    2010-01-01

    In adipocytes and myocytes, insulin stimulation translocates glucose transporter 4 (Glut4) storage vesicles (GSVs) from their intracellular storage sites to the plasma membrane (PM) where they dock with the PM. Then, Glut4 is inserted into the PM and initiates glucose uptake into these cells. Previous studies using chemical inhibitors demonstrated that myosin II participates in fusion of GSVs and the PM and increase in the intrinsic activity of Glut4. In this study, the effect of myosin IIA on GSV trafficking was examined by knocking down myosin IIA expression. Myosin IIA knockdown decreased both glucose uptake and exposures of myc-tagged Glut4 to the cell surface in insulin-stimulated cells, but did not affect insulin signal transduction. Interestingly, myosin IIA knockdown failed to decrease insulin-dependent trafficking of Glut4 to the PM. Moreover, in myosin IIA knockdown cells, insulin-stimulated binding of GSV SNARE protein, vesicle-associated membrane protein 2 (VAMP2) to PM SNARE protein, syntaxin 4 was inhibited. These data suggest that myosin IIA plays a role in insulin-stimulated docking of GSVs to the PM in 3T3-L1 adipocytes through SNARE complex formation.

  19. Tanshinone IIA inhibits apoptosis in the myocardium by inducing microRNA-152-3p expression and thereby downregulating PTEN.

    PubMed

    Zhang, Zhen; Li, Yumei; Sheng, Chuqiao; Yang, Chunfeng; Chen, Liping; Sun, Jinghui

    2016-01-01

    Progressive loss of cardiac myocytes through apoptosis contributes to heart failure (HF). In this study, we tested whether tanshinone IIA, one of the most abundant constituents of the root of Salvia miltiorrhiza, protects rat myocardium-derived H9C2 cells against apoptosis. Treatment of H9C2 cells with tanshinone IIA inhibited angiotensin II-induced apoptosis by downregulating the expression of PTEN (phosphatase and tensin homolog), a tumor suppressor that plays a critical role in apoptosis. Furthermore, tanshinone IIA was found to inhibit PTEN expression by upregulating the microRNA miR-152-3p, a potential PTEN regulator that is highly conserved in both rat and human. Notably, the antiapoptotic effect of tanshinone IIA was partially reversed when H9C2 cells were transfected with an inhibitor of miR-152-3p. Collectively, our findings reveal a previously unrecognized mechanism underlying the cardioprotective role of tanshinone IIA, and further suggest that tanshinone IIA could represent a promising drug candidate for HF therapy. PMID:27508033

  20. Tanshinone IIA inhibits apoptosis in the myocardium by inducing microRNA-152-3p expression and thereby downregulating PTEN

    PubMed Central

    Zhang, Zhen; Li, Yumei; Sheng, Chuqiao; Yang, Chunfeng; Chen, Liping; Sun, Jinghui

    2016-01-01

    Progressive loss of cardiac myocytes through apoptosis contributes to heart failure (HF). In this study, we tested whether tanshinone IIA, one of the most abundant constituents of the root of Salvia miltiorrhiza, protects rat myocardium-derived H9C2 cells against apoptosis. Treatment of H9C2 cells with tanshinone IIA inhibited angiotensin II-induced apoptosis by downregulating the expression of PTEN (phosphatase and tensin homolog), a tumor suppressor that plays a critical role in apoptosis. Furthermore, tanshinone IIA was found to inhibit PTEN expression by upregulating the microRNA miR-152-3p, a potential PTEN regulator that is highly conserved in both rat and human. Notably, the antiapoptotic effect of tanshinone IIA was partially reversed when H9C2 cells were transfected with an inhibitor of miR-152-3p. Collectively, our findings reveal a previously unrecognized mechanism underlying the cardioprotective role of tanshinone IIA, and further suggest that tanshinone IIA could represent a promising drug candidate for HF therapy. PMID:27508033

  1. Apoptosis Induced by Tanshinone IIA and Cryptotanshinone Is Mediated by Distinct JAK/STAT3/5 and SHP1/2 Signaling in Chronic Myeloid Leukemia K562 Cells

    PubMed Central

    Jung, Ji Hoon; Kwon, Tae-Rin; Jeong, Soo-Jin; Kim, Eun-Ok; Sohn, Eun Jung; Yun, Miyong; Kim, Sung-Hoon

    2013-01-01

    Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear. In the present study, we investigated the effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. We found that both tanshinone IIA and cryptotanshinone induced apoptosis by activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3. In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells. Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells. PMID:23878608

  2. Heat-Labile Enterotoxin IIa, a Platform To Deliver Heterologous Proteins into Neurons

    PubMed Central

    Chen, Chen; Przedpelski, Amanda; Tepp, William H.; Pellett, Sabine; Johnson, Eric A.

    2015-01-01

    ABSTRACT Cholera toxin (CT) and the related heat-labile enterotoxins (LT) of Escherichia coli have been implicated as adjuvants in human therapies, but reactivity upon intranasal delivery dampened efforts to develop other clinical applications. However, each CT family member variant has unique biological properties that may warrant development as therapeutic platforms. In the current study, a nontoxic variant of the heat-labile enterotoxin IIa (LTIIa) was engineered to deliver heterologous, functional proteins into the cytosol of neurons. As proof of principle, the LTIIa variant delivered two cargos into neurons. LTIIa delivered β-lactamase efficiently into cells containing complex gangliosides, such as GD1b, as host receptors. LTIIa delivery of β-lactamase was sensitive to brefeldin A, an inhibitor that collapses the Golgi compartment into the endoplasmic reticulum, but not sensitive to treatment with botulinum neurotoxin D (BoNT/D), an inhibitor of synaptic vesicle cycling. LTIIa delivered a single-chain, anti-BoNT/A camelid antibody that inhibited SNAP25 cleavage during post-BoNT/A exposure of neurons. Delivery of functional, heterologous protein cargos into neurons demonstrates the potential of LTII variants as platforms to deliver therapies to inactivate toxins and microbial infections and to reverse the pathology of human neurodegenerative diseases. PMID:26265718

  3. IIA: a novel method to optimize media instruction set of embedded processor

    NASA Astrophysics Data System (ADS)

    Chen, Keming; Yu, Guojun; Liu, Peng; Yao, Qingdong

    2006-02-01

    To accelerate media processing, many media enhancement instructions have been adopted into the instruction set of embedded processors. In this paper, a novel method, called interaction between instructions and algorithms (IIA), is proposed to optimize these media enhancement instructions. Based on the analysis for inherent characteristics of video processing algorithms and processor's architecture, three measures are proposed: three single-cycle instructions for manipulation on bit level are implemented to speed up variable-length decoding; a data path is designed to solve data misalignment in SIMD processing instead of software programs; a memory architecture is proposed to support 128-bit word parallel processing. All these suggestions are used in the optimization of an embedded processor, MediaDSP3200 which fuses RISC architecture and DSP computation capability thoroughly and achieves reduced instruction and 64-bit SIMD instruction set with various addressing mode in a unified RISC pipeline stage architecture. Simulation results show that this optimization method can reduce more than 26.4% of clock cycles for VLD, 47.8% for IDCT and 66.8% for MC in real-time processing.

  4. Fc gamma receptor IIa (CD32) polymorphism in fulminant meningococcal septic shock in children.

    PubMed

    Bredius, R G; Derkx, B H; Fijen, C A; de Wit, T P; de Haas, M; Weening, R S; van de Winkel, J G; Out, T A

    1994-10-01

    Antibodies are essential in host defense against Neisseria meningitidis. Therefore, interactions among IgG and Fc receptors (Fc gamma R) on phagocytes may be crucial. Genetic polymorphic forms of Fc gamma RIIa (CD32) express different functional activities. In a retrospective study, Fc gamma R polymorphisms were determined in 25 children who survived fulminant meningococcal septic shock: 11 had Fc gamma RIIa-R/R131, the poor IgG2-binding allotype, which is a significantly more frequent rate than found in a healthy white population (44% vs. 23%; P = .028; odds ratio = 2.67; 95% confidence interval, 1.09-6.53). The relevance of this finding was further supported by the fact that neutrophils with the Fc gamma RIIa-R/R131 allotype phagocytized N. meningitidis opsonized with polyclonal IgG2 antibodies less effectively than did IIa-H/H131 neutrophils. Our findings suggest an important role for anti-N. meningitidis IgG2 and the Fc gamma RIIa polymorphism in host defense against systemic meningococcal infections. PMID:7930726

  5. Preparation, characterization, and in vivo evaluation of tanshinone IIA solid dispersions with silica nanoparticles

    PubMed Central

    Jiang, Yan-rong; Zhang, Zhen-hai; Liu, Qi-yuan; Hu, Shao-ying; Chen, Xiao-yun; Jia, Xiao-bin

    2013-01-01

    We prepared solid dispersions (SDs) of tanshinone IIA (TSIIA) with silica nanoparticles, which function as dispersing carriers, using a spray-drying method and evaluated their in vitro dissolution and in vivo performance. The extent of TSIIA dissolution in the silica nanoparticles/TSIIA system (weight ratio, 5:1) was approximately 92% higher than that of the pure drug after 60 minutes. However, increasing the content of silica nanoparticles from 5:1 to 7:1 in this system did not significantly increase the rate or extent of TSIIA dissolution. The physicochemical properties of SDs were investigated using scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, and Fourier transforms infrared spectroscopy. Studying the stability of the SDs of TSIIA revealed that the drug content of the formulation and dissolution behavior was unchanged under the applied storage conditions. In vivo tests showed that SDs of the silica nanoparticles/TSIIA had a significantly larger area under the concentration-time curve, which was 1.27 times more than that of TSIIA (P < 0.01). Additionally, the values of maximum plasma concentration and the time to reach maximum plasma concentration of the SDs were higher than those of TSIIA and the physical mixing system. Based on these results, we conclude that the silica nanoparticle based SDs achieved complete dissolution, increased absorption rate, maintained drug stability, and showed improved oral bioavailability compared to TSIIA alone. PMID:23836971

  6. Glucose-Specific Enzyme IIA Has Unique Binding Partners in The Vibrio cholerae Biofilm

    PubMed Central

    Pickering, Bradley S.; Smith, Daniel R.; Watnick, Paula I.

    2012-01-01

    ABSTRACT Glucose-specific enzyme IIA (EIIAGlc) is a central regulator of bacterial metabolism and an intermediate in the phosphoenolpyruvate phosphotransferase system (PTS), a conserved phosphotransfer cascade that controls carbohydrate transport. We previously reported that EIIAGlc activates transcription of the genes required for Vibrio cholerae biofilm formation. While EIIAGlc modulates the function of many proteins through a direct interaction, none of the known regulatory binding partners of EIIAGlc activates biofilm formation. Therefore, we used tandem affinity purification (TAP) to compare binding partners of EIIAGlc in both planktonic and biofilm cells. A surprising number of novel EIIAGlc binding partners were identified predominantly under one condition or the other. Studies of planktonic cells revealed established partners of EIIAGlc, such as adenylate cyclase and glycerol kinase. In biofilms, MshH, a homolog of Escherichia coli CsrD, was found to be a dominant binding partner of EIIAGlc. Further studies revealed that MshH inhibits biofilm formation. This function was independent of the Carbon storage regulator (Csr) pathway and dependent on EIIAGlc. To explore the existence of multiprotein complexes centered on EIIAGlc, we also affinity purified the binding partners of adenylate cyclase from biofilm cells. In addition to EIIAGlc, this analysis yielded many of the same proteins that copurified with EIIAGlc. We hypothesize that EIIAGlc serves as a hub for multiprotein complexes and furthermore that these complexes may provide a mechanism for competitive and cooperative interactions between binding partners. PMID:23131828

  7. Tanshinone IIA enhances chemosensitivity of colon cancer cells by suppressing nuclear factor-κB

    PubMed Central

    BAI, YANGQIU; ZHANG, LIDA; FANG, XINHUI; YANG, YUXIU

    2016-01-01

    The aim of the present study was to investigate the effect and molecular mechanism of tanshinone IIA (TSA) on colon cancer cells. Cell viability was determined using Cell Counting kit-8 assay and the results demonstrated that TSA treatment significantly decreased the cell viability of HCT1116 and COLO205 cells in a dose-dependent manner. TSA treatment also sensitized HCT1116 and COLO205 cells to fluorouracil therapy in a concentration-dependent manner. Western blotting was performed in order to investigate the molecular mechanisms of TSA action and determine the level of phosporylated p65 and nuclear factor-κB (NF-κB)-regulated genes, including vascular endothelial growth factor (VEGF), c-Myc, cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2). The results revealed that TSA treatment greatly decreased the level of phosphorylated p65 in the nucleus, which indicated the inhibition of NF-κB activation by TSA treatment. TSA also decreased the expression levels of VEGF, c-Myc, COX-2 and Bcl-2. Furthermore, the inhibition of NF-κB activation with the specific inhibitor, pyrrolidine dithiocarbamate, increased the induction of cell death and chemosensitization effect of TSA in colon cancer cells. In conclusion, these results suggest that TSA induces cell death and chemosensitizes colon cancer cells through the suppression of NF-κB signaling. PMID:26998041

  8. Tanshinone IIA Alleviates the AD Phenotypes in APP and PS1 Transgenic Mice

    PubMed Central

    Li, Fengling; Han, Guosheng; Wu, Kexiang

    2016-01-01

    Therapeutic approach for Alzheimer's disease (AD) is still deficient. To find active compounds from herbal medicine is of interest in the alleviation of AD symptoms. This study aimed to investigate the protective effects of Tanshinone IIA (TIIA) on memory performance and synaptic plasticity in a transgenic AD model at the early phase. 25–100 mg/kg TIIA (intraperitoneal injection, i.p.) was administered to the six-month-old APP and PS1 transgenic mice for 30 consecutive days. After treatment, spatial memory, synaptic plasticity, and related mechanisms were investigated. Our result showed that memory impairment in AD mice was mitigated by 50 and 100 mg/kg TIIA treatments. Hippocampal long-term potentiation was impaired in AD model but rescued by 100 mg/kg TIIA treatment. Mechanically, TIIA treatment reduced the accumulations of beta-amyloid 1–42, C-terminal fragments (CTFs), and p-Tau in the AD model. TIIA did not affect basal BDNF but promoted depolarization-induced BDNF synthesis in the AD mice. Taken together, TIIA repairs hippocampal LTP and memory, likely, through facilitating the clearance of AD-related proteins and activating synaptic BDNF synthesis. TIIA might be a candidate drug for AD treatment. PMID:27274990

  9. Metabolism of tanshinone IIA, cryptotanshinone and tanshinone I from Radix Salvia miltiorrhiza in zebrafish.

    PubMed

    Wei, Yingjie; Li, Ping; Wang, Changmei; Peng, Yunru; Shu, Luan; Jia, Xiaobin; Ma, Wenquan; Wang, Bing

    2012-01-01

    The study aimed to investigate the potential of zebrafish in imitating mammal phase I metabolism of natural compounds. Three diterpenoid quinones from Radix Salvia miltiorrhiza, namely tanshinone IIA (TIIA), cryptotanshinone (Cry) and tanshinone I (TI) were selected as model compounds, and their metabolites mediated by zebrafish were characterized using a high-performance liquid chromatography coupled ion-trap mass spectrometry (HPLC/IT-MSn) method with electrospray ionization in positive mode. The separation was performed with a Zorbax C-18 column using a binary gradient elution of 0.05% formic acid acetonitrile/0.05% formic acid water. According to the MS spectra and after comparison with reference standards and literature reports, hydroxylation, dehydrogenation or D-ring hydrolysis metabolites of TIIA and Cry but not of TI were characterized, which coincided with those reported using regular in vivo or in vitro metabolic analysis methods, thus verifying that zebrafish can successfully imitate mammalian phase I metabolism which instills further confidence in using zebrafish as a novel and prospective metabolism model. PMID:22810195

  10. The interplay between autophagy and apoptosis induced by tanshinone IIA in prostate cancer cells.

    PubMed

    Li, Chunlong; Han, Xiancheng; Zhang, Hong; Wu, Jinsheng; Li, Bao

    2016-06-01

    Tanshinone IIA (T2A), a derivative of phenanthrenequinone and also the major active ingredient of Danshen, has been paid extensive attention as a promising cancer therapy for its potential anti-cancer activities. In this study, the apoptosis and autophagy of human prostate cancer PC-3 cells were observed after 5 μM T2A treatment, as well as their relevance. Mitochondrial-dependent apoptosis was firstly detected through morphological observation and biochemical analysis. Meanwhile, 5 μM T2A successfully triggered the autophagy of PC-3 cells, indicated by increased expression of Beclin1, and LC3 II. Validation experiments were conducted to further consolidate T2A's contribution to autophagy: Pretreatment with autophagy inhibitor 3-methyladenine (3-MA) provided protection against autophagy and enhanced T2A-induced apoptosis. Besides, the apoptosis suppressor z-VAD-fmk failed to facilitate the formation of autophagic vacuoles, which also proved the T2A-induced autophagy independent of apoptosis. Moreover, the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) efficiently inhibited the expression of Beclin1, LC3-II, and cleaved caspase-3, which indicated apoptosis and autophagy with dependence on intracellular ROS production. Taken together, these results demonstrated that autophagy is the cytoprotective mechanism in this experimental system, and the ROS resulted from T2A treatment played a critical role in apoptosis and autophagy initiation. PMID:26687918

  11. Tanshinone IIA blocks dexamethasone-induced apoptosis in osteoblasts through inhibiting Nox4-derived ROS production

    PubMed Central

    Li, Jia; He, Chongru; Tong, Wenwen; Zou, Yuming; Li, Dahe; Zhang, Chen; Xu, Weidong

    2015-01-01

    Apoptosis of osteoblasts caused by glucocorticoids has been identified as an important contributor to the development of osteoporosis. Tanshinone IIA (Tan), an active ingredient extracted from the rhizome of the Salvia miltiorrhiza Bunge (Danshen), has been reported to cast positive effects on osteoporosis. However, the precise mechanisms accounting this action remain elusive. In this study, by using osteoblastic MC3T3-E1 cells as a model, we confirmed the protective effects of Tan against dexamethasone (Dex)-induced cell apoptosis and further clarified its molecular mechanism of action. Our results showed that treatment with Dex caused cell injury, increased cytosol cytochrome c level and Nox expression, induced apoptosis in caspase-9-dependent manner, and enhanced reactive oxygen species (ROS) production. Tan attenuated these deleterious consequence triggered by Dex. Moreover, Dex-induced ROS production and cell injury were inhibited by antioxidant, NADPH oxidases inhibitors, Nox4 inhibitor, and Nox4 small interfering RNA (siRNA). Overexpression of Nox4 almost abolished the inhibitory effect of Tan on Dex-induced cell injury and apoptosis. The results also demonstrated significant involvement of Nox4 in the Dex-induced apoptosis. Nox4-derived ROS led to apoptosis through activation of intrinsic mitochondrial pathway. Additionally, we evidenced that Tan reversed Dex-induced apoptosis via inactivation of Nox4. The present findings suggest that inhibition of Nox4 may be a novel therapeutic approach of Tan to prevent against glucocorticoids-induced osteoblasts apoptosis and osteoporosis. PMID:26722597

  12. Tanshinone IIA decreases the levels of inflammation induced by Aβ1-42 in brain tissues of Alzheimer's disease model rats.

    PubMed

    Lu, Bei-Ling; Li, Jian; Zhou, Jun; Li, Wen-Wen; Wu, Heng-Fei

    2016-08-17

    To study the pathogenesis of Alzheimer's disease (AD) and explore the possible anti-inflammatory mechanism of tanshinone IIA (TanIIA), we evaluated the quantity of neurons and the expression levels of interleukin-1β (IL-1β), IL-6, glial fibrillary acidic protein, CD11b, C1q, C3c, and C3d in brain tissues of AD rats treated with TanIIA. Thirty male Sprague-Dawley rats were randomized into three groups: sham group, TanIIA treatment group, and Aβ1-42 group. Aβ1-42 treatment was performed by injecting Aβ into the hippocampus of rats and then tagged position. Brain tissue morphological structure has been observed with HE staining and the staining of exogenously injected Aβ1-42 was observed by immunohistochemistry, which confirms the success of the Aβ1-42 group. After TanIIA treatment, levels of IL-1β, IL-6, glial fibrillary acidic protein, CD11b, C1q, C3c, and C3d were measured in paraffinized brain tissue sections from all groups by immunohistochemistry staining. The results showed that no 6E10 was detected in the control group, and the difference in the expression levels of 6E10 between the Aβ1-42 group and the TanIIA treatment group was not significant (P>0.05), suggesting that both the Aβ1-42 group and the TanIIA treatment group received the same amount of Aβ. The Aβ1-42 group showed a significant increase in the expression levels of inflammatory markers compared with the sham group (P<0.05) and the TanIIA treatment group showed a partial improvement in reducing inflammation. Therefore, Aβ triggered brain inflammation and activated the complement system. TanIIA treatment reduced the number of astrocytes and microglial cells, and induced a partial decrease in complement molecules in the brain of AD rats. These findings suggested that TanIIA may represent a potential therapeutic treatment in neurodegenerative diseases such as AD to support the survival of neurons by reducing expression levels of inflammatory factors. PMID:27348015

  13. Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation

    PubMed Central

    Boykin, C; Zhang, G; Chen, Y-H; Zhang, R-W; Fan, X-E; Yang, W-M; Lu, Q

    2011-01-01

    Background: Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti-inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer. Method: We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo. Results: Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein δ-catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity. Conclusion: Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3. PMID:21304528

  14. Differential Expression of sPLA2 Following Spinal Cord Injury and a Functional Role for sPLA2-IIA in Mediating Oligodendrocyte Death

    PubMed Central

    Titsworth, W. Lee; Cheng, Xiaoxin; Ke, Yan; Deng, Lingxiao; Burckardt, Kenneth A.; Pendleton, Chris; Liu, Nai-Kui; Shao, Hui; Cao, Qi-Lin; Xu, Xiao-Ming

    2015-01-01

    After the initial mechanical insult of spinal cord injury (SCI), secondary mediators propagate a massive loss of oligodendrocytes. We previously showed that following SCI both the total phospholipases activity and cytosolic PLA2-IVα protein expression increased. However, the expression of secreted isoforms of PLA2 (sPLA2) and their possible roles in oligodendrocyte death following SCI remains unclear. Here we report that mRNAs extracted 15 min, 4 hr, 1 day, or 1 month after cervical SCI show marked upregulation of sPLA2-IIA and IIE at 4 hr after injury. In contrast, SCI induced down regulation of sPLA2-X, and no change in sPLA2-IB, IIC, V, and XIIA expression. At the lesion site, sPLA2-IIA and IIE expression were localized to oligodendrocytes. Recombinant human sPLA2-IIA (0.01, 0.1, or 2 μM) induced a dose-dependent cytotoxicity in differentiated adult oligodendrocyte precursor cells but not primary astrocytes or Schwann cells in vitro. Most importantly, pretreatment with S3319, a sPLA2-IIA inhibitor, before a 30 min H2O2 injury (1 or 10 mM) significantly reduced oligodendrocyte cell death at 48 hr. Similarly, pretreatment with S3319 before injury with IL-1β and TNFα prevented cell death and loss of oligodendrocyte processes at 72 hr. Collectively, these findings suggest that sPLA2-IIA and IIE are increased following SCI, that increased sPLA2-IIA can be cytotoxic to oligodendrocytes, and that in vitro blockade of sPLA2 can create sparing of oligodendrocytes in two distinct injury models. Therefore sPLA2-IIA may be an important mediator of oligodendrocyte death and a novel target for therapeutic intervention following SCI. PMID:19306380

  15. Anti-Inflammatory Activity of Tanshinone IIA in LPS-Stimulated RAW264.7 Macrophages via miRNAs and TLR4-NF-κB Pathway.

    PubMed

    Fan, Guanwei; Jiang, Xiaorui; Wu, Xiaoyan; Fordjour, Patrick Asare; Miao, Lin; Zhang, Han; Zhu, Yan; Gao, Xiumei

    2016-02-01

    Inflammation is a physiological response to infection or injury and involves the innate and adaptive immune system. Tanshinone IIA (Tan IIA) is a well-known flavonoid that elicits an important therapeutic effect by inhibiting inflammatory response. In this study, we examined whether Tan IIA exerts anti-inflammatory activity and investigated the possible mechanisms, including Toll-like receptor 4 (TLR4)-MyD88-nuclear factor kappa B (NF-κB) signaling pathway and microRNA expression in lipopolysaccharide (LPS)-induced RAW264.7 cells. Tan IIA could attenuate the inflammatory reaction via decreasing cytokine, chemokine, and acute-phase protein production, including GM-CSF, sICAM-1, cxcl-1, MIP-1α, and tumor necrosis factor alpha (TNF-α), analyzed by Proteome profile array in LPS-induced RAW264.7 cells. Concurrently, the messenger RNA (mRNA) expressions of IL-1β, TNF-α, and COX-2 were also significantly reduced by Tan IIA. Additionally, Tan IIA decreased LPS-induced NF-κB activation and downregulated TLR4 and MyD88 protein expression levels. We also observed reduced microRNA-155, miR-147, miR-184, miR-29b, and miR-34c expression levels, while LPS-induced microRNA-105, miR-145a, miR-194, miR-383, miR-132, and miR-451a expression levels were upregulated using microRNA (miRNA) qPCR array. Our results indicate that Tan IIA could exert an anti-inflammatory effect on LPS-induced RAW264.7 cells by decreasing TLR4-MyD88-NF-κB signaling pathway and regulating a series of cytokine production and miRNA expression. PMID:26639663

  16. Effect of sodium tanshinone IIA sulfonate treatment in a rat model of preeclampsia.

    PubMed

    Morton, Jude S; Quon, Anita; Cheung, Po-Yin; Sawamura, Tatsuya; Davidge, Sandra T

    2015-02-01

    Preeclampsia is a disorder of pregnancy with a significant impact on maternal and fetal health. The complexity of this multifactorial condition has precluded development of effective therapies and, although many potential pathways have been investigated, the etiology still requires clarification. Our group has investigated the scavenger lectin-like oxidized LDL (LOX-1) receptor, which may respond to factors released from the distressed placenta that contribute to the vascular pathologies observed in preeclampsia. Given the known beneficial effects of sodium tanshinone IIA sulfonate (STS; a component of Salvia miltiorrhiza) on vasodilation, reduction of oxidative stress, and lipid profiles, we have investigated its role as a potential treatment strategy. We hypothesized that STS would improve vascular endothelial function and, combined with a reduction in oxidative stress, would improve pregnancy outcomes in a rat model of preeclampsia (reduced uteroplacental perfusion pressure, RUPP). We further hypothesized this may occur via the action of STS on the LOX-1 and/or platelet-activating factor (PAF) receptor axes. The RUPP model increased maternal blood pressure, vascular oxidative stress, and involvement of the vascular PAF receptor. Treatment with STS during pregnancy decreased both oxidative stress and involvement of the PAF receptor; however, it also increased involvement of the LOX-1 receptor, which is in line with the concept that scavenger receptors, such as LOX-1 and PAF, are upregulated in response to ligand binding and/or under pathological conditions. In this model of preeclampsia, however, the vascular actions of STS did not lead to improvements in pregnancy outcome such as fetal biometrics or maternal blood pressure. PMID:25477421

  17. Enhanced dissolution and stability of Tanshinone IIA base by solid dispersion system with nano-hydroxyapatite

    PubMed Central

    Jiang, Yan-rong; Zhang, Zhen-hai; Huang, Sai-yan; Lu, Yan; Ma, Tian-tian; Jia, Xiao-bin

    2014-01-01

    Background: Tanshinone IIA (TSIIA) exhibits a variety of cardiovascular effects; however, it has low solubility in water. The preparation of poorly soluble drugs for oral delivery is one of the greatest challenges in the field of formulation research. Among the approaches available, solid dispersion (SD) technique has proven to be one of the most commonly used these methods for improving dissolution and bioavailability of drugs, because of its relative simplicity and economy in terms of both preparation and evaluation. Objective: This study was aimed at investigating the dissolution behavior and physical stability of SDs of TSIIA by employing nano-hydroxyapatite (n-HAp). Materials and Methods: The TSIIA SDs was prepared to use a spray-drying method. First, an in vitro dissolution test was performed to assess dissolution characteristics. Next, a set of complementary techniques (differential scanning calorimetry, scanning electron microscopy, X-ray powder diffraction, and Fourier transform infrared spectroscopy) was used to monitor the physicochemical properties of the SDs. The SDs was stored at 40°C/75% relative humidity for 6 months, after which their stability was assessed. Results: TSIIA dissolution remarkably improved because of the formulation of the SDs with n-HAp particles. Comparisons with the corresponding physical mixtures revealed changes in the SDs and explained the formation of the amorphous phase. In the stability test, virtually no time-dependent decrease was observed in either in vitro drug dissolution or drug content. Conclusion: SD formulation with n-HAp may be a promising approach for enhancing the dissolution and stability of TSIIA. PMID:25210322

  18. Adjuvant radiotherapy following radical hysterectomy for patients with stage IB and IIA cervical cancer

    SciTech Connect

    Soisson, A.P.; Soper, J.T.; Clarke-Pearson, D.L.; Berchuck, A.; Montana, G.; Creasman, W.T. )

    1990-06-01

    From 1971 through 1984, 320 women underwent radical hysterectomy as primary therapy of stage IB and IIA cervical cancer. Two hundred forty-eight patients (78%) were treated with surgery alone and 72 patients (22%) received adjuvant postoperative external-beam radiotherapy. Presence of lymph node metastasis, large lesion (greater than 4 cm in diameter), histologic grade, race (noncaucasian), and age (greater than 40 years) were significant poor prognostic factors for the entire group of patients. Patients treated with surgery alone had a better disease-free survival than those who received combination therapy (P less than 0.001). However, patients receiving adjuvant radiation therapy had a higher incidence of lymphatic metastases, tumor involvement of the surgical margin, and large cervical lesions. Adjuvant pelvic radiation therapy did not improve the survival of patients with unilateral nodal metastases or those who had a large cervical lesion with free surgical margins and the absence of nodal involvement. Radiation therapy appears to reduce the incidence of pelvic recurrences. Unfortunately, 84% of patients who developed recurrent tumor after combination therapy had a component of distant failure. The incidence of severe gastrointestinal or genitourinary tract complications was not different in the two treatment groups. However, the incidence of lymphedema was increased in patients who received adjuvant radiation therapy. Although adjuvant radiation therapy appears to be tolerated without a significant increase in serious complications, the extent to which it may improve local control rates and survival in high-risk patients appears to be limited. In view of the high incidence of distant metastases in high-risk patients, consideration should be given to adjuvant systemic chemotherapy in addition to radiation therapy.

  19. Biochemical and Kinetic Characterization of the Eukaryotic Phosphotransacetylase Class IIa Enzyme from Phytophthora ramorum

    PubMed Central

    Taylor, Tonya; Ingram-Smith, Cheryl

    2015-01-01

    Phosphotransacetylase (Pta), a key enzyme in bacterial metabolism, catalyzes the reversible transfer of an acetyl group from acetyl phosphate to coenzyme A (CoA) to produce acetyl-CoA and Pi. Two classes of Pta have been identified based on the absence (PtaI) or presence (PtaII) of an N-terminal regulatory domain. PtaI has been fairly well studied in bacteria and one genus of archaea; however, only the Escherichia coli and Salmonella enterica PtaII enzymes have been biochemically characterized, and they are allosterically regulated. Here, we describe the first biochemical and kinetic characterization of a eukaryotic Pta from the oomycete Phytophthora ramorum. The two Ptas from P. ramorum, designated PrPtaII1 and PrPtaII2, both belong to class II. PrPtaII1 displayed positive cooperativity for both acetyl phosphate and CoA and is allosterically regulated. We compared the effects of different metabolites on PrPtaII1 and the S. enterica PtaII and found that, although the N-terminal regulatory domains share only 19% identity, both enzymes are inhibited by ATP, NADP, NADH, phosphoenolpyruvate (PEP), and pyruvate in the acetyl-CoA/Pi-forming direction but are differentially regulated by AMP. Phylogenetic analysis of bacterial, archaeal, and eukaryotic sequences identified four subtypes of PtaII based on the presence or absence of the P-loop and DRTGG subdomains within the N-terminal regulatory domain. Although the E. coli, S. enterica, and P. ramorum enzymes all belong to the IIa subclass, our kinetic analysis has indicated that enzymes within a subclass can still display differences in their allosteric regulation. PMID:25956919

  20. The Relationship between Muscle Fiber Type-Specific PGC-1α Content and Mitochondrial Content Varies between Rodent Models and Humans

    PubMed Central

    Gouspillou, Gilles; Sgarioto, Nicolas; Norris, Brandon; Barbat-Artigas, Sébastien; Aubertin-Leheudre, Mylène; Morais, Jose A.; Burelle, Yan; Taivassalo, Tanja; Hepple, Russell T.

    2014-01-01

    PGC-1α regulates critical processes in muscle physiology, including mitochondrial biogenesis, lipid metabolism and angiogenesis. Furthermore, PGC-1α was suggested as an important regulator of fiber type determination. However, whether a muscle fiber type-specific PGC-1α content exists, whether PGC-1α content relates to basal levels of mitochondrial content, and whether such relationships are preserved between humans and classically used rodent models are all questions that have been either poorly addressed or never investigated. To address these issues, we investigated the fiber type-specific content of PGC-1α and its relationship to basal mitochondrial content in mouse, rat and human muscles using in situ immunolabeling and histochemical methods on muscle serial cross-sections. Whereas type IIa fibers exhibited the highest PGC-1α in all three species, other fiber types displayed a hierarchy of type IIx>I>IIb in mouse, type I = IIx> IIb in rat, and type IIx>I in human. In terms of mitochondrial content, we observed a hierarchy of IIa>IIx>I>IIb in mouse, IIa >I>IIx> IIb in rat, and I>IIa> IIx in human skeletal muscle. We also found in rat skeletal muscle that type I fibers displayed the highest capillarization followed by type IIa >IIx>IIb. Finally, we found in human skeletal muscle that type I fibers display the highest lipid content, followed by type IIa>IIx. Altogether, our results reveal that (i) the fiber type-specific PGC-1α and mitochondrial contents were only matched in mouse, (ii) the patterns of PGC-1α and mitochondrial contents observed in mice and rats do not correspond to that seen in humans in several respects, and (iii) the classical phenotypes thought to be regulated by PGC-1α do not vary exclusively as a function of PGC-1α content in rat and human muscles. PMID:25121500

  1. CD64 and Group II Secretory Phospholipase A2 (sPLA2-IIA) as Biomarkers for Distinguishing Adult Sepsis and Bacterial Infections in the Emergency Department

    PubMed Central

    Tan, Toh Leong; Ahmad, Nurul Saadah; Nasuruddin, Dian Nasriana; Ithnin, Azlin; Tajul Arifin, Khaizurin; Zaini, Ida Zarina; Wan Ngah, Wan Zurinah

    2016-01-01

    Introduction Early diagnosis of sepsis and bacterial infection is imperative as treatment relies on early antibiotic administration. There is a need to develop new biomarkers to detect patients with sepsis and bacterial infection as early as possible, thereby enabling prompt antibiotic treatment and improving the survival rate. Methods Fifty-one adult patients with suspected bacterial sepsis on admission to the Emergency Department (ED) of a teaching hospital were included into the study. All relevant cultures and serology tests were performed. Serum levels for Group II Secretory Phospholipase A2 (sPLA2-IIA) and CD64 were subsequently analyzed. Results and Discussion Sepsis was confirmed in 42 patients from a total of 51 recruited subjects. Twenty-one patients had culture-confirmed bacterial infections. Both biomarkers were shown to be good in distinguishing sepsis from non-sepsis groups. CD64 and sPLA2-IIA also demonstrated a strong correlation with early sepsis diagnosis in adults. The area under the curve (AUC) of both Receiver Operating Characteristic curves showed that sPLA2-IIA was better than CD64 (AUC = 0.93, 95% confidence interval (CI) = 0.83–0.97 and AUC = 0.88, 95% CI = 0.82–0.99, respectively). The optimum cutoff value was 2.13μg/l for sPLA2-IIA (sensitivity = 91%, specificity = 78%) and 45 antigen bound cell (abc) for CD64 (sensitivity = 81%, specificity = 89%). In diagnosing bacterial infections, sPLA2-IIA showed superiority over CD64 (AUC = 0.97, 95% CI = 0.85–0.96, and AUC = 0.95, 95% CI = 0.93–1.00, respectively). The optimum cutoff value for bacterial infection was 5.63μg/l for sPLA2-IIA (sensitivity = 94%, specificity = 94%) and 46abc for CD64 (sensitivity = 94%, specificity = 83%). Conclusions sPLA2-IIA showed superior performance in sepsis and bacterial infection diagnosis compared to CD64. sPLA2-IIA appears to be an excellent biomarker for sepsis screening and for diagnosing bacterial infections, whereas CD64 could be used for

  2. Effects of escins Ia, Ib, IIa, and IIb from horse chestnut, the seeds of Aesculus hippocastanum L., on acute inflammation in animals.

    PubMed

    Matsuda, H; Li, Y; Murakami, T; Ninomiya, K; Yamahara, J; Yoshikawa, M

    1997-10-01

    We investigated the effects of escins Ia, Ib, and IIb isolated from horse chestnut, the seeds of Aesculus hippocastanum L., and desacylescins I and II obtained by alkaline hydrolysis of escins on acute inflammation in animals (p.o.). Escins Ia, Ib, IIa, and IIb (50-200 mg/kg) inhibited the increase of vascular permeability induced by both acetic acid in mice and histamine in rats. Escins Ib, IIa, and IIb (50-200 mg/kg) also inhibited that induced by serotonin in rats, but escin Ia didn't. Escins Ia, Ib, IIa, and IIb (200 mg/kg) inhibited the hind paw edema induced by carrageenin at the first phase in rats. Escin Ia (200 mg/kg) and escins Ib, IIa, and IIb (50-200 mg/kg) inhibited the scratching behavior induced by compound 48/80 in mice, but escin Ia was weakest. Desacylescins I and II (200 mg/kg) showed no effect. With regard to the relationship between their chemical structures and activities, the acyl groups in escins were essential. Escins Ib, IIa, and IIb with either the 21-angeloyl group or the 2'-O-xylopyranosyl moiety showed more potent activities than escin Ia which had both the 21-tigloyl group and the 2'-O-glucopyranosyl moiety. PMID:9353571

  3. A Precision Measurement of the W Boson Mass with 1 Inverse Femtobarn of DZero Run IIa Data

    SciTech Connect

    Osta, Jyotsna

    2009-12-01

    This thesis is a detailed presentation of a precision measurement of the mass of the W boson. It has been obtained by analyzing W → ev decays. The data used for this analysis was collected from 2002 to 2006 with the D0 detector, during Run IIa of the Fermilab Tevatron collider. It corresponds to a total integrated luminosity of 1 fb-1. With a sample of 499,830 W → ev candidate events, we obtain a mass measurement of MW = 80.401 ± 0.043 GeV. This is the most precise measurement from a single experiment to date.

  4. Evidence of Blood Stage Efficacy with a Virosomal Malaria Vaccine in a Phase IIa Clinical Trial

    PubMed Central

    Thompson, Fiona M.; Porter, David W.; Okitsu, Shinji L.; Westerfeld, Nicole; Vogel, Denise; Todryk, Stephen; Poulton, Ian; Correa, Simon; Hutchings, Claire; Berthoud, Tamara; Dunachie, Susanna; Andrews, Laura; Williams, Jack L.; Sinden, Robert; Gilbert, Sarah C.; Pluschke, Gerd; Zurbriggen, Rinaldo; Hill, Adrian V. S.

    2008-01-01

    Background Previous research indicates that a combination vaccine targeting different stages of the malaria life cycle is likely to provide the most effective malaria vaccine. This trial was the first to combine two existing vaccination strategies to produce a vaccine that induces immune responses to both the pre-erythrocytic and blood stages of the P. falciparum life cycle. Methods This was a Phase I/IIa study of a new combination malaria vaccine FFM ME-TRAP+PEV3A. PEV3A includes peptides from both the pre-erythrocytic circumsporozoite protein and the blood-stage antigen AMA-1. This study was conducted at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK. The participants were healthy, malaria naïve volunteers, from Oxford. The interventions were vaccination with PEV3A alone, or PEV3A+FFM ME-TRAP. The main outcome measure was protection from malaria in a sporozoite challenge model. Other outcomes included measures of parasite specific immune responses induced by either vaccine; and safety, assessed by collection of adverse event data. Results We observed evidence of blood stage immunity in PEV3A vaccinated volunteers, but no volunteers were completely protected from malaria. PEV3A induced high antibody titres, and antibodies bound parasites in immunofluorescence assays. Moreover, we observed boosting of the vaccine-induced immune response by sporozoite challenge. Immune responses induced by FFM ME-TRAP were unexpectedly low. The vaccines were safe, with comparable side effect profiles to previous trials. Although there was no sterile protection two major observations support an effect of the vaccine-induced response on blood stage parasites: (i) Lower rates of parasite growth were observed in volunteers vaccinated with PEV3A compared to unvaccinated controls (p = 0.012), and this was reflected in the PCR results from PEV3A vaccinated volunteers. These showed early control of parasitaemia by some volunteers in this

  5. Advanced Start of Combustion Sensor Phases I and II-A: Feasibility Demonstration, Design and Optimization

    SciTech Connect

    Chad Smutzer

    2010-01-31

    Homogeneous Compressed Charge Ignition (HCCI) has elevated the need for Start of Combustion (SOC) sensors. HCCI engines have been the exciting focus of engine research recently, primarily because HCCI offers higher thermal efficiency than the conventional Spark Ignition (SI) engines and significantly lower NOx and soot emissions than conventional Compression Ignition (CI) engines, and could be fuel neutral. HCCI has the potential to unify all the internal combustion engine technology to achieve the high-efficiency, low-emission goal. However, these advantages do not come easy. It is well known that the problems encountered with HCCI combustion center on the difficulty of controlling the Start of Combustion. TIAX has an SOC sensor under development which has shown promise. In previous work, including a DOE-sponsored SBIR project, TIAX has developed an accelerometer-based method which was able to determine SOC within a few degrees crank angle for a range of operating conditions. A signal processing protocol allows reconstruction of the combustion pressure event signal imbedded in the background engine vibration recorded by the accelerometer. From this reconstructed pressure trace, an algorithm locates the SOC. This SOC sensor approach is nonintrusive, rugged, and is particularly robust when the pressure event is strong relative to background engine vibration (at medium to high engine load). Phase I of this project refined the previously developed technology with an engine-generic and robust algorithm. The objective of the Phase I research was to answer two fundamental questions: Can the accelerometer-based SOC sensor provide adequate SOC event capture to control an HCCI engine in a feedback loop? And, will the sensor system meet cost, durability, and software efficiency (speed) targets? Based upon the results, the answer to both questions was 'YES'. The objective of Phase II-A was to complete the parameter optimization of the SOC sensor prototype in order to reach a

  6. Glycyrrhetinic acid-decorated and reduction-sensitive micelles to enhance the bioavailability and anti-hepatocellular carcinoma efficacy of tanshinone IIA.

    PubMed

    Chen, Fengqian; Zhang, Jinming; He, Yao; Fang, Xiefan; Wang, Yitao; Chen, Meiwan

    2016-01-01

    It remains a challenge to increase drug tumor-specific accumulation as well as to achieve intracellular-controlled drug release for hepatocellular carcinoma (HCC) chemotherapy. Herein, we developed a dual-functional biodegradable micellar system constituted by glycyrrhetinic acid coupling poly(ethylene glycol)-disulfide linkage-poly(lactic-co-glycolic acid) (GA-PEG-SS-PLGA) to achieve both hepatoma-targeting and redox-responsive intracellular drug release. Tanshinone IIA (TAN IIA), an effective anti-HCC drug, was encapsulated. Notably, it exhibited rapid aggregation and faster drug release in 10 mM dithiothreitol compared with the redox-insensitive control. Furthermore, GA-decorated micelles revealed HCC-specific cellular uptake in human liver cancer HepG2 cells with an energy-dependent manner, in which micropinocytosis and caveolae-mediated endocytosis were demonstrated as the major cellular pathways. The enhanced cytotoxicity and pro-apoptotic effects against HepG2 cells in vitro were observed, mediated by up-regulation of the intracellular ROS level, the increased cell cycle arrest at S phase, enhanced necrocytosis and up-regulation of caspase 3/7, P38 protein expression. In addition, TAN IIA-loaded micelles had a significantly prolonged circulation time, improved bioavailability, and resulted in an increased accumulation of TAN IIA in the liver. With the synergistic effects of HCC-targeting and controlled drug release, TAN IIA-loaded GA-PEG-SS-PLGA micelles significantly inhibited tumor growth and increased survival time in a mouse HCC-xenograft model. Collectively, the GA-PEG-SS-PLGA micelles with HCC-targeting and redox-sensitive characters would provide a novel strategy to deliver TAN IIA effectively for HCC therapy. PMID:26484363

  7. M theory on deformed superspace

    NASA Astrophysics Data System (ADS)

    Faizal, Mir

    2011-11-01

    In this paper we will analyze a noncommutative deformation of the Aharony-Bergman-Jafferis-Maldacena (ABJM) theory in N=1 superspace formalism. We will then analyze the Becchi-Rouet-Stora-Tyutin (BRST) and anti-BRST symmetries for this deformed ABJM theory, and its linear as well as nonlinear gauges. We will show that the sum of the gauge fixing term and the ghost term for this deformed ABJM theory can be expressed as a combination of the total BRST and the total anti-BRST variation, in Landau and nonlinear gauges. We will show that in Landau and Curci-Ferrari gauges deformed ABJM theory is invariant under an additional set of symmetry transformations. We will also discuss the effect that the addition of a bare mass term has on this theory.

  8. The structural, electronic and optical response of IIA-VIA compounds through the modified Becke-Johnson potential

    NASA Astrophysics Data System (ADS)

    Ali, Roshan; Mohammad, S.; Ullah, Hamid; Khan, S. A.; Uddin, H.; Khan, M.; Khan, N. U.

    2013-02-01

    The structural, electronic and optical properties of IIA-VIA compounds are performed, by using the full-potential linearized augmented plan wave (FP-LAPW) method within DFT, by using the (PBEsol-GGA 2008) version. We have compared the modified Becke-Johnson (mBJ) potential to LDA, GGA and EV-GGA approximations. The IIA-VIA compounds have rock salt structure (B1) and zinc-blend structure (B3). The results obtained for band structure using mBJ show a significant improvement over previous theoretical work and give closer values to the experimental results. The bandgaps less than 3.1 eV are used in the visible light devices applications, while those with bandgaps bigger than 3.1 eV, used in UV devices applications. Optical parameters, like the dielectric constant, refractive indices, reflectivity, optical conductivity and absorption coefficient are calculated and analyzed. Refractive index lesser than unity (vg=c/n) shows that the group velocity of the incident radiation is greater than the speed of light.

  9. Isolated flexor digitorum profundus tendon injuries in zones IIA and IIB repaired with figure of eight sutures.

    PubMed

    Al-Qattan, M M

    2011-02-01

    The 'figure of eight' suture technique for flexor tendon repair is known to be simple and strong but it has the major disadvantage of being bulky, with the knots outside the repair site. When the superficialis tendon is intact it may cause impingement and/or increase the work of flexion with postoperative mobilization and it is not known whether this bulky repair is suitable for isolated profundus injuries in zone II. A series of 36 patients (36 fingers) with clean-cut isolated flexor digitorum profundus tendon injuries in zones IIA/IIB were reviewed retrospectively. Repairs were done with three 'figure of eight' sutures and the pulleys proximal to the tendon laceration level were vented. Postoperatively, early active exercises were carried out. There were no ruptures. At a mean final follow-up of 6 months, the outcome (in range of motion) was excellent in 27 fingers and good in the remaining nine fingers by the Strickland criteria. It was concluded that the bulky 'figure of eight' technique can be used in isolated profundus tendon injuries in zones IIA/IIB. PMID:21045020

  10. Neutrons, gamma rays, and beta particles interactions with IIaO films flown on Astro I and Astro II and comparison with IIaO flown on the get-away-special STS-7

    SciTech Connect

    Hammond, E.C. Jr.; Peters, K.; Boone, K.

    1995-09-01

    The current requirements for the Laboratory for Astronomy and Solar Physics, sends rocket satellites and in the near future will involve flights in the shuttle to the upper reaches of the Earth`s atmosphere where they will be subjected to the atomic particles and electromagnetic radiation produced by the Sun and other cosmic radiation. It is therefore appropriate to examine the effect of neutrons, gamma rays, beta particles, and X-rays on the film currently being used by the Laboratory for current and future research requirements. It is also hoped by examining these particles in their effect that the authors will have simulated the space environment of the rockets, satellites, and shuttles. Several samples of the IIaO film were exposed to a neutron howitzer with a source energy of approximately 106 neutrons/steradians. They exposed several samples of the film to a 10 second blast of neutrons in both metal and plastic containers which exhibited higher density readings which indicated the possibility of some secondary nuclear interactions between neutrons and the aluminum container. The plastic container showed some variations at the higher densities. Exposure of the samples of IIaO film to a neutron beam of approximately 10 neutrons per steradians for eight minutes produces approximately a 13% difference in the density readings of the dark density grids. It is not noticeable that at the lighter density grid the neutrons have minimal effects, but on a whole the trend of the eight minute exposed IIaO film density grids at the darker end had a 7.1% difference than the control. Further analysis is anticipated by increasing the exposure time. Two sets of film were exposed to a beta source in a plastic container. The beta source was placed at the bottom so that the cone of rays striking the film would be conical for a period of seven days. It was observed in the films, designated 4a and 4b, a dramatic increase in the grid densities had occurred.

  11. Sodium Tanshinone IIA Silate Inhibits High Glucose-Induced Vascular Smooth Muscle Cell Proliferation and Migration through Activation of AMP-Activated Protein Kinase

    PubMed Central

    Wu, Wen-yu; Yan, Hong; Wang, Xin-bo; Gui, Yu-zhou; Gao, Fei; Tang, Xi-lan; Qin, Yin-lin; Su, Mei; Chen, Tao; Wang, Yi-ping

    2014-01-01

    The proliferation of vascular smooth muscle cells may perform a crucial role in the pathogenesis of diabetic vascular disease. AMPK additionally exerts several salutary effects on vascular function and improves vascular abnormalities. The current study sought to determine whether sodium tanshinone IIA silate (STS) has an inhibitory effect on vascular smooth muscle cell (VSMC) proliferation and migration under high glucose conditions mimicking diabetes without dyslipidemia, and establish the underlying mechanism. In this study, STS promoted the phosphorylation of AMP-activated protein kinase (AMPK) at T172 in VSMCs. VSMC proliferation was enhanced under high glucose (25 mM glucose, HG) versus normal glucose conditions (5.5 mM glucose, NG), and this increase was inhibited significantly by STS treatment. We utilized western blotting analysis to evaluate the effects of STS on cell-cycle regulatory proteins and found that STS increased the expression of p53 and the Cdk inhibitor, p21, subsequent decreased the expression of cell cycle-associated protein, cyclin D1. We further observed that STS arrested cell cycle progression at the G0/G1 phase. Additionally, expression and enzymatic activity of MMP-2, translocation of NF-κB, as well as VSMC migration were suppressed in the presence of STS. Notably, Compound C (CC), a specific inhibitor of AMPK, as well as AMPK siRNA blocked STS-mediated inhibition of VSMC proliferation and migration. We further evaluated its potential for activating AMPK in aortas in animal models of type 2 diabetes and found that Oral administration of STS for 10 days resulted in activation of AMPK in aortas from ob/ob or db/db mice. In conclusion, STS inhibits high glucose-induced VSMC proliferation and migration, possibly through AMPK activation. The growth suppression effect may be attributable to activation of AMPK-p53-p21 signaling, and the inhibitory effect on migration to the AMPK/NF-κB signaling axis. PMID:24739942

  12. Activated T Cell Trans-Endothelial Migration Relies on Myosin-IIA Contractility for Squeezing the Cell Nucleus through Endothelial Cell Barriers

    PubMed Central

    Jacobelli, Jordan; Estin Matthews, Miriam; Chen, Stephanie; Krummel, Matthew F.

    2013-01-01

    Following activation, T cells are released from lymph nodes to traffic via the blood to effector sites. The re-entry of these activated T cells into tissues represents a critical step for them to carry out local effector functions. Here we have assessed defects in effector T cells that are acutely depleted in Myosin-IIA (MyoIIA) and show a T cell intrinsic requirement for this motor to facilitate the diapedesis step of extravasation. We show that MyoIIA accumulates at the rear of T cells undergoing trans-endothelial migration. T cells can extend protrusions and project a substantial portion of their cytoplasm through the endothelial wall in the absence of MyoIIA. However, this motor protein plays a crucial role in allowing T cells to complete the movement of their relatively rigid nucleus through the endothelial junctions. In vivo, this defect manifests as poor entry into lymph nodes, tumors and into the spinal cord, during tissue-specific autoimmunity, but not the spleen. This suggests that therapeutic targeting of this molecule may allow for differential attenuation of tissue-specific inflammatory responses. PMID:24069389

  13. 30 CFR 57.22235 - Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in the... reaches 1.0 percent at a work place and there has been a failure of the main ventilation system,...

  14. 30 CFR 57.22235 - Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in the... reaches 1.0 percent at a work place and there has been a failure of the main ventilation system,...

  15. Charters, Constitutions and By-Laws of the Indian Tribes of North America. Part IIa: The Northern Plains. Occasional Publications in Anthropology, Ethnology Series, No. 3.

    ERIC Educational Resources Information Center

    Fay, George E., Comp.

    Part IIa of a series of publications consisting of American Indian tribal governmental documents, this volume contains charters, constitutions, and by-laws of Indian tribes in the Northern Plains (Montana and North Dakota). Documents are presented relative to the Assiniboine and Sioux Tribes of the Fort Peck Reservation, the Blackfeet Tribe of the…

  16. SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites

    PubMed Central

    Soriano, Francesc X; Chawla, Sangeeta; Skehel, Paul; Hardingham, Giles E

    2013-01-01

    The Class IIa histone deacetylases (HDAC)4 and HDAC5 play a role in neuronal survival and behavioral adaptation in the CNS. Phosphorylation at 2/3 N-terminal sites promote their nuclear export. We investigated whether non-canonical signaling routes to Class IIa HDAC export exist because of their association with the co-repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N-terminal phosphorylation sites (HDAC4MUT, HDAC5MUT) are constitutively nuclear, co-expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 (RD3) is critical for co-shuttling of HDAC5MUT, consistent with the role for this domain in Class IIa HDAC association. In the context of BDNF signaling, we found that HDAC5WT, which was more cytoplasmic than HDAC5MUT, accumulated in the nucleus after BDNF treatment. However, co-expression of SMRT blocked BDNF-induced HDAC5WT import in a RD3-dependent manner. In effect, SMRT-mediated HDAC5WT export was opposing the BDNF-induced HDAC5 nuclear accumulation observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs exportable by a wider range of signals than those which simply promote direct phosphorylation. PMID:23083128

  17. 30 CFR 57.22205 - Doors on main fans (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Doors on main fans (I-A, II-A, III, and V-A... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22205 Doors on... installation shall be equipped with noncombustible doors. Such doors shall automatically close to prevent...

  18. 30 CFR 57.22205 - Doors on main fans (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Doors on main fans (I-A, II-A, III, and V-A... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22205 Doors on... installation shall be equipped with noncombustible doors. Such doors shall automatically close to prevent...

  19. 30 CFR 57.22205 - Doors on main fans (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Doors on main fans (I-A, II-A, III, and V-A... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22205 Doors on... installation shall be equipped with noncombustible doors. Such doors shall automatically close to prevent...

  20. 30 CFR 57.22205 - Doors on main fans (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Doors on main fans (I-A, II-A, III, and V-A... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22205 Doors on... installation shall be equipped with noncombustible doors. Such doors shall automatically close to prevent...

  1. 30 CFR 57.22205 - Doors on main fans (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Doors on main fans (I-A, II-A, III, and V-A... NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22205 Doors on... installation shall be equipped with noncombustible doors. Such doors shall automatically close to prevent...

  2. Intraoperative validation of CT-based lymph nodal levels, sublevels IIa and IIb: Is it of clinical relevance in selective radiation therapy?

    SciTech Connect

    Levendag, Peter . E-mail: p.levendag@erasmusmc.nl; Gregoire, Vincent; Hamoir, Marc; Voet, Peter; Est, Henrie van der; Heijmen, Ben; Kerrebijn, Jeroen

    2005-07-01

    Purpose: The objectives of this study are to discuss the intraoperative validation of CT-based boundaries of lymph nodal levels in the neck, and in particular the clinical relevance of the delineation of sublevels IIa and IIb in case of selective radiation therapy (RT). Methods and Materials: To validate the radiologically defined level contours, clips were positioned intraoperatively at the level boundaries defined by surgical anatomy. In 10 consecutive patients, clips were placed, at the time of a neck dissection being performed, at the most cranial border of the neck. Anterior-posterior and lateral X-ray films were obtained intraoperatively. Next, in 3 patients, neck levels were contoured on preoperative contrast-enhanced CT scans according to the international consensus guidelines. From each of these 3 patients, an intraoperative CT scan was also obtained, with clips placed at the surgical-anatomy-based level boundaries. The preoperative (CT-based) and intraoperative (surgery-defined) CT scans were matched. Results: Clips placed at the most cranial part of the neck lined up at the caudal part of the transverse process of the cervical vertebra C-I. The posterior border of surgical level IIa (spinal accessory nerve [SAN]) did not match with the posterior border of CT-based level IIa (internal jugular vein [IJV]). Other surgical boundaries and CT-based contours were in good agreement. Conclusions: The cranial border of the neck, i.e., the cranial border of level IIa/IIb, corresponds to the caudal edge of the lateral process of C-I. Except for the posterior border between level IIa and level IIb, a perfect match was observed between the other surgical-clip-identified levels II-V boundaries (surgical-anatomy) and the CT-based delineation contours. It is argued that (1) because of the parotid gland overlapping part of level II, and (2) the frequent infestation of occult metastatic cells in the lymph channels around the IJV, the division of level II into radiologic

  3. Distinct electrophysiological properties in subtypes of nonspiking olfactory local interneurons correlate with their cell type-specific Ca2+ current profiles.

    PubMed

    Husch, Andreas; Paehler, Moritz; Fusca, Debora; Paeger, Lars; Kloppenburg, Peter

    2009-11-01

    A diverse population of local interneurons (LNs) helps to process, structure, and spatially represent olfactory information in the insect antennal lobe. In Periplaneta americana, we identified two subtypes of nonspiking local interneurons (type II LNs) by their distinct morphological and intrinsic electrophysiological properties. As an important step toward a better understanding of the cellular mechanisms that mediate odor information processing, we present a detailed analysis of their distinct voltage-activated Ca(2+) currents, which clearly correlated with their distinct intrinsic electrophysiological properties. Both type II LNs did not posses voltage-activated Na(+) currents and apparently innervated all glomeruli including the macroglomerulus. Type IIa LNs had significant longer and thicker low-order neurites and innervated each glomerulus entirely and homogeneously, whereas type IIb LNs innervated only parts of each glomerulus. All type II LNs were broadly tuned and responded to odorants of many chemical classes with graded changes in the membrane potential. Type IIa LNs responded with odor-specific elaborate patterns of excitation that could also include "spikelets" riding on the depolarizations and periods of inhibition. In contrast, type IIb LNs responded mostly with sustained, relatively smooth depolarizations. Consistent with the strong active membrane properties of type IIa LNs versus type IIb LNs, the voltage-activated Ca(2+) current of type IIa LNs activated at more hyperpolarized membrane potentials and had a larger transient component. PMID:19759323

  4. Evaluating a novel treatment for coronary artery inflammation in acute Kawasaki disease: A Phase I/IIa trial of atorvastatin

    PubMed Central

    Tremoulet, Adriana H; Jain, Sonia; Burns, Jane C

    2016-01-01

    Introduction Since the 1980s, the primary treatment of acute Kawasaki disease (KD) has been intravenous immunoglobulin and aspirin. However, 5-10% of children with acute KD will develop coronary artery abnormalities despite treatment within the first ten days after fever onset. There is no approved adjunctive therapy to prevent progression of coronary artery damage in these patients Areas covered The rationale and study design of a Phase I/IIa trial of atorvastatin in children with acute KD and coronary artery inflammation is presented. The studies of host genetics and KD pathogenesis leading up to this trial are reviewed. Expert opinion The repurposing of well-studied drugs used in the adult population is a cost-effective and efficient strategy to identify new therapies for pediatric diseases. Exploiting the anti-inflammatory, non-lipid-lowering effects of statins may open up new applications for this class of drugs for the pediatric age group.

  5. Results of the Lasagna{trademark} Phase IIa field demonstration for the remediation of TCE in clay soils

    SciTech Connect

    Athmer, C.J.; Ho, S.V.; Hughes, B.M.; Clausen, J.L.; Johnstone, F.; Hines, R.L.

    1998-12-31

    The Lasagna{trademark} technology is an integrated in-situ treatment in which established geotechnical methods are used to install degradation zones directly in the contaminated soil and electrokinetics is utilized to move the contaminants through those zones until the treatment is completed. The Phase IIa demonstration was the second field demonstration at a trichloroethylene (TCE) contaminated site in Paducah, Ky. The first demonstration, Phase I, proved that TCE could be mobilized and captured using Lasagna{trademark}. This second demonstration measured 30 feet by 21 feet by 45 feet deep and showed for the first time TCE, including pure phase residual TCE, could be mobilized in tight soils using electrokinetics and degraded in-situ using iron filings. Over 95% removal of TCE was observed in areas of the demonstration site including pure phase residual TCE regions.

  6. Effects of tanshinone IIA on fibrosis in a rat model of cirrhosis through heme oxygenase-1, inflammation, oxidative stress and apoptosis.

    PubMed

    Shu, Ming; Hu, Xiao-Rong; Hung, Zuo-An; Huang, Dam-Dan; Zhang, Shun

    2016-04-01

    Tanshinone IIA is extracted from the root of Salvia miltiorrhiza and used in traditional Chinese medicine for its anti-inflammatory activity and antioxidant effects. The aim of the present study was to investigate the potential protective effects of tanshinone IIA against fibrosis in a rat model of cirrhosis and to elucidate the underlying mechanisms. Male Sprague Dawley rats were used as the model of cirrhosis in the present study. In the cirrhotic rats, the extent of fibrosis, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), heme oxygenase‑1 (HO‑1) protein expression, serum levels of nuclear factor (NF)‑κB, tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH‑PX), and the protein expression levels of phosphorylated‑p38 mitogen‑activated protein kinase (MAPK) were all significantly increased. However, the serum malondialdehyde (MDA) activity and protein kinase B (Akt) protein expression were suppressed in cirrhotic rats compared with the sham (control) group. Compared with the cirrhotic group, administration of tanshinone IIA reduced the extent of fibrosis, levels of ALT and AST, HO‑1 protein expression, serum NF‑κB, TNF‑α, IL‑1β and IL‑6 levels, and the activity of SOD, CAT and GSH‑PX. Furthermore, administration of tanshinone IIA significantly increased the inhibition of the serum MDA activity and the Akt protein expression in cirrhotic rats compared with those in the cirrhotic group. The protective effect of tanshinone IIA suppresses fibrosis in a rat model of cirrhosis, and reduces inflammation and oxidative stress, via the HO‑1, Akt and p38 MAPK signaling pathway. PMID:26936326

  7. Inhibition of Tanshinone IIA, salvianolic acid A and salvianolic acid B on Areca nut extract-induced oral submucous fibrosis in vitro.

    PubMed

    Dai, Jian-Ping; Zhu, Dan-Xia; Sheng, Jiang-Tao; Chen, Xiao-Xuan; Li, Wei-Zhong; Wang, Ge-Fei; Li, Kang-Sheng; Su, Yun

    2015-01-01

    Salvia miltiorrhiza Bunge has been reported to possess excellent antifibrotic activity. In this study, we have investigated the effect and mechanism of tanshinone IIA (Tan-IIA), salvianolic acid A (Sal-A) and salvianolic acid B (Sal-B), the important active compounds of Salvia miltiorrhiza Bunge, on areca nut extract (ANE)-induced oral submucous fibrosis (OSF) in vitro. Through human procollagen gene promoter luciferase reporter plasmid assay, hydroxyproline assay, gelatin zymography assay, qRT-PCR, ELISA and Western blot assay, the influence of these three compounds on ANE-stimulated cell viability, collagen accumulation, procollagen gene transcription, MMP-2/-9 activity, MMP-1/-13 and TIMP-1/-2 expression, cytokine secretion and the activation of PI3K/AKT, ERK/JNK/p38 MAPK and TGF-β/Smads pathways were detected. The results showed that Tan-IIA, Sal-A and Sal-B could significantly inhibit the ANE-stimulated abnormal viability and collagen accumulation of mice oral mucosal fibroblasts (MOMFs), inhibit the transcription of procollagen gene COL1A1 and COL3A1, increase MMP-2/-9 activity, decrease TIMP-1/-2 expression and inhibit the transcription and release of CTGF, TGF-β1, IL-6 and TNF-α; Tan-IIA, Sal-A and Sal-B also inhibited the ANE-induced activation of AKT and ERK MAPK pathways in MOMFs and the activation of TGF-β/Smads pathway in HaCaT cells. In conclusion, Tan-IIA, Sal-A and Sal-B possess excellent antifibrotic activity in vitro and can possibly be used to promote the rehabilitation of OSF patients. PMID:25884554

  8. Effects of tanshinone IIA on fibrosis in a rat model of cirrhosis through heme oxygenase-1, inflammation, oxidative stress and apoptosis

    PubMed Central

    SHU, MING; HU, XIAO-RONG; HUNG, ZUO-AN; HUANG, DAM-DAN; ZHANG, SHUN

    2016-01-01

    Tanshinone IIA is extracted from the root of Salvia miltiorrhiza and used in traditional Chinese medicine for its anti-inflammatory activity and antioxidant effects. The aim of the present study was to investigate the potential protective effects of tanshinone IIA against fibrosis in a rat model of cirrhosis and to elucidate the underlying mechanisms. Male Sprague Dawley rats were used as the model of cirrhosis in the present study. In the cirrhotic rats, the extent of fibrosis, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), heme oxygenase-1 (HO-1) protein expression, serum levels of nuclear factor (NF)-κB, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX), and the protein expression levels of phosphorylated-p38 mitogen-activated protein kinase (MAPK) were all significantly increased. However, the serum malondialdehyde (MDA) activity and protein kinase B (Akt) protein expression were suppressed in cirrhotic rats compared with the sham (control) group. Compared with the cirrhotic group, administration of tanshinone IIA reduced the extent of fibrosis, levels of ALT and AST, HO-1 protein expression, serum NF-κB, TNF-α, IL-1β and IL-6 levels, and the activity of SOD, CAT and GSH-PX. Furthermore, administration of tanshinone IIA significantly increased the inhibition of the serum MDA activity and the Akt protein expression in cirrhotic rats compared with those in the cirrhotic group. The protective effect of tanshinone IIA suppresses fibrosis in a rat model of cirrhosis, and reduces inflammation and oxidative stress, via the HO-1, Akt and p38 MAPK signaling pathway. PMID:26936326

  9. Nasal immunization with mannan-decorated mucoadhesive HPMCP microspheres containing ApxIIA toxin induces protective immunity against challenge infection with Actinobacillus pleuropneumoiae in mice.

    PubMed

    Li, Hui-Shan; Shin, Min-Kyoung; Singh, Bijay; Maharjan, Sushila; Park, Tae-Eun; Kang, Sang-Kee; Yoo, Han-Sang; Hong, Zhong-Shan; Cho, Chong-Su; Choi, Yun-Jaie

    2016-07-10

    The development of subunit mucosal vaccines requires an appropriate delivery system or an immune modulator such as an adjuvant to improve antigen immunogenicity. The nasal route for vaccine delivery by microparticles has attracted considerable interest, although challenges such as the rapid mucociliary clearance in the respiratory mucosa and the low immunogenicity of subunit vaccine still remain. Here, we aimed to develop mannan-decorated mucoadhesive thiolated hydroxypropylmethyl cellulose phthalate (HPMCP) microspheres (Man-THM) that contain ApxIIA subunit vaccine - an exotoxin fragment as a candidate for a subunit nasal vaccine against Actinobacillus pleuropneumoniae. For adjuvant activity, mucoadhesive thiolated HPMCP microspheres decorated with mannan could be targeted to the PRRs (pathogen recognition receptors) and mannose receptors (MR) of antigen presenting cells (APCs) in the respiratory immune system. The potential adjuvant ability of Man-THM for intranasal immunization was confirmed by in vitro and in vivo experiments. In a mechanistic study using APCs in vitro, it was found that Man-THM enhanced receptor-mediated endocytosis by stimulating the MR of APCs. In vivo, the nasal vaccination of ApxIIA-loaded Man-THM in mice resulted in higher levels of mucosal sIgA and serum IgG than mice in the ApxIIA and ApxIIA-loaded THM groups due to the specific recognition of the mannan in the Man-THM by the MRs of the APCs. Moreover, ApxIIA-containing Man-THM protected immunized mice when challenged with strains of A. pleuropneumoniae serotype 5. These results suggest that mucoadhesive Man-THM may be a promising candidate for a nasal vaccine delivery system to elicit systemic and mucosal immunity that can protect from pathogenic bacteria infection. PMID:27189136

  10. Inhibition of Group IIA Secretory Phospholipase A2 and its Inflammatory Reactions in Mice by Ethanolic Extract of Andrographis paniculata, a Well-known Medicinal Food

    PubMed Central

    Kishore, V.; Yarla, N. S.; Zameer, F.; Nagendra Prasad, M. N.; Santosh, M. S.; More, S. S.; Rao, D. G.; Dhananjaya, Bhadrapura Lakkappa

    2016-01-01

    Andrographis paniculata Nees is an important medicinal plant found in the tropical regions of the world, which has been traditionally used in Indian and Chinese medicinal systems. It is also used as medicinal food. A. paniculata is found to exhibit anti-inflammatory activities; however, its inhibitory potential on inflammatory Group IIA phospholipases A2 (PLA2) and its associated inflammatory reactions are not clearly understood. The aim of the present study is to evaluate the inhibitory/neutralizing potential of ethanolic extract of A. paniculata on the isolated inflammatory PLA2 (VRV-PL-VIIIa) from Daboii rusellii pulchella (belonging to Group IIA inflammatory secretory PLA2 [sPLA2]) and its associated edema-induced activities in Swiss albino mice. A. paniculata extract dose dependently inhibited the Group IIA sPLA2 enzymatic activity with an IC50 value of 10.3 ± 0.5 μg/ml. Further, the extract dose dependently inhibited the edema formation, when co-injected with enzyme indicating that a strong correlation exists between lipolytic and pro-inflammatory activities of the enzyme. In conclusion, results of this study shows that the ethanolic extract of A. paniculata effectively inhibits Group IIA sPLA2 and its associated inflammatory activities, which substantiate its anti-inflammatory properties. The results of the present study warranted further studies to develop bioactive compound (s) in ethanolic extract of A. paniculata as potent therapeutic agent (s) for inflammatory diseases. SUMMARY This study emphasis the anti-inflammatory effect of A. paniculata by inhibiting the inflammatory Group IIA sPLA2 and its associated inflammatory activities such as edema. It was found that there is a strong correlation between lipolytic activity and pro-inflammatory activity inhibition. Therefore, the study suggests that the extract processes potent anti-inflammatory agents, which could be developed as a potential therapeutic agent against inflammatory and related diseases

  11. Reproducibility of the anti-Factor Xa and anti-Factor IIa assays applied to enoxaparin solution.

    PubMed

    Martinez, Céline; Savadogo, Adama; Agut, Christophe; Anger, Pascal

    2013-01-01

    Enoxaparin is a widely used subcutaneously administered antithrombotic agent comprising a complex mixture of glycosaminoglycan chains. Owing to this complexity, its antithrombotic potency cannot be defined by physicochemical methods and is therefore evaluated using an enzymatic assay of anti-Xa and anti-IIa activity. Maintaining consistent anti-Xa activity in the final medicinal product allows physicians to ensure administration of the appropriate dosage to their patients. Bioassays are usually complex and display poorer reproducibility than physicochemical tests such as HPLC assays. Here, we describe the implementation of a common robotic platform and standard release potency testing procedures for enoxaparin sodium injection (Lovenox, Sanofi, Paris, France) products at seven quality control sites within Sanofi. Qualification and analytical procedures, as well as data handling, were optimized and harmonized to improve assay reproducibility. An inter-laboratory study was performed in routine-release conditions. The coefficients of variation for repeatability and reproducibility in assessments of anti-Xa activity were 1.0% and 1.2%, respectively. The tolerance interval in reproducibility precision conditions, expressed as percentage potency, was 96.8-103.2% of the drug product target of 10,000 IU/ml, comparing favorably with the United States of America Pharmacopeia specification (90-110%). The maximum difference between assays in two different laboratories is expected to be 4.1%. The reproducibility characteristics of anti-IIa activity assessments were found to be similar. These results demonstrate the effectiveness of the standardization process established and allow for further improvements to quality control in Lovenox manufacture. This process guarantees closeness between actual and target potencies, as exemplified by the results of release assays obtained during a three-year period. PMID:23644908

  12. Bioactive saponins and glycosides. III. Horse chestnut. (1): The structures, inhibitory effects on ethanol absorption, and hypoglycemic activity of escins Ia, Ib, IIa, IIb, and IIIa from the seeds of Aesculus hippocastanum L.

    PubMed

    Yoshikawa, M; Murakami, T; Matsuda, H; Yamahara, J; Murakami, N; Kitagawa, I

    1996-08-01

    Five bioactive triterpene oligoglycosides named escins, Ia, Ib, IIa, IIb, and IIIa were isolated from the seeds of horse chestnut tree, Aesculus hippocastanum L. (Hippocastanaceae). The chemical structures of escins Ia, Ib, IIa, IIb, and IIIa were determine on the basis of chemical and physicochemical evidence, which included selective cleavage of the glucuronide linkage using photochemical reaction and lead tetraacetate decarboxylation reaction. Escins Ia, Ib, IIa, and IIb were found to exhibit an ethanol absorption-inhibitory effect and hypoglycemic activity in the oral glucose tolerance test in rats. Some structure-activity relationships are reported. PMID:8795266

  13. Escins-Ia, Ib, IIa, IIb, and IIIa, bioactive triterpene oligoglycosides from the seeds of Aesculus hippocastanum L.: their inhibitory effects on ethanol absorption and hypoglycemic activity on glucose tolerance test.

    PubMed

    Yoshikawa, M; Harada, E; Murakami, T; Matsuda, H; Wariishi, N; Yamahara, J; Murakami, N; Kitagawa, I

    1994-06-01

    Five triterpene oligoglycosides named escins-Ia, Ib, IIa, IIb, and IIIa were isolated from the seeds of Aesculus hippocastanum L. and their chemical structures were determined on the basis of chemical and physicochemical evidence. Escins-Ia, Ib, IIa, and IIb were found to exhibit inhibitory effect on ethanol absorption and hypoglycemic activity on oral glucose tolerance test in rats. Among them, escins-IIa and IIb showed the higher activities for both bioassays, while desacylescins-I and II had no activity. PMID:8069982

  14. Laparoscopic ligation of inferior mesenteric artery and internal iliac artery for the treatment of symptomatic type II endoleak after endovascular aneurysm repair.

    PubMed

    Zou, Junjie; Sun, Yueming; Yang, Hongyu; Ma, Hao; Jiang, Jun; Jiao, Yuangyong; Zhang, Xiwei

    2014-01-01

    We present a case undergoing successful laparoscopic ligation of the inferior mesenteric artery (IMA) and internal iliac artery (IIA) for the treatment of a symptomatic type II endoleak (T2E) after endovascular aneurysm repair (EVAR). The patient presented with abdominal and back pain 1 year after EVAR. Subsequent enhanced computed tomography scan showed aneurysm sac enlargement from 60 mm to 70 mm, and digital substraction angiography revealed a T2E caused by patent IMA and right IIA. Then the patient underwent successful laparoscopic ligation of the IMA and right IIA. Postprocedural angiogram demonstrated complete resolution of the type II endoleak, and no intraoperative complications occurred. Also, there was no remaining abdominal pain or back pain after the operation. PMID:25216443

  15. Structure of the IIA domain of the glucose permease of Bacillus subtilis at 2.2-A resolution.

    PubMed

    Liao, D I; Kapadia, G; Reddy, P; Saier, M H; Reizer, J; Herzberg, O

    1991-10-01

    The crystal structure of the IIA domain of the glucose permease of the phosphoenolpyruvate:sugar phosphotransferase system (PTS) from Bacillus subtilis has been determined at 2.2-A resolution. Refinement of the structure is in progress, and the current R-factor is 0.201 (R = sigma h parallel Fo magnitude of - Fc parallel/sigma h magnitude of Fo, where magnitude of Fo and magnitude of Fc are the observed and calculated structure factor amplitudes, respectively) for data between 6.0- and 2.2-A resolution for which F greater than or equal to 2 sigma (F). This is an antiparallel beta-barrel structure that incorporates "Greek key" and "jellyroll" topological motifs. A shallow depression is formed at the active site by part of the beta-sheet and an omega-loop flanking one side of the sheet. His83, the histidyl residue which is the phosphorylation target of HPr and which transfers the phosphoryl group to the IIB domain of the permease, is located at the C-terminus of a beta-strand. The N epsilon atom is partially solvated and also interacts with the N epsilon atom of a second histidyl residue, His68, located at the N-terminus of an adjacent beta-strand, suggesting they share a proton. The geometry of the hydrogen bond is imperfect, though. Electrostatic interactions with other polar groups and van der Waals contacts with the side chains of two flanking phenylalanine residues assure the precise orientation of the imidazole rings. The hydrophobic nature of the surface around the His83-His68 pair may be required for protein-protein recognition by HPr or/and by the IIB domain of the permease. The side chains of two aspartyl residues, Asp31 and Asp87, are oriented toward each other across a narrow groove, about 7 A from the active-site His83, suggesting they may play a role in protein-protein interaction. A model of the phosphorylated form of the molecule is proposed, in which oxygen atoms of the phosphoryl group interact with the side chain of His68 and with the main

  16. The calibration of photographic and spectroscopic films: Reciprocity failure and thermal responses of IIaO film at liquid nitrogen temperatures

    NASA Technical Reports Server (NTRS)

    Hammond, E. C., Jr.; Peters, K. A.; Gunther, S. O.; Cunningham, L. M.; Wright, D. D.

    1985-01-01

    Reciprocity failure was examined for IIaO spectroscopic film. The results indicate reciprocity failure occurs at three distinct minimum points in time; 15 min, 30 min and 90 min. The results are unique because theory suggests only one minimum reciprocity failure point should occur. When incubating 70mm IIaO film for 15 and 30 min at temperatures of 30, 40, 50, and 60 C and then placing in a liquid nitrogen bath at a temperature of -190 C the film demonstrated an increase of the optical density when developed at a warm-up time of 30 min. Longer warm-up periods of 1, 2 and 3 hrs yield a decrease in optical density of the darker wedge patterns; whereas, shorter warm-up times yield an overall increase in the optical densities.

  17. 30 CFR 57.22201 - Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22201 Section 57.22201 Mineral Resources MINE SAFETY AND HEALTH....22201 Mechanical ventilation (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). All mines...

  18. 30 CFR 57.22501 - Personal electric lamps (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Personal electric lamps (I-A, I-B, I-C, II-A... Illumination § 57.22501 Personal electric lamps (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). Electric lamps used for personal illumination shall be approved by MSHA under the requirements of 30...

  19. The antitumor effect of tanshinone IIA on anti-proliferation and decreasing VEGF/VEGFR2 expression on the human non-small cell lung cancer A549 cell line

    PubMed Central

    Xie, Jun; Liu, Jiahui; Liu, Heng; Liang, Shihui; Lin, Meigui; Gu, Yueyu; Liu, Taoli; Wang, Dongmei; Ge, Hui; Mo, Sui-lin

    2015-01-01

    The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGF/VEGFR signal pathway were investigated. The exploration of the interaction between tanshinone IIA and its target proteins provides a feasible platform for studying the anticancer mechanism of active components of herbs. The CCK-8 assay was used to evaluate the proliferative activity of A549 cells treated with tanshinone IIA (2.5−80 μmol/L) for 24, 48 and 72 h, respectively. Flow cytometry was used for the detection of cell apoptosis and cell cycle perturbation. VEGF and VEGFR2 expression were studied by Western blotting. The binding mode of tanshinone IIA within the crystal structure of the VEGFR2 protein was evaluated with molecular docking analysis by use of the CDOCKER algorithm in Discovery Studio 2.1. The CCK-8 results showed that tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. Flow cytometry results showed that the apoptosis rate of tested group was higher than the vehicle control, and tanshinone IIA-treated cells accumulated at the S phase, which was higher than the vehicle control. Furthermore, the expression of VEGF and VEGFR2 was decreased in Western blot. Finally, molecular docking analysis revealed that tanshinone IIA could be stably docked into the kinase domain of VEGFR2 protein with its unique modes to form H-bonds with Cys917 and π–π stacking interactions with Val848. In conclusion, tanshinone IIA may suppress A549 proliferation, induce apoptosis and cell cycle arrest at the S phase. This drug may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2. PMID:26713270

  20. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). 57.22202 Section 57.22202 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for...

  1. 30 CFR 57.22202 - Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Main fans (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). 57.22202 Section 57.22202 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for...

  2. Association of Transcription Factor IIA with TATA Binding Protein Is Required for Transcriptional Activation of a Subset of Promoters and Cell Cycle Progression in Saccharomyces cerevisiae

    PubMed Central

    Ozer, Josef; Lezina, Larissa E.; Ewing, Joshua; Audi, Salma; Lieberman, Paul M.

    1998-01-01

    The general transcription factor IIA (TFIIA) interacts with the TATA binding protein (TBP) and promoter DNA to mediate transcription activation in vitro. To determine if this interaction is generally required for activation of all class II genes in vivo, we have constructed substitution mutations in yeast TFIIA which compromise its ability to bind TBP. Substitution mutations in the small subunit of TFIIA (Toa2) at residue Y69 or W76 significantly impaired the ability of TFIIA to stimulate TBP-promoter binding in vitro. Gene replacement of wild-type TOA2 with a W76E or Y69A/W76A mutant was lethal in Saccharomyces cerevisiae, while the Y69F/W76F mutant exhibited extremely slow growth at 30°C. Both the Y69A and W76A mutants were conditionally lethal at higher temperatures. Light microscopy indicated that viable toa2 mutant strains accumulate as equal-size dumbbells and multibudded clumps. Transcription of the cell cycle-regulatory genes CLB1, CLB2, CLN1, and CTS1 was significantly reduced in the toa2 mutant strains, while the noncycling genes PMA1 and ENO2 were only modestly affected, suggesting that these toa2 mutant alleles disrupt cell cycle progression. The differential effect of these toa2 mutants on gene transcription was examined for a number of other genes. toa2 mutant strains supported high levels of CUP1, PHO5, TRP3, and GAL1 gene activation, but the constitutive expression of DED1 was significantly reduced. Activator-induced start site expression for HIS3, GAL80, URA1, and URA3 promoters was defective in toa2 mutant strains, suggesting that the TFIIA-TBP complex is important for promoters which require an activator-dependent start site selection from constitutive to regulated expression. We present evidence to indicate that transcription defects in toa2 mutants can be both activator and promoter dependent. These results suggest that the association of TFIIA with TBP regulates activator-induced start site selection and cell cycle progression in S

  3. A densitometric analysis of IIaO film flown aboard the space shuttle transportation system STS-3, STS-8, and STS-7

    NASA Technical Reports Server (NTRS)

    Hammond, E. C., Jr.; Peters, K. A.; Atkinson, P. F.

    1986-01-01

    Three canisters of IIaO film were prepared along with packets of color film from the National Geographic Society, which were then placed on the Space Shuttle #3. The ultimate goal was to obtain reasonably accurate data concerning the background fogging effects on IIaO film as it relates to the film's total environmental experience. This includes: the ground based packing, and loading of the film from Goddard Space Flight Center to Cape Kennedy; the effects of the solar wind, humidity, and cosmic rays; the Van Allen Belt radiation exposure; various thermal effect; reentry and off-loading of the film during take off, and 8 day, 3 hour 15 minutes orbits. The total densitometric change caused by all of the above factors were examined. The results of these studies have implications for the utilization of IIaO spectroscopic film on the future shuttle and space lab missions. These responses to standard photonic energy sources will have immediate application for the uneven responses of the film photographing a star field in a terrestrial or extraterrestrial environment with associated digital imaging equipment.

  4. Developing an Anticancer Copper(II) Pro-Drug Based on the His242 Residue of the Human Serum Albumin Carrier IIA Subdomain.

    PubMed

    Qi, Jinxu; Zhang, Yao; Gou, Yi; Zhang, Zhenlei; Zhou, Zuping; Wu, Xiaoyang; Yang, Feng; Liang, Hong

    2016-05-01

    To increase delivery efficiency, anticancer activity, and selectivity of anticancer metal agents in vivo, we proposed to develop the anticancer metal pro-drug based on His242 residue of the human serum albumin (HSA) carrier IIA subdomain. To confirm our hypothesis, we prepared two Cu(II) compounds [Cu(P4 mT)Cl and Cu(Bp44 mT)Cl] by modifying Cu(II) compound ligand structure. Studies with two HSA complex structures revealed that Cu(P4 mT)Cl bound to the HSA subdomain IIA via hydrophobic interactions, but Cu(Bp44 mT)Cl bound to the HSA subdomain IIA via His242 replacement of a Cl atom of Cu(Bp44 mT)Cl, and a coordination to Cu(2+). Furthermore, Cu(II) compounds released from HSA could be regulated at different pHs. In vivo data revealed that the HSA-Cu(Bp44 mT) complex increased copper's selectivity and capacity of inhibiting tumor growth compared to Cu(Bp44 mT)Cl alone. PMID:27017838

  5. Randomized study of preoperative radiation and surgery or irradiation alone in the treatment of Stage IB and IIA carcinoma of the uterine cervix

    SciTech Connect

    Perez, C.A.; Camel, H.M.; Kao, M.S.; Askin, F.

    1980-06-01

    A prospective randomized study in selected patients with Stage IB and IIA carcinoma of the uterine cervix was carried out. Patients were randomized to be treated with 1) irradiation alone consisting of 1000 rad whole pelvis, additional 4000 rads to the parametria with a step wedge midline block, and two intracavitary insertions for 7500 mgh; and 2) irradiation and surgery, consisting of 2000 rad whole pelvis irradiation, one intracavitary insertion for 5000 to 6000 mgh followed in two to six weeks later by a radical hysterectomy with pelvic lymphadenectomy. The five-year, tumor-free actuarial survival for Stage IB patients treated with radiation was 87% and with preoperative radiation and surgery 82%. In Stage IIA, the actuarial five-year survival NED was 57% for the irradiation alone group and 71% for the patients treated with preoperative radiation and radical hysterectomy. Major complications of therapy were slightly higher in the patients trated with radiation alone (9.4%, consisting of one recto-vaginal fistula and one vesico-vaginal fistula and a combined recto-vesico-vaginal fistula in another patient). In the preoperative radiation group, only two ureteral strictures (4.1%) were noted. The present study shows no significant difference in therapeutic results or morbidity for invasive carcinoma of the uterine cervix Stage IB or IIA treated with irradiation alone or combined with a radical hysterectomy.

  6. Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex

    PubMed Central

    Le, Kang; Li, Chun-Chun; Ye, Guan; Moss, Joel; Vaughan, Martha

    2013-01-01

    Brefeldin A-inhibited guanine nucleotide-exchange factors BIG1 and BIG2 activate, through their Sec7 domains, ADP ribosylation factors (Arfs) by accelerating the replacement of Arf-bound GDP with GTP for initiation of vesicular transport or activation of specific enzymes that modify important phospholipids. They are also implicated in regulation of cell polarization and actin dynamics for directed migration. Reciprocal coimmunoprecipitation of endogenous HeLa cell BIG1 and BIG2 with myosin IIA was demonstrably independent of Arf guanine nucleotide-exchange factor activity, because effects of BIG1 and BIG2 depletion were reversed by overexpression of the cognate BIG molecule C-terminal sequence that follows the Arf activation site. Selective depletion of BIG1 or BIG2 enhanced specific phosphorylation of myosin regulatory light chain (T18/S19) and F-actin content, which impaired cell migration in Transwell assays. Our data are clear evidence of these newly recognized functions for BIG1 and BIG2 in transduction or integration of mechanical signals from integrin adhesions and myosin IIA-dependent actin dynamics. Thus, by anchoring or scaffolding the assembly, organization, and efficient operation of multimolecular myosin phosphatase complexes that include myosin IIA, protein phosphatase 1δ, and myosin phosphatase-targeting subunit 1, BIG1 and BIG2 serve to integrate diverse biophysical and biochemical events in cells. PMID:23918382

  7. Tanshinone IIA decreases the protein expression of EGFR, and IGFR blocking the PI3K/Akt/mTOR pathway in gastric carcinoma AGS cells both in vitro and in vivo.

    PubMed

    Su, Chin-Cheng; Chiu, Tsung-Lang

    2016-08-01

    Tan-IIA exerts powerful inhibitory effects in gastric cancer AGS cells. The PI3K/AKT/mTOR pathway is one of the most frequently dysregulated kinase cascades in human cancer. In the present study, we investigated the protein expression levels of PI3K, AKT and mTOR in AGS cells treated with Tan-IIA both in vitro and in vivo. The AGS cells were treated with Tan-IIA for different durations in vitro. In the in vivo study, AGS cell xerograft SCID mice were treated with Tan-IIA for 8 weeks. Subsequently, the protein expression of EGFR, IGFR, PI3K, AKT and mTOR was measured by western blotting. The results showed that Tan-IIA was able to decrease the protein expression levels of EGFR, IGFR, PI3K, AKT and mTOR significantly and dose-dependently in vitro and in vivo. In conclusion, these findings indicate Tan-IIA could inhibit AGS cells through decreasing the protein expression of EGFR, IGFR and blocking PI3K/AKT/mTOR pathway both in vitro and in vivo. PMID:27277844

  8. Crystal structure of the S100A4-nonmuscle myosin IIA tail fragment complex reveals an asymmetric target binding mechanism.

    PubMed

    Kiss, Bence; Duelli, Annette; Radnai, László; Kékesi, Katalin A; Katona, Gergely; Nyitray, László

    2012-04-17

    S100A4 is a member of the S100 family of calcium-binding proteins that is directly involved in tumor metastasis. It binds to the nonmuscle myosin IIA (NMIIA) tail near the assembly competence domain (ACD) promoting filament disassembly, which could be associated with increasing metastatic potential of tumor cells. Here, we investigate the mechanism of S100A4-NMIIA interaction based on binding studies and the crystal structure of S100A4 in complex with a 45-residue-long myosin heavy chain fragment. Interestingly, we also find that S100A4 binds as strongly to a homologous heavy chain fragment of nonmuscle myosin IIC as to NMIIA. The structure of the S100A4-NMIIA complex reveals a unique mode of interaction in the S100 family: A single, predominantly α-helical myosin chain is wrapped around the Ca(2+)-bound S100A4 dimer occupying both hydrophobic binding pockets. Thermal denaturation experiments of coiled-coil forming NMIIA fragments indicate that the coiled-coil partially unwinds upon S100A4 binding. Based on these results, we propose a model for NMIIA filament disassembly: Part of the random coil tailpiece and the C-terminal residues of the coiled-coil are wrapped around an S100A4 dimer disrupting the ACD and resulting in filament dissociation. The description of the complex will facilitate the design of specific drugs that interfere with the S100A4-NMIIA interaction. PMID:22460785

  9. Dlc1 interaction with non-muscle myosin heavy chain II-A (Myh9) and Rac1 activation

    PubMed Central

    Sabbir, Mohammad G.; Dillon, Rachelle; Mowat, Michael R. A.

    2016-01-01

    ABSTRACT The Deleted in liver cancer 1 (Dlc1) gene codes for a Rho GTPase-activating protein that also acts as a tumour suppressor gene. Several studies have consistently found that overexpression leads to excessive cell elongation, cytoskeleton changes and subsequent cell death. However, none of these studies have been able to satisfactorily explain the Dlc1-induced cell morphological phenotypes and the function of the different Dlc1 isoforms. Therefore, we have studied the interacting proteins associated with the three major Dlc1 transcriptional isoforms using a mass spectrometric approach in Dlc1 overexpressing cells. We have found and validated novel interacting partners in constitutive Dlc1-expressing cells. Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. These data support a role for Dlc1 in induced cell elongation morphology and provide some molecular targets for further analysis of this phenotype. PMID:26977077

  10. Correlation of dysfunction of nonmuscle myosin IIA with increased induction of Cyp1a1 in Hepa-1 cells.

    PubMed

    Ebina, Masayuki; Shibazaki, Masahiko; Kudo, Kyoko; Kasai, Shuya; Kikuchi, Hideaki

    2011-03-01

    The aryl hydrocarbon receptor (AhR) is one of the best known ligand-activated transcription factors and it induces Cyp1a1 transcription by binding with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recent focus has been on the relationship of AhR with signaling pathways that modulate cell shape and migration. In nonmuscle cells, nonmuscle myosin II is one of the key determinants of cell morphology, but it has not been investigated whether its function is related to Cyp1a1 induction. In this study, we observed that (-)-blebbistatin, which is a specific inhibitor of nonmuscle myosin II, increased the level of CYP1A1-mRNA in Hepa-1 cells. Comparison of (-)-blebbistatin with (+)-blebbistatin, which is an inactive enantiomer, indicated that the increase of CYP1A1-mRNA was due to nonmuscle myosin II inhibition. Subsequent knockdown experiments observed that reduction of nonmuscle myosin IIA, which is only an isoform of nonmuscle myosin II expressed in Hepa-1 cells, was related to the enhancement of TCDD-dependent Cyp1a1 induction. Moreover, chromatin immunoprecipitation assay indicated that the increase of Cyp1a1 induction was the result of transcriptional activation due to increased binding of AhR and RNA polymerase II to the enhancer and proximal promoter regions of Cyp1a1, respectively. These findings provide a new insight into the correlation between the function of nonmuscle myosin II and gene induction. PMID:21216307

  11. Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion

    PubMed Central

    Dong, Chang Zhi; Plocki, Stéphanie; Tsagris, Lydia; Rannou, François; Massicot, France; Djimdé, Atimé; El-Hayek, Elissar; Shi, Yiming; Heymans, Françoise; Gresh, Nohad; Chauvet, Caroline

    2010-01-01

    Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints. PMID:20531958

  12. Characterization of 40 full-length MHC class IIA functional alleles in miiuy croaker: Polymorphism and positive selection.

    PubMed

    Xu, Tianjun; Liu, Jiang; Sun, Yueyan; Zhu, Zhihuang; Liu, Tianxing

    2016-02-01

    The major histocompatibility complex is a highly polymorphic gene superfamily in vertebrates that plays an important role in adaptive immune response. In the present study, we identified 40 full-length miiuy croaker MHC class IIA (Mimi-DAA) functional alleles from 26 miiuy croaker individuals and found that the alleles encode 30 amino acid sequences. A high level of polymorphism in Mimi-DAA was detected in miiuy croaker. The rate of non-synonymous substitutions (d(N)) occurred at a significantly higher frequency than that of synonymous substitutions (d(S)) in the peptide-binding region (PBR) and non-PBR. This result suggests that balancing selection maintains polymorphisms at the Mimi-DAA locus. Phylogenetic analysis based on the full-length sequences showed that the Mimi-DAA alleles clustered into three groups. However, the phylogenetic tree constructed using the exon 2 sequences indicated that the Mimi-DAA alleles clustered into two groups. A total of 22 positively selected sites were identified on the Mimi-DAA alleles after testing for positive selection, and five sites were predicted to be associated with the binding of peptide antigen, suggesting that a few selected residues may play a significant role in immune function. PMID:26598111

  13. Quinoline-2-carboxaldehyde thiosemicarbazones and their Cu(II) and Ni(II) complexes as topoisomerase IIa inhibitors.

    PubMed

    Bisceglie, Franco; Musiari, Anastasia; Pinelli, Silvana; Alinovi, Rossella; Menozzi, Ilaria; Polverini, Eugenia; Tarasconi, Pieralberto; Tavone, Matteo; Pelosi, Giorgio

    2015-11-01

    A series of quinoline-2-carboxaldehyde thiosemicarbazones and their copper(II) and nickel(II) complexes were synthesized and characterized. In all complexes the ligands are in the E configuration with respect to the imino bond and behave as terdentate. The copper(II) complexes form square planar derivatives with one molecule of terdentate ligand and chloride ion. A further non-coordinated chloride ion compensates the overall charge. Nickel(II) ions form instead octahedral complexes with two ligands for each metal ion, independently from the stoichiometric metal:ligand ratio used in the synthesis. Ligands and complexes were tested for their antiproliferative properties on histiocytic lymphoma cell line U937. Copper(II) derivatives are systematically more active than the ligands and the nickel complexes. All copper derivatives result in inhibiting topoisomerase IIa in vitro. Computational methods were used to propose a model to explain the different extent of inhibition presented by these compounds. The positive charge of the dissociated form of the copper complexes may play a key role in their action. PMID:26335598

  14. Dlc1 interaction with non-muscle myosin heavy chain II-A (Myh9) and Rac1 activation.

    PubMed

    Sabbir, Mohammad G; Dillon, Rachelle; Mowat, Michael R A

    2016-01-01

    The Deleted in liver cancer 1 (Dlc1) gene codes for a Rho GTPase-activating protein that also acts as a tumour suppressor gene. Several studies have consistently found that overexpression leads to excessive cell elongation, cytoskeleton changes and subsequent cell death. However, none of these studies have been able to satisfactorily explain the Dlc1-induced cell morphological phenotypes and the function of the different Dlc1 isoforms. Therefore, we have studied the interacting proteins associated with the three major Dlc1 transcriptional isoforms using a mass spectrometric approach in Dlc1 overexpressing cells. We have found and validated novel interacting partners in constitutive Dlc1-expressing cells. Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. These data support a role for Dlc1 in induced cell elongation morphology and provide some molecular targets for further analysis of this phenotype. PMID:26977077

  15. Binding of cations of group IA and IIA to bovine serum amine oxidase: effect on the activity.

    PubMed Central

    Di Paolo, Maria Luisa; Scarpa, Marina; Corazza, Alessandra; Stevanato, Roberto; Rigo, Adelio

    2002-01-01

    In this paper, we report on the presence of cation binding areas on bovine serum amine oxidase, where metal ions of the groups IA and IIA, such as Na(+), K(+), Cs(+), Mg(2+), and Ca(2+), bind with various affinities. We found a cation-binding area that influences the enzyme activity if occupied, so that the catalytic reaction may be altered by some physiologically relevant cations, such as Ca(2+) and K(+). This binding area appears to be localized inside the enzyme active site, because some of these cations act as competitive inhibitors when highly charged amines, such as spermine and spermidine, are used as substrates. In particular, dissociation constant values (K(d)) of 23 and 27 mM were measured for Cs(+) and Ca(2+), respectively, using, as substrate, spermine, a polyamine of plasma. An additional cation-binding area, where metal ions such as Cs(+) (K(d) congruent with 0.1 mM) and Na(+) (K(d) congruent with 54 mM) bind without affecting the enzyme activity, was found by NMR. PMID:12324440

  16. Clinical value of tumor doubling estimations in multiple endocrine neoplasia type II.

    PubMed

    Jackson, C E; Talpos, G B; Block, M A; Norum, R A; Lloyd, R V; Tashjian, A H

    1984-12-01

    Experience with children with multiple endocrine neoplasia (MEN) type IIb has emphasized that medullary thyroid cancer (MTC) in MEN IIb is more aggressive than in MEN IIa. Earlier ages of onset and apparently more rapid growth of MTC in MEN IIb suggest that these tumors have earlier ages of conversion to malignant states and/or shorter doubling times. The age at which a hyperplastic C cell becomes a malignant cell and the true doubling time cannot be estimated presently. Maximum volume-doubling times of 35 and 75 days (21 to 26 doublings) were calculated from tumor size and age at operation in five patients with MEN IIb aged 2 to 5 years. Calculations in 20 patients with MEN IIa revealed maximum doubling times of 110 to 440 days, with ages ranging from 7 to 29 years and number of doubling ranging from 18 to 38. Positive provocative calcitonin tests in two adult patients with MEN IIa after 10 to 11 years of repeated negative tests suggest a minimum doubling time of 190 to 210 days. Such experience emphasizes that negative stimulated calcitonin tests less than 11 years after operation do not provide assurance of cures for MTC in MEN IIa although negative tests after more than 5 years for MEN IIb are encouraging. Calculations of volume doublings accounting for various-sized tumors are compatible with Knudson's two-mutational-event theory on the initiation of neoplasia. PMID:6150555

  17. Effects of congruency on localization of audiovisual three-dimensional speech sounds Part IIa

    NASA Astrophysics Data System (ADS)

    Riederer, Klaus A. J.

    2003-10-01

    Part two of the current study [J. Acoust. Soc. Am., this issue] investigated localization of virtual audiovisual speech under exactly the same conditions. Perceived directions were signified by pushing keypad-buttons. Inside-the-head localization occurred almost only for the median-plane stimuli, being insignificant of the stimulus type (7.62% congruent, 9.38% incongruent, and 6.54% auditory-only) and disregarded from further analyses. The mean of correct answers was 46.81%. Factorial within-subjects ANOVA showed no significance on acoustic stimuli (/ipi/, /iti/) or stimulus type but showed strong dependence on direction (p=0.000015) and its interactions with acoustic stimuli (p=0.015374) and stimulus type (p=0.00812). Reaction times were highly dependent on direction (p=0.000002). From the 384 frontal location answers (azimuths 0°, +/-40°) 25.52% congruent, 28.39% incongruent, and 28.65% auditory-only were perceived as backward confused, for 0° azimuth only the corresponding values were 28.13%, 28.13%, and 35.94%. Back-front confusions were 13.80%, 9.64%, and 8.85% (azimuths 180°, +/-130°), and 18.75%, 14.06%, and 14.06% (azimuth 180°). Seeing the (congruently) talking face biased the localization more to the front, especially for the median-backward sounds. Obviously, vision overcomes weaker monaural localization cues as in the ventriloquism effect [Driver, Nature (London) 381, 66-68 (1996)]. [Work supported by Graduate School of Electronics, Telecommunication and Automation.

  18. Co-Circulation of Canine Coronavirus I and IIa/b with High Prevalence and Genetic Diversity in Heilongjiang Province, Northeast China

    PubMed Central

    Wang, Xinyu; Li, Chunqiu; Guo, Donghua; Wang, Xinyu; Wei, Shan; Geng, Yufei; Wang, Enyu; Wang, Zhihui; Zhao, Xiwen; Su, Mingjun; Liu, Qiujin; Zhang, Siyao; Feng, Li; Sun, Dongbo

    2016-01-01

    To trace the evolution of canine coronavirus (CCoV), 201 stool samples from diarrheic dogs in northeast China were subjected to reverse transcription-polymerase chain reactions (RT-PCRs) targeting the partial M and S genes of CCoV, followed by an epidemiological analysis. M gene RT-PCRs showed that 28.36% (57/201) of the samples were positive for CCoV; of the 57 positive samples, CCoV-I and CCoV-II accounted for 15.79% (9/57) and 84.21% (48/57), respectively. A sequence comparison of the partial M gene revealed nucleotide homologies of 88.4%–100% among the 57 CCoV strains, and 88.7%–96.2% identity between the 57 CCoV strains and the Chinese reference strain HF3. The CCoV-I and CCoV-II strains exhibited genetic diversity when compared with reference strains from China and other countries. The 57 CCoV strains exhibited high co-infection rates with canine kobuvirus (CaKV) (33.33%) and canine parvovirus-2 (CPV-2) (31.58%). The CCoV prevalence in diarrheic dogs differed significantly with immunization status, regions, seasons, and ages. Moreover, 28 S genes were amplified from the 57 CCoV-positive samples, including 26 CCoV-IIa strains, one CCoV-IIb strain, and one CCoV-I strain. A sequence comparison of the partial S gene revealed 86.3%–100% nucleotide identity among the 26 CCoV-IIa strains, and 89.6%–92.2% identity between the 26 CCoV-IIa strains and the Chinese reference strain V1. The 26 CCoV-IIa strains showed genetic diversity when compared with reference strains from China and other countries. Our data provide evidence that CCoV-I, CCoV-IIa, and CCoV-IIb strains co-circulate in the diarrhoetic dogs in northeast China, high co-infection rates with CaKV and CPV-2 were observed, and the CCoV-II strains exhibited high prevalence and genetic diversity. PMID:26771312

  19. Characterization of subdomain IIA binding site of human serum albumin in its native, unfolded, and refolded states using small molecular probes.

    PubMed

    Abou-Zied, Osama K; Al-Shihi, Othman I K

    2008-08-13

    Subdomain IIA binding site of human serum albumin (HSA) was characterized by examining the change in HSA fluorescence in the native, unfolded, and refolded states. The study was carried out in the absence and presence of small molecular probes using steady-state and time-resolved fluorescence measurements. 2-Pyridone, 3-pyridone, and 4-pyridone bear similar molecular structures to those found in many drugs and are used here as probes. They are found to specifically bind in subdomain IIA and cause a reduction in the fluorescence intensity and lifetime of the Trp-214 residue in native HSA which is located in the same subdomain. The efficiency of energy transfer from Trp-214 fluorescence to the probes was found to depend on the degree of the spectral overlap between the donor's fluorescence and the acceptor's absorption. After probe binding in subdomain IIA, the distance between the donor and acceptor was calculated using Forster theory. The calculated quenching rate constants and binding constants were also shown to depend on the degree of spectral overlap. The results point to a static quenching mechanism operating in the complexes. Denaturation of HSA in the presence of guanidine hydrochloride (GdnHCl) starts at [GdnHCl] > 1.0 M and is complete at [GdnHCl] > or = 6.0 M. Upon unfolding, two fluorescence peaks were observed. One peak was assigned to the fluorescence of Trp-214 in a polar environment, and the other peak was assigned to tyrosine fluorescence. A reduction of the fluorescence intensity of the two peaks upon binding of the probes to the denatured HSA indicates that Tyr-263 in subdomain IIA is one of the tyrosine residues responsible for the second fluorescence peak. The results were confirmed by measuring the fluorescence spectra and lifetimes of denatured HSA at different excitation wavelengths, and of L-tryptophan and L-tyrosine free in buffer. The measured lifetimes of denatured HSA are typical of tryptophan in a polar environment and are slightly

  20. Co-Circulation of Canine Coronavirus I and IIa/b with High Prevalence and Genetic Diversity in Heilongjiang Province, Northeast China.

    PubMed

    Wang, Xinyu; Li, Chunqiu; Guo, Donghua; Wang, Xinyu; Wei, Shan; Geng, Yufei; Wang, Enyu; Wang, Zhihui; Zhao, Xiwen; Su, Mingjun; Liu, Qiujin; Zhang, Siyao; Feng, Li; Sun, Dongbo

    2016-01-01

    To trace the evolution of canine coronavirus (CCoV), 201 stool samples from diarrheic dogs in northeast China were subjected to reverse transcription-polymerase chain reactions (RT-PCRs) targeting the partial M and S genes of CCoV, followed by an epidemiological analysis. M gene RT-PCRs showed that 28.36% (57/201) of the samples were positive for CCoV; of the 57 positive samples, CCoV-I and CCoV-II accounted for 15.79% (9/57) and 84.21% (48/57), respectively. A sequence comparison of the partial M gene revealed nucleotide homologies of 88.4%-100% among the 57 CCoV strains, and 88.7%-96.2% identity between the 57 CCoV strains and the Chinese reference strain HF3. The CCoV-I and CCoV-II strains exhibited genetic diversity when compared with reference strains from China and other countries. The 57 CCoV strains exhibited high co-infection rates with canine kobuvirus (CaKV) (33.33%) and canine parvovirus-2 (CPV-2) (31.58%). The CCoV prevalence in diarrheic dogs differed significantly with immunization status, regions, seasons, and ages. Moreover, 28 S genes were amplified from the 57 CCoV-positive samples, including 26 CCoV-IIa strains, one CCoV-IIb strain, and one CCoV-I strain. A sequence comparison of the partial S gene revealed 86.3%-100% nucleotide identity among the 26 CCoV-IIa strains, and 89.6%-92.2% identity between the 26 CCoV-IIa strains and the Chinese reference strain V1. The 26 CCoV-IIa strains showed genetic diversity when compared with reference strains from China and other countries. Our data provide evidence that CCoV-I, CCoV-IIa, and CCoV-IIb strains co-circulate in the diarrhoetic dogs in northeast China, high co-infection rates with CaKV and CPV-2 were observed, and the CCoV-II strains exhibited high prevalence and genetic diversity. PMID:26771312

  1. Effects of salvianolic acid B and tanshinone IIA on the pharmacokinetics of losartan in rats by regulating the activities and expression of CYP3A4 and CYP2C9.

    PubMed

    Wang, Rong; Zhang, Hai; Wang, Yujie; Yu, Xiaoyan; Yuan, Yongfang

    2016-03-01

    Losartan (LST) is a common chemical drug used to treat high blood pressure and reduce the risk of stroke in certain people with heart disease. Danshen, prepared from the dried root and rhizome of Salvia miltiorrhiza Bunge, has been widely used for prevention and treatment of various cardiovascular and cerebrovascular diseases. There are more than 35 formulations containing Danshen indexed in the 2010 Chinese Pharmacopoeia, which are often combined with LST to treat cardiovascular and cerebrovascular diseases in the clinic. The effects of the two major components of Danshen, salvianolic acid B (SA-B) and tanshinone IIA (Tan IIA), on the pharmacokinetics of losartan and its metabolite, EXP3174, in rats were investigated by liquid chromatography coupled with mass spectrometry (LC-MS). Male Sprague-Dawley rats were randomly assigned to 3 groups: LST, LST+SA-B and LST+Tan IIA, and the main pharmacokinetic parameters were estimated after oral administration of LST, LST+SA-B and LST+Tan IIA. It was found that there are significant differences in the pharmacokinetic parameters among the three groups: Cmax, t1/2, AUC, AUMC in the LST+SA-B group was smaller than those in group LST, while larger in group LST+Tan IIA. Further, the effects of SA-B and Tan IIA on the metabolism of losartan was also investigated using rat liver microsomes in vitro. The results indicated that SA-B can induce the metabolism of LST, while Tan IIA can inhibit the metabolism of LST in rat liver microsomes in vitro by regulating activities of CYP450 enzymes. In addition, the effect of SA-B and Tan IIA on CYP3A4 and CYP2C9 expression was studied in Chang liver cells by western-blotting and Real-time PCR. It was concluded that the two components of Danshen, SA-B and Tan IIA have different influences on the metabolism of LST: SA-B can obviously speed up the metabolism of LST by inducing CYP3A4/CYP2C9 activities and expression, however, Tan IIA can slow down the metabolism of LST by inhibiting CYP3A4/CYP2C

  2. A Noncompetitive Inhibitor for Mycobacterium tuberculosis's Class IIa Fructose 1,6-Bisphosphate Aldolase

    PubMed Central

    Capodagli, Glenn C.; Sedhom, Wafik G.; Jackson, Mary; Ahrendt, Kateri A.; Pegan, Scott D.

    2014-01-01

    Class II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis. Importantly, humans lack this type of aldolase, having instead a class I FBA that is structurally and mechanistically distinct from class II FBAs. As such, class II FBA is considered a putative pharmacological target for the development of novel antibiotics against pathogenic bacteria such as Mycobacterium tuberculosis, the causative agent for tuberculosis (TB). To date, several competitive class II FBA substrate mimic-styled inhibitors have been developed; however, they lack either specificity, potency, or properties that limit their potential as possible therapeutics. Recently, through the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA) that has an IC50 of 10 ± 1 μM for the class II FBA present in M. tuberculosis (MtFBA). As opposed to previous inhibitors, HCA behaves in a noncompetitive manner, shows no inhibitory properties toward human and rabbit class I FBAs, and possesses anti-TB properties. Furthermore, we were able to determine the crystal structure of HCA bound to MtFBA to 2.1 Å. HCA also demonstrates inhibitory effects for other class II FBAs, including pathogenic bacteria such as methicillin-resistant Staphylococcus aureus. With its broad-spectrum potential, unique inhibitory characteristics, and flexibility of functionalization, the HCA scaffold likely represents an important advancement in the development of class II FBA inhibitors that can serve as viable preclinical candidates. PMID:24325645

  3. Tanshinone IIA - loaded pellets developed for angina chronotherapy: Deconvolution-based formulation design and optimization, pharmacokinetic and pharmacodynamic evaluation.

    PubMed

    Yan, Hong-Xiang; Li, Jin; Li, Zheng-Hua; Zhang, Wen-Li; Liu, Jian-Ping

    2015-08-30

    This paper put forward a deconvolution-based method for designing and optimizing tanshinone IIA sustained-release pellets (TA-SRPs) with improved efficacy in the treatment of variant angina. TA-SRPs were prepared by coating TA ternary solid dispersion immediate-release pellets (TA-tSD-IRPs) with the blends of polyvinyl acetate (PVAc) and polyvinyl alcohol-polyethylene glycol (PVA-PEG) using fluidized bed technology. The plasma concentration-time curve of TA-tSD-IRPs following oral administration as a weight function was investigated in New Zealand white rabbits. The predicted/expected plasma concentration-time curve of TA-SRPs as a response function was simulated according to the circadian rhythm of variant angina during 24h based on chronotherapy theory. The desired drug release profile of TA-SRPs was obtained via the point-area deconvolution procedure using the weight function and response function, and used for formulation optimization of TA-SRPs. The coating formulation of TA-SRPs was optimized as 70:30 (w/w) PVAc/PVA-PEG with 5% (w/w) coating weight due to in vitro drug release profile of these TA-SRPs was similar to the desired release profile (similarity factor f2=64.90). Pharmacokinetic studies of these optimized TA-SRPs validated that their actual plasma concentration-time curve possessed a basically consistent trend with the predicted plasma concentration-time curve and the absolute percent errors (%PE) of concentrations in 8-12h were less than 10%. Pharmacodynamic studies further demonstrated that these TA-SRPs had stable and improved efficacy with almost simultaneous drug concentration-efficacy. In conclusion, deconvolution could be employed in the development of TA-SRPs for angina chronotherapy with simultaneous drug efficacy and reduced design blindness and complexity. PMID:25976225

  4. Interleukin-22-Induced Antimicrobial Phospholipase A2 Group IIA Mediates Protective Innate Immunity of Nonhematopoietic Cells against Listeria monocytogenes.

    PubMed

    Okita, Yamato; Shiono, Takeru; Yahagi, Ayano; Hamada, Satoru; Umemura, Masayuki; Matsuzaki, Goro

    2016-02-01

    Listeria monocytogenes is a bacterial pathogen which establishes intracellular parasitism in various cells, including macrophages and nonhematopoietic cells, such as hepatocytes. It has been reported that several proinflammatory cytokines have pivotal roles in innate protection against L. monocytogenes infection. We found that a proinflammatory cytokine, interleukin 22 (IL-22), was expressed by CD3(+) CD4(+) T cells at an early stage of L. monocytogenes infection in mice. To assess the influence of IL-22 on L. monocytogenes infection in hepatocytes, cells of a human hepatocellular carcinoma line, HepG2, were treated with IL-22 before L. monocytogenes infection in vitro. Gene expression analysis of the IL-22-treated HepG2 cells identified phospholipase A2 group IIA (PLA2G2A) as an upregulated antimicrobial molecule. Addition of recombinant PLA2G2A to the HepG2 culture significantly suppressed L. monocytogenes infection. Culture supernatant of the IL-22-treated HepG2 cells contained bactericidal activity against L. monocytogenes, and the activity was abrogated by a specific PLA2G2A inhibitor, demonstrating that HepG2 cells secreted PLA2G2A, which killed extracellular L. monocytogenes. Furthermore, colocalization of PLA2G2A and L. monocytogenes was detected in the IL-22-treated infected HepG2 cells, which suggests involvement of PLA2G2A in the mechanism of intracellular killing of L. monocytogenes by HepG2 cells. These results suggest that IL-22 induced at an early stage of L. monocytogenes infection enhances innate immunity against L. monocytogenes in the liver by stimulating hepatocytes to produce an antimicrobial molecule, PLA2G2A. PMID:26644377

  5. Tanshinone IIA Pretreatment Renders Free Flaps against Hypoxic Injury through Activating Wnt Signaling and Upregulating Stem Cell-Related Biomarkers

    PubMed Central

    Xu, Zihan; Zhang, Zhenxin; Wu, Lijun; Sun, Yaowen; Guo, Yadong; Qin, Gaoping; Mu, Shengzhi; Fan, Ronghui; Wang, Benfeng; Gao, Wenjie

    2014-01-01

    Partial or total flap necrosis after flap transplantation is sometimes clinically encountered in reconstructive surgery, often as a result of a period of hypoxia that exceeds the tolerance of the flap tissue. In this study, we determine whether tanshinone IIA (TSA) pretreatment can protect flap tissue against hypoxic injury and improve its viability. Primary epithelial cells isolated from the dorsal skin of mice were pretreated with TSA for two weeks. Cell counting kit-8 and Trypan Blue assays were carried out to examine the proliferation of TSA-pretreated cells after exposure to cobalt chloride. Then, Polymerase chain reaction and Western blot analysis were used to determine the expression of β-catenin, GSK-3β, SOX2, and OCT4 in TSA-treated cells. In vivo, after mice were pretreated with TSA for two weeks, a reproducible ischemic flap model was implemented, and the area of surviving tissue in the transplanted flaps was measured. Immunohistochemistry was also conducted to examine the related biomarkers mentioned above. Results show that epidermal cells, pretreated with TSA, showed enhanced resistance to hypoxia. Activation of the Wnt signaling pathway in TSA-pretreated cells was characterized by the upregulation of β-catenin and the downregulation of GSK-3β. The expression of SOX2 and OCT4 controlled by Wnt signaling were also found higher in TSA pretreated epithelial cells. In the reproducible ischaemic flap model, pretreatment with TSA enhanced resistance to hypoxia and increased the area of surviving tissue in transplanted flaps. The expression of Wnt signaling pathway components, stem-cell related biomarkers, and CD34, which are involved in the regeneration of blood vessels, was also upregulated in TSA-pretreated flap tissue. The results show that TSA pretreatment protects free flaps against hypoxic injury and increases the area of surviving tissue by activating Wnt signaling and upregulating stem cell-related biomarkers. PMID:25302618

  6. Interleukin-22-Induced Antimicrobial Phospholipase A2 Group IIA Mediates Protective Innate Immunity of Nonhematopoietic Cells against Listeria monocytogenes

    PubMed Central

    Okita, Yamato; Shiono, Takeru; Yahagi, Ayano; Hamada, Satoru; Umemura, Masayuki

    2015-01-01

    Listeria monocytogenes is a bacterial pathogen which establishes intracellular parasitism in various cells, including macrophages and nonhematopoietic cells, such as hepatocytes. It has been reported that several proinflammatory cytokines have pivotal roles in innate protection against L. monocytogenes infection. We found that a proinflammatory cytokine, interleukin 22 (IL-22), was expressed by CD3+ CD4+ T cells at an early stage of L. monocytogenes infection in mice. To assess the influence of IL-22 on L. monocytogenes infection in hepatocytes, cells of a human hepatocellular carcinoma line, HepG2, were treated with IL-22 before L. monocytogenes infection in vitro. Gene expression analysis of the IL-22-treated HepG2 cells identified phospholipase A2 group IIA (PLA2G2A) as an upregulated antimicrobial molecule. Addition of recombinant PLA2G2A to the HepG2 culture significantly suppressed L. monocytogenes infection. Culture supernatant of the IL-22-treated HepG2 cells contained bactericidal activity against L. monocytogenes, and the activity was abrogated by a specific PLA2G2A inhibitor, demonstrating that HepG2 cells secreted PLA2G2A, which killed extracellular L. monocytogenes. Furthermore, colocalization of PLA2G2A and L. monocytogenes was detected in the IL-22-treated infected HepG2 cells, which suggests involvement of PLA2G2A in the mechanism of intracellular killing of L. monocytogenes by HepG2 cells. These results suggest that IL-22 induced at an early stage of L. monocytogenes infection enhances innate immunity against L. monocytogenes in the liver by stimulating hepatocytes to produce an antimicrobial molecule, PLA2G2A. PMID:26644377

  7. Myosin heavy chain-based fibre types in red cell hyper- and normovolaemic Standardbred trotters.

    PubMed

    Karlström, K; Essén-Gustavsson, B

    2002-09-01

    An assumed link between red cell hypervolaemia, an excessive amount of training and impaired performance of hypervolaemic horses has led to a theory that the muscle fibres could be affected. Myosin heavy chain (MHC)-based fibre type composition in gluteus medius muscle of red blood cell normo- (NV) and hypervolaemic (HV) Standardbred trotters was evaluated using immunohistochemistry. Muscle biopsies were obtained from 13 NV and 16 HV horses. Serial transverse sections were cut and reacted with antibodies against different isoforms of the myosin heavy chains MHCI, MHCIIA and MHCIIX. Sections were also stained for myofibrillar ATPase pH 4,6 to identify types I, IIA and IIB, and NADH tetrazolium reductase to evaluate the oxidative capacity. The results show that types I and IIA fibres corresponded between staining methods, whereas IIB fibres in the ATPase stains were more numerous than pure MHCIIX fibres from immunohistochemistry. Many fibres identified histochemically as type IIB fibres contained both MHC isoforms IIA and IIX (MHCIIAX). Most fibres had a high oxidative capacity, but among the fibres within a section, the lowest was seen subjectively in pure MHCIIX fibres. Immunohistochemical stains make it possible to detect differences in fibre type composition that are not observed with myosin ATPase stainings, as it was found that HV horses had a lower percentage of MHCIIX fibres than NV horses. Immunohistochemical methods are, therefore, valuable for use in further research and clinical studies concerning muscle adaptations. PMID:12405701

  8. Foscarnet, an inhibitor of the sodium-phosphate cotransporter NaPi-IIa, inhibits phosphorylation of glycogen synthase kinase-3β by lithium in the rat kidney cortex.

    PubMed

    Uwai, Yuichi; Kawasaki, Tatsuya; Nabekura, Tomohiro

    2016-06-01

    Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3β (GSK3β) by producing its phosphorylated form (p-GSK3β). GSK3β plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3β is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney. In the present study, the phosphorylation status of GSK3β in the kidney cortex of rats administered lithium chloride and foscarnet, a typical inhibitor of NaPi-IIa, was examined using Western blotting. Under a 2-h infusion of lithium chloride, the plasma concentration of lithium was 1.06 mEq/l, and its renal clearance was calculated as 1.18 ml/min/kg, which was 29.6% of creatinine clearance. The abundance of p-GSK3β in the kidney cortex was augmented by the administration of lithium. The simultaneous infusion of foscarnet increased the renal clearance of lithium and its ratio to creatinine clearance as well as the urinary excretion of phosphate. Foscarnet also inhibited the lithium-induced phosphorylation of GSK3β. These results suggest that the reabsorption of lithium by NaPi-IIa triggers the phosphorylation of GSK3β in the rat kidney cortex. PMID:27238574

  9. Lethal hypophosphatasia, spur type: case report and fetopathological study.

    PubMed

    Vandevijver, N; De Die-Smulders, C E; Offermans, J P; Van Der Linden, E S; Arends, J W; Sastrowijoto, S H; Moerman, P; Fryns, J P

    1998-01-01

    Lethal hypophosphatasia, spur type: case report and fetopathological study: Hypophosphatasia (HP) is characterised by severe undermineralisation of the skeleton owing to deficiency of tissue nonspecific alkaline phosphatase. Clinically a perinatal, infantile, childhood and adult type is distinguished. Clinical signs in the perinatal type of HP show considerable overlap with other skeletal dysplasias such as osteogenesis imperfecta type IIA and type IIC, and achondrogenesis type IA. If present, "spurs" of the limbs are diagnostic for HP. We present a prenatally diagnosed case of HP and discuss the differential diagnosis based on clinical, radiological and pathological findings. Our findings indicate that two types of spurs can be distinguished in hypophosphatasia: midshaft type and joint type. PMID:9777343

  10. Activin receptor IIA ligand trap in chronic kidney disease: 1 drug to prevent 2 complications-or even more?

    PubMed

    Massy, Ziad A; Drueke, Tilman B

    2016-06-01

    Vascular calcification and kidney fibrosis are 2 important features of chronic kidney disease. Bone morphogenetic proteins/growth differentiation factors and their receptors are implicated in the pathogenesis of both processes. Modulation of the bone morphogenetic protein/growth differentiation factor pathways by a soluble chimeric protein that contains the activin receptor IIA (ActRIIA) domain and acts as an ActRIIA ligand trap for activin and other ligands could become a new therapeutic strategy for vascular calcification and kidney fibrosis in chronic kidney disease. PMID:27181771

  11. The calibration of photographic and spectroscopic films: A densitometric analysis of IIaO film flown aboard the Space Shuttle 3

    NASA Technical Reports Server (NTRS)

    Hammond, E. C., Jr.; Stobor, A.; Peters, K.

    1984-01-01

    Three canisters of IIaO film were prepared along with packets of color film from the National Geographic Society, which were placed on the Space Shuttle. The ultimate aim was to obtain reasonably accurate data concerning the background fogging effects as related to the total environment experience of the film including the groundbased packing and loading of the film from Goddard Space Flight Center to Cape Kennedy. The affects of solar wind, humidity, cosmic rays, the Van Allen Belt radiation exposure, various thermal effects, and reentry and off-loading of the film during takeoff and 8 days, 3 hour 15 minute orbit are of particular interest.

  12. The 2010 ILSO-ISRU Field Test at Mauna Kea, Hawaii: Results from the Miniaturised Mossbauer Spectrometers Mimos II and Mimos IIA

    NASA Technical Reports Server (NTRS)

    Klingelhoefer, G.; Morris, R. V.; Blumers, M.; Bernhardt, B.; Graff, T.

    2011-01-01

    For the advanced Moessbauer instrument MIMOS IIA, the new detector technologies and electronic components increase sensitivity and performance significantly. In combination with the high energy resolution of the SDD it is possible to perform X-ray fluorescence analysis simultaneously to Moessbauer spectroscopy. In addition to the Fe-mineralogy, information on the sample's elemental composition will be gathered. The ISRU 2010 field campaign demonstrated that in-situ Moessbauer spectroscopy is an effective tool for both science and feedstock exploration and process monitoring. Engineering tests showed that a compact nickel metal hydride battery provided sufficient power for over 12 hr of continuous operation for the MIMOS instruments.

  13. Muscle fibre types in the human vastus lateralis muscles: do symmetrical sites differ in their composition?

    PubMed

    Erzen, I; Pernus, F; Sirca, A

    1990-01-01

    Muscle samples obtained from distinct symmetrical sites of left and right vastus lateralis muscles from 10 young healthy males were analysed. A computer-aided system was applied for the determination of muscle fibre types I, IIA, IIB and IIC and for their quantitative analysis. No statistically significant differences were established regarding percentage and surface area of all the four fibre types studied. In 2 cases of IIA and in one case of IIB fibre type significantly different diameters were measured between the left and right muscle. Regarding percentage and surface area no differences were proved between superficial and deep layers of the muscles observed. Fibre diameter but differed significantly in many muscles, there was no rule about whether it was larger in superficial or in deep muscle layers. One biopsy sample can not represent the whole muscle, especially as far as the relative number and surface area of the type IIA and IIB fibres are concerned. A slight asymmetry in fibre diameters of biopsy samples from both legs does not indicate any pathological change and can still be taken for normal. PMID:2403213

  14. Perinatal lethal type II osteogenesis imperfecta: a case report

    PubMed Central

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Rebeh, Rania Ben; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy termination; they felt that the diagnosis was late. At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure. PMID:26401205

  15. A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury.

    PubMed

    Fehlings, Michael G; Theodore, Nicholas; Harrop, James; Maurais, Gilles; Kuntz, Charles; Shaffrey, Chris I; Kwon, Brian K; Chapman, Jens; Yee, Albert; Tighe, Allyson; McKerracher, Lisa

    2011-05-01

    Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3 mg to 9 mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8±5.1) and larger in cervical patients (18.6±19.3). The largest change in motor score was observed in the cervical patients treated with 3 mg of Cethrin in whom a 27.3±13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial

  16. Histochemical type I fibres in the soleus of the rat.

    PubMed

    Dekleva, A; Sirca, A

    1978-12-01

    Based on oxidative enzyme activity levels, fibres exhibiting moderate and high levels may be identified in the soleus of the rat. Fibres showing moderate activity are classified as Type I fibres, while those showing high activity may belong to Type I or Type II. According to the level of ATPase activity in fixed sections, we can distinguish three types of fibres in the soleus of the rat (IA, IB and II) and, by application of acid pre-incubation, also sub-classes of Type II (IIA and IIC). Type IB fibres possess high oxidative and glycolytic enzyme activities, moderate ATPase activity after fixation, and behave in the same way as Type I fibres after alkaline and acid pre-incubation. For the histochemical classificationof fibre types, we should consider not only reactions to ATPase, and after acid pre-incubation, but also reactions to the enzymes of oxidative and glycolytic metabolism. PMID:154494

  17. Histochemical type I fibres in the soleus of the rat.

    PubMed Central

    Dekleva, A; Sirca, A

    1978-01-01

    Based on oxidative enzyme activity levels, fibres exhibiting moderate and high levels may be identified in the soleus of the rat. Fibres showing moderate activity are classified as Type I fibres, while those showing high activity may belong to Type I or Type II. According to the level of ATPase activity in fixed sections, we can distinguish three types of fibres in the soleus of the rat (IA, IB and II) and, by application of acid pre-incubation, also sub-classes of Type II (IIA and IIC). Type IB fibres possess high oxidative and glycolytic enzyme activities, moderate ATPase activity after fixation, and behave in the same way as Type I fibres after alkaline and acid pre-incubation. For the histochemical classificationof fibre types, we should consider not only reactions to ATPase, and after acid pre-incubation, but also reactions to the enzymes of oxidative and glycolytic metabolism. Images Fig. 1 Fig. 2 PMID:154494

  18. Nasal immunization with M cell-targeting ligand-conjugated ApxIIA toxin fragment induces protective immunity against Actinobacillus pleuropneumoniae infection in a murine model.

    PubMed

    Park, Jisang; Seo, Ki-Weon; Kim, Sae-Hae; Lee, Ha-Yan; Kim, Bumseok; Lim, Chae Woong; Kim, Jin-Hee; Yoo, Han Sang; Jang, Yong-Suk

    2015-05-15

    Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia and severe economic loss in the swine industry has been caused by the infection. Therefore, the development of an effective vaccine against the bacteria is necessary. ApxII toxin, among several virulence factors expressed by the bacteria, is considered to be a promising vaccine candidate because ApxII toxin not only accompanies cytotoxic and hemolytic activities, but is also expressed in all 15 serotypes of bacteria except serotypes 10 and 14. In this study, we identified the peptide ligand capable of targeting the ligand-conjugated ApxIIA #5 fragment antigen to nasopharynx-associated lymphoid tissue. It was found that nasal immunization with ligand-conjugated ApxIIA #5 induced efficient mucosal and systemic immune responses measured at the levels of antigen-specific antibodies, cytokine-secreting cells after antigen exposure, and antigen-specific lymphocyte proliferation. More importantly, the nasal immunization induced protective immunity against nasal challenge infection of the bacteria, which was confirmed by histopathological studies and bacterial clearance after challenge infection. Collectively, we confirmed that the ligand capable of targeting the ligand-conjugated antigen to nasopharynx-associated lymphoid tissue can be used as an effective nasal vaccine adjuvant to induce protective immunity against A. pleuropneumoniae infection. PMID:25818577

  19. Comparative Adjuvant Effects of Type II Heat-Labile Enterotoxins in Combination with Two Different Candidate Ricin Toxin Vaccine Antigens

    PubMed Central

    Vance, David J.; Greene, Christopher J.; Rong, Yinghui; Mandell, Lorrie M.; Connell, Terry D.

    2015-01-01

    Type II heat-labile enterotoxins (HLTs) constitute a promising set of adjuvants that have been shown to enhance humoral and cellular immune responses when coadministered with an array of different proteins, including several pathogen-associated antigens. However, the adjuvant activities of the four best-studied HLTs, LT-IIa, LT-IIb, LT-IIbT13I, and LT-IIc, have never been compared side by side. We therefore conducted immunization studies in which LT-IIa, LT-IIb, LT-IIbT13I, and LT-IIc were coadministered by the intradermal route to mice with two clinically relevant protein subunit vaccine antigens derived from the enzymatic A subunit (RTA) of ricin toxin, RiVax and RVEc. The HLTs were tested with low and high doses of antigen and were assessed for their abilities to stimulate antigen-specific serum IgG titers, ricin toxin-neutralizing activity (TNA), and protective immunity. We found that all four HLTs tested were effective adjuvants when coadministered with RiVax or RVEc. LT-IIa was of particular interest because as little as 0.03 μg when coadministered with RiVax or RVEc proved effective at augmenting ricin toxin-specific serum antibody titers with nominal evidence of local inflammation. Collectively, these results justify the need for further studies into the mechanism(s) underlying LT-IIa adjuvant activity, with the long-term goal of evaluating LT-IIa's activity in humans. PMID:26491037

  20. The calibration of photographic and spectroscopic films. A densitometric analysis of IIaO film flown aboard the space shuttle transportation system STS3, STS8, and STS7

    NASA Technical Reports Server (NTRS)

    Hammond, Ernest C., Jr.

    1987-01-01

    The results of these studies have implications for the utilization of the IIaO spectroscopic film on the future shuttle and space lab missions. These responses to standard photonic energy sources will have immediate application for the uneven responses of the film photographing a star field in a terrestrial or extraterrestrial environment with associated digital imaging equipment.

  1. Chondrule Glass Alteration in Type IIA Chondrules in the CR2 Chondrites EET 87770 and EET 92105: Insights into Elemental Exchange Between Chondrules and Matrices

    NASA Technical Reports Server (NTRS)

    Burger, Paul V.; Brearley, Adrian J.

    2004-01-01

    CR2 carbonaceous chondrites are a primitive group of meteorites that preserve evidence of a variety of processes that occurred in the solar nebula as well as on asteroidal parent bodies. CR2 chondrites are distinct from other carbonaceous chondrites by (among other properties) their relatively high abundance of chondrules (50-60 vol. %) and Fe,Ni metal (5-8 vol. %) [1]. Like the CM2 chondrites, the CRs have been affected by aqueous alteration and according to [2] show a range of degrees of alteration. In weakly- altered CR chondrites, fine-grained matrices and chondrule rims have been partially altered and chondrule mesostases show evidence of incipient aqueous alteration. In these meteorites, glassy mesostasis is still common. However, some CR chondrites, (e.g. Renazzo and Al Rais) show evidence of much more extensive alteration with complete replacement of chondrule mesostasis [2] by chlorite and serpentine. Although the general characteristics of alteration of the CR chondrites have been described, the details of alteration reactions in these meteorites remain unclear. In addition, the setting for aqueous alteration is poorly understood: both asteroidal and preaccretionary alteration scenarios have been proposed [2].

  2. Mean carrier transport properties and charge collection dynamics of single-crystal, natural type IIa diamonds from ion-induced conductivity measurements

    SciTech Connect

    Han, S.S.

    1993-09-01

    Ion-induced conductivity has been used to investigate the detector characteristics of diamond detectors. Both integrated-charge, and time-resolved current measurements were performed to examine the mean carrier transport properties of diamond and the dynamics of charge collection under highly-localized and high-density excitation conditions. The integrated-charge measurements were conducted with a standard pulse-counting system with {sup 241}Am radioactivity as the excitation source for the detectors. The time-resolved current measurements were performed using a 70 GHz random sampling oscilloscope with the detectors incorporated into high-speed microstrip transmission lines and the excitation source for these measurements was an ion beam of either 5-MeV He{sup +} or 10-MeV Si{sup 3+}. The detectors used in both experiments can be described as metal-semiconductor-metal (MSM) devices where a volume of the detector material is sandwiched between two metal plates. A charge collection model was developed to interpret the integrated-charge measurements which enabled estimation of the energy required to produce an electron-hole pair ({epsilon}{sub di}) and the mean carrier transport properties in diamond, such as carrier mobility and lifetime, and the behavior of the electrical contacts to diamond.

  3. Deletion of PHO13, Encoding Haloacid Dehalogenase Type IIA Phosphatase, Results in Upregulation of the Pentose Phosphate Pathway in Saccharomyces cerevisiae

    PubMed Central

    Xu, Haiqing; Lesmana, Anastashia; Kuzmanovic, Uros; Au, Matthew; Florencia, Clarissa; Oh, Eun Joong; Zhang, Guochang

    2014-01-01

    The haloacid dehalogenase (HAD) superfamily is one of the largest enzyme families, consisting mainly of phosphatases. Although intracellular phosphate plays important roles in many cellular activities, the biological functions of HAD enzymes are largely unknown. Pho13 is 1 of 16 putative HAD enzymes in Saccharomyces cerevisiae. Pho13 has not been studied extensively, but previous studies have identified PHO13 to be a deletion target for the generation of industrially attractive phenotypes, namely, efficient xylose fermentation and high tolerance to fermentation inhibitors. In order to understand the molecular mechanisms underlying the improved xylose-fermenting phenotype produced by deletion of PHO13 (pho13Δ), we investigated the response of S. cerevisiae to pho13Δ at the transcriptomic level when cells were grown on glucose or xylose. Transcriptome sequencing analysis revealed that pho13Δ resulted in upregulation of the pentose phosphate (PP) pathway and NADPH-producing enzymes when cells were grown on glucose or xylose. We also found that the transcriptional changes induced by pho13Δ required the transcription factor Stb5, which is activated specifically under NADPH-limiting conditions. Thus, pho13Δ resulted in the upregulation of the PP pathway and NADPH-producing enzymes as a part of an oxidative stress response mediated by activation of Stb5. Because the PP pathway is the primary pathway for xylose, its upregulation by pho13Δ might explain the improved xylose metabolism. These findings will be useful for understanding the biological function of S. cerevisiae Pho13 and the HAD superfamily enzymes and for developing S. cerevisiae strains with industrially attractive phenotypes. PMID:25527558

  4. The combined Mössbauer and XRF Spectrometer MIMOS IIA for In-Situ Geochemical and Mineralogical Analysis of Planetary Surfaces.

    NASA Astrophysics Data System (ADS)

    Klingelhoefer, Goestar; Morris, Richard; Blumers, Mathias; Girones-Lopez, Jordi; Bernhardt, Bodo; Henkel, Hartmut; D'Uston, Claude; Brueckner, Johannes; Rodionov, Daniel; Strueder, Lothar

    The Miniaturised Mössbauer Spectrometers MIMOS II on board the two NASA Mars Exploration Rovers (MER) have now collected valuable scientific data for more than ten years [1-4]. This mission has demonstrated that Mössbauer spectroscopy is extremely valuable for the in situ exploration of extraterrestrial bodies and the study of Fe-bearing samples. A MIMOS instrument was also on the scientific payload of the Russian mission Phobos Grunt [5]. The instrument MIMOS IIA originally developed for the ESA ExoMars mission (now 2018) will use newly de-signed Si-Drift detectors with circular geometry (SDD) [6,7] allowing high resolution X-ray fluorescence spectroscopy simultaneously to Mössbauer measurements. The new design of the improved MIMOS II instrument is reduced in total mass (less than 400 g). The sensorhead of MIMOS IIA will be equipped with a ring of Silicon Drift Detectors (SDD) optimized for the backscatter geometry of the miniaturized Mössbauer spectrometer. The main goal of the new detector system design was to combine high energy resolution at high counting rates and large detector area while making maximum use of the area close to the collimator of the 57Co Mössbauer source. The active area per SDD segment is 2x45 mm2. The energy resolution at 5.9 keV is < 280 eV at room temperature and 131 eV FWHM at -40oC. This performance will increase the signal to noise ratio (SNR) and reduce the integration time of Mössbauer measurement by a factor of up to 10. In addition to the Mössbauer analysis simultaneous acquisition of the X-ray fluorescence spectrum will provide data on the sample's elemental composition [7]. Preliminary studies at room temperature and normal pressure show detection of X-rays down to ~1 keV. A new control- and readout electronics for MIMOS IIA allows spectra acquisition at highest possible countrates available at about 360 mm2 total detector area. A prototype of MIMOS IIA has been tested successfully during a field test at Mauna Kea

  5. [Bioactive saponins and glycosides. XIII. Horse chestnut. (3): Quantitative analysis of escins Ia, Ib, IIa, and IIb by means of high performance liquid chromatography].

    PubMed

    Yoshikawa, M; Murakami, T; Otuki, K; Yamahara, J; Matsuda, H

    1999-01-01

    As a part of our studies on the characterization of bioactive saponin constituents of horse chestnut trees, a quantitative method using high performance liquid chromatography (HPLC) has been developed for four principle saponin constituents, such as escins Ia, Ib, IIa, and IIb, isolated from the seeds of European horse chestnut trees (Aesculus hippocastanum L., Hippocastanaceae). As an application of this HPLC method, we examined the contents and compositions of these escins in the seeds of Japanese horse chestnut trees (A. turbinata BLUME) and in several commercial materials named as "beta-escin". Additionally, the distribution of escins in the Japanese horse chestnut trees was examined, and escins were found to be contained only in the seeds. PMID:9922711

  6. Immunocytochemistry for the heavy chain of the non-muscle myosin IIA as a diagnostic tool for MYH9-related disorders.

    PubMed

    Pecci, Alessandro; Noris, Patrizia; Invernizzi, Rosangela; Savoia, Anna; Seri, Marco; Ghiggeri, Gian Marco; Sartore, Saverio; Gangarossa, Simone; Bizzaro, Nicola; Balduini, Carlo L

    2002-04-01

    May-Hegglin anomaly (MHA), Sebastian syndrome (SBS) and Fechtner syndrome (FTNS) are autosomal-dominant macrothrombocytopenias with Döhle-like leucocyte inclusions. These diseases are due to mutations of the MHY9 gene, encoding the heavy chain of non-muscle myosin IIA (NMMHC-A). We investigated the NMMHC-A localization in blood cells from eight MHA, SBS or FTNS patients with known MYH9 mutations. All the patients showed an altered localization of NMMHC-A in granulocytes and platelets, suggesting that Döhle-like bodies are due to the aggregation of NMMHC-A in the cytoplasm. Therefore, immunocytochemistry for NMMHC-A is a simple and sensitive method to detect pathological phenotypes of granulocytes and platelets in the diagnosis of MYH9-related disorders. PMID:11918549

  7. Carcinoma of the intact uterine cervix, stage IB-IIA-B, greater than or equal to 6 cm in diameter: irradiation alone vs preoperative irradiation and surgery

    SciTech Connect

    Weems, D.H.; Mendenhall, W.M.; Bova, F.J.; Marcus, R.B. Jr.; Morgan, L.S.; Million, R.R.

    1985-11-01

    This is an analysis of 123 patients with Stage IB-IIA-B carcinoma of the intact uterine cervix, 6 cm or greater in diameter, who were treated with curative intent at the University of Florida with radiation alone or radiation followed by a hysterectomy between October 1964 and February 1982. There is a minimum follow-up of 2 years in all patients; 87% of all recurrences and 91% of pelvic recurrences occurred within this time period. Examination of pelvic control rates, as well as disease-free survival, showed no significant advantage in pelvic control, disease-free survival, or absolute survival for either treatment group when compared by stage and tumor size. The incidence of severe complications was 6% for patients treated with irradiation alone and 15% for those treated with irradiation and surgery.

  8. Results of treatment in patients with IIa - IIIast. breast cancer treated by combination of low-level laser therapy (LLLT) and surgery (5-year experience)

    NASA Astrophysics Data System (ADS)

    Mikhailov, V. A.; Skobelkin, Oleg K.; Denisov, I. N.; Frank, George A.; Voltchenko, N. N.

    1996-01-01

    Laser therapy with semiconductor laser (wavelength 890 nm) was performed in 41 patients with IIa - IIIast. breast cancer. LLLT was used before surgery and in postoperative period during 2 years. LLLT decreased postoperative complications by 15.3% and decreased duration of lymphorrhea. 5 years survival in patients with IIast. breast cancer treated by LLLT was 100%, in control group--85.71%. In patients with IIIast. breast cancer treated by LLLT survival was 94.44%, in control group--78.94%. 91.3% of patients with IIast. treated by LLLT had not recurrences in 5 year period, in the controls they were in about 77.7%. 82.35% of patients with IIIast. treated by laser therapy had no recurrences in 5 year period, in control group--60%.

  9. Serum protein profiling using an aptamer array predicts clinical outcomes of stage IIA colon cancer: A leave-one-out crossvalidation

    PubMed Central

    Huh, Jung Wook; Kim, Sung Chun; Sohn, Insuk; Jung, Sin-Ho; Kim, Hee Cheol

    2016-01-01

    Background In this study, we established and validated a model for predicting prognosis of stage IIA colon cancer patients based on expression profiles of aptamers in serum. Methods Bloods samples were collected from 227 consecutive patients with pathologic T3N0M0 (stage IIA) colon cancer. We incubated 1,149 serum molecule-binding aptamer pools of clinical significance with serum from patients to obtain aptamers bound to serum molecules, which were then amplified and marked. Oligonucleotide arrays were constructed with the base sequences of the 1,149 aptamers, and the marked products identified above were reacted with one another to produce profiles of the aptamers bound to serum molecules. These profiles were organized into low- and high-risk groups of colon cancer patients based on clinical information for the serum samples. Cox proportional hazards model and leave-one-out cross-validation (LOOCV) were used to evaluate predictive performance. Results During a median follow-up period of 5 years, 29 of the 227 patients (11.9%) experienced recurrence. There were 212 patients (93.4%) in the low-risk group and 15 patients (6.6%) in the high-risk group in our aptamer prognosis model. Postoperative recurrence significantly correlated with age and aptamer risk stratification (p = 0.046 and p = 0.001, respectively). In multivariate analysis, aptamer risk stratification (p < 0.001) was an independent predictor of recurrence. Disease-free survival curves calculated according to aptamer risk level predicted through a LOOCV procedure and age showed significant differences (p < 0.001 from permutations). Conclusion Aptamer risk stratification can be a valuable prognostic factor in stage II colon cancer patients. PMID:26908450

  10. First Clinical Experience of Intra-Operative High Intensity Focused Ultrasound in Patients with Colorectal Liver Metastases: A Phase I-IIa Study

    PubMed Central

    Dupré, Aurélien; Melodelima, David; Pérol, David; Chen, Yao; Vincenot, Jérémy; Chapelon, Jean-Yves; Rivoire, Michel

    2015-01-01

    Background Surgery is the only curative treatment in patients with colorectal liver metastases (CLM), but only 10–20% of patients are eligible. High Intensity Focused Ultrasound (HIFU) technology is of proven value in several indications, notably prostate cancer. Its intra-operative use in patients with CLM has not previously been studied. Preclinical work suggested the safety and feasibility of a new HIFU device capable of ablating volumes of up to 2cm x 2cm in a few seconds. Methods We conducted a prospective, single-centre phase I-IIa trial. HIFU was delivered immediately before scheduled hepatectomy. To demonstrate the safety and efficacy of rapidly ablating liver parenchyma, ablations were performed on healthy tissue within the areas scheduled for resection. Results In total, 30 ablations were carried out in 15 patients. These ablations were all generated within 40 seconds and on average measured 27.5mm x 21.0mm. The phase I study (n = 6) showed that use of the HIFU device was feasible and safe and did not damage neighbouring tissue. The phase IIa study (n = 9) showed both that the area of ablation could be precisely targeted on a previously implanted metallic mark (used to represent a major anatomical structure) and that ablations could be undertaken deliberately to avoid such a mark. Ablations were achieved with a precision of 1–2 mm. Conclusion HIFU was feasible, safe and effective in ablating areas of liver scheduled for resection. The next stage is a phase IIb study which will attempt ablation of small metastases with a 5 mm margin, again prior to planned resection. Trial Registration ClinicalTrials.govNCT01489787 PMID:25719540

  11. Phase IIa Clinical Trial of Trans-1-Amino-3-18F-Fluoro-Cyclobutane Carboxylic Acid in Metastatic Prostate Cancer

    PubMed Central

    Inoue, Yusuke; Asano, Yuji; Satoh, Takefumi; Tabata, Ken-ichi; Kikuchi, Kei; Woodhams, Reiko; Baba, Shiro; Hayakawa, Kazushige

    2014-01-01

    Objective(s): We performed a phase IIa clinical trial of trans-1-amino-3-18F-fluoro-cyclobutane carboxylic acid (anti-18F-FACBC), a synthetic amino acid analog for PET, in patients with metastatic prostate cancer. Methods: The study subjects consisted of 10 untreated prostate cancer patients having lymph node and/or bone metastasis. Five patients underwent whole-body PET 5 and 30 min after intravenous injection of anti-18F-FACBC. The other five patients underwent 60 min dynamic PET of the pelvis. Safety assessment was performed before and 24 h after injection. PET/CT images were assessed visually, and time courses of anti-18F-FACBC uptake were evaluated from dynamic imaging. Results: Two mild adverse events were observed and resolved without treatment. All 10 patients showed increased accumulation of anti-18F-FACBC in the primary prostate lesion. CT revealed five enlarged lymph nodes indicating metastasis, and all showed increased uptake. Additionally, anti-18F-FACBC PET delineated unenlarged lymph nodes as hot spots. Anti-18F-FACBC PET demonstrated metastatic bone lesions, similar to conventional imaging. In one of two patients with lung metastasis, some lesions showed increased uptake. Regarding the time course, increased uptake of anti-18F-FACBC in the lesion was demonstrated immediately after injection, followed by gradual washout. Conclusion: The results of this phase IIa clinical trial indicated the safety of anti-18F-FACBC in patients with prostate cancer and the potential of anti-18F-FACBC PET to delineate primary prostate lesions and metastatic lesions. This clinical trial was registered as JapicCTI-101326.

  12. The symmetry of M-theories

    NASA Astrophysics Data System (ADS)

    Englert, François; Houart, Laurent; Taormina, Anne; West, Peter

    2003-09-01

    We consider the Cartan subalgebra of any very extended algebra Script G+++ where Script G is a simple Lie algebra and let the parameters be space-time fields. These are identified with diagonal metrics and dilatons. Using the properties of the algebra, we find that for all very extensions Script G+++ of simple Lie algebras there are theories of gravity and matter, which admit classical solutions carrying representations of the Weyl group of Script G+++. We also identify the T and S-dualities of superstrings and of the bosonic string with Weyl reflections and outer automorphisms of well-chosen very extended algebras and we exhibit specific features of the very extensions. We take these results as indication that very extended algebras underlie symmetries of any consistent theory of gravity and matter, and might encode basic information for the construction of such theory.

  13. Dynamics of M-theory vacua

    NASA Astrophysics Data System (ADS)

    Donoghue, John F.

    2004-05-01

    At very early times, the Universe was not in a vacuum state. Under the assumption that the deviation from equilibrium was large, in particular, that it is higher than the scale of inflation, we analyze the conditions for local transitions between states that are related to different vacua. All pathways lead to an attractor solution of a description of the Universe by eternal inflation with domains that have different low energy parameters. The generic case favors transitions between states that have significantly different parameters rather than jumps between nearby states in parameter space. I argue that the strong CP problem presents a potential difficulty for this picture, more difficult than the hierarchy problem or the cosmological constant problem. Finally, I describe how the spectrum of quark masses may be a probe of the early dynamics of vacuum states. As an example, by specializing to the case of intersecting braneworld models, I show that the observed mass spectrum, which is approximately scale invariant, corresponds to a flat distribution in the intersection area of the branes, with a maximum area Amax˜100α'.

  14. How do type II topoisomerases use ATP hydrolysis to simplify DNA topology beyond equilibrium? Investigating the relaxation reaction of nonsupercoiling type II topoisomerases.

    PubMed

    Stuchinskaya, Tanya; Mitchenall, Lesley A; Schoeffler, Allyn J; Corbett, Kevin D; Berger, James M; Bates, Andrew D; Maxwell, Anthony

    2009-02-01

    DNA topoisomerases control the topology of DNA (e.g., the level of supercoiling) in all cells. Type IIA topoisomerases are ATP-dependent enzymes that have been shown to simplify the topology of their DNA substrates to a level beyond that expected at equilibrium (i.e., more relaxed than the product of relaxation by ATP-independent enzymes, such as type I topoisomerases, or a lower-than-equilibrium level of catenation). The mechanism of this effect is currently unknown, although several models have been suggested. We have analyzed the DNA relaxation reactions of type II topoisomerases to further explore this phenomenon. We find that all type IIA topoisomerases tested exhibit the effect to a similar degree and that it is not dependent on the supercoil-sensing C-terminal domains of the enzymes. As recently reported, the type IIB topoisomerase, topoisomerase VI (which is only distantly related to type IIA enzymes), does not exhibit topology simplification. We find that topology simplification is not significantly dependent on circle size in the range approximately 2-9 kbp and is not altered by reducing the free energy available from ATP hydrolysis by varying the ADP:ATP ratio. A direct test of one model (DNA tracking; i.e., sliding of a protein clamp along DNA to trap supercoils) suggests that this is unlikely to be the explanation for the effect. We conclude that geometric selection of DNA segments by the enzymes is likely to be a primary source of the effect, but that it is possible that other kinetic factors contribute. We also speculate whether topology simplification might simply be an evolutionary relic, with no adaptive significance. PMID:19094994

  15. 7 CFR 42.110 - Sampling plans for tightened condition of container inspection; Tables II and II-A.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF... Container Inspection Code Lot size ranges—Number of containers in lot Type of Plan Acceptable quality...

  16. 7 CFR 42.110 - Sampling plans for tightened condition of container inspection; Tables II and II-A.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF... Inspection Code Lot size ranges—Number of containers in lot Type of plan AQL 0.15 Sample size Ac Re Sample... Condition of Container Inspection Code Lot size ranges—No. of containers in lot Type of plan Sample...

  17. 7 CFR 42.110 - Sampling plans for tightened condition of container inspection; Tables II and II-A.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF... Inspection Code Lot size ranges—Number of containers in lot Type of plan AQL 0.15 Sample size Ac Re Sample... Condition of Container Inspection Code Lot size ranges—No. of containers in lot Type of plan Sample...

  18. 7 CFR 42.110 - Sampling plans for tightened condition of container inspection; Tables II and II-A.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF... Inspection Code Lot size ranges—Number of containers in lot Type of plan AQL 0.15 Sample size Ac Re Sample... Condition of Container Inspection Code Lot size ranges—No. of containers in lot Type of plan Sample...

  19. Aging, muscle fiber type, and contractile function in sprint-trained athletes.

    PubMed

    Korhonen, Marko T; Cristea, Alexander; Alén, Markku; Häkkinen, Keijo; Sipilä, Sarianna; Mero, Antti; Viitasalo, Jukka T; Larsson, Lars; Suominen, Harri

    2006-09-01

    Biopsy samples were taken from the vastus lateralis of 18- to 84-yr-old male sprinters (n = 91). Fiber-type distribution, cross-sectional area, and myosin heavy chain (MHC) isoform content were identified using ATPase histochemistry and SDS-PAGE. Specific tension and maximum shortening velocity (V(o)) were determined in 144 single skinned fibers from younger (18-33 yr, n = 8) and older (53-77 yr, n = 9) runners. Force-time characteristics of the knee extensors were determined by using isometric contraction. The cross-sectional area of type I fibers was unchanged with age, whereas that of type II fibers was reduced (P < 0.001). With age there was an increased MHC I (P < 0.01) and reduced MHC IIx isoform content (P < 0.05) but no differences in MHC IIa. Specific tension of type I and IIa MHC fibers did not differ between younger and older subjects. V(o) of fibers expressing type I MHC was lower (P < 0.05) in older than in younger subjects, but there was no difference in V(o) of type IIa MHC fibers. An aging-related decline of maximal isometric force (P < 0.001) and normalized rate of force development (P < 0.05) of knee extensors was observed. Normalized rate of force development was positively associated with MHC II (P < 0.05). The sprint-trained athletes experienced the typical aging-related reduction in the size of fast fibers, a shift toward a slower MHC isoform profile, and a lower V(o) of type I MHC fibers, which played a role in the decline in explosive force production. However, the muscle characteristics were preserved at a high level in the oldest runners, underlining the favorable impact of sprint exercise on aging muscle. PMID:16690791

  20. Muscle fibre types in the suprahyoid muscles of the rat

    PubMed Central

    COBOS, A. R.; SEGADE, L. A. G.; FUENTES, I.

    2001-01-01

    Five muscle fibre types (I, IIc, IIa, IIx and IIb) were found in the suprahyoid muscles (mylohyoid, geniohyoid, and the anterior and posterior bellies of the digastric) of the rat using immuno and enzyme histochemical techniques. More than 90% of fibres in the muscles examined were fast contracting fibres (types IIa, IIx and IIb). The geniohyoid and the anterior belly of the digastric had the greatest number of IIb fibres, whilst the mylohyoid was almost exclusively formed by aerobic fibres. The posterior belly of the digastric contained a greater percentage of aerobic fibres (83.4%) than the anterior belly (67.8%). With the exception of the geniohyoid, the percentage of type I and IIc fibres, which have slow myosin heavy chain (MHCβ), was relatively high and greater than has been previously reported in the jaw-closing muscles of the rat, such as the superficial masseter. The geniohyoid and mylohyoid exhibited a mosaic fibre type distribution, without any apparent regionalisation, although in the later MHCβ-containing fibres (types I and IIc) were primarily located in the rostral 2/3 region. In contrast, the anterior and posterior bellies of the digastric revealed a clear regionalisation. In the anterior belly of the digastric 2 regions were observed: both a central region, which was almost exclusively formed by aerobic fibres and where all of the type I and IIc fibres were located, and a peripheral region, where type IIb fibres predominated. The posterior belly of the digastric showed a deep aerobic region which was greater in size and where type I and IIc fibres were confined, and a superficial region, where primarily type IIx and IIb fibres were observed. PMID:11322721

  1. The combined Mössbauer and XRF Spectrometer MIMOS IIA for In-Situ Geochemical and Mineralogical Analysis of Planetary Surfaces

    NASA Astrophysics Data System (ADS)

    Klingelhöfer, Göstar; Blumers, Mathias; Girones-Lopez, Jordi; Bernhardt, Bodo; Lechner, Peter; Str, Lothar; Maul, Jasmine; Soltau, Heike; Henkel, Hartmut; Br, Johannes; Claude, D.; Henrich, Cristina

    The Miniaturised Müssbauer Spectrometers MIMOS II on board the two NASA Mars Explo-o ration Rovers (MER) have now collected valuable scientific data for more than six years [1-4]. This mission has demonstrated that Müss-bauer spectroscopy is extremely valuable for the in situ exploration of extraterrestrial bodies and the study of Fe-bearing samples. A MIMOS instrument is also on the scientific payload of the Russian mission Phobos Grunt sched-uled for 2011 [5]. The instrument MIMOS IIA originally developed for the ESA ExoMars mission (now 2018) will use newly designed Si-Drift detectors with circular geometry (SDD) [6,7] allowing high resolution X-ray fluores-cence spectroscopy simultaneously to Müssbauer measurements. The new design of the improved MIMOS II instrument is reduced in total mass (less than 400 g). The sensorhead of MIMOS IIA will be equipped with a ring of Silicon Drift Detectors (SDD) optimized for the backscatter geometry of the miniaturized Müssbauer spectrometer. The main goal of the new detector system design was to combine high energy resolution at high counting rates and large detector area while making maximum use of the area close to the collimator of the 57Co Müssbauer source. The active area per SDD segment is 2x45 mm2. The energy resolution at 5.9 keV is ¡ 280 eV at room temperature and 131 eV FWHM at -40oC. This performance will increase the signal to noise ratio (SNR) and reduce the integration time of Müssbauer measurement by a factor of up to 10. In addition to the Müssbauer analysis simultaneous acquisition of the X-ray fluorescence spectrum will provide data on the sample's elemental composition [7]. Preliminary studies at room temperature and normal pressure show detec-tion of X-rays down to 1 keV. A new control-and readout electronics for MIMOS IIA allows spectra acquisition at highest possible countrates available at about 360 mm2 total detector area. This is possible due to digital pulse shap-ing and pulsed JFET reset

  2. Critical Role of TLR2 and MyD88 for Functional Response of Macrophages to a Group IIA-Secreted Phospholipase A2 from Snake Venom

    PubMed Central

    Leiguez, Elbio; Giannotti, Karina Cristina; Moreira, Vanessa; Matsubara, Márcio Hideki; Gutiérrez, José María; Lomonte, Bruno; Rodríguez, Juan Pablo; Balsinde, Jesús; Teixeira, Catarina

    2014-01-01

    The snake venom MT-III is a group IIA secreted phospholipase A2 (sPLA2) enzyme with functional and structural similarities with mammalian pro-inflammatory sPLA2s of the same group. Previously, we demonstrated that MT-III directly activates the innate inflammatory response of macrophages, including release of inflammatory mediators and formation of lipid droplets (LDs). However, the mechanisms coordinating these processes remain unclear. In the present study, by using TLR2−/− or MyD88−/− or C57BL/6 (WT) male mice, we report that TLR2 and MyD88 signaling have a critical role in MT-III-induced inflammatory response in macrophages. MT-III caused a marked release of PGE2, PGD2, PGJ2, IL-1β and IL-10 and increased the number of LDs in WT macrophages. In MT-III-stimulated TLR2−/− macrophages, formation of LDs and release of eicosanoids and cytokines were abrogated. In MyD88−/− macrophages, MT-III-induced release of PGE2, IL-1β and IL-10 was abrogated, but release of PGD2 and PGJ2 was maintained. In addition, COX-2 protein expression seen in MT-III-stimulated WT macrophages was abolished in both TLR2−/− and MyD88−/− cells, while perilipin 2 expression was abolished only in MyD88−/− cells. We further demonstrated a reduction of saturated, monounsaturated and polyunsaturated fatty acids and a release of the TLR2 agonists palmitic and oleic acid from MT-III-stimulated WT macrophages compared with WT control cells, thus suggesting these fatty acids as major messengers for MT-III-induced engagement of TLR2/MyD88 signaling. Collectively, our findings identify for the first time a TLR2 and MyD88-dependent mechanism that underlies group IIA sPLA2-induced inflammatory response in macrophages. PMID:24718259

  3. 30 CFR 57.22227 - Approved testing devices (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Approved testing devices (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22227 Section 57.22227 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL...

  4. 30 CFR 57.22227 - Approved testing devices (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Approved testing devices (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). 57.22227 Section 57.22227 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL...

  5. DVC1-0101 to Treat Peripheral Arterial Disease: A Phase I/IIa Open-label Dose-escalation Clinical Trial

    PubMed Central

    Yonemitsu, Yoshikazu; Matsumoto, Takuya; Itoh, Hiroyuki; Okazaki, Jin; Uchiyama, Makiko; Yoshida, Kumi; Onimaru, Mitsuho; Onohara, Toshihiro; Inoguchi, Hiroyuki; Kyuragi, Ryoichi; Shimokawa, Mototsugu; Ban, Hiroshi; Tanaka, Michiko; Inoue, Makoto; Shu, Tsugumine; Hasegawa, Mamoru; Nakanishi, Yoichi; Maehara, Yoshihiko

    2013-01-01

    We here report the results of a Phase I/IIa open-label four dose-escalation clinical study assessing the safety, tolerability, and possible therapeutic efficacy of a single intramuscular administration of DVC1-0101, a new gene transfer vector based on a nontransmissible recombinant Sendai virus (rSeV) expressing the human fibroblast growth factor-2 (FGF-2) gene (rSeV/dF-hFGF2), in patients with peripheral arterial disease (PAD). Gene transfer was done in 12 limbs of 12 patients with rest pain, and three of them had ischemic ulcer(s). No cardiovascular or other serious adverse events (SAEs) caused by gene transfer were detected in the patients over a 6-month follow-up. No infectious viral particles, as assessed by hemagglutination activity, were detected in any patient during the study. No representative elevation of proinflammatory cytokines or plasma FGF-2 was seen. Significant and continuous improvements in Rutherford category, absolute claudication distance (ACD), and rest pain were observed (P < 0.05 to 0.01). To the best of our knowledge, this is the first clinical trial of the use of a gene transfer vector based on rSeV. The single intramuscular administration of DVC1-0101 to PAD patients was safe and well tolerated, and resulted in significant improvements of limb function. Larger pivotal studies are warranted as a next step. PMID:23319060

  6. A Phase IIa Trial of the New Tuberculosis Vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis–infected Adults

    PubMed Central

    Tameris, Michele; Smit, Erica; van der Merwe, Linda; Hughes, E. Jane; Kadira, Blessing; Mauff, Katya; Moyo, Sizulu; Brittain, Nathaniel; Lawrie, Alison; Mulenga, Humphrey; de Kock, Marwou; Makhethe, Lebohang; Janse van Rensburg, Esme; Gelderbloem, Sebastian; Veldsman, Ashley; Hatherill, Mark; Geldenhuys, Hendrik; Hill, Adrian V. S.; Hawkridge, Anthony; Hussey, Gregory D.; Hanekom, Willem A.; McShane, Helen; Mahomed, Hassan

    2012-01-01

    Rationale: Novel tuberculosis (TB) vaccines should be safe and effective in populations infected with Mycobacterium tuberculosis (M.tb) and/or HIV for effective TB control. Objective: To determine the safety and immunogenicity of MVA85A, a novel TB vaccine, among M.tb- and/or HIV-infected persons in a setting where TB and HIV are endemic. Methods: An open-label, phase IIa trial was conducted in 48 adults with M.tb and/or HIV infection. Safety and immunogenicity were analyzed up to 52 weeks after intradermal vaccination with 5 × 107 plaque-forming units of MVA85A. Specific T-cell responses were characterized by IFN-γ enzyme-linked immunospot and whole blood intracellular cytokine staining assays. Measurements and Main Results: MVA85A was well tolerated and no vaccine-related serious adverse events were recorded. MVA85A induced robust and durable response of mostly polyfunctional CD4+ T cells, coexpressing IFN-γ, tumor necrosis factor-α, and IL-2. Magnitudes of pre- and postvaccination T-cell responses were lower in HIV-infected, compared with HIV-uninfected, vaccinees. No significant effect of antiretroviral therapy on immunogenicity of MVA85A was observed. Conclusions: MVA85A was safe and immunogenic in persons with HIV and/or M.tb infection. These results support further evaluation of safety and efficacy of this vaccine for prevention of TB in these target populations. PMID:22281831

  7. The role of Rab6a and phosphorylation of non-muscle myosin IIA tailpiece in alcohol-induced Golgi disorganization

    PubMed Central

    Petrosyan, Armen; Casey, Carol A.; Cheng, Pi-Wan

    2016-01-01

    Abnormalities in the Golgi apparatus function are important to the development of alcoholic liver injury. We recently reported that Golgi disorganization in ethanol (EtOH)-treated hepatocytes is caused by impaired dimerization of the largest Golgi matrix protein, giantin. However, little is known about the mechanism which forces fragmentation. Here, in both HepG2 cells overexpressing alcohol dehydrogenase and in rat hepatocytes, we found that EtOH administration reduces the complex between giantin and Rab6a GTPase and results in the S1943 phosphorylation of non-muscle Myosin IIA (NMIIA) heavy chain, thus facilitating NMIIA association with Golgi enzymes, as detected by biochemical approaches and 3D Structured Illumination Microscopy. We revealed that NMIIA-P-S1943 competes with giantin for the Rab6a dimer, which was converted to monomer after Golgi fragmentation. Therefore, Rab6a plays a dual role in the Golgi, serving as master regulator of Golgi organization and disorganization, and that NMIIA and giantin engage in a “tug-of-war”. However, the inhibition of F-actin and downregulation of NMIIA or overexpression of NMHC-IIAΔtailpiece, as well the overexpression of dominant negative Rab6a(T27N), preserved a compact Golgi phenotype. Thus, the actomyosin complex forces EtOH-induced Golgi disorganization, and the targeting of NMIIA-P-S1943 may be important for preventing the damaging effects of alcohol metabolism on the cell. PMID:27535804

  8. Tanshinone IIA represses inflammatory response and reduces radiculopathic pain by inhibiting IRAK-1 and NF-κB/p38/JNK signaling.

    PubMed

    Li, Wei; Zhang, Yu; Xing, Cuiyan; Zhang, Mengyuan

    2015-09-01

    Intervertebral disc (IVD) disease, a most common cause of disc failure and low back pain, is characterized by age-related changes in the adult disc. In this study we aimed to investigate the potential of Tanshinone IIA (TSA) for the treatment of IVD disease, through exploring its anti-inflammatory and anti-catabolic activities in both in vitro IVD cell culture and in vivo animal models. After the inflammatory response was induced in IVD cells by IL-1β, the activity and expression of inflammatory mediators, and potentially involved pathways were investigated in the presence or absence of TSA. The p38-MAPK inhibitor, SB239063, was also used to investigate the involvement of the MAPK signaling pathway in the observed effects. Meanwhile, the analgesic properties of TSA were analyzed by the von Frey filament test in Sprague-Dawley rats. Our results indicated that TSA significantly inhibited the expression of pro-inflammatory mediators and matrix metalloproteinases in vitro, as well as radiculopathic pain in vivo, probably by modulation of the activity of interleukin-1 receptor-associated kinase 1 (IRAK-1) and its downstream effectors p38, JNK and NF-κB. Our current study strongly demonstrates the potential of TSA for the treatment of inflammation and followed pain in degenerative disc disease. PMID:26163178

  9. Proteomics Analysis of the Non-Muscle Myosin Heavy Chain IIa-Enriched Actin-Myosin Complex Reveals Multiple Functions within the Podocyte

    PubMed Central

    Hays, Thomas; Ma’ayan, Avi; Clark, Neil R.; Tan, Christopher M.; Teixeira, Avelino; Teixeira, Angela; Choi, Jae W.; Burdis, Nora; Jung, Sung Yun; Bajaj, Amol O.; O’Malley, Bert W.; He, John C.; Hyink, Deborah P.; Klotman, Paul E.

    2014-01-01

    MYH9 encodes non-muscle myosin heavy chain IIA (NMMHCIIA), the predominant force-generating ATPase in non-muscle cells. Several lines of evidence implicate a role for MYH9 in podocytopathies. However, NMMHCIIA‘s function in podocytes remains unknown. To better understand this function, we performed immuno-precipitation followed by mass-spectrometry proteomics to identify proteins interacting with the NMMHCIIA-enriched actin-myosin complexes. Computational analyses revealed that these proteins belong to functional networks including regulators of cytoskeletal organization, metabolism and networks regulated by the HIV-1 gene nef. We further characterized the subcellular localization of NMMHCIIA within podocytes in vivo, and found it to be present within the podocyte major foot processes. Finally, we tested the effect of loss of MYH9 expression in podocytes in vitro, and found that it was necessary for cytoskeletal organization. Our results provide the first survey of NMMHCIIA-enriched actin-myosin-interacting proteins within the podocyte, demonstrating the important role of NMMHCIIA in organizing the elaborate cytoskeleton structure of podocytes. Our characterization of NMMHCIIA’s functions goes beyond the podocyte, providing important insights into its general molecular role. PMID:24949636

  10. Determination of Sodium Tanshinone IIA Sulfonate in human plasma by LC-MS/MS and its application to a clinical pharmacokinetic study.

    PubMed

    Qin, WeiWei; Wang, Bin; Lu, XiaoPei; Liu, HaiMing; Wang, Li; Qi, WeiLin

    2016-03-20

    An assay based on protein precipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative analysis of Sodium Tanshinone IIA Sulfonate (STS) in human plasma. After the addition of dehydroepiandrosterone-D5-3-sulfate sodium salt (DHEAS-D5) as internal standard (IS) and formic acid, plasma samples were prepared by one-step protein precipitation with a mixture of acetonitrile and methanol. Isocratic mobile phase consisted of 0.4 mmol/L ammonium formate buffer (16 ppm formic acid)/acetonitrile (40/60, v/v) on a XSELECT™ HSS T3 column. Detection was performed on a triple-quadrupole mass spectrometer utilizing an electrospray ionization (ESI) interface operating in positive ion and selected reaction monitoring (SRM) mode with the precursor to product ion transitions m/z 373.3→357.1 for STS and m/z 373.0→97.8 for the IS. Calibration curves of STS in human plasma were linear (r=0.9957-0.9998) over the concentration range of 2-1000 ng/mL with acceptable accuracy and precision. The lower limit of quantification in human plasma was 2 ng/mL. The validated LC-MS/MS method has been successfully applied to a pharmacokinetic study of STS in Chinese healthy male volunteers. PMID:26812478

  11. The role of Rab6a and phosphorylation of non-muscle myosin IIA tailpiece in alcohol-induced Golgi disorganization.

    PubMed

    Petrosyan, Armen; Casey, Carol A; Cheng, Pi-Wan

    2016-01-01

    Abnormalities in the Golgi apparatus function are important to the development of alcoholic liver injury. We recently reported that Golgi disorganization in ethanol (EtOH)-treated hepatocytes is caused by impaired dimerization of the largest Golgi matrix protein, giantin. However, little is known about the mechanism which forces fragmentation. Here, in both HepG2 cells overexpressing alcohol dehydrogenase and in rat hepatocytes, we found that EtOH administration reduces the complex between giantin and Rab6a GTPase and results in the S1943 phosphorylation of non-muscle Myosin IIA (NMIIA) heavy chain, thus facilitating NMIIA association with Golgi enzymes, as detected by biochemical approaches and 3D Structured Illumination Microscopy. We revealed that NMIIA-P-S1943 competes with giantin for the Rab6a dimer, which was converted to monomer after Golgi fragmentation. Therefore, Rab6a plays a dual role in the Golgi, serving as master regulator of Golgi organization and disorganization, and that NMIIA and giantin engage in a "tug-of-war". However, the inhibition of F-actin and downregulation of NMIIA or overexpression of NMHC-IIAΔtailpiece, as well the overexpression of dominant negative Rab6a(T27N), preserved a compact Golgi phenotype. Thus, the actomyosin complex forces EtOH-induced Golgi disorganization, and the targeting of NMIIA-P-S1943 may be important for preventing the damaging effects of alcohol metabolism on the cell. PMID:27535804

  12. Allelic Analysis of the Maize amylose-extender Locus Suggests That Independent Genes Encode Starch-Branching Enzymes IIa and IIb.

    PubMed Central

    Fisher, D. K.; Gao, M.; Kim, K. N.; Boyer, C. D.; Guiltinan, M. J.

    1996-01-01

    Starch branching enzymes (SBE) catalyze the formation of [alpha]-1,6-glucan linkages in the biosynthesis of starch. Three distinct SBE isoforms have been identified in maize (Zea mays L.) endosperm, SBEI, IIa, and IIb. Independent genes have been identified that encode maize SBEI and IIb; however, it has remained controversial as to whether SBEIIa and IIb result from posttranscriptional processes acting on the product of a single gene or whether they are encoded by separate genes. To investigate this question, we analyzed 16 isogenic lines carrying independent alleles of the maize amylose-extender (ae) locus, the structural gene for SBEIIb. We show that 22 d after pollination ae-B1 endosperm expressed little Sbe2b (ae)-hybridizing transcript, and as expected, ae-B1 endosperm also lacked detectable SBEIIb enzymatic activity. Significantly, we show that ae-B1 endosperm contained SBEIIa enzymatic activity, strongly supporting the hypothesis that endosperm SBEIIa and IIb are encoded by separate genes. Furthermore, we show that in addition to encoding the predominant Sbe2b-hybridizing message expressed in endosperm, the ae gene also encodes the major Sbe2b-like transcript expressed in developing embryos and tassels. PMID:12226207

  13. Altered fibre types in gastrocnemius muscle of high wheel-running selected mice with mini-muscle phenotypes.

    PubMed

    Guderley, Helga; Joanisse, Denis R; Mokas, Sophie; Bilodeau, Geneviève M; Garland, Theodore

    2008-03-01

    Selective breeding of mice for high voluntary wheel running has favoured characteristics that facilitate sustained, aerobically supported activity, including a "mini-muscle" phenotype with markedly reduced hind limb muscle mass, increased mass-specific activities of oxidative enzymes, decreased % myosin heavy chain IIb, and, in the medial gastrocnemius, reduced twitch speed, reduced mass-specific isotonic power, and increased fatigue resistance. To evaluate whether selection has altered fibre type expression in mice with either "mini" or normal muscle phenotypes, we examined fibre types of red and white gastrocnemius. In both the medial and lateral gastrocnemius, the mini-phenotype increased activities of oxidative enzymes and decreased activities of glycolytic enzymes. In red muscle samples, the mini-phenotype markedly changed fibre types, with the % type I and type IIA fibres and the surface area of type IIA fibres increasing; in addition, mice from selected lines in general had an increased % type IIA fibres and larger type I fibres as compared with mice from control lines. White muscle samples from mini-mice showed dramatic structural alterations, with an atypical distribution of extremely small, unidentifiable fibres surrounded by larger, more oxidative fibres than normally present in white muscle. The increased proportion of oxidative fibres and these atypical small fibres together may explain the reduced mass and increased mitochondrial enzyme activities in mini-muscles. These and previous results demonstrate that extension of selective breeding beyond the time when the response of the selected trait (i.e. distance run) has levelled off can still modify the mechanistic underpinnings of this behaviour. PMID:18226573

  14. Myofibrillar ATPase activity in skinned human skeletal muscle fibres: fibre type and temperature dependence.

    PubMed Central

    Stienen, G J; Kiers, J L; Bottinelli, R; Reggiani, C

    1996-01-01

    1. Myofibrillar ATP consumption and isometric tension (P0) were determined in chemically skinned skeletal muscle fibres from human rectus abdominis and vastus lateralis muscle. Fibres were classified in four groups (I, IIA, IIB, IIA/B or mixed) based on myosin heavy chain composition. 2. ATP consumption (+/- S.E.M.) at 20 degrees C varied from 0.41 +/- 0.06 mmol l-1 s-1 in type IIB fibres (n = 5) to 0.10 +/- 0.01 mmol l-1 s-1 in type I fibres (n = 13). 3. The ratio between ATPase activity and P0 (tension cost) differed significantly between fast type II and slow type I fibres. At 12 degrees C tension cost was lower than the values found previously in corresponding fibre types in the rat. 4. The relative increase in ATPase activity for a 10 degrees C temperature change (Q10), determined in the range from 12 to 30 degrees C, was temperature independent and amounted to 2.60 +/- 0.06. The increase in P0 with temperature was smaller and declined when the temperature increased. 5. From these measurements, estimates were obtained for the maximum rate of isometric ATP consumption and force development at muscle temperature in vivo (35 degrees C). Images Figure 1 PMID:8782097

  15. Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure

    NASA Technical Reports Server (NTRS)

    Delp, M. D.; Duan, C.; Mattson, J. P.; Musch, T. I.

    1997-01-01

    One of the primary consequences of left ventricular dysfunction (LVD) after myocardial infarction is a decrement in exercise capacity. Several factors have been hypothesized to account for this decrement, including alterations in skeletal muscle metabolism and aerobic capacity. The purpose of this study was to determine whether LVD-induced alterations in skeletal muscle enzyme activities, fiber composition, and fiber size are 1) generalized in muscles or specific to muscles composed primarily of a given fiber type and 2) related to the severity of the LVD. Female Wistar rats were divided into three groups: sham-operated controls (n = 13) and rats with moderate (n = 10) and severe (n = 7) LVD. LVD was surgically induced by ligating the left main coronary artery and resulted in elevations (P < 0.05) in left ventricular end-diastolic pressure (sham, 5 +/- 1 mmHg; moderate LVD, 11 +/- 1 mmHg; severe LVD, 25 +/- 1 mmHg). Moderate LVD decreased the activities of phosphofructokinase (PFK) and citrate synthase in one muscle composed of type IIB fibers but did not modify fiber composition or size of any muscle studied. However, severe LVD diminished the activity of enzymes involved in terminal and beta-oxidation in muscles composed primarily of type I fibers, type IIA fibers, and type IIB fibers. In addition, severe LVD induced a reduction in the activity of PFK in type IIB muscle, a 10% reduction in the percentage of type IID/X fibers, and a corresponding increase in the portion of type IIB fibers. Atrophy of type I fibers, type IIA fibers, and/or type IIB fibers occurred in soleus and plantaris muscles of rats with severe LVD. These data indicate that rats with severe LVD after myocardial infarction exhibit 1) decrements in mitochondrial enzyme activities independent of muscle fiber composition, 2) a reduction in PFK activity in type IIB muscle, 3) transformation of type IID/X to type IIB fibers, and 4) atrophy of type I, IIA, and IIB fibers.

  16. Cohesive energy and structural parameters of binary oxides of groups IIA and IIIB from diffusion quantum Monte Carlo

    NASA Astrophysics Data System (ADS)

    Santana, Juan A.; Krogel, Jaron T.; Kent, Paul R. C.; Reboredo, Fernando A.

    2016-05-01

    We have applied the diffusion quantum Monte Carlo (DMC) method to calculate the cohesive energy and the structural parameters of the binary oxides CaO, SrO, BaO, Sc2O3, Y2O3, and La2O3. The aim of our calculations is to systematically quantify the accuracy of the DMC method to study this type of metal oxides. The DMC results were compared with local, semi-local, and hybrid Density Functional Theory (DFT) approximations as well as with experimental measurements. The DMC method yields cohesive energies for these oxides with a mean absolute deviation from experimental measurements of 0.18(2) eV, while with local, semi-local, and hybrid DFT approximations, the deviation is 3.06, 0.94, and 1.23 eV, respectively. For lattice constants, the mean absolute deviations in DMC, local, semi-local, and hybrid DFT approximations are 0.017(1), 0.07, 0.05, and 0.04 Å, respectively. DMC is a highly accurate method, outperforming the DFT approximations in describing the cohesive energies and structural parameters of these binary oxides.

  17. Minimizing systematic errors from atmospheric multiple scattering and satellite viewing geometry in coastal zone color scanner level IIA imagery

    NASA Technical Reports Server (NTRS)

    Martin, D. L.; Perry, M. J.

    1994-01-01

    Water-leaving radiances and phytoplankton pigment concentrations are calculated from coastal zone color scanner (CZCS) radiance measurements by removing atmospheric Rayleigh and aerosol radiances from the total radiance signal measured at the satellite. The single greatest source of error in CZCS atmospheric correction algorithms in the assumption that these Rayleigh and aerosol radiances are separable. Multiple-scattering interactions between Rayleigh and aerosol components cause systematic errors in calculated aerosol radiances, and the magnitude of these errors is dependent on aerosol type and optical depth and on satellite viewing geometry. A technique was developed which extends the results of previous radiative transfer modeling by Gordon and Castano to predict the magnitude of these systematic errors for simulated CZCS orbital passes in which the ocean is viewed through a modeled, physically realistic atmosphere. The simulated image mathematically duplicates the exact satellite, Sun, and pixel locations of an actual CZCS image. Errors in the aerosol radiance at 443 nm are calculated for a range of aerosol optical depths. When pixels in the simulated image exceed an error threshhold, the corresponding pixels in the actual CZCS image are flagged and excluded from further analysis or from use in image compositing or compilation of pigment concentration databases. Studies based on time series analyses or compositing of CZCS imagery which do not address Rayleigh-aerosol multiple scattering should be interpreted cautiously, since the fundamental assumption used in their atmospheric correction algorithm is flawed.

  18. Cohesive energy and structural parameters of binary oxides of groups IIA and IIIB from diffusion quantum Monte Carlo.

    PubMed

    Santana, Juan A; Krogel, Jaron T; Kent, Paul R C; Reboredo, Fernando A

    2016-05-01

    We have applied the diffusion quantum Monte Carlo (DMC) method to calculate the cohesive energy and the structural parameters of the binary oxides CaO, SrO, BaO, Sc2O3, Y2O3, and La2O3. The aim of our calculations is to systematically quantify the accuracy of the DMC method to study this type of metal oxides. The DMC results were compared with local, semi-local, and hybrid Density Functional Theory (DFT) approximations as well as with experimental measurements. The DMC method yields cohesive energies for these oxides with a mean absolute deviation from experimental measurements of 0.18(2) eV, while with local, semi-local, and hybrid DFT approximations, the deviation is 3.06, 0.94, and 1.23 eV, respectively. For lattice constants, the mean absolute deviations in DMC, local, semi-local, and hybrid DFT approximations are 0.017(1), 0.07, 0.05, and 0.04 Å, respectively. DMC is a highly accurate method, outperforming the DFT approximations in describing the cohesive energies and structural parameters of these binary oxides. PMID:27155647

  19. RNA-dependent association with myosin IIA promotes F-actin-guided trafficking of the ELAV-like protein HuR to polysomes

    PubMed Central

    Doller, Anke; Schulz, Sebastian; Pfeilschifter, Josef; Eberhardt, Wolfgang

    2013-01-01

    The role of the mRNA-binding protein human antigen R (HuR) in stabilization and translation of AU-rich elements (ARE) containing mRNAs is well established. However, the trafficking of HuR and bound mRNA cargo, which comprises a fundamental requirement for the aforementioned HuR functions is only poorly understood. By administering different cytoskeletal inhibitors, we found that the protein kinase Cδ (PKCδ)-triggered accumulation of cytoplasmic HuR by Angiotensin II (AngII) is an actin-myosin driven process functionally relevant for stabilization of ARE-bearing mRNAs. Furthermore, we show that the AngII-induced recruitment of HuR and its bound mRNA from ribonucleoprotein particles to free and cytoskeleton bound polysomes strongly depended on an intact actomyosin cytoskeleton. In addition, HuR allocation to free and cytoskeletal bound polysomes is highly sensitive toward RNase and PPtase and structurally depends on serine 318 (S318) located within the C-terminal RNA recognition motif (RRM3). Conversely, the trafficking of the phosphomimetic HuRS318D, mimicking HuR phosphorylation at S318 by the PKCδ remained PPtase resistant. Co-immunoprecipitation experiments with truncated HuR proteins revealed that the stimulus-induced association of HuR with myosin IIA is strictly RNA dependent and mediated via the RRM3. Our data implicate a microfilament dependent transport of HuR, which is relevant for stimulus-induced targeting of ARE-bearing mRNAs from translational inactive ribonucleoprotein particles to polysomes. PMID:23921630

  20. Preoperative Concurrent Radiation Therapy and Chemotherapy for Bulky Stage IB2, IIA, and IIB Carcinoma of the Uterine Cervix With Proximal Parametrial Invasion

    SciTech Connect

    Huguet, Florence; Cojocariu, Oana-Maria; Levy, Pierre; Lefranc, Jean-Pierre; Darai, Emile; Jannet, Denis; Ansquer, Yan; Lhuillier, Pierre-Eugene; Benifla, Jean-Louis; Seince, Nathalie; Touboul, Emmanuel

    2008-12-01

    Purpose: To evaluate toxicity, local tumor control, and survival after preoperative chemoradiation for operable bulky cervical carcinoma. Methods and Materials: Between December 1991 and July 2006, 92 patients with operable bulky stage IB2, IIA, and IIB cervical carcinoma without pelvic or para-aortic nodes on pretreatment imaging were treated. Treatment consisted of preoperative external beam pelvic radiation therapy (EBRT) and concomitant chemotherapy (CT) during the first and fourth weeks of radiation combining 5-fluorouracil and cisplatin. The pelvic radiation dose was 40.5 Gy over 4.5 weeks. EBRT was followed by low-dose rate uterovaginal brachytherapy with a total dose of 20 Gy in 62 patients. After a median rest period of 44 days, all patients underwent Class II modified radical hysterectomy with bilateral pelvic lymphadenectomy. Thirty patients who had not received preoperative uterovaginal brachytherapy underwent postoperative low-dose-rate vaginal brachytherapy at a dose of 20 Gy. The mean follow-up was 46 months. Results: Pathologic residual tumor was observed in 43 patients. After multivariate analysis, additional preoperative uterovaginal brachytherapy was the single significant predictive factor for pathologic complete response rate (p = 0.019). The 2- and 5-year disease-free survival (DFS) rates were 80.4% and 72.2%, respectively. Pathologic residual cervical tumor was the single independent factor decreasing the probability of DFS (p = 0.020). Acute toxicities were moderate. Two severe ureteral complications requiring surgical intervention were observed. Conclusions: Concomitant chemoradiation followed by surgery for operable bulky stage I-II cervical carcinoma without clinical lymph node involvement can be used with acceptable toxicity. Pathologic complete response increases the probability of DFS.

  1. Phase Ib-IIa study to reverse platinum resistance by the use of a hypomethylating agent azacitidine in platinum-resistant or refractory epithelial ovarian cancer

    PubMed Central

    Fu, Siqing; Hu, Wei; Iyer, Revathy; Kavanagh, John J.; Coleman, Robert L.; Levenback, Charles F.; Sood, Anil K.; Wolf, Judith K.; Gershenson, David M.; Markman, Maurie; Hennessy, Bryan T.; Kurzrock, Razelle; Bast, Robert C.

    2010-01-01

    Background Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. We initiated a phase Ib-IIa clinical trial of this sequential combination of azacitidine and carboplatin in platinum-resistant or refractory epithelial ovarian cancer. Methods Patients with pathologically confirmed intermediate- or high-grade epithelial ovarian cancer who had disease progression within 6 months (resistant, n = 18) or during a platinum-based therapy (refractory, n = 12) were eligible. All patients had measurable disease. Results Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 CR, 3 PR (ORR: 13.8%), and 10 SD among 29 evaluable patients. For those who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median PFS and OS for all patients were 3.7 months and 14 months, respectively. Patients with platinum resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies showed that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 non-responders (38%). Conclusions To our knowledge, this study provides the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted. PMID:21472713

  2. An attempt to stabilize tanshinone IIA solid dispersion by the use of ternary systems with nano-CaCO3 and poloxamer 188

    PubMed Central

    Yan, Hong-mei; Zhang, Zhen-hai; Jiang, Yan-rong; Ding, Dong-mei; Sun, E.; Jia, Xiao-bin

    2014-01-01

    Background: Tanshinone IIA (TSIIA) on solid dispersions (SDs) has thermodynamical instability of amorphous drug. Ternary solid dispersions (tSDs) can extend the stability of the amorphous form of drug. Poloxamer 188 was used as a SD carrier. Nano-CaCO3 played an important role in adsorption of biomolecules and is being developed for a host of biotechnological applications. Objective: The aim of the present study was to investigate the dissolution behavior and accelerated stability of TSIIA on solid dispersions (SDs) by the use of ternary systems with nano-CaCO3 and poloxamer 188. Materials and Methods: The TSIIA tSDs were prepared by a spray-drying method. First, the effect of combination of poloxamer 188 and nano-CaCO3 on TSIIA dissolution was studied. Subsequently, a set of complementary techniques (DSC, XRPD, SEM and FTIR) was used to monitor the physical changes of TSIIA in the SDs. Finally, stability test was carried out under the conditions 40°C/75% RH for 6 months. Results: The characterization of tSDs by differential scanning calorimetry analysis (DSC) and X-ray powder diffraction (XRPD) showed that TSIIA was present in its amorphous form. Fourier transforms infrared spectroscopy (FTIR) suggested the presence of interactions between TSIIA and carriers in tSDs. Improvement in the dissolution rate was observed for all SDs. The stability study conducted on SDs with nano-CaCO3 showed stable drug content and dissolution behavior, over the period of 6 months as compared with freshly prepared SDs. Conclusion: SDs preparation with nano-CaCO3 and poloxamer 188 may be a promising approach to enhance the dissolution and stability of TSIIA. PMID:24991109

  3. The ISRU Field Tests 2010 and 2012 at Mauna Kea, Hawaii: Results from the Miniaturised Mossbauer Spectrometers Mimos II and Mimos IIA

    NASA Technical Reports Server (NTRS)

    Klingelhoefer, G.; Morris, R. V.; Blumers, M; Bernhardt, B.; Graff, T.

    2014-01-01

    The 2010 and 2012 In-Situ Resource Utilization Analogue Test (ISRU) [1] on the Mauna Kea volcano in Hawai'i was coordinated by the Northern Centre for Advanced Technology (NORCAT) in collaboration with the Canadian Space Agency (CSA), the German Aerospace Center (DLR), and the National Aeronautics and Space Administration (NASA), through the PISCES program. Several instruments were tested as reference candidates for future analogue testing at the new field test site at the Mauna Kea volcano in Hawai'i. The fine-grained, volcanic nature of the material is a suitable lunar and martian analogue, and can be used to test excavation, site preparation, and resource utilization techniques. The 2010 location Pu'u Hiwahine, a cinder cone located below the summit of Mauna Kea (19deg45'39.29" N, 155deg28'14.56" W) at an elevation of 2800 m, provides a large number of slopes, rock avalanches, etc. to perform mobility tests, site preparation or resource prospecting. Besides hardware testing of technologies and systems related to resource identification, also in situ science measurements played a significant role in integration of ISRU and science instruments. For the advanced Mössbauer instrument MIMOS IIA, the new detector technologies and electronic components increase sensitivity and performance significantly. In combination with the high energy resolution of the SDD it is possible to perform Xray fluorescence analysis simultaneously to Mössbauer spectroscopy. In addition to the Fe-mineralogy, information on the sample's elemental composition will be gathered. The 2010 and 2012 field campaigns demonstrated that in-situ Mössbauer spectroscopy is an effective tool for both science and feedstock exploration and process monitoring. Engineering tests showed that a compact nickel metal hydride battery provided sufficient power for over 12 hr of continuous operation for the MIMOS instruments.

  4. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial

    PubMed Central

    Spiera, Robert F; Gordon, Jessica K; Mersten, Jamie N; Magro, Cynthia M; Mehta, Mansi; Wildman, Horatio F; Kloiber, Stacey; Kirou, Kyriakos A; Lyman, Stephen; Crow, Mary K

    2011-01-01

    Objective To assess the safety and effectiveness of imatinib mesylate in the treatment of diffuse cutaneous systemic sclerosis (dcSSc). Methods In this phase IIa, open-label, single-arm clinical trial, 30 patients with dcSSc were treated with imatinib 400 mg daily. Patients were monitored monthly for safety assessments. Modified Rodnan skin scores (MRSS) were assessed every 3 months. Pulmonary function testing, chest radiography, echocardiography and skin biopsies were performed at baseline and after 12 months of treatment. Results Twenty-four patients completed 12 months of therapy. 171 adverse events (AE) with possible relation to imatinib were identified; 97.6% were grade 1 or 2. Twenty-four serious AE were identified, two of which were attributed to study medication. MRSS decreased by 6.6 points or 22.4% at 12 months (p=0.001). This change was evident starting at the 6-month time point (Δ=−4.5; p<0.001) and was seen in patients with both early and late-stage disease. Forced vital capacity (FVC) improved by 6.4% predicted (p=0.008), and the diffusion capacity remained stable. The improvement in FVC was significantly greater in patients without interstitial lung disease. Health-related quality of life measures improved or remained stable. Blinded dermatopathological analysis confirmed a significant decrease in skin thickness and improvement in skin morphology. Conclusions Treatment with imatinib was tolerated by most patients in this cohort. Although AE were common, most were mild to moderate. In this open-label experience, improvements in skin thickening and FVC were observed. Further investigation of tyrosine kinase inhibition for dcSSc in a double-blind randomised placebo controlled trial is warranted. ClinicalTrials.gov, NCT00555581 PMID:21398330

  5. Efficacy of mirtazapine for the treatment of fibromyalgia without concomitant depression: a randomized, double-blind, placebo-controlled phase IIa study in Japan

    PubMed Central

    Miki, Kenji; Murakami, Masato; Oka, Hiroshi; Onozawa, Kaname; Yoshida, Sadahiro; Osada, Kenichi

    2016-01-01

    Abstract To evaluate the efficacy and safety of mirtazapine in Japanese patients with fibromyalgia (FM), a parallel-group, randomized, double-blind, placebo-controlled phase IIa study was conducted at 57 sites between November 2012 and February 2014. Patients aged 20 to 64 years who met the American College of Rheumatology 1990 diagnostic FM criteria and had stably high pain scores during a placebo run-in period were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to receive mirtazapine orally (15 mg/d for 1 week and then 30 mg/d) or matching placebo for 12 weeks. The primary endpoint was change in mean numerical rating scale (NRS) pain score from baseline to endpoint (week 12 or early discontinuation). Of the 430 patients randomized (n = 215 each group), 422 (n = 211 each group) were analyzed for the primary endpoint. At the study endpoint, mirtazapine caused a significantly greater reduction in the mean NRS pain score compared with placebo (difference, 0.44; 95% confidence interval, −0.72 to −0.17; P = 0.0018). The reduction by mirtazapine remained significantly greater compared with placebo from week 6 onward. More patients treated with mirtazapine had their NRS pain score reduced by ≥30% from baseline (45.5% vs 30.8%). Mirtazapine also improved pain-related quality of life assessed by the Japanese version of the Fibromyalgia Impact Questionnaire and the Short-Form 36 Questionnaire. Adverse events were more common with mirtazapine than placebo (68.8% vs 56.7%), including somnolence (32.1% vs 7.4%), weight gain (17.7% vs 0.9%), and increased appetite (11.6% vs 3.3%). In conclusion, mirtazapine was an effective and safe treatment for Japanese patients with FM. PMID:27218868

  6. An update on laboratory measurements of Dabigatran: Smart specific and calibrated dedicated assays for measuring anti-IIa activity in plasma.

    PubMed

    Amiral, Jean; Dunois, Claire; Amiral, Cédric; Seghatchian, Jerard

    2016-06-01

    Use of Direct Oral Anticoagulants (DOACs) is continuously increasing for clinical application. The first product released was Dabigatran, which was proposed for many preventive and curative applications, especially for prevention of stroke in patients with non-valvular atrial fibrillation. Although measurement of Dabigatran Anti-IIa activity in plasma is not requested on a routine basis, in some situations its measurement is clinically useful. Especially, before an emergency surgery in treated patients, where its presence at high concentrations, which will expose the patient at an increased bleeding risk, has to be excluded. Hence, smart, specific, rapid and accurate quantitative assays are warranted as an essential required. Hemoclot™ Thrombin Inhibitors and Biophen® DTI were specifically designed for these applications, and can be used on all automated instruments with a standard range protocol for measuring concentrations at peak, or with a low range protocol for testing residual concentrations. Both functional assays have a good correlation with the reference LC-MS/MS method, and concentrations measured are similar. Performances of these assays and interferences of various substances or drugs are discussed. Some differences in variations of clotting times are observed between mechanical or optical clot detection instruments, which could be explained by the fibrin clot structure, altered by direct Factor Xa inhibitors, and more especially Rivaroxaban. Both clotting and chromogenic assays offer a safe and accurate quantitative measurement of Dabigatran in plasma in all situations where this determination is requested. In short this manuscript provides an in depth update on current opinions on laboratory aspects of measuring Dabigatran concentrations in plasma, when required. PMID:27216543

  7. Micro-environmental control of cell migration – myosin IIA is required for efficient migration in fibrillar environments through control of cell adhesion dynamics

    PubMed Central

    Doyle, Andrew D.; Kutys, Matthew L.; Conti, Mary Anne; Matsumoto, Kazue; Adelstein, Robert S.; Yamada, Kenneth M.

    2012-01-01

    Recent evidence suggests that organization of the extracellular matrix (ECM) into aligned fibrils or fibril-like ECM topographies promotes rapid migration in fibroblasts. However, the mechanisms of cell migration that are altered by these changes in micro-environmental topography remain unknown. Here, using 1D fibrillar migration as a model system for oriented fibrillar 3D matrices, we find that fibroblast leading-edge dynamics are enhanced by 1D fibrillar micropatterns and demonstrate a dependence on the spatial positioning of cell adhesions. Although 1D, 2D and 3D matrix adhesions have similar assembly kinetics, both 1D and 3D adhesions are stabilized for prolonged periods, whereas both paxillin and vinculin show slower turnover rates in 1D adhesions. Moreover, actin in 1D adhesions undergoes slower retrograde flow than the actin that is present in 2D lamellipodia. These data suggest an increase in mechanical coupling between adhesions and protrusive machinery. Experimental reduction of contractility resulted in the loss of 1D adhesion structure and stability, with scattered small and unstable adhesions, and an uncoupling of adhesion protein-integrin stability. Genetic ablation of myosin IIA (MIIA) or myosin IIB (MIIB) isoforms revealed that MIIA is required for efficient migration in restricted environments as well as adhesion maturation, whereas MIIB helps to stabilize adhesions beneath the cell body. These data suggest that restricted cell environments, such as 1D patterns, require cellular contraction through MIIA to enhance adhesion stability and coupling to integrins behind the leading edge. This increase in mechanical coupling allows for greater leading-edge protrusion and rapid cell migration. PMID:22328520

  8. Efficacy of mirtazapine for the treatment of fibromyalgia without concomitant depression: a randomized, double-blind, placebo-controlled phase IIa study in Japan.

    PubMed

    Miki, Kenji; Murakami, Masato; Oka, Hiroshi; Onozawa, Kaname; Yoshida, Sadahiro; Osada, Kenichi

    2016-09-01

    To evaluate the efficacy and safety of mirtazapine in Japanese patients with fibromyalgia (FM), a parallel-group, randomized, double-blind, placebo-controlled phase IIa study was conducted at 57 sites between November 2012 and February 2014. Patients aged 20 to 64 years who met the American College of Rheumatology 1990 diagnostic FM criteria and had stably high pain scores during a placebo run-in period were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to receive mirtazapine orally (15 mg/d for 1 week and then 30 mg/d) or matching placebo for 12 weeks. The primary endpoint was change in mean numerical rating scale (NRS) pain score from baseline to endpoint (week 12 or early discontinuation). Of the 430 patients randomized (n = 215 each group), 422 (n = 211 each group) were analyzed for the primary endpoint. At the study endpoint, mirtazapine caused a significantly greater reduction in the mean NRS pain score compared with placebo (difference, 0.44; 95% confidence interval, -0.72 to -0.17; P = 0.0018). The reduction by mirtazapine remained significantly greater compared with placebo from week 6 onward. More patients treated with mirtazapine had their NRS pain score reduced by ≥30% from baseline (45.5% vs 30.8%). Mirtazapine also improved pain-related quality of life assessed by the Japanese version of the Fibromyalgia Impact Questionnaire and the Short-Form 36 Questionnaire. Adverse events were more common with mirtazapine than placebo (68.8% vs 56.7%), including somnolence (32.1% vs 7.4%), weight gain (17.7% vs 0.9%), and increased appetite (11.6% vs 3.3%). In conclusion, mirtazapine was an effective and safe treatment for Japanese patients with FM. PMID:27218868

  9. A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED)

    PubMed Central

    2013-01-01

    Background 5% of first time pregnancies are complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful screening test exists; consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROvED Consortium members have pioneered a personalised medicine approach to identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The key objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia. Methods/Design We report the design of a multicentre, phase IIa clinical study aiming to recruit 5000 low risk primiparous women to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves maternal phlebotomy at 15 and 20 weeks’ gestation, with optional testing and biobanking at 11 and 34 weeks. Blood samples will be analysed using two innovative, proprietary prototype platforms; one metabolomic based and one proteomic based, both of which outperform current biomarker based screening tests at comparable gestations. Analytical and clinical data will be collated and analysed via the Copenhagen Trials Unit. Discussion The IMPROvED study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If ‘at risk’ patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROvED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome. Trial registration Trial registration number NCT01891240 The IMPROvED project is funded by the seventh framework

  10. Identification of cellular targets of a series of boron heterocycles using TIPA II-A sensitive target identification platform.

    PubMed

    Ward, Matthew S; Silva, Isba; Martinez, Walfre; Jefferson, Jameka; Rahman, Shakila; Garcia, Jeanie M; Kanichar, Divya; Roppiyakuda, Lance; Kosmowska, Ewa; Faust, Michelle A; Tran, Kim P; Chow, Felicia; Buglo, Elena; Zhou, Feimeng; Groziak, Michael P; Xu, H Howard

    2016-08-01

    One of the hurdles in the discovery of antibiotics is the difficulty of linking antibacterial compounds to their cellular targets. Our laboratory has employed a genome-wide approach of over-expressing essential genes in order to identify cellular targets of antibacterial inhibitors. Our objective in this project was to develop and validate a more sensitive disk diffusion based platform of target identification (Target Identification Platform for Antibacterials version 2; TIPA II) using a collection of cell clones in an Escherichia coli mutant (AS19) host with increased outer membrane permeability. Five known antibiotics/inhibitors and 28 boron heterocycles were tested by TIPA II assay, in conjunction with the original assay TIPA. The TIPA II was more sensitive than TIPA because eight boron heterocycles previously found to be inactive to AG1 cells in TIPA assays exhibited activity to AS19 cells. For 15 boron heterocycles, resistant colonies were observed within the zones of inhibition only on the inducing plates in TIPA II assays. DNA sequencing confirmed that resistant clones harbor plasmids with fabI gene as insert, indicating that these boron heterocycles all target enoyl ACP reductase. Additionally, cell-based assays and dose response curved obtained indicated that for two boron heterocycle inhibitors, the fabI cell clone in AG1 (wild-type) host cells exhibited at least 11 fold more resistance under induced conditions than under non-induced conditions. Moreover, TIPA II also identified cellular targets of known antibacterial inhibitors triclosan, phosphomycin, trimethoprim, diazaborine and thiolactomycin, further validating the utility of the new system. PMID:27301675

  11. Thin filament diversity and physiological properties of fast and slow fiber types in astronaut leg muscles

    NASA Technical Reports Server (NTRS)

    Riley, Danny A.; Bain, James L W.; Thompson, Joyce L.; Fitts, Robert H.; Widrick, Jeffrey J.; Trappe, Scott W.; Trappe, Todd A.; Costill, David L.

    2002-01-01

    Slow type I fibers in soleus and fast white (IIa/IIx, IIx), fast red (IIa), and slow red (I) fibers in gastrocnemius were examined electron microscopically and physiologically from pre- and postflight biopsies of four astronauts from the 17-day, Life and Microgravity Sciences Spacelab Shuttle Transport System-78 mission. At 2.5-microm sarcomere length, thick filament density is approximately 1,012 filaments/microm(2) in all fiber types and unchanged by spaceflight. In preflight aldehyde-fixed biopsies, gastrocnemius fibers possess higher percentages (approximately 23%) of short thin filaments than soleus (9%). In type I fibers, spaceflight increases short, thin filament content from 9 to 24% in soleus and from 26 to 31% in gastrocnemius. Thick and thin filament spacing is wider at short sarcomere lengths. The Z-band lattice is also expanded, except for soleus type I fibers with presumably stiffer Z bands. Thin filament packing density correlates directly with specific tension for gastrocnemius fibers but not soleus. Thin filament density is inversely related to shortening velocity in all fibers. Thin filament structural variation contributes to the functional diversity of normal and spaceflight-unloaded muscles.

  12. The finding of a group IIE phospholipase A2 gene in a specified segment of Protobothrops flavoviridis genome and its possible evolutionary relationship to group IIA phospholipase A2 genes.

    PubMed

    Yamaguchi, Kazuaki; Chijiwa, Takahito; Ikeda, Naoki; Shibata, Hiroki; Fukumaki, Yasuyuki; Oda-Ueda, Naoko; Hattori, Shosaku; Ohno, Motonori

    2014-01-01

    The genes encoding group IIE phospholipase A2, abbreviated as IIE PLA2, and its 5' and 3' flanking regions of Crotalinae snakes such as Protobothrops flavoviridis, P. tokarensis, P. elegans, and Ovophis okinavensis, were found and sequenced. The genes consisted of four exons and three introns and coded for 22 or 24 amino acid residues of the signal peptides and 134 amino acid residues of the mature proteins. These IIE PLA2s show high similarity to those from mammals and Colubridae snakes. The high expression level of IIE PLA2s in Crotalinae venom glands suggests that they should work as venomous proteins. The blast analysis indicated that the gene encoding OTUD3, which is ovarian tumor domain-containing protein 3, is located in the 3' downstream of IIE PLA2 gene. Moreover, a group IIA PLA2 gene was found in the 5' upstream of IIE PLA2 gene linked to the OTUD3 gene (OTUD3) in the P. flavoviridis genome. It became evident that the specified arrangement of IIA PLA2 gene, IIE PLA2 gene, and OTUD3 in this order is common in the genomes of humans to snakes. The present finding that the genes encoding various secretory PLA2s form a cluster in the genomes of humans to birds is closely related to the previous finding that six venom PLA2 isozyme genes are densely clustered in the so-called NIS-1 fragment of the P. flavoviridis genome. It is also suggested that venom IIA PLA2 genes may be evolutionarily derived from the IIE PLA2 gene. PMID:25529307

  13. Loss of function of 1-FEH IIb has more impact on post-harvest inulin degradation in Cichorium intybus than copy number variation of its close paralog 1-FEH IIa.

    PubMed

    Dauchot, Nicolas; Raulier, Pierre; Maudoux, Olivier; Notté, Christine; Draye, Xavier; Van Cutsem, Pierre

    2015-01-01

    Key Message: The loss of mini-exon 2 in the 1-FEH IIb glycosyl-hydrolase results in a putative non-functional allele. This loss of function has a strong impact on the susceptibility to post-harvest inulin depolymerization. Significant variation of copy number was identified in its close paralog 1-FEH IIa, but no quantitative effect of copy number on carbohydrates-related phenotypes was detected. Inulin polyfructan is the second most abundant storage carbohydrate in flowering plants. After harvest, it is depolymerized by fructan exohydrolases (FEHs) as an adaptive response to end-season cold temperatures. In chicory, the intensity of this depolymerization differs between cultivars but also between individuals within a cultivar. Regarding this phenotypic variability, we recently identified statistically significant associations between inulin degradation and genetic polymorphisms located in three FEHs. We present here new results of a systematic analysis of copy number variation (CNV) in five key members of the chicory (Cichorium intybus) GH32 multigenic family, including three FEH genes and the two inulin biosynthesis genes: 1-SST and 1-FFT. qPCR analysis identified a significant variability of relative copy number only in the 1-FEH IIa gene. However, this CNV had no quantitative effect. Instead, cloning of the full length gDNA of a close paralogous sequence (1-FEH IIb) identified a 1028 bp deletion in lines less susceptible to post-harvest inulin depolymerization. This region comprises a 9 bp mini-exon containing one of the three conserved residues of the active site. This results in a putative non-functional 1-FEH IIb allele and an observed lower inulin depolymerization. Extensive genotyping confirmed that the loss of mini-exon 2 in 1-FEH IIb and the previously identified 47 bp duplication located in the 3'UTR of 1-FEH IIa belong to a single haplotype, both being statistically associated with reduced susceptibility to post-harvest inulin depolymerization

  14. More Accurate Definition of Clinical Target Volume Based on the Measurement of Microscopic Extensions of the Primary Tumor Toward the Uterus Body in International Federation of Gynecology and Obstetrics Ib-IIa Squamous Cell Carcinoma of the Cervix

    SciTech Connect

    Xie, Wen-Jia; Wu, Xiao; Xue, Ren-Liang; Lin, Xiang-Ying; Kidd, Elizabeth A.; Yan, Shu-Mei; Zhang, Yao-Hong; Zhai, Tian-Tian; Lu, Jia-Yang; Wu, Li-Li; Zhang, Hao; Huang, Hai-Hua; Chen, Zhi-Jian; Li, De-Rui; Xie, Liang-Xi

    2015-01-01

    Purpose: To more accurately define clinical target volume for cervical cancer radiation treatment planning by evaluating tumor microscopic extension toward the uterus body (METU) in International Federation of Gynecology and Obstetrics stage Ib-IIa squamous cell carcinoma of the cervix (SCCC). Patients and Methods: In this multicenter study, surgical resection specimens from 318 cases of stage Ib-IIa SCCC that underwent radical hysterectomy were included. Patients who had undergone preoperative chemotherapy, radiation, or both were excluded from this study. Microscopic extension of primary tumor toward the uterus body was measured. The association between other pathologic factors and METU was analyzed. Results: Microscopic extension toward the uterus body was not common, with only 12.3% of patients (39 of 318) demonstrating METU. The mean (±SD) distance of METU was 0.32 ± 1.079 mm (range, 0-10 mm). Lymphovascular space invasion was associated with METU distance and occurrence rate. A margin of 5 mm added to gross tumor would adequately cover 99.4% and 99% of the METU in the whole group and in patients with lymphovascular space invasion, respectively. Conclusion: According to our analysis of 318 SCCC specimens for METU, using a 5-mm gross tumor volume to clinical target volume margin in the direction of the uterus should be adequate for International Federation of Gynecology and Obstetrics stage Ib-IIa SCCC. Considering the discrepancy between imaging and pathologic methods in determining gross tumor volume extent, we recommend a safer 10-mm margin in the uterine direction as the standard for clinical practice when using MRI for contouring tumor volume.

  15. The Finding of a Group IIE Phospholipase A2 Gene in a Specified Segment of Protobothrops flavoviridis Genome and Its Possible Evolutionary Relationship to Group IIA Phospholipase A2 Genes

    PubMed Central

    Yamaguchi, Kazuaki; Chijiwa, Takahito; Ikeda, Naoki; Shibata, Hiroki; Fukumaki, Yasuyuki; Oda-Ueda, Naoko; Hattori, Shosaku; Ohno, Motonori

    2014-01-01

    The genes encoding group IIE phospholipase A2, abbreviated as IIE PLA2, and its 5' and 3' flanking regions of Crotalinae snakes such as Protobothrops flavoviridis, P. tokarensis, P. elegans, and Ovophis okinavensis, were found and sequenced. The genes consisted of four exons and three introns and coded for 22 or 24 amino acid residues of the signal peptides and 134 amino acid residues of the mature proteins. These IIE PLA2s show high similarity to those from mammals and Colubridae snakes. The high expression level of IIE PLA2s in Crotalinae venom glands suggests that they should work as venomous proteins. The blast analysis indicated that the gene encoding OTUD3, which is ovarian tumor domain-containing protein 3, is located in the 3' downstream of IIE PLA2 gene. Moreover, a group IIA PLA2 gene was found in the 5' upstream of IIE PLA2 gene linked to the OTUD3 gene (OTUD3) in the P. flavoviridis genome. It became evident that the specified arrangement of IIA PLA2 gene, IIE PLA2 gene, and OTUD3 in this order is common in the genomes of humans to snakes. The present finding that the genes encoding various secretory PLA2s form a cluster in the genomes of humans to birds is closely related to the previous finding that six venom PLA2 isozyme genes are densely clustered in the so-called NIS-1 fragment of the P. flavoviridis genome. It is also suggested that venom IIA PLA2 genes may be evolutionarily derived from the IIE PLA2 gene. PMID:25529307

  16. Rapid Healing of Cutaneous Leishmaniasis by High-Frequency Electrocauterization and Hydrogel Wound Care with or without DAC N-055: A Randomized Controlled Phase IIa Trial in Kabul

    PubMed Central

    Steiner, Reto; Wentker, Pia; Mahfuz, Farouq; Stahl, Hans-Christian; Amin, Faquir Mohammad; Bogdan, Christian; Stahl, Kurt-Wilhelm

    2014-01-01

    Background Anthroponotic cutaneous leishmaniasis (CL) due to Leishmania (L.) tropica infection is a chronic, frequently disfiguring skin disease with limited therapeutic options. In endemic countries healing of ulcerative lesions is often delayed by bacterial and/or fungal infections. Here, we studied a novel therapeutic concept to prevent superinfections, accelerate wound closure, and improve the cosmetic outcome of ACL. Methodology/Principal Findings From 2004 to 2008 we performed a two-armed, randomized, double-blinded, phase IIa trial in Kabul, Afghanistan, with patients suffering from L. tropica CL. The skin lesions were treated with bipolar high-frequency electrocauterization (EC) followed by daily moist-wound-treatment (MWT) with polyacrylate hydrogel with (group I) or without (group II) pharmaceutical sodium chlorite (DAC N-055). Patients below age 5, with facial lesions, pregnancy, or serious comorbidities were excluded. The primary, photodocumented outcome was the time needed for complete lesion epithelialization. Biopsies for parasitological and (immuno)histopathological analyses were taken prior to EC (1st), after wound closure (2nd) and after 6 months (3rd). The mean duration for complete wound closure was short and indifferent in group I (59 patients, 43.1 d) and II (54 patients, 42 d; p = 0.83). In patients with Leishmania-positive 2nd biopsies DAC N-055 caused a more rapid wound epithelialization (37.2 d vs. 58.3 d; p = 0.08). Superinfections occurred in both groups at the same rate (8.8%). Except for one patient, reulcerations (10.2% in group I, 18.5% in group II; p = 0.158) were confined to cases with persistent high parasite loads after healing. In vitro, DAC N-055 showed a leishmanicidal effect on pro- and amastigotes. Conclusions/Significance Compared to previous results with intralesional antimony injections, the EC plus MWT protocol led to more rapid wound closure. The tentatively lower rate of relapses and the acceleration of

  17. Sodium Tanshinone IIA Sulfonate Ameliorates Bladder Fibrosis in a Rat Model of Partial Bladder Outlet Obstruction by Inhibiting the TGF-β/Smad Pathway Activation.

    PubMed

    Jiang, Xiaoxiao; Chen, Yaping; Zhu, Haitao; Wang, Bo; Qu, Ping; Chen, Renfu; Sun, Xiaoqing

    2015-01-01

    Transforming growth factor (TGF)-β1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-β/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO) is yet to be conclusively. Using a rat PBOO model, we investigated TGF-β1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS) could inhibit TGF-β/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty-eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16), PBOO operation without STS treatment group (n = 16) and PBOO operation with STS treatment group (n = 16). Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16) or vehicle (n = 16) two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF-β/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR). One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-β1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (α-SMA), collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-β/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO operation

  18. Sodium Tanshinone IIA Sulfonate Ameliorates Bladder Fibrosis in a Rat Model of Partial Bladder Outlet Obstruction by Inhibiting the TGF-β/Smad Pathway Activation

    PubMed Central

    Wang, Bo; Qu, Ping; Chen, Renfu; Sun, Xiaoqing

    2015-01-01

    Transforming growth factor (TGF)-β1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-β/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO) is yet to be conclusively. Using a rat PBOO model, we investigated TGF-β1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS) could inhibit TGF-β/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty-eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16), PBOO operation without STS treatment group (n = 16) and PBOO operation with STS treatment group (n = 16). Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16) or vehicle (n = 16) two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF-β/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR). One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-β1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (α-SMA), collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-β/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO operation

  19. Supermembrane actions for Gaiotto-Maldacena backgrounds

    NASA Astrophysics Data System (ADS)

    Stefański, Bogdan

    2014-06-01

    We write down the supermembrane actions for M-theory backgrounds dual to general N=2 four-dimensional superconformal field theories. The actions are given to all orders in fermions and are in a particular κ-gauge. When an extra U(1) isometry is present, our actions reduce to κ-gauge fixed Green-Schwarz actions for the corresponding Type IIA backgrounds.

  20. Relationships between type I and type II chondrules: Implications on chondrule formation processes

    NASA Astrophysics Data System (ADS)

    Villeneuve, Johan; Libourel, Guy; Soulié, Camille

    2015-07-01

    In unequilibrated chondrites, the ferromagnesian silicates in chondrules exhibit wide ranges of mg# = Mg/(Mg + Fe), allowing to sub-divide porphyritic chondrules into either type I (mg# > 0.9) or type II (mg# < 0.9). Although both chondrule types formed under oxidizing conditions relative to the canonical solar nebula, it is generally inferred that type II chondrules formed in more oxidizing conditions than type I. In order to check whether this redox difference was established during chondrule formation, or reflects differences in their precursors, we have undertaken a set of experiments aimed at heating type I olivine-rich (A) chondrule proxy, i.e. forsterite + Fe metal + Ca-Mg-Si-Al glass mixtures, under oxidizing conditions. We show that high temperature (isothermal) oxidation of type IA-like assemblages is a very efficient and rapid process (e.g. few tens of minutes) to form textures similar to type IIA chondrules. Due to the rapid dissolution of Fe metal blebs, a FeO increase in the melt and in combination with the dissolution of magnesian olivine allows the melt to reach ferroan olivine saturation. Crystallization of ferroan olivine occurs either as new crystal in the mesostasis or as overgrowths on the remaining unresorbed forsterite grains (relicts). Interruption of this process at any time before its completion by rapid cooling allows to reproduce the whole range of textures and chemical diversity observed in type A chondrules, i.e. from type I to type II. Several implications on chondrule formation processes can be inferred from the presented experiments. Type I chondrules or fragments of type I chondrules are very likely the main precursor material involved in the formation of most type II chondrules. Formation of porphyritic olivine type II chondrules is very likely the result of processes generating crystal growth by chemical disequilibrium at high temperature rather than processes generating crystallization only by cooling rates. This questions the

  1. Establishment of an interleukin-1β-induced inflammation-activated endothelial cell-smooth muscle cell-mononuclear cell co-culture model and evaluation of the anti-inflammatory effects of tanshinone IIA on atherosclerosis.

    PubMed

    Li, Yujie; Guo, Yan; Chen, Ying; Wang, Yajie; You, Yun; Yang, Qing; Weng, Xiaogang; Li, Qi; Zhu, Xiaoxin; Zhou, Bingbing; Liu, Xucen; Gong, Zaipeng; Zhang, Ruijie

    2015-08-01

    Increasing evidence supports the hypothesis that inflammatory reactions serves an important function in the formation, progression and plaque rupture of atherosclerosis. Interleukin (IL)-1 primarily induces inflammation and is closely associated with the inflammatory environment and the formation of atherosclerosis. The present study aimed to establish an in vitro model for the evaluation of drug efficacy in the intervention of atherosclerosis from the inflammatory perspective, and to observe the anti-inflammatory effects of tanshinone IIA and andrographolide on atherosclerosis. The IL-1β-induced inflammation-activated endothelial cell (EC)-smooth muscle cell (SMC)-mononuclear cell (MC) co-culture model was established, based on the changes in a series of atherosclerosis-associated inflammatory markers secreted by ECs and SMCs. The expression of connexin in ECs, adhesion of MCs and changes in inflammatory signalling molecules were selected as evaluation indices for the inflammatory microenvironment of atherosclerosis. The use of this model revealed that tanshinone IIA exhibited significant efficacy against atherosclerosis and its inflammatory reactions. Inflammatory reactions were regarded as the primary mechanism underlying atherosclerosis. The established model simulated a series of relevant changes in the arterial wall under the inflammatory cytokines with oxidized low-density lipoprotein during the atherosclerotic process. The present study presented a reliable method for the identification of drugs with potential anti-inflammatory activity in atherosclerosis, for investigating the mechanisms of action, considering the improvement of the inflammatory state and the increase in plaque stability observed. PMID:25936371

  2. Occurrence and activity of a type II CRISPR-Cas system in Lactobacillus gasseri.

    PubMed

    Sanozky-Dawes, Rosemary; Selle, Kurt; O'Flaherty, Sarah; Klaenhammer, Todd; Barrangou, Rodolphe

    2015-09-01

    Bacteria encode clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated genes (cas), which collectively form an RNA-guided adaptive immune system against invasive genetic elements. In silico surveys have revealed that lactic acid bacteria harbour a prolific and diverse set of CRISPR-Cas systems. Thus, the natural evolutionary role of CRISPR-Cas systems may be investigated in these ecologically, industrially, scientifically and medically important microbes. In this study, 17 Lactobacillus gasseri strains were investigated and 6 harboured a type II-A CRISPR-Cas system, with considerable diversity in array size and spacer content. Several of the spacers showed similarity to phage and plasmid sequences, which are typical targets of CRISPR-Cas immune systems. Aligning the protospacers facilitated inference of the protospacer adjacent motif sequence, determined to be 5'-NTAA-3' flanking the 3' end of the protospacer. The system in L. gasseri JV-V03 and NCK 1342 interfered with transforming plasmids containing sequences matching the most recently acquired CRISPR spacers in each strain. We report the distribution and function of a native type II-A CRISPR-Cas system in the commensal species L. gasseri. Collectively, these results open avenues for applications for bacteriophage protection and genome modification in L. gasseri, and contribute to the fundamental understanding of CRISPR-Cas systems in bacteria. PMID:26297561

  3. DNA G-segment bending is not the sole determinant of topology simplification by type II DNA topoisomerases.

    PubMed

    Thomson, Neil H; Santos, Sergio; Mitchenall, Lesley A; Stuchinskaya, Tanya; Taylor, James A; Maxwell, Anthony

    2014-01-01

    DNA topoisomerases control the topology of DNA. Type II topoisomerases exhibit topology simplification, whereby products of their reactions are simplified beyond that expected based on thermodynamic equilibrium. The molecular basis for this process is unknown, although DNA bending has been implicated. To investigate the role of bending in topology simplification, the DNA bend angles of four enzymes of different types (IIA and IIB) were measured using atomic force microscopy (AFM). The enzymes tested were Escherichia coli topo IV and yeast topo II (type IIA enzymes that exhibit topology simplification), and Methanosarcina mazei topo VI and Sulfolobus shibatae topo VI (type IIB enzymes, which do not). Bend angles were measured using the manual tangent method from topographical AFM images taken with a novel amplitude-modulated imaging mode: small amplitude small set-point (SASS), which optimises resolution for a given AFM tip size and minimises tip convolution with the sample. This gave improved accuracy and reliability and revealed that all 4 topoisomerases bend DNA by a similar amount: ~120° between the DNA entering and exiting the enzyme complex. These data indicate that DNA bending alone is insufficient to explain topology simplification and that the 'exit gate' may be an important determinant of this process. PMID:25142513

  4. Blood typing

    MedlinePlus

    ... typing. The liquid part of your blood without cells (serum) is mixed with blood that is known to be type ... ABO typing: If your blood cells stick together when mixed with: Anti-A serum, you have type A blood Anti-B serum, you have type B blood Both anti-A and ...

  5. Loss of function of 1-FEH IIb has more impact on post-harvest inulin degradation in Cichorium intybus than copy number variation of its close paralog 1-FEH IIa

    PubMed Central

    Dauchot, Nicolas; Raulier, Pierre; Maudoux, Olivier; Notté, Christine; Draye, Xavier; Van Cutsem, Pierre

    2015-01-01

    Key Message: The loss of mini-exon 2 in the 1-FEH IIb glycosyl-hydrolase results in a putative non-functional allele. This loss of function has a strong impact on the susceptibility to post-harvest inulin depolymerization. Significant variation of copy number was identified in its close paralog 1-FEH IIa, but no quantitative effect of copy number on carbohydrates-related phenotypes was detected. Inulin polyfructan is the second most abundant storage carbohydrate in flowering plants. After harvest, it is depolymerized by fructan exohydrolases (FEHs) as an adaptive response to end-season cold temperatures. In chicory, the intensity of this depolymerization differs between cultivars but also between individuals within a cultivar. Regarding this phenotypic variability, we recently identified statistically significant associations between inulin degradation and genetic polymorphisms located in three FEHs. We present here new results of a systematic analysis of copy number variation (CNV) in five key members of the chicory (Cichorium intybus) GH32 multigenic family, including three FEH genes and the two inulin biosynthesis genes: 1-SST and 1-FFT. qPCR analysis identified a significant variability of relative copy number only in the 1-FEH IIa gene. However, this CNV had no quantitative effect. Instead, cloning of the full length gDNA of a close paralogous sequence (1-FEH IIb) identified a 1028 bp deletion in lines less susceptible to post-harvest inulin depolymerization. This region comprises a 9 bp mini-exon containing one of the three conserved residues of the active site. This results in a putative non-functional 1-FEH IIb allele and an observed lower inulin depolymerization. Extensive genotyping confirmed that the loss of mini-exon 2 in 1-FEH IIb and the previously identified 47 bp duplication located in the 3′UTR of 1-FEH IIa belong to a single haplotype, both being statistically associated with reduced susceptibility to post-harvest inulin depolymerization

  6. [Hereditary sensory and autonomic neuropathy type II A: early neurological and skeletal findings].

    PubMed

    Esmer, C; Díaz Zambrano, S; Santos Díaz, M A; González Huerta, L M; Cuevas Covarrubias, S A; Bravo Oro, A

    2014-04-01

    The hereditary sensory and autonomic neuropathies are genetic disorders characterized by the loss of sensation including pain, tactile and temperature. Its clinical and molecular features vary widely; the symptoms may begin from birth or be noticed in the first or second decade, with different types of complications of trauma to the extremities such as ulcers, mutilations and acral amputations. They are classified into six groups from I to VI, determined by the abnormality in eleven genes leading to phenotypic variations in the age of onset and the presence or absence of dysautonomia signs. With the exception of type I, all are autosomal recessive. The type II of these neuropathies is characterized by insensitivity to pain, heat and proprioception. We describe three members of a Mexican family with WNK1 gene mutation that caused hereditary neuropathy IIA. PMID:23831200

  7. Sturge-Weber Syndrome Is Associated with Cortical Dysplasia ILAE Type IIIc and Excessive Hypertrophic Pyramidal Neurons in Brain Resections for Intractable Epilepsy.

    PubMed

    Wang, Dan-Dan; Blümcke, Ingmar; Coras, Roland; Zhou, Wen-Jing; Lu, De-Hong; Gui, Qiu-Ping; Hu, Jing-Xia; Zuo, Huan-Cong; Chen, Shi-Yun; Piao, Yue-Shan

    2015-05-01

    Sturge-Weber syndrome (SWS) is a rare syndrome characterized by capillary-venous malformations involving skin and brain. Many patients with SWS also suffer from drug-resistant epilepsy. We retrospectively studied a series of six SWS patients with epilepsy and extensive neurosurgical resections. At time of surgery, the patients' age ranged from 11 to 35 years (with a mean of 20.2 years). All surgical specimens were well preserved, which allowed a systematic microscopical inspection utilizing the 2011 ILAE classification for focal cortical dysplasia (FCD). Neuropathology revealed dysmorphic-like neurons with hypertrophic cell bodies reminiscent to those described for FCD type IIa in all cases. However, gross architectural abnormalities of neocortical layering typical for FCD type IIa were missing, and we propose to classify this pattern as FCD ILAE type IIIc. In addition, our patients with earliest seizure onset also showed polymicrogyria (PMG; n = 4). The ictal onset zones were identified in all patients by subdural electrodes, and these areas always showed histopathological evidence for FCD type IIIc. Four out of five patients had favorable seizure control after surgery with a mean follow-up period of 1.7 years. We concluded from our study that FCD type IIIc and PMG are frequently associated findings in SWS. FCD type IIIc may play a major epileptogenic role in SWS and complete resection of the associated FCD should be considered a prognostic key factor to achieve seizure control. PMID:25040707

  8. A comparative dosimetric study of volumetric-modulated arc therapy vs. fixed field intensity-modulated radiotherapy in postoperative irradiation of stage IB-IIA high-risk cervical cancer

    PubMed Central

    QIAO, LILI; CHENG, JIAN; LIANG, NING; XIE, JIAN; LUO, HUI; ZHANG, JIANDONG

    2016-01-01

    The aim of the present study was to compare the dosimetry features of volumetric-modulated arc therapy (VMAT) and fixed field intensity-modulated radiotherapy (f-IMRT) in postoperative irradiation of stage IB-IIA high-risk cervical cancer. Fifteen patients exhibiting stage IB-IIA high-risk cervical cancer, who had been treated with postoperative adjuvant concurrent radiochemotherapy, were selected. The clinical target volume (CTV) and organs at risk (OARs) were delineated according to contrast computed tomography images. The planning target volume (PTV) was subsequently produced by using 1 cm uniform expansion of the CTV. The treatment plans were intended to deliver 50 Gy in 25 fractions. The OARs that were contoured included the bladder, rectum, small bowel and femoral heads. Dose volume histograms were used to evaluate the dose distribution in the PTV and OARs. VMAT and f-IMRT treatment plans resulted in similar dose coverage of the PTV. VMAT was superior to f-IMRT in conformity (P<0.05), and resulted in a reduction of OARs irradiated at high dose levels (V40 and V50) compared with f-IMRT (P<0.05), particularly for the bladder. However, the doses of low levels (V10 and V20) delivered to OARs with f-IMRT were slightly reduced compared with VMAT (P<0.05). For ambilateral femoral heads, VMAT demonstrated improved sparing compared with f-IMRT, with regard to D5 (P<0.05). Furthermore, VMAT treatment plans revealed a significant reduction in monitor units (MU) and treatment time. VMAT techniques exhibited similar PTV coverage compared with f-IMRT. At doses of high levels delivered to OARs, VMAT demonstrated improved sparing compared with f-IMRT, particularly for the bladder, while significantly reducing treatment time and MU number. PMID:26893675

  9. On aspects of holographic thermal QCD at finite coupling

    NASA Astrophysics Data System (ADS)

    Sil, Karunava; Misra, Aalok

    2016-09-01

    In the context of string theoretic dual of thermal QCD-like theories at finite gauge/string coupling of [1] (as part of the 'MQGP' limit of [2]), we obtain the QCD deconfinement temperature compatible with lattice results for the right number of light flavors Nf = 3, and the correct mass scale of the light (first generation) quarks. The type IIB background of [1] is also shown to be thermodynamically stable. Further, we show that the temperature dependence of DC electrical conductivity mimics a one-dimensional Luttinger liquid, and the requirement of the Einstein relation (ratio of electrical conductivity and charge susceptibility equal to the diffusion constant) to be satisfied requires a specific dependence of the Ouyang embedding parameter on the horizon radius. These results arise due to the non-Kählerity and non-conformality of the type IIB background. On the geometrical side we quantify the former (non-Kählerity) by evaluating the SU (3) /G2-structure torsion classes of the local type IIA mirror/M-theory uplift. Analogous to what was shown for the type IIB background in [5], we first show that the type IIA delocalized SYZ mirror (after fine tuning) can also be approximately supersymmetric. We then work out the G2-structure torsion classes of the local M-theory uplift of the mirror type IIA metric - in the large-N limit at finite coupling, G2 structure approaches G2 holonomy.

  10. Intrauterine growth-restricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term.

    PubMed

    Yates, Dustin T; Cadaret, Caitlin N; Beede, Kristin A; Riley, Hannah E; Macko, Antoni R; Anderson, Miranda J; Camacho, Leticia E; Limesand, Sean W

    2016-06-01

    Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fiber-type ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers. Placental insufficiency-induced IUGR fetuses were ∼54% smaller (P < 0.05) than controls and exhibited hypoxemia and hypoglycemia, which contributed to 6.9-fold greater (P < 0.05) plasma norepinephrine and ∼53% lower (P < 0.05) plasma insulin concentrations. IUGR semitendinosus muscles contained less (P < 0.05) myosin heavy chain-I protein (MyHC-I) and proportionally fewer (P < 0.05) Type I and Type I/IIa fibers than controls, but MyHC-II protein concentrations, Type II fibers, and Type IIx fibers were not different. IUGR biceps femoris muscles exhibited similar albeit less dramatic differences in fiber type proportions. Type I and IIa fibers are more responsive to adrenergic and insulin regulation than Type IIx and may be more profoundly impaired by the high catecholamines and low insulin in our IUGR fetuses, leading to their proportional reduction. In both muscles, fibers of each type were uniformly smaller (P < 0.05) in IUGR fetuses than controls, which indicates that fiber hypertrophy is not dependent on type but rather on other factors such as myoblast differentiation or protein synthesis. Together, our findings show that IUGR fetal muscles develop smaller fibers and have proportionally fewer Type I fibers, which is indicative of developmental adaptations that may help explain the link between IUGR and adulthood insulin resistance. PMID:27053651

  11. Algebraic geometry realization of quantum Hall soliton

    NASA Astrophysics Data System (ADS)

    Abounasr, R.; Ait Ben Haddou, M.; El Rhalami, A.; Saidi, E. H.

    2005-02-01

    Using the Iqbal-Netzike-Vafa dictionary giving the correspondence between the H2 homology of del Pezzo surfaces and p-branes, we develop a way to approach the system of brane bounds in M-theory on S1. We first review the structure of 10-dimensional quantum Hall soliton (QHS) from the view of M-theory on S1. Then, we show how the D0 dissolution in D2-brane is realized in M-theory language and derive the p-brane constraint equations used to define appropriately the QHS. Finally, we build an algebraic geometry realization of the QHS in type IIA superstring and show how to get its type IIB dual. Other aspects are also discussed.

  12. Effects of estrogen on genioglossal muscle contractile properties and fiber-type distribution in chronic intermittent hypoxia rats.

    PubMed

    Liu, Yue-Hua; Huang, Yan; Shao, Xiao

    2009-12-01

    Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a highly prevalent disorder that is characterized by recurrent sleep-induced collapse of the upper airway. Genioglossus is an important pharyngeal dilator muscle that helps to maintain the patency of the upper airway. The effect of female hormones on pharyngeal dilator muscle activity may be one possible explanation for the differences observed in the prevalence of OSAHS between genders. The aim of this research was to investigate the influence of estrogen on genioglossus activity in rats exposed to chronic intermittent hypoxia (CIH). Eight-wk-old female rats were ovariectomized or sham-operated, received 5-wk of estrogen replacement therapy, and/or were exposed to CIH. The contractile properties of the genioglossus were measured. ATPase staining was performed to determine the per cent fiber-type distribution and to measure the cross-sectional area (CSA) of muscle fibers. Myosin heavy chain phenotypes were determined by gel electrophoresis. Chronic intermittent hypoxia reduced the contractile properties of the genioglossus muscle, decreased the CSA of type IIA fibers, and decreased the proportion of myosin heavy chain IIA, and ovariectomy exacerbated this effect. However, estrogen replacement can partially reverse the effect of CIH in ovariectomized rats. It is concluded that a low female hormone level and CIH may increase fatigue and alter genioglossus structure and function, and may compromise the maintenance of upper airway patency, while estrogen may help to reverse this effect. PMID:20121931

  13. Reversible changes in the reflectivity of different types of fibre Bragg gratings

    SciTech Connect

    Gnusin, P I; Vasil'ev, Sergei A; Medvedkov, O I; Dianov, Evgenii M

    2010-12-09

    We have studied strain- and temperature-induced reversible changes in the reflectivity of different types of fibre Bragg gratings. The results demonstrate that the strain sensitivity of the reflectivity of type I and IIa Bragg gratings is mainly due to the photoinduced reduction in the elasto-optic coefficient p{sub 12} of the core glass and that its temperature sensitivity results from the increase in the thermo-optic coefficient of the glass. UV exposure of fibres loaded with molecular hydrogen has an insignificant effect on these material coefficients. We also analyse the effects of UV fluence and germanium concentration in the fibre core on the reversible changes in the reflectivity of the grating. (optical fibres)

  14. Effect of acute and chronic eccentric exercise on FOXO1 mRNA expression as fiber type transition factor in rat skeletal muscles.

    PubMed

    Azad, Milad; Khaledi, Neda; Hedayati, Mehdi

    2016-06-15

    Skeletal muscle is a highly elastic tissue which can respond to various functional demands by altering fiber-type composition. Exercise affects muscle fiber phenotype. One of the transcription factors that induce fiber-type transition is forkhead box O1 (FOXO1). Since eccentric contraction considered an essential part of exercise, so we are interested to see the effects of eccentric exercise (acute/chronic) on FOXO1 as an important factor of fiber-type transition in rat skeletal muscles. Twenty-four Sprague-Dawley rats (190-235g) were divided to 3 groups of 8 rats: 1) chronic eccentric exercise (CEE), 2) acute eccentric exercise (AEE), and 3) control (C). The exercise groups underwent downhill running protocol. CEE was running on treadmill in 3days of week for 9weeks, that slope and duration gradually managed from -4° to -16° and 15 to 90min, respectively. AEE group was running with 16m/min on -16° slope for 3 consecutive days that included 18 sets of 5min with rest interval of 2min in between. Soleus and super vastus lateralis (SVL) muscles mRNA were analyzed by real-time RT-PCR. SVL FOXO1 mRNA levels increased by 3.92-fold in the AEE and decreased 0.56-fold in the CEE group and were not significant in soleus muscle. In soleus muscle, myosin heavy chain (MHC) IIa, IIx, and IIb decreased in the AEE group and MHC IIa and IIx decreased in the CEE group. In SVL muscle, MHC I, IIa, and IIx increased in the AEE group and MHC IIa and IIX increased in the CEE group. In summary, both acute and chronic eccentric exercise could lead to change in FOXO1 mRNA only in fast SVL muscle of rat and so could induce fiber-type transition in both muscles regardless of changes in expression of FOXO1. So, oxidative stress can play important role in change of FOXO1. PMID:26915490

  15. Nitrate Intake Promotes Shift in Muscle Fiber Type Composition during Sprint Interval Training in Hypoxia

    PubMed Central

    De Smet, Stefan; Van Thienen, Ruud; Deldicque, Louise; James, Ruth; Sale, Craig; Bishop, David J.; Hespel, Peter

    2016-01-01

    Purpose: We investigated the effect of sprint interval training (SIT) in normoxia, vs. SIT in hypoxia alone or in conjunction with oral nitrate intake, on buffering capacity of homogenized muscle (βhm) and fiber type distribution, as well as on sprint and endurance performance. Methods: Twenty-seven moderately-trained participants were allocated to one of three experimental groups: SIT in normoxia (20.9% FiO2) + placebo (N), SIT in hypoxia (15% FiO2) + placebo (H), or SIT in hypoxia + nitrate supplementation (HN). All participated in 5 weeks of SIT on a cycle ergometer (30-s sprints interspersed by 4.5 min recovery-intervals, 3 weekly sessions, 4–6 sprints per session). Nitrate (6.45 mmol NaNO3) or placebo capsules were administered 3 h before each session. Before and after SIT participants performed an incremental VO2max-test, a 30-min simulated cycling time-trial, as well as a 30-s cycling sprint test. Muscle biopsies were taken from m. vastus lateralis. Results: SIT decreased the proportion of type IIx muscle fibers in all groups (P < 0.05). The relative number of type IIa fibers increased (P < 0.05) in HN (P < 0.05 vs. H), but not in the other groups. SIT had no significant effect on βhm. Compared with H, SIT tended to enhance 30-s sprint performance more in HN than in H (P = 0.085). VO2max and 30-min time-trial performance increased in all groups to a similar extent. Conclusion: SIT in hypoxia combined with nitrate supplementation increases the proportion of type IIa fibers in muscle, which may be associated with enhanced performance in short maximal exercise. Compared with normoxic training, hypoxic SIT does not alter βhm or endurance and sprinting exercise performance. PMID:27378942

  16. Indirect myosin immunocytochemistry for the identification of fibre types in equine skeletal muscle

    NASA Technical Reports Server (NTRS)

    Sinha, A. K.; Rose, R. J.; Pozgaj, I.; Hoh, J. F.

    1992-01-01

    The histochemical ATPase method for muscle fibre typing was first described by Brooke and Kaiser in 1970. However, problems have been found with the subdivision of type II fibres using this technique. To determine whether indirect myosin immunocytochemistry using anti-slow (5-4D), anti-fast (1A10) and anti-fast red (5-2B) monoclonal antibodies with cross reactivity for type I, II and IIa fibres, respectively, in a number of species, could identify three fibre types in equine skeletal muscle, data on fibre type composition and fibre size obtained using the two different techniques were compared. Results indicate that different myosin heavy chains can coexist in single equine muscle fibres. Type I and type II fibres were identified by immunocytochemistry, but subdivision of type II fibres was not possible. Although the percentage of type I and type II fibres was not significantly different for the two techniques, a few fibres reacted with both the 1A10 and 5-4D antibodies.

  17. Matrix composition of cartilaginous anlagen in achondrogenesis type II (Langer-Saldino).

    PubMed

    Dertinger, Susanne; Söeder, Stephan; Bösch, Hubert; Aigner, Thomas

    2005-01-01

    Skeletal dysplasias represent in vivo models of genetic defects. Achondrogenesis type II (Langer-Saldino), caused by a genetic defect in the major cartilage matrix protein, collagen type II, is a rare and severe skeletal dysplasia. It comprises a severe derangement of the fetal growth plate cartilage with subsequent ossification defects. In this study, we analyzed the matrix composition and cell differentiation pattern in 3 relatives with achondrogenesis type II. Most strikingly we found a strongly reduced collagen type II and moderately reduced aggrecan proteoglycan content in the dysplastic cartilage matrix. Type II collagen is, at least to some extent, replaced by collagens type I III, and VI. Ultrastructural analysis of the dysplastic cartilage matrix demonstrated a distended rER (rough endoplasmic reticulum), which is typical for this condition and most likely related to improper processing and retention of genetically altered type II collagen. Immunostaining for type IIA and X collagens suggest a severe delay in chondrocyte maturation. Thus, the genetic defect in the present cases leads most likely to a severe retention of collagen type II in the rER and, therefore, a strongly reduced collagen deposition and replacement by other interstitial collagens. However, the latter are less efficient in binding aggrecan proteoglycans in the dysplastic cartilage matrix. Additionally, a delay in chondrocyte maturation appears to be important in achondrogenesis type II. PMID:15574381

  18. Connective tissue reflex massage for type 2 diabetic patients with peripheral arterial disease: randomized controlled trial.

    PubMed

    Castro-Sánchez, Adelaida María; Moreno-Lorenzo, Carmen; Matarán-Peñarrocha, Guillermo A; Feriche-Fernández-Castanys, Belen; Granados-Gámez, Genoveva; Quesada-Rubio, José Manuel

    2011-01-01

    The objective of this study was to evaluate the efficacy of connective tissue massage to improve blood circulation and intermittent claudication symptoms in type 2 diabetic patients. A randomized, placebo-controlled trial was undertaken. Ninety-eight type 2 diabetes patients with stage I or II-a peripheral arterial disease (PAD) (Leriche-Fontaine classification) were randomly assigned to a massage group or to a placebo group treated using disconnected magnetotherapy equipment. Peripheral arterial circulation was determined by measuring differential segmental arterial pressure, heart rate, skin temperature, oxygen saturation and skin blood flow. Measurements were taken before and at 30 min, 6 months and 1 year after the 15-week treatment. After the 15-week program, the groups differed (P < .05) in differential segmental arterial pressure in right lower limb (lower one-third of thigh, upper and lower one-third of leg) and left lower limb (lower one-third of thigh and upper and lower one-third of leg). A significant difference (P < .05) was also observed in skin blood flow in digits 1 and 4 of right foot and digits 2, 4 and 5 of left foot. ANOVA results were significant (P < .05) for right and left foot oxygen saturation but not for heart rate and temperature. At 6 months and 1 year, the groups differed in differential segmental arterial pressure in upper third of left and right legs. Connective tissue massage improves blood circulation in the lower limbs of type 2 diabetic patients at stage I or II-a and may be useful to slow the progression of PAD. PMID:19933770

  19. Gonadotrophins modulate hormone secretion and steady-state mRNA levels for activin receptors (type I, IIA, IIB) and inhibin co-receptor (betaglycan) in granulosa and theca cells from chicken prehierarchical and preovulatory follicles.

    PubMed

    Lovell, Tristan M; Al-Musawi, Sara L; Gladwell, Richard T; Knight, Philip G

    2007-06-01

    Ovarian follicle development is regulated through endocrine and local mechanisms. Increasing evidence indicates roles for transforming growth factor beta superfamily members, including inhibins and activins. We recently identified divergent expression of mRNAs encoding activin receptors (ActR) and inhibin co-receptor betaglycan in chicken follicles at different stages of maturation. Here, we compare the actions of LH and FSH (0, 1, 10, 100 ng/ml) on levels of mRNA for ActRI, ActRIIA, ActRIIB and betaglycan in chicken granulosa and theca cells (GC and TC) from preovulatory (F1) and prehierarchical (6-8 mm) follicles. The expression of mRNAs for LH-R and FSH-R and production of inhibin A, oestradiol and progesterone were also quantified. FSH decreased ActRIIB and ActRI mRNA levels in 6-8 mm GC, whereas LH increased the mRNA levels. Both LH and FSH enhanced ActRIIA (5- and 8.5-fold) and betaglycan mRNA expression (2- and 3.5-fold) in 6-8 mm GC. In 6-8 mm TC, LH and FSH both increased the betaglycan mRNA level (7- and 3.5-fold respectively) but did not affect ActRI, ActRIIA and ActRIIB transcript levels. In F1 GC, both LH and FSH stimulated ActRI (2- and 2.4-fold), ActRIIB (3.2- and 2.7-fold) and betaglycan (7- and 4-fold) mRNA levels, while ActRIIA mRNA was unaffected. In F1 TC, LH and FSH reduced ActRIIA (35-50%) and increased (4.5- and 7.6-fold) betaglycan mRNA, but had no effect on ActRI and ActRIIB transcript levels. Results support the hypothesis that expression of ActR and betaglycan are differentially regulated by gonadotrophins during follicle maturation in the hen. This may represent an important mechanism for fine-tuning follicle responsiveness to local and systemic activins and inhibins. PMID:17636170

  20. Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading

    NASA Technical Reports Server (NTRS)

    Carlson, C. J.; Booth, F. W.; Gordon, S. E.

    1999-01-01

    Transgenic mice lacking a functional myostatin (MSTN) gene demonstrate greater skeletal muscle mass resulting from muscle fiber hypertrophy and hyperplasia (McPherron, A. C., A. M. Lawler, and S. -J. Lee. Nature 387: 83-90, 1997). Therefore, we hypothesized that, in normal mice, MSTN may act as a negative regulator of muscle mass. Specifically, we hypothesized that the predominately slow (type I) soleus muscle, which demonstrates greater atrophy than the fast (type II) gastrocnemius-plantaris complex (Gast/PLT), would show more elevation in MSTN mRNA abundance during hindlimb unloading (HU). Surprisingly, MSTN mRNA was not detectable in weight-bearing or HU soleus muscle, which atrophied 42% by the 7th day of HU in female ICR mice. In contrast, MSTN mRNA was present in weight-bearing Gast/PLT muscle and was significantly elevated (67%) at 1 day but not at 3 or 7 days of HU. However, the Gast/PLT muscle had only atrophied 17% by the 7th day of HU. Because the soleus is composed only of type I and IIa fibers, whereas the Gast/PLT expresses type IId/x and IIb in addition to type I and IIa, it was necessary to perform a more careful analysis of the relationship between MSTN mRNA levels and myosin heavy-chain (MHC) isoform expression (as a marker of fiber type). A significant correlation (r = 0.725, P < 0. 0005) was noted between the percentage of MHC isoform IIb expression and MSTN mRNA abundance in several muscles of the mouse hindlimb. These results indicate that MSTN expression is not strongly associated with muscle atrophy induced by HU; however, it is strongly associated with MHC isoform IIb expression in normal muscle.

  1. The calibration of photographic and spectroscopic films. Part 1: Film batch variations of reciprocity failure in IIaO film. Part 2: Thermal and aging effects in relationship to reciprocity failure. P art 3: Shifting of reciprocity failure points as a function of thermal and aging effects

    NASA Technical Reports Server (NTRS)

    Peters, Kevin A.; Atkinson, Pamela F.; Hammond, Ernest C., Jr

    1987-01-01

    Reciprocity failure was examined for IIaO spectroscopic film. Three separate experiments were performed in order to study film batch variations, thermal and aging effects in relationship to reciprocity failure, and shifting of reciprocity failure points as a function of thermal and aging effects. The failure was examined over ranges of time between 5 and 60 seconds. The variation to illuminance was obtained by using thirty neutral density filters. A standard sensitometer device imprinted the wedge pattern on the film as exposure time was subjected to variation. Results indicate that film batch differences, temperature, and aging play an important role in reciprocity failure of IIaO spectroscopic film. A shifting of the failure points was also observed in various batches of film.

  2. The calibration of photographic and spectroscopic films. 1: Film batch variations of reciprocity failure in IIaO film. 2: Thermal and aging effects in relationship to reciprocity failure. 3: Shifting of reciprocity failure points as a function of thermal and aging effects

    NASA Technical Reports Server (NTRS)

    Peters, K. A.; Atkinson, P. F.; Hammond, E. C., Jr.

    1986-01-01

    Reciprocity failure was examined for IIaO spectroscopic film. Three separate experiments were performed in order to study film batch variations, thermal and aging effects in relationship to reciprocity failure, and shifting of reciprocity failure points as a function of thermal and aging effects. The failure was examined over ranges of time between 5 and 60 seconds. The variation to illuminance was obtained by using thirty neutral density filters. A standard sensitometer device imprinted the wedge pattern on the film as exposure time was subjected to variation. The results indicate that film batch differences, temperature, and aging play an important role in reciprocity failure of IIaO spectroscopic film. A shifting of the failure points was also observed in various batches of film.

  3. Blood Typing

    MedlinePlus

    ... this page helpful? Also known as: Blood Group; Rh Factor Formal name: ABO Group and Rh Type Related ... mother's and baby's ABO blood groups, not the Rh factor. However, ABO grouping cannot be used to predict ...

  4. Blood typing

    MedlinePlus

    ... whether or not there are certain proteins, called antigens, on your red blood cells. Blood is often ... There are many antigens besides the major ones (A, B, and Rh). Many minor ones are not routinely detected during blood typing. If ...

  5. E10 and a Small Tension Expansion of M Theory

    NASA Astrophysics Data System (ADS)

    Damour, T.; Henneaux, M.; Nicolai, H.

    2002-11-01

    A formal ``small tension'' expansion of D=11 supergravity near a spacelike singularity is shown to be equivalent, at least up to 30th order in height, to a null geodesic motion in the infinite-dimensional coset space E10/K(E10), where K(E10) is the maximal compact subgroup of the hyperbolic Kac-Moody group E10(R). For the proof we make use of a novel decomposition of E10 into irreducible representations of its SL(10,R) subgroup. We explicitly show how to identify the first four rungs of the E10 coset fields with the values of geometric quantities constructed from D=11 supergravity fields and their spatial gradients taken at some comoving spatial point.

  6. Geometry of extended null supersymmetry in M theory

    SciTech Connect

    Conamhna, Oisin A.P. Mac

    2006-02-15

    For supersymmetric spacetimes in 11 dimensions admitting a null Killing spinor, a set of explicit necessary and sufficient conditions for the existence of any number of arbitrary additional Killing spinors is derived. The necessary and sufficient conditions are comprised of algebraic relationships, linear in the spinorial components, between the spinorial components and their first derivatives, and the components of the spin connection and four-form. The integrability conditions for the Killing spinor equation are also analyzed in detail, to determine which components of the field equations are implied by arbitrary additional supersymmetries and the four-form Bianchi identity. This provides a complete formalism for the systematic and exhaustive investigation of all spacetimes with extended null supersymmetry in 11 dimensions. The formalism is employed to show that the general bosonic solution of 11 dimensional supergravity admitting a G{sub 2} structure defined by four Killing spinors is either locally the direct product of R{sup 1,3} with a seven-manifold of G{sub 2} holonomy, or locally the Freund-Rubin direct product of AdS{sub 4} with a seven-manifold of weak G{sub 2} holonomy. In addition, all supersymmetric spacetimes admitting a (G{sub 2}xR{sup 7})xR{sup 2} structure are classified.

  7. Layer-Specific Input to Distinct Cell Types in Layer 6 of Monkey Primary Visual Cortex

    PubMed Central

    Briggs, Farran; Callaway, Edward M.

    2007-01-01

    Layer 6 of monkey V1 contains a physiologically and anatomically diverse population of excitatory pyramidal neurons. Distinctive arborization patterns of axons and dendrites within the functionally specialized cortical layers define eight types of layer 6 pyramidal neurons and suggest unique information processing roles for each cell type. To address how input sources contribute to cellular function, we examined the laminar sources of functional excitatory input onto individual layer 6 pyramidal neurons using scanning laser photostimulation. We find that excitatory input sources correlate with cell type. Class I neurons with axonal arbors selectively targeting magnocellular (M) recipient layer 4Cα receive input from M-dominated layer 4B, whereas class I neurons whose axonal arbors target parvocellular (P) recipient layer 4Cβ receive input from P-dominated layer 2/3. Surprisingly, these neuronal types do not differ significantly in the inputs they receive directly from layers 4Cα or 4Cβ. Class II cells, which lack dense axonal arbors within layer 4C, receive excitatory input from layers targeted by their local axons. Specifically, type IIA cells project axons to and receive input from the deep but not superficial layers. Type IIB neurons project to and receive input from the deepest and most superficial, but not middle layers. Type IIC neurons arborize throughout the cortical layers and tend to receive inputs from all cortical layers. These observations have implications for the functional roles of different layer 6 cell types in visual information processing. PMID:11331389

  8. A highly sensitive HPLC-MS/MS method for quantification of 20(S)-protopanaxadiol in human plasma and its application in phase IIa clinical trial of a novel antidepressant agent.

    PubMed

    Ling, Jin; Yu, Yingjia; Zhu, Jiajun; Li, Yan; Ling, Li; Wang, Liping; Xu, Changjiang; Duan, Gengli

    2016-09-15

    A highly sensitive HPLC-MS/MS assay method was established to quantify 20(S)-protopanaxadiol (PPD) in human plasma with dexamethasone as an internal standard. The electrospray ion mass spectrometry (ESI-MS) was operated under the multiple reactions monitoring mode (MRM) using positive ion mode. PPD was extracted from 500μL plasma samples by liquid-liquid extraction then separated by a C18 analytical column with gradient elution. The concentration of PPD could be determined by this HPLC-MS/MS method over the range of 0.05-20ng/mL with the lower limit of quantification (LLOQ) of 0.05ng/mL. The method was successfully applied to phase IIa clinical trial of Yuxintine (PPD capsule) in which plasma samples of 87 subjects were analyzed following 6 weeks of oral administration of placebo or PPD capsules in 5 different doses. In this study, the measured concentration was linearly related to the oral dosage with R=0.9901. The minimum and maximum values of measured concentration were 0.06 and 11.60ng/mL, respectively. In addition, plasma concentrations of PPD in depression patients were reported for the first time in our study. PMID:27507666

  9. Fiber type effects on contraction-stimulated glucose uptake and GLUT4 abundance in single fibers from rat skeletal muscle

    PubMed Central

    Castorena, Carlos M.; Arias, Edward B.; Sharma, Naveen; Bogan, Jonathan S.

    2014-01-01

    To fully understand skeletal muscle at the cellular level, it is essential to evaluate single muscle fibers. Accordingly, the major goals of this study were to determine if there are fiber type-related differences in single fibers from rat skeletal muscle for: 1) contraction-stimulated glucose uptake and/or 2) the abundance of GLUT4 and other metabolically relevant proteins. Paired epitrochlearis muscles isolated from Wistar rats were either electrically stimulated to contract (E-Stim) or remained resting (No E-Stim). Single fibers isolated from muscles incubated with 2-deoxy-d-[3H]glucose (2-DG) were used to determine fiber type [myosin heavy chain (MHC) isoform protein expression], 2-DG uptake, and abundance of metabolically relevant proteins, including the GLUT4 glucose transporter. E-Stim, relative to No E-Stim, fibers had greater (P < 0.05) 2-DG uptake for each of the isolated fiber types (MHC-IIa, MHC-IIax, MHC-IIx, MHC-IIxb, and MHC-IIb). However, 2-DG uptake for E-Stim fibers was not significantly different among these five fiber types. GLUT4, tethering protein containing a UBX domain for GLUT4 (TUG), cytochrome c oxidase IV (COX IV), and filamin C protein levels were significantly greater (P < 0.05) in MHC-IIa vs. MHC-IIx, MHC-IIxb, or MHC-IIb fibers. TUG and COX IV in either MHC-IIax or MHC-IIx fibers exceeded values for MHC-IIxb or MHC-IIb fibers. GLUT4 levels for MHC-IIax fibers exceeded MHC-IIxb fibers. GLUT4, COX IV, filamin C, and TUG abundance in single fibers was significantly (P < 0.05) correlated with each other. Differences in GLUT4 abundance among the fiber types were not accompanied by significant differences in contraction-stimulated glucose uptake. PMID:25491725

  10. PGC-1α plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis but not fiber-type transformation in mouse skeletal muscle

    PubMed Central

    Geng, Tuoyu; Li, Ping; Okutsu, Mitsuharu; Yin, Xinhe; Kwek, Jyeyi; Zhang, Mei

    2010-01-01

    Endurance exercise stimulates peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression in skeletal muscle, and forced expression of PGC-1α changes muscle metabolism and exercise capacity in mice. However, it is unclear if PGC-1α is indispensible for endurance exercise-induced metabolic and contractile adaptations in skeletal muscle. In this study, we showed that endurance exercise-induced expression of mitochondrial enzymes (cytochrome oxidase IV and cytochrome c) and increases of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31)-positive endothelial cells in skeletal muscle, but not IIb-to-IIa fiber-type transformation, were significantly attenuated in muscle-specific Pgc-1α knockout mice. Interestingly, voluntary running effectively restored the compromised mitochondrial integrity and superoxide dismutase 2 (SOD2) protein expression in skeletal muscle in Pgc-1α knockout mice. Thus, PGC-1α plays a functional role in endurance exercise-induced mitochondrial biogenesis and angiogenesis, but not IIb-to-IIa fiber-type transformation in mouse skeletal muscle, and the improvement of mitochondrial morphology and antioxidant defense in response to endurance exercise may occur independently of PGC-1α function. We conclude that PGC-1α is required for complete skeletal muscle adaptations induced by endurance exercise in mice. PMID:20032509

  11. Non-BPS D-brane solutions in six dimensional orbifolds

    NASA Astrophysics Data System (ADS)

    Lozano, Y.

    2000-08-01

    Starting with the non-BPS D0-brane solution of IIB/(-1)FLI4 constructed recently by Eyras and Panda we construct via T-duality the non-BPS D2-brane and D1-brane solutions of IIB/(-1)FLI4 and IIA/(-1)FLI4 predicted by Sen. The D2-brane couples magnetically to the vector field of the NS5B-brane living in the twisted sector of the Type IIB orbifold, whereas the D1-brane couples (electrically and magnetically) to the self-dual 2-form potential of the NS5A-brane that is present in the twisted sector of the Type IIA orbifold construction. Finally we discuss the eleven dimensional interpretation of these branes as originating from a non-BPS M1-brane solution of M-theory orientifolded by ΩρI5.

  12. Morpho-functional relationship between muscular architecture and proportion of myofiber types in ovine antebrachial musculature.

    PubMed

    Konno, Toshihiro; Watanabe, Kouichi

    2012-01-01

    The antebrachium of domestic animals supports the trunk against gravity and generates propulsive force. The antigravity action of antebrachium is attributed to the contraction of flexor muscles of the carpal and digital joints. Mammalian skeletal muscles consist of myofibers, which are histochemically classified into type I, type IIA, and type IIB myofibers, of which composition reflects the proportional involvement of the muscle in varying function, such as posture maintenance and locomotion. The physiological cross-sectional area (PCSA), which are calculated from muscle volume, myofiber length, and pennation angle, reflects the maximum force of muscle. In the present study, we evaluated the PCSA of myofiber types in the antebrachial musculature and determined the magnitude of contribution from individual muscles toward varying actions of carpal and digital joints. The extensor carpi ulnaris and flexor digitorum superficialis muscles possessed a large proportional PCSA of type I myofibers, indicating the role for these muscles in maintaining a standing posture. The additional force required for walking/running was primarily provided by the flexor digitorum profundus caput humerale and extensor carpi radialis muscles. The proportional PCSA of myofiber types reflected the force generated for varying muscular function and provided insights into the dynamics of carpal and digital joints. PMID:23117305

  13. The effect of ubiquinone and combined antioxidant therapy on oxidative stress markers in non-proliferative diabetic retinopathy: A phase IIa, randomized, double-blind, and placebo-controlled study.

    PubMed

    Rodríguez-Carrizalez, Adolfo Daniel; Castellanos-González, José Alberto; Martínez-Romero, Esaú César; Miller-Arrevillaga, Guillermo; Pacheco-Moisés, Fermín Paul; Román-Pintos, Luis Miguel; Miranda-Díaz, Alejandra Guillermina

    2016-07-01

    Objective To evaluate the effect of ubiquinone (Coenzyme Q10) and combined antioxidant therapy (CAT) on oxidative stress markers in non-proliferative diabetic retinopathy (NPDR) under clinical management. Study design In a randomized, double-blind, phase IIa, placebo-controlled, clinical trial, three study groups were formed and administered medications as follows: Group 1, Coenzyme Q10; Group 2, CAT; and Group 3, placebo. Methods Serum levels of the products of lipid peroxidation (LPO) and nitrites/nitrates, as markers of oxidative/nitrosative stress, were measured. As antioxidants, the total antioxidant capacity (TAC), catalase activity, and glutathione peroxidase (GPx) activity were measured. Results Baseline serum levels of LPO and nitrites/nitrates were significantly elevated in the three groups vs. healthy group (P < 0.0001), while final levels in the Coenzyme Q10 and CAT groups were decreased vs. normal levels (P < 0.0001). The baseline TAC was consumed in the three groups (P < 0.0001), while final results in the Coenzyme Q10 and CAT groups improved (P < 0.0001). Baseline catalase activity was increased in all groups vs. normal values (P < 0.001), while final levels in the Coenzyme Q10 (P < 0.001) and CAT groups (P < 0.0001) were decreased. GPx behaved similarly to catalase and improved in the final results (P < 0.0001). Discussion Adjunctive antioxidant treatment for 6 months was effective and safe for improving the oxidative stress in NPDR. PMID:26321469

  14. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation

    PubMed Central

    Clancy, JP; Rowe, Steven M; Accurso, Frank J; Aitken, Moira L; Amin, Raouf S; Ashlock, Melissa A; Ballmann, Manfred; Boyle, Michael P; Bronsveld, Inez; Campbell, Preston W; DeBoeck, Kris; Donaldson, Scott H; Dorkin, Henry L; Dunitz, Jordan M; Durie, Peter R; Jain, Manu; Leonard, Anissa; McCoy, Karen S; Moss, Richard B; Pilewski, Joseph M; Rosenbluth, Daniel B; Rubenstein, Ronald C; Schechter, Michael S; Botfield, Martyn; Ordoñez, Claudia L; Spencer-Green, George T; Vernillet, Laurent; Wisseh, Steve; Yen, Karl; Konstan, Michael W

    2013-01-01

    Background VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. Methods A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. Results The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. Conclusions In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. Clinical trial number NCT00865904 PMID:21825083

  15. Skeletal muscle lipid content and oxidative activity in relation to muscle fiber type in aging and metabolic syndrome.

    PubMed

    Gueugneau, Marine; Coudy-Gandilhon, Cécile; Théron, Laëtitia; Meunier, Bruno; Barboiron, Christiane; Combaret, Lydie; Taillandier, Daniel; Polge, Cécile; Attaix, Didier; Picard, Brigitte; Verney, Julien; Roche, Frédéric; Féasson, Léonard; Barthélémy, Jean-Claude; Béchet, Daniel

    2015-05-01

    One of the most noticeable effects of aging is the reduction in skeletal muscle mass and strength (sarcopenia). The metabolic syndrome (MS) is also prevalent in old subjects, but its relevance to skeletal muscle characteristics has poorly been investigated. Immunohistochemical studies were performed with muscle biopsies from young (22 years) and old (73 years) men with and without MS to reveal age-dependent and MS-associated modifications of fiber-type characteristics. Atrophy of type II fibers and altered fiber shape characterized muscle aging in lean healthy men. In contrast, increased cross-sectional area of the most abundant type I and type IIA fibers, and reduced cytochrome c oxidase content in all fiber types, characterized MS. Aging and particularly MS were associated with accumulation of intramyocellular lipid droplets. Although lipids mostly accumulated in type I fibers, matrix-assisted laser desorption/ionization-mass spectrometry imaging of intramyocellular lipids did not distinguish fiber types, but clearly separated young, old, and MS subjects. In conclusion, our study suggests that MS in the elderly persons is associated with alterations in skeletal muscle at a fiber-type specific level. Overall, these fiber type-specific modifications may be important both for the age-related loss of muscle mass and strength and for the increased prevalence of MS in elderly subjects. PMID:24939997

  16. Overexpression of the Mitochondrial T3 Receptor p43 Induces a Shift in Skeletal Muscle Fiber Types

    PubMed Central

    Casas, François; Pessemesse, Laurence; Grandemange, Stéphanie; Seyer, Pascal; Gueguen, Naïg; Baris, Olivier; Lepourry, Laurence; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2008-01-01

    In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation.We have generated mice overexpressing p43 under control of the human α-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8°C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1α and PPARδ, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1α and PPARδ. PMID:18575627

  17. An Optimized Histochemical Method to Assess Skeletal Muscle Glycogen and Lipid Stores Reveals Two Metabolically Distinct Populations of Type I Muscle Fibers

    PubMed Central

    Prats, Clara; Gomez-Cabello, Alba; Nordby, Pernille; Andersen, Jesper L.; Helge, Jørn W.; Dela, Flemming; Baba, Otto; Ploug, Thorkil

    2013-01-01

    Skeletal muscle energy metabolism has been a research focus of physiologists for more than a century. Yet, how the use of intramuscular carbohydrate and lipid energy stores are coordinated during different types of exercise remains a subject of debate. Controversy arises from contradicting data from numerous studies, which used different methodological approaches. Here we review the “pros and cons” of previously used histochemical methods and describe an optimized method to ensure the preservation and specificity of detection of both intramyocellular carbohydrate and lipid stores. For optimal preservation of muscle energy stores, air drying cryosections or cycles of freezing-thawing need to be avoided. Furthermore, optimization of the imaging settings in order to specifically image intracellular lipid droplets stained with oil red O or Bodipy-493/503 is shown. When co-staining lipid droplets with associated proteins, Bodipy-493/503 should be the dye of choice, since oil red O creates precipitates on the lipid droplets blocking the light. In order to increase the specificity of glycogen stain, an antibody against glycogen is used. The resulting method reveals the existence of two metabolically distinct myosin heavy chain I expressing fibers: I-1 fibers have a smaller crossectional area, a higher density of lipid droplets, and a tendency to lower glycogen content compared to I-2 fibers. Type I-2 fibers have similar lipid content than IIA. Exhaustive exercise lead to glycogen depletion in type IIA and IIX fibers, a reduction in lipid droplets density in both type I-1 and I-2 fibers, and a decrease in the size of lipid droplets exclusively in type I-1 fibers. PMID:24204959

  18. Priming with a Simplified Intradermal HIV-1 DNA Vaccine Regimen followed by Boosting with Recombinant HIV-1 MVA Vaccine Is Safe and Immunogenic: A Phase IIa Randomized Clinical Trial

    PubMed Central

    Nilsson, Charlotta; Joachim, Agricola; Geldmacher, Christof; Mann, Philipp; Moshiro, Candida; Aboud, Said; Lyamuya, Eligius; Maboko, Leonard; Missanga, Marco; Kaluwa, Bahati; Mfinanga, Sayoki; Podola, Lilly; Bauer, Asli; Godoy-Ramirez, Karina; Marovich, Mary; Moss, Bernard; Hoelscher, Michael; Gotch, Frances; Stöhr, Wolfgang; Stout, Richard; McCormack, Sheena; Wahren, Britta; Mhalu, Fred; Robb, Merlin L.; Biberfeld, Gunnel; Sandström, Eric; Bakari, Muhammad

    2015-01-01

    Background Intradermal priming with HIV-1 DNA plasmids followed by HIV-1MVA boosting induces strong and broad cellular and humoral immune responses. In our previous HIVIS-03 trial, we used 5 injections with 2 pools of HIV-DNA at separate sites for each priming immunization. The present study explores whether HIV-DNA priming can be simplified by reducing the number of DNA injections and administration of combined versus separated plasmid pools. Methods In this phase IIa, randomized trial, priming was performed using 5 injections of HIV-DNA, 1000 μg total dose, (3 Env and 2 Gag encoding plasmids) compared to two “simplified” regimens of 2 injections of HIV-DNA, 600 μg total dose, of Env- and Gag-encoding plasmid pools with each pool either administered separately or combined. HIV-DNA immunizations were given intradermally at weeks 0, 4, and 12. Boosting was performed intramuscularly with 108 pfu HIV-MVA at weeks 30 and 46. Results 129 healthy Tanzanian participants were enrolled. There were no differences in adverse events between the groups. The proportion of IFN-γ ELISpot responders to Gag and/or Env peptides after the second HIV-MVA boost did not differ significantly between the groups primed with 2 injections of combined HIV-DNA pools, 2 injections with separated pools, and 5 injections with separated pools (90%, 97% and 97%). There were no significant differences in the magnitude of Gag and/or Env IFN-γ ELISpot responses, in CD4+ and CD8+ T cell responses measured as IFN-γ/IL-2 production by intracellular cytokine staining (ICS) or in response rates and median titers for binding antibodies to Env gp160 between study groups. Conclusions A simplified intradermal vaccination regimen with 2 injections of a total of 600 μg with combined HIV-DNA plasmids primed cellular responses as efficiently as the standard regimen of 5 injections of a total of 1000 μg with separated plasmid pools after boosting twice with HIV-MVA. Trial Registration World Health

  19. Effect of 23-day muscle disuse on sarcoplasmic reticulum Ca2+ properties and contractility in human type I and type II skeletal muscle fibers.

    PubMed

    Lamboley, C R; Wyckelsma, V L; Perry, B D; McKenna, M J; Lamb, G D

    2016-08-01

    Inactivity negatively impacts on skeletal muscle function mainly through muscle atrophy. However, recent evidence suggests that the quality of individual muscle fibers is also altered. This study examined the effects of 23 days of unilateral lower limb suspension (ULLS) on specific force and sarcoplasmic reticulum (SR) Ca(2+) content in individual skinned muscle fibers. Muscle biopsies of the vastus lateralis were taken from six young healthy adults prior to and following ULLS. After disuse, the endogenous SR Ca(2+) content was ∼8% lower in type I fibers and maximal SR Ca(2+) capacity was lower in both type I and type II fibers (-11 and -5%, respectively). The specific force, measured in single skinned fibers from three subjects, decreased significantly after ULLS in type II fibers (-23%) but not in type I fibers (-9%). Western blot analyses showed no significant change in the amounts of myosin heavy chain (MHC) I and MHC IIa following the disuse, whereas the amounts of sarco(endo)plasmic reticulum Ca(2+)-ATPase 1 (SERCA1) and calsequestrin increased by ∼120 and ∼20%, respectively, and the amount of troponin I decreased by ∼21%. These findings suggest that the decline in force and power occurring with muscle disuse is likely to be exacerbated in part by reductions in maximum specific force in type II fibers, and in the amount of releasable SR Ca(2+) in both fiber types, the latter not being attributable to a reduced calsequestrin level. Furthermore, the ∼3-wk disuse in human elicits change in SR properties, in particular a more than twofold upregulation in SERCA1 density, before any fiber-type shift. PMID:27365282

  20. Mild Hyperbaric Oxygen Improves Decreased Oxidative Capacity of Spinal Motoneurons Innervating the Soleus Muscle of Rats with Type 2 Diabetes.

    PubMed

    Takemura, Ai; Ishihara, Akihiko

    2016-09-01

    Rats with type 2 diabetes exhibit decreased oxidative capacity, such as reduced oxidative enzyme activity, low-intensity staining for oxidative enzymes in fibers, and no high-oxidative type IIA fibers, in the skeletal muscle, especially in the soleus muscle. In contrast, there are no data available concerning the oxidative capacity of spinal motoneurons innervating skeletal muscle of rats with type 2 diabetes. This study examined the oxidative capacity of motoneurons innervating the soleus muscle of non-obese rats with type 2 diabetes. In addition, this study examined the effects of mild hyperbaric oxygen at 1.25 atmospheres absolute with 36 % oxygen for 10 weeks on the oxidative capacity of motoneurons innervating the soleus muscle because mild hyperbaric oxygen improves the decreased oxidative capacity of the soleus muscle in non-obese rats with type 2 diabetes. Spinal motoneurons innervating the soleus muscle were identified using nuclear yellow, a retrograde fluorescent neuronal tracer. Thereafter, the cell body sizes and succinate dehydrogenase activity of identified motoneurons were analyzed. Decreased succinate dehydrogenase activity of small-sized alpha motoneurons innervating the soleus muscle was observed in rats with type 2 diabetes. The decreased succinate dehydrogenase activity of these motoneurons was improved by mild hyperbaric oxygen. Therefore, we concluded that rats with type 2 diabetes have decreased oxidative capacity in motoneurons innervating the soleus muscle and this decreased oxidative capacity is improved by mild hyperbaric oxygen. PMID:27220333