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Sample records for m-theory type iia

  1. M-theory on Manifolds of G{sub 2} Holonomy and Type IIA Orientifolds

    SciTech Connect

    Kachru, Shamit

    2001-07-25

    We demonstrate that M-theory compactifications on 7-manifolds of G{sub 2} holonomy, which yield 4d N = 1 supersymmetric systems, often admit at special loci in their moduli space a description as type IIA orientifolds. In this way, we are able to find new dualities of special IIA orientifolds, including dualities which relate orientifolds of IIA strings on manifolds of different topology with different numbers of wrapped D-branes. We also discuss models which incorporate, in a natural way, compact embeddings of gauge theory/gravity dualities similar to those studied in the recent work of Atiyah, Maldacena and Vafa.

  2. Rational sphere valued supercocycles in M-theory and type IIA string theory

    NASA Astrophysics Data System (ADS)

    Fiorenza, Domenico; Sati, Hisham; Schreiber, Urs

    2017-04-01

    We show that supercocycles on super L∞-algebras capture, at the rational level, the twisted cohomological charge structure of the fields of M-theory and of type IIA string theory. We show that rational 4-sphere-valued supercocycles for M-branes in M-theory descend to supercocycles in type IIA string theory with coefficients in the free loop space of the 4-sphere, to yield the Ramond-Ramond fields in the rational image of twisted K-theory, with the twist given by the B-field. In particular, we derive the M2/M5 ↔ F1/Dp/NS5 correspondence via dimensional reduction of sphere-valued super-L∞-cocycles.

  3. New spin(7) holonomy metrics admitting G2 holonomy reductions and M-theory/type-IIA dualities

    NASA Astrophysics Data System (ADS)

    Salur, S.; Santillan, O.

    2009-04-01

    As is well known, when D6 branes wrap a special Lagrangian cycle on a noncompact Calabi-Yau threefold in such a way that the internal string frame metric is a Kähler one there exists a dual description, which is given in terms of a purely geometrical 11-dimensional background with an internal metric of G2 holonomy. It is also known that when D6 branes wrap a coassociative cycle of a noncompact G2 manifold in the presence of a self-dual two-form strength the internal part of the string frame metric is conformal to the G2 metric and there exists a dual description, which is expressed in terms of a purely geometrical 11-dimensional background with an internal noncompact metric of spin(7) holonomy. In the present work it is shown that any G2 metric participating in the first of these dualities necessarily participates in one of the second type. Additionally, several explicit spin(7) holonomy metrics admitting a G2 holonomy reduction along one isometry are constructed. These metrics can be described as R fibrations over a 6-dimensional Kähler metric, thus realizing the pattern spin(7)→G2→(Kahler) mentioned above. Several of these examples are further described as fibrations over the Eguchi-Hanson gravitational instanton and, to the best of our knowledge, have not been previously considered in the literature.

  4. New spin(7) holonomy metrics admitting G{sub 2} holonomy reductions and M-theory/type-IIA dualities

    SciTech Connect

    Salur, S.; Santillan, O.

    2009-04-15

    As is well known, when D6 branes wrap a special Lagrangian cycle on a noncompact Calabi-Yau threefold in such a way that the internal string frame metric is a Kaehler one there exists a dual description, which is given in terms of a purely geometrical 11-dimensional background with an internal metric of G{sub 2} holonomy. It is also known that when D6 branes wrap a coassociative cycle of a noncompact G{sub 2} manifold in the presence of a self-dual two-form strength the internal part of the string frame metric is conformal to the G{sub 2} metric and there exists a dual description, which is expressed in terms of a purely geometrical 11-dimensional background with an internal noncompact metric of spin(7) holonomy. In the present work it is shown that any G{sub 2} metric participating in the first of these dualities necessarily participates in one of the second type. Additionally, several explicit spin(7) holonomy metrics admitting a G{sub 2} holonomy reduction along one isometry are constructed. These metrics can be described as R fibrations over a 6-dimensional Kaehler metric, thus realizing the pattern spin(7){yields}G{sub 2}{yields}(Kahler) mentioned above. Several of these examples are further described as fibrations over the Eguchi-Hanson gravitational instanton and, to the best of our knowledge, have not been previously considered in the literature.

  5. D=4, N=1, type IIA orientifolds

    NASA Astrophysics Data System (ADS)

    Ishihara, S.; Kataoka, H.; Sato, Hikaru

    1999-12-01

    We study a D=4, N=1, type IIA orientifold with an orbifold group ZN and ZN×ZM. We calculate the one-loop vacuum amplitudes for the Klein bottle, cylinder, and Möbius strip and extract the tadpole divergences. We find that the tadpole cancellation conditions thus obtained are satisfied by the Z4, Z8, Z'8, Z'12 orientifolds while there is no solution for Z3, Z7, Z6, Z'6, Z12. The Z4×Z4 type IIA orientifold is also constructed by introducing four different configurations of 6-branes. We argue about perturbative versus nonperturbative orientifold vacua under T duality between the type IIA and the type IIB ZN orientifolds in four dimensions.

  6. 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

  7. Phacomatosis pigmentovascularis type IIa--case report.

    PubMed

    Segatto, Majoriê Mergen; Schmitt, Eloísa Unfer; Hagemann, Laura Netto; Silva, Roberta Castilhos da; 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.

  8. 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.

  9. Threefold extremal contractions of type (IIA). I

    NASA Astrophysics Data System (ADS)

    Mori, Sh; Prokhorov, Yu G.

    2016-10-01

    Let (X,C) be a germ of a threefold X with terminal singularities along an irreducible reduced complete curve C with a contraction f\\colon(X,C)\\to(Z,o) such that C=f-1(o){red} and -K_X is ample. Assume that (X,C) contains a point of type ({IIA}) and that a general member H\\in\\vert\\mathscr O_X\\vert containing C is normal. We classify such germs in terms of H.

  10. 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.

  11. Script N = 2 solutions of massive type IIA and their Chern-Simons duals

    NASA Astrophysics Data System (ADS)

    Petrini, Michela; Zaffaroni, Alberto

    2009-09-01

    We find explicit AdS4 solutions of massive type IIA with Script N = 2 supersymmetry obtained deforming with a Roman mass the type IIA supersymmetric reduction of the M theory background AdS4 × M111. The family of solutions have SU(3) × SU(3) structure and isometry SU(3) × U(1)2. They are conjectured to be dual to three-dimensional Script N = 2 Chern-Simons theories with generic Chern-Simons couplings and gauge group ranks.

  12. [Type IIA juxtafoveal telangiectasis associated with subretinal neovascularisation].

    PubMed

    Stinghe, Alina L

    2009-01-01

    This is a case report of a type IIA juxtafoveal telangiectasia complicated with secondary subretinal neovascularization in one eye and treated with VEGF inhibitor that succeeded in at least temporary inactivating the neovascular membrane.

  13. Type I/heterotic duality and M-theory amplitudes

    NASA Astrophysics Data System (ADS)

    Green, Michael B.; Rudra, Arnab

    2016-12-01

    This paper investigates relationships between low-energy four-particle scattering amplitudes with external gauge particles and gravitons in the E 8 × E 8 and SO(32) heterotic string theories and the type I and type IA superstring theories by considering a variety of tree level and one-loop Feynman diagrams describing such amplitudes in eleven-dimensional supergravity in a Horava-Witten background compactified on a circle. This accounts for a number of perturbative and non-perturbative aspects of low order higher derivative terms in the low-energy expansion of string theory amplitudes, which are expected to be protected by half maximal supersymmetry from receiving corrections beyond one or two loops. It also suggests the manner in which type I/heterotic duality may be realised for certain higher derivative interactions that are not so obviously protected. For example, our considerations suggest that R 4 interactions (where R is the Riemann curvature) might receive no perturbative corrections beyond one loop by virtue of a conspiracy involving contributions from (non-BPS) {Z}_2 D-instantons in the type I and heterotic SO(32) theories.

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

    PubMed

    Choi, Seung Jun; Lim, Jae-Young; Nibaldi, Eva G; Phillips, Edward M; Frontera, Walter R; Fielding, Roger A; Widrick, Jeffrey J

    2012-02-01

    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 vastus lateralis biopsies of elderly men and women (78 ± 2 years, N = 8), were subjected to a standardized eccentric contraction (strain, 0.25 fiber length; velocity, 0.50 unloaded shortening velocity). Injury was assessed by evaluating pre- and post-eccentric peak Ca(2+)-activated force per fiber cross-sectional area (F (max)). Over 90% of the variability in post-eccentric F (max) could be explained by a multiple linear regression model consisting of an MHC-independent slope, where injury was directly related to pre-eccentric F (max), and MHC-dependent y-intercepts, where the susceptibility to injury could be described as type IIa/IIx fibers > type IIa fibers > type I fibers. We previously reported that fiber type susceptibility to the same standardized eccentric protocol was type IIa/IIx > type IIa = type I for vastus lateralis fibers of 25-year-old adults (Choi and Widrick, Am J Physiol Cell Physiol 299:C1409-C1417, 2010). Modeling combined data sets revealed significant age by fiber type interactions, with post-eccentric F (max) deficits greater for type IIa and type IIa/IIx fibers from elderly vs. young subjects at constant pre-eccentric F (max). We conclude that the resistance of the myofilament lattice to mechanical strain has deteriorated for type IIa and type IIa/IIx, but not for type I, vastus lateralis fibers of elderly adults.

  15. N=4 supersymmetry breaking in type IIA superstrings

    SciTech Connect

    Aldabe, F.

    1997-01-01

    We construct the two parameter K3 surface and show that there is a point in its moduli space where cycles vanish which do not lead to an enhancement of symmetry in a type IIA superstring. At this point we also find two soliton states which are massless. We then consider a type IIA superstring compactified on K3{times}T{sup 2}. For this theory, the massless solitons belong to an N=2 hypermultiplet because there is no enhancement of gauge symmetry. Thus, the N=4 supersymmetry found when the soliton states are massive, breaks down to N=2 supersymmetry when the soliton states are massless. The renormalization of the gauge couplings confirm this result. {copyright} {ital 1997} {ital The American Physical Society}

  16. Surgical vs nonoperative treatment of Hadley type IIA odontoid fractures.

    PubMed

    Aldrian, Silke; Erhart, Jochen; Schuster, Rupert; Wernhart, Simon; Domaszewski, Florian; Ostermann, Roman; Widhalm, Harald; Platzer, Patrick

    2012-03-01

    Type II odontoid fractures with additional chip fragments are rare in clinical practice, accounting for < 10% of all odontoid fractures. Hadley et al were the first to describe these fractures as an individual subtype (IIA). To analyze the outcome of patients after surgical or nonoperative treatment of Hadley type IIA odontoid fractures. We analyzed the records of 46 patients at an average of 64 years of age at the time of injury. Twenty-five patients underwent surgical stabilization by anterior screw fixation and were entered into study group A; 21 patients were treated nonoperatively by halo vest immobilization and included in study group B. Thirty-seven patients (84%) returned to their preinjury activity level and were satisfied with their treatment. Using the Cervical Spine Outcomes Questionnaire to quantify the clinical outcome, we had an overall outcome score of 21.8. We did not find a significant difference in the overall clinical outcome between study groups. Bony fusion was achieved in 35 patients (80%). We had a nonunion rate of 13% after anterior screw fixation and a significantly higher rate of 30% after halo vest immobilization. Failure of reduction or fixation occurred in 12 patients (27%), with a significantly higher failure rate after halo vest immobilization. Hadley type IIA odontoid fractures are inherently unstable and impede proper realignment. These fractures have a significantly increased risk for secondary loss of reduction and bony nonunion, particularly after nonoperative management. Early surgery should be considered to avoid further complications.

  17. Emergence of dengue virus type 4 genotype IIA in Malaysia.

    PubMed

    AbuBakar, Sazaly; Wong, Pooi-Fong; Chan, Yoke-Fun

    2002-10-01

    Phylogenetic analyses of the envelope (E) gene sequence of five recently isolated dengue virus type 4 (DENV-4) suggested the emergence of a distinct geographical and temporal DENV-4 subgenotype IIA in Malaysia. Four of the isolates had direct ancestral lineage with DENV-4 Indonesia 1973 and showed evidence of intra-serotypic recombination with the other recently isolated DENV-4, MY01-22713. The E gene of isolate MY01-22713 had strong evidence of an earlier recombination involving DENV-4 genotype II Indonesia 1976 and genotype I Malaysia 1969. These results suggest that intra-serotypic recombination amongst DENV-4 from independent ancestral lineages may have contributed to the emergence of DENV-4 subgenotype IIA in Malaysia.

  18. Extracellular regulation of type IIa receptor protein tyrosine phosphatases: mechanistic insights from structural analyses

    PubMed Central

    Coles, Charlotte H.; Jones, E. Yvonne; Aricescu, A. Radu

    2016-01-01

    The receptor protein tyrosine phosphatases (RPTPs) exhibit a wide repertoire of cellular signalling functions. In particular, type IIa RPTP family members have recently been highlighted as hubs for extracellular interactions in neurons, regulating neuronal extension and guidance, as well as synaptic organisation. In this review, we will discuss the recent progress of structural biology investigations into the architecture of type IIa RPTP ectodomains and their interactions with extracellular ligands. Structural insights, in combination with biophysical and cellular studies, allow us to begin to piece together molecular mechanisms for the transduction and integration of type IIa RPTP signals and to propose hypotheses for future experimental validation. PMID:25234613

  19. 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.

  20. Direct measurement of DNA bending by type IIA topoisomerases: implications for non-equilibrium topology simplification

    PubMed Central

    Hardin, Ashley H.; Sarkar, Susanta K.; Seol, Yeonee; Liou, Grace F.; Osheroff, Neil; Neuman, Keir C.

    2011-01-01

    Type IIA topoisomerases modify DNA topology by passing one segment of duplex DNA (transfer or T–segment) through a transient double-strand break in a second segment of DNA (gate or G–segment) in an ATP-dependent reaction. Type IIA topoisomerases decatenate, unknot and relax supercoiled DNA to levels below equilibrium, resulting in global topology simplification. The mechanism underlying this non-equilibrium topology simplification remains speculative. The bend angle model postulates that non-equilibrium topology simplification scales with the bend angle imposed on the G–segment DNA by the binding of a type IIA topoisomerase. To test this bend angle model, we used atomic force microscopy and single-molecule Förster resonance energy transfer to measure the extent of bending imposed on DNA by three type IIA topoisomerases that span the range of topology simplification activity. We found that Escherichia coli topoisomerase IV, yeast topoisomerase II and human topoisomerase IIα each bend DNA to a similar degree. These data suggest that DNA bending is not the sole determinant of non-equilibrium topology simplification. Rather, they suggest a fundamental and conserved role for DNA bending in the enzymatic cycle of type IIA topoisomerases. PMID:21421557

  1. Constraining gravitational interactions in the M theory effective action

    NASA Astrophysics Data System (ADS)

    Basu, Anirban

    2014-08-01

    We consider purely gravitational interactions of the type {{D}^{6n}}{{{ R}}^{4}} in the effective action of M theory in 11 dimensional flat spacetime. The duality between M theory on S 1 and type IIA string theory relates them to the type IIA interactions of the form {{e}^{2n{{\\phi }_{A}}}}{{D}^{6n}}{{{ R}}^{4}} where {{\\phi }_{A}} is the type IIA dilaton. The coefficients of the M theory interactions are determined by the strongly coupled type IIA theory. Given the nature of the dilaton dependence, it is plausible that for low values of n, the coefficient has a similar structure as the genus (n+1) string amplitude of the type IIA {{D}^{6n}}{{{ R}}^{4}} interaction, namely the transcendental nature. Assuming this, and focussing on the even-even spin structure part of the type IIA string amplitude, this coefficient is given by the type IIB genus (n+1) amplitude, which we constrain using supersymmetry, S-duality and maximal supergravity. The source terms of the Poisson equations satisfied by the S-duality invariant IIB couplings play a central role in the analysis. This procedure yields partial contributions to several multi-loop type IIB string amplitudes, from which we extract the transcendental nature of the corresponding M theory couplings. For n\\leqslant 2, all possible source terms involve only BPS couplings. While the {{{ R}}^{4}} and {{D}^{6}}{{{ R}}^{4}} M theory couplings agree with known results, the coefficient of the {{D}^{12}}{{{ R}}^{4}} interaction takes the form \\zeta {{(2)}^{3}}({{\\Omega }_{1}}+{{\\Omega }_{2}}\\zeta (3)). We also analyze the {{D}^{18}}{{{ R}}^{4}} and {{D}^{24}}{{{ R}}^{4}} interactions, and show that their coefficients have at least the terms \\zeta {{(2)}^{4}}({{\\tilde{\\Omega }}_{1}}+{{\\tilde{\\Omega }}_{2}}\\zeta (3)+{{\\tilde{\\Omega }}_{3}}\\zeta (5)) and \\zeta {{(2)}^{5}}({{\\underline{\\Omega }}_{1}}+{{\\underline{\\Omega }}_{2}}\\zeta (3)+{{\\underline{\\Omega }}_{3}}\\zeta (5) +\\;{{\\underline{\\Omega }}_{4

  2. MOUSE TRANSGENIC LINES THAT SELECTIVELY LABEL TYPE I, TYPE IIA AND TYPES IIX+B SKELETAL MUSCLE FIBERS

    PubMed Central

    Chakkalakal, Joe V.; Kuang, Shihuan; Buffelli, Mario; Lichtman, Jeff W.; Sanes, Joshua R.

    2014-01-01

    Skeletal muscle fibers vary in contractile and metabolic properties. Four main fiber types are present in mammalian trunk and limb muscles; they are called I, IIA, IIX and IIB, ranging from slowest- to fastest-contracting. Individual muscles contain stereotyped proportions of two or more fiber types. Fiber type is determined by a combination of nerve-dependent and –independent influences, leading to formation of “homogeneous motor units” in which all branches of a single motor neuron form synapses on fibers of a single type. Fiber type composition of muscles can be altered in adulthood by multiple factors including exercise, denervation, hormones and aging. To facilitate analysis of muscle development, plasticity and innervation, we generated transgenic mouse lines in which Type I, Type IIA, and Type IIX+B fibers can be selectively labeled with distinguishable fluorophores. We demonstrate their use for motor unit reconstruction and live imaging of nerve-dependent alterations in fiber type. PMID:21898764

  3. Type IIa hyperlipoproteinemia and HLA-A and B antigens: no association.

    PubMed

    Dufosse, F; Ferraz, M E; Goudemand, J; Rouget, J P; Dewailly, P; Jaillard, J

    1984-04-01

    One hundred unrelated patients with type IIa hyperlipoproteinemia have been investigated for their HLA-A and B antigens and compared to 171 normal controls. This study does not support the significant increase of HLA-B17 and Bw35 previously reported by others.

  4. In front of and behind the replication fork: bacterial type IIA topoisomerases.

    PubMed

    Sissi, Claudia; Palumbo, Manlio

    2010-06-01

    Topoisomerases are vital enzymes specialized in controlling DNA topology, in particular supercoiling and decatenation, to properly handle nucleic acid packing and cell dynamics. The type IIA enzymes act by cleaving both strands of a double helix and having another strand from the same or another molecule cross the DNA gate before a re-sealing event completes the catalytic cycle. Here, we will consider the two types of IIA prokaryotic topoisomerases, DNA Gyrase and Topoisomerase IV, as crucial regulators of bacterial cell cycle progression. Their synergistic action allows control of chromosome packing and grants occurrence of functional transcription and replication processes. In addition to displaying a fascinating molecular mechanism of action, which transduces chemical energy into mechanical energy by means of large conformational changes, these enzymes represent attractive pharmacological targets for antibacterial chemotherapy.

  5. The effect of carbon and nitrogen implantation on the abrasion resistance of type IIa (110) diamond

    NASA Astrophysics Data System (ADS)

    Anderson, Gregory C.; Prawer, Steven; Johnston, Peter; McCulloch, Dougal

    1993-06-01

    The possibility of enhancing the wear characteristics of diamond has generated considerable interest. In the present study type IIa diamond has been implanted with 100 keV carbon and nitrogen ions at temperatures of 150, 470 and 920 K. These temperatures correspond to different defect mobility regimes, whilst nitrogen and carbon were chosen in an attempt to examine possible chemical effects of the ion species on the abrasion resistance of type IIa diamond. The results of abrasion testing using low load multiple pass scratch testing with a Rockwell diamond indenter are presented. These indicate that there is an increase in wear rate in both the soft <100> and hard < overline110> directions following ion implantation. For a given dose the wear rate increases as the implant temperature is reduced. Optical transmission spectra taken in the wavelength region 200 to 750 nm show a corresponding trend in that the implantation induced absorption increases with decreasing implant temperature.

  6. No inflation in type IIA strings on rigid Calabi-Yau spaces

    NASA Astrophysics Data System (ADS)

    Wakimoto, Yuki; Ketov, Sergei V.

    2017-08-01

    We investigate whether cosmological inflation is possible in a class of flux compactifications of type IIA strings on rigid Calabi-Yau manifolds, when all perturbative string corrections are taken into account. We confine ourselves to the universal hypermultiplet and an Abelian vector multiplet, representing matter in four dimensions. Since all axions can be stabilized by D-instantons, we choose the dilaton and a Kähler modulus as the only running scalars. Though positivity of their scalar potential can be achieved, we find that there is no slow roll (ɛ > 13/6), and no graceful exit because the scalar potential has the runaway behavior resulting in decompactification. We conclude that it is impossible to generate phenomenologically viable inflation in the given class of flux compactifications of type IIA strings without explicit breaking of the N=2 local supersymmetry of the low-energy effective action.

  7. Sling left pulmonary artery with patent type IIA tracheobronchial anomaly and imperforate anus.

    PubMed

    Rosenbaum, Daniel G; Kasdorf, Ericalyn; Renjen, Pooja; Brill, Paula; Kovanlikaya, Arzu

    2014-01-01

    We present a 3-month-old boy with a type IIA sling left pulmonary artery associated with imperforate anus and rectourethral fistula. Tracheobronchial abnormalities are demonstrated using multidetector CT with 3-D volume rendering of the airways. This case represents a novel variant of an already rare entity with an unusually high right upper lobe bronchus and no evidence of associated tracheobronchial stenosis. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. 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.

  9. Conserved DNA motifs in the type II-A CRISPR leader region

    PubMed Central

    Babu, Kesavan; Najar, Fares Z.

    2017-01-01

    The Clustered Regularly Interspaced Short Palindromic Repeats associated (CRISPR-Cas) systems consist of RNA-protein complexes that provide bacteria and archaea with sequence-specific immunity against bacteriophages, plasmids, and other mobile genetic elements. Bacteria and archaea become immune to phage or plasmid infections by inserting short pieces of the intruder DNA (spacer) site-specifically into the leader-repeat junction in a process called adaptation. Previous studies have shown that parts of the leader region, especially the 3′ end of the leader, are indispensable for adaptation. However, a comprehensive analysis of leader ends remains absent. Here, we have analyzed the leader, repeat, and Cas proteins from 167 type II-A CRISPR loci. Our results indicate two distinct conserved DNA motifs at the 3′ leader end: ATTTGAG (noted previously in the CRISPR1 locus of Streptococcus thermophilus DGCC7710) and a newly defined CTRCGAG, associated with the CRISPR3 locus of S. thermophilus DGCC7710. A third group with a very short CG DNA conservation at the 3′ leader end is observed mostly in lactobacilli. Analysis of the repeats and Cas proteins revealed clustering of these CRISPR components that mirrors the leader motif clustering, in agreement with the coevolution of CRISPR-Cas components. Based on our analysis of the type II-A CRISPR loci, we implicate leader end sequences that could confer site-specificity for the adaptation-machinery in the different subsets of type II-A CRISPR loci. PMID:28392985

  10. General N=1 supersymmetric flux vacua of massive type IIA string theory.

    PubMed

    Behrndt, Klaus; Cvetic, Mirjam

    2005-07-08

    We derive conditions for the existence of four-dimensional N=1 supersymmetric flux vacua of massive type IIA string theory with general supergravity fluxes turned on. For an SU(3) singlet Killing spinor, we show that such flux vacua exist when the internal geometry is nearly Kähler. The geometry is not warped, all the allowed fluxes are proportional to the mass parameter, and the dilaton is fixed by a ratio of (quantized) fluxes. The four-dimensional cosmological constant, while negative, becomes small in the vacuum with the weak string coupling.

  11. Non-perturbative scalar potential inspired by type IIA strings on rigid CY

    NASA Astrophysics Data System (ADS)

    Alexandrov, Sergei; Ketov, Sergei V.; Wakimoto, Yuki

    2016-11-01

    Motivated by a class of flux compactifications of type IIA strings on rigid Calabi-Yau manifolds, preserving N = 2 local supersymmetry in four dimensions, we derive a non-perturbative potential of all scalar fields from the exact D-instanton corrected metric on the hypermultiplet moduli space. Applying this potential to moduli stabilization, we find a discrete set of exact vacua for axions. At these critical points, the stability problem is decoupled into two subspaces spanned by the axions and the other fields (dilaton and Kähler moduli), respectively. Whereas the stability of the axions is easily achieved, numerical analysis shows instabilities in the second subspace.

  12. Moduli Potentials in Type IIA Compactifications with RR and NS Flux

    SciTech Connect

    Kachru, S.

    2004-12-01

    We describe a simple class of type IIA string compactifications on Calabi-Yau manifolds where background fluxes generate a potential for the complex structure moduli, the dilaton, and the Kaehler moduli. This class of models corresponds to gauged {Nu} = 2 supergravities, and the potential is completely determined by a choice of gauging and by data of the {Nu} = 2 Calabi-Yau model--the prepotential for vector multiplets and the quaternionic metric on the hypermultiplet moduli space. Using mirror symmetry, one can determine many (though not all) of the quantum corrections which are relevant in these models.

  13. Novel hydroxyl tricyclics (e.g., GSK966587) 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; Huang, Jianzhong; Jones, Graham E; Sukmar, Senthill K Kusalakumari; Spitzfaden, Claus; Markwell, Roger E; Minthorn, Elisabeth A; Rittenhouse, Steve; Gwynn, Michael N; Pearson, Neil D

    2013-10-01

    During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.

  14. 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.

  15. Immunohistochemical study of collagen types I and II and procollagen IIA in human cartilage repair tissue following autologous chondrocyte implantation.

    PubMed

    Roberts, S; Menage, J; Sandell, L J; Evans, E H; Richardson, J B

    2009-10-01

    This study has assessed the relative proportions of type I and II collagens and IIA procollagen in full depth biopsies of repair tissue in a large sample of patients treated with autologous chondrocyte implantation (ACI). Sixty five full depth biopsies were obtained from knees of 58 patients 8-60 months after treatment by ACI alone (n=55) or in combination with mosaicplasty (n=10). In addition articular cartilage was examined from eight individuals (aged 10-50) as controls. Morphology and semi-quantitative immunohistochemistry for collagen types I and II and procollagen IIA in the repair tissue were studied. Repair cartilage thickness was 2.89+/-1.5 mm and there was good basal integration between the repair cartilage, calcified cartilage and subchondral bone. Sixty five percent of the biopsies were predominantly fibrocartilage (mostly type I collagen and IIA procollagen), 15% were hyaline cartilage (mostly type II collagen), 17% were of mixed morphology and 3% were fibrous tissue (mostly type I collagen). Type II collagen and IIA procollagen were usually found in the lower regions near the bone and most type II collagen was present 30-60 months after treatment. The presence of type IIA procollagen in the repair tissue supports our hypothesis that this is indicative of a developing cartilage, with the ratio of type II collagen:procollagen IIA increasing from <2% in the first two years post-treatment to 30% three to five years after treatment. This suggests that cartilage repair tissue produced following ACI treatment, is likely to take some years to mature.

  16. Supersymmetric Intersecting Branes on the Type IIA T6/Bbb Z4 Orientifold

    NASA Astrophysics Data System (ADS)

    Blumenhagen, Ralph; Görlich, Lars; Ott, Tassilo

    2003-01-01

    We study supersymmetric intersecting D6-branes wrapping 3-cycles in the Type IIA T6/Z4 orientifold background. As a new feature, the 3-cycles in this orbifold space arise both from the untwisted and the Z2 twisted sectors. We present an integral basis for the homology lattice, H3(M,Z), in terms of fractional 3-cycles, for which the intersection form involves the Cartan matrix of E8. We show that these fractional D6-branes can be used to construct supersymmetric brane configurations realizing a three generation Pati-Salam model. Via brane recombination processes preserving supersymmetry, this GUT model can be broken down to a standard-like model.

  17. 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.

  18. Type IIA Monteggia Fracture Dislocation with Ipsilateral Distal Radius Fracture in Adult – A Rare Association

    PubMed Central

    James, Boblee

    2016-01-01

    Monteggia fracture constitutes about 5-10% of the forearm fractures. Monteggia fracture by definition is proximal ulnar fracture with disruption of proximal radioulnar joint. Bado classified Monteggia fracture dislocation into four types and Jupiter subclassified type II Bado’s fractures into four types. The associated injury in the form of distal radial fractures and distal humerus fractures are rare though many cases of distal radial physeal injuries have been reported in paediatric population. Hereby we report a rare association of type IIA Monteggia fracture dislocation with ipsilateral distal radius fracture in an adult patient. This case report also highlights on proper examination and full length radiographs of forearm to avoid missing injury at wrist in cases of elbow injuries. Management of such complex injuries included open reduction and internal fixation of olecronon fracture, distal radius fracture and radial head resection. Functional outcome at six months was good at wrist whereas at elbow, stiffness was a major concern with elbow range of movement from 40°-110°. PMID:27656518

  19. UCP3 Protein Regulation in Human Skeletal Muscle Fibre Types I, IIa and IIx is Dependent on Exercise Intensity

    PubMed Central

    Russell, Aaron P; Somm, Emmanuel; Praz, Manu; Crettenand, Antoinette; Hartley, Oliver; Melotti, Astrid; Giacobino, Jean-Paul; Muzzin, Patrick; Gobelet, Charles; Dériaz, Olivier

    2003-01-01

    It has been proposed that mitochondrial uncoupling protein 3 (UCP3) behaves as an uncoupler of oxidative phosphorylation. In a cross-sectional study, UCP3 protein levels were found to be lower in all fibre types of endurance-trained cyclists as compared to healthy controls. This decrease was greatest in the type I oxidative fibres, and it was hypothesised that this may be due to the preferential recruitment of these fibres during endurance training. To test this hypothesis, we compared the effects of 6 weeks of endurance (ETr) and sprint (STr) running training on UCP3 mRNA expression and fibre-type protein content using real-time PCR and immunofluorescence techniques, respectively. UCP3 mRNA and protein levels were downregulated similarly in ETr and STr (UCP3 mRNA: by 65 and 50 %, respectively; protein: by 30 and 27 %, respectively). ETr significantly reduced UCP3 protein content in type I, IIa and IIx muscle fibres by 54, 29 and 16 %, respectively. STr significantly reduced UCP3 protein content in type I, IIa and IIx muscle fibres by 24, 31 and 26 %, respectively. The fibre-type reductions in UCP3 due to ETr, but not STr, were significantly different from each other, with the effect being greater in type I than in type IIa, and in type IIa than in type IIx fibres. As a result, compared to STr, ETr reduced UCP3 expression significantly more in fibre type I and significantly less in fibre types IIx. This suggests that the more a fibre is recruited, the more it adapts to training by a decrease in its UCP3 expression. In addition, the more a fibre type depends on fatty acid β oxidation and oxidative phosphorylation, the more it responds to ETr by a decrease in its UCP3 content. PMID:12794174

  20. HPHT growth and x-ray characterization of high-quality type IIa diamond.

    PubMed

    Burns, R C; Chumakov, A I; Connell, S H; Dube, D; Godfried, H P; Hansen, J O; Härtwig, J; Hoszowska, J; Masiello, F; Mkhonza, L; Rebak, M; Rommevaux, A; Setshedi, R; Van Vaerenbergh, P

    2009-09-09

    The trend in synchrotron radiation (x-rays) is towards higher brilliance. This may lead to a very high power density, of the order of hundreds of watts per square millimetre at the x-ray optical elements. These elements are, typically, windows, polarizers, filters and monochromators. The preferred material for Bragg diffracting optical elements at present is silicon, which can be grown to a very high crystal perfection and workable size as well as rather easily processed to the required surface quality. This allows x-ray optical elements to be built with a sufficient degree of lattice perfection and crystal processing that they may preserve transversal coherence in the x-ray beam. This is important for the new techniques which include phase-sensitive imaging experiments like holo-tomography, x-ray photon correlation spectroscopy, coherent diffraction imaging and nanofocusing. Diamond has a lower absorption coefficient than silicon, a better thermal conductivity and lower thermal expansion coefficient which would make it the preferred material if the crystal perfection (bulk and surface) could be improved. Synthetic HPHT-grown (high pressure, high temperature) type Ib material can readily be produced in the necessary sizes of 4-8 mm square and with a nitrogen content of typically a few hundred parts per million. This material has applications in the less demanding roles such as phase plates: however, in a coherence-preserving beamline, where all elements must be of the same high quality, its quality is far from sufficient. Advances in HPHT synthesis methods have allowed the growth of type IIa diamond crystals of the same size as type Ib, but with substantially lower nitrogen content. Characterization of this high purity type IIa material has been carried out with the result that the crystalline (bulk) perfection of some of the HPHT-grown materials is approaching the quality required for the more demanding applications such as imaging applications and imaging

  1. Type IIA topoisomerase inhibition by a new class of antibacterial agents.

    PubMed

    Bax, Benjamin D; Chan, Pan F; Eggleston, Drake S; Fosberry, Andrew; Gentry, Daniel R; Gorrec, Fabrice; Giordano, Ilaria; Hann, Michael M; Hennessy, Alan; Hibbs, Martin; Huang, Jianzhong; Jones, Emma; Jones, Jo; Brown, Kristin Koretke; Lewis, Ceri J; May, Earl W; Saunders, Martin R; Singh, Onkar; Spitzfaden, Claus E; Shen, Carol; Shillings, Anthony; Theobald, Andrew J; Wohlkonig, Alexandre; Pearson, Neil D; Gwynn, Michael N

    2010-08-19

    Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.

  2. 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

  3. Ubiquitin Ligase, MuRF-1 regulates myosin heavy chain type IIa transcripts during muscle atrophy under microgravity conditions

    NASA Astrophysics Data System (ADS)

    Kagawa, Sachiko

    Skeletal muscles are vulnerable to marked atrophy under microgravity conditions. We previously reported that gastrocnemius muscle atrophy by spaceflight was specifically sensitive to the ubiquitin-proteasome proteolytic pathway. We also screened more over 26,000 skeletal muscle genes in rats exposed to real weightlessness and found that the expression of Ubiquitin Ligase, Muscle specific Ring Finger-1 (MuRF-1) upregulated under microgravity. In the present study, we examined the role of MuRF-1 in microgravity-induced muscle atrophy. The amounts of MuRF-1 transcripts significantly increased in skeletal muscle after denervation, an in vivo model of microgravity-induced unloading. MuRF-1 deficient (MuRF-1-/-) mice significantly inhibited reduction of muscle weight for muscle atrophy, compared with wild type mice. Interestingly, MuRF-1-/- mice significantly inhibited upregulation of myosin heavy chain (MyHC) type IIa transcrips, while wild type mice significantly increased expression of MyHC type IIa transcripts in denervated skeletal muscle. Our present results suggest that MuRF-1 may play an important role in regulation of MyHC type IIa during muscle atrophy under microgravity conditions.

  4. Molecular properties and fibril ultrastructure of types II and XI collagens in cartilage of mice expressing exclusively the α1(IIA) collagen isoform.

    PubMed

    McAlinden, Audrey; Traeger, Geoffrey; Hansen, Uwe; Weis, Mary Ann; Ravindran, Soumya; Wirthlin, Louisa; Eyre, David R; Fernandes, Russell J

    2014-02-01

    Until now, no biological tools have been available to determine if a cross-linked collagen fibrillar network derived entirely from type IIA procollagen isoforms, can form in the extracellular matrix (ECM) of cartilage. Recently, homozygous knock-in transgenic mice (Col2a1(+ex2), ki/ki) were generated that exclusively express the IIA procollagen isoform during post-natal development while type IIB procollagen, normally present in the ECM of wild type mice, is absent. The difference between these Col2a1 isoforms is the inclusion (IIA) or exclusion (IIB) of exon 2 that is alternatively spliced in a developmentally regulated manner. Specifically, chondroprogenitor cells synthesize predominantly IIA mRNA isoforms while differentiated chondrocytes produce mainly IIB mRNA isoforms. Recent characterization of the Col2a1(+ex2) mice has surprisingly shown that disruption of alternative splicing does not affect overt cartilage formation. In the present study, biochemical analyses showed that type IIA collagen extracted from ki/ki mouse rib cartilage can form homopolymers that are stabilized predominantly by hydroxylysyl pyridinoline (HP) cross-links at levels that differed from wild type rib cartilage. The findings indicate that mature type II collagen derived exclusively from type IIA procollagen molecules can form hetero-fibrils with type XI collagen and contribute to cartilage structure and function. Heteropolymers with type XI collagen also formed. Electron microscopy revealed mainly thin type IIA collagen fibrils in ki/ki mouse rib cartilage. Immunoprecipitation and mass spectrometry of purified type XI collagen revealed a heterotrimeric molecular composition of α1(XI)α2(XI)α1(IIA) chains where the α1(IIA) chain is the IIA form of the α3(XI) chain. Since the N-propeptide of type XI collagen regulates type II collagen fibril diameter in cartilage, the retention of the exon 2-encoded IIA globular domain would structurally alter the N-propeptide of type XI collagen

  5. Molecular properties and fibril ultrastructure of types II and XI collagens in cartilage of mice expressing exclusively the α1(IIA) collagen isoform

    PubMed Central

    McAlinden, Audrey; Traeger, Geoffrey; Hansen, Uwe; Weis, Mary Ann; Ravindran, Soumya; Wirthlin, Louisa; Eyre, David R.; Fernandes, Russell J.

    2013-01-01

    Until now, no biological tools have been available to determine if a cross-linked collagen fibrillar network derived entirely from type IIA procollagen isoforms, can form in the extracellular matrix (ECM) of cartilage. Recently, homozygous knock-in transgenic mice (Col2a1+ex2, ki/ki) were generated that exclusively express the IIA procollagen isoform during post-natal development while type IIB procollagen, normally present in the ECM of wild type mice, is absent. The difference between these Col2a1 isoforms is the inclusion (IIA) or exclusion (IIB) of exon 2 that is alternatively spliced in a developmentally regulated manner. Specifically, chondroprogenitor cells synthesize predominantly IIA mRNA isoforms while differentiated chondrocytes produce mainly IIB mRNA isoforms. Recent characterization of the Col2a1+ex2 mice has surprisingly shown that disruption of alternative splicing does not affect overt cartilage formation. In the present study, biochemical analyses showed that type IIA collagen extracted from ki/ki mouse rib cartilage can form homopolymers that are stabilized predominantly by hydroxylysyl pyridinoline (HP) cross-links at levels that differed from wild type rib cartilage. The findings indicate that mature type II collagen derived exclusively from type IIA procollagen molecules can form hetero-fibrils with type XI collagen and contribute to cartilage structure and function. Heteropolymers with type XI collagen also formed. Electron microscopy revealed mainly thin type IIA collagen fibrils in ki/ki mouse rib cartilage. Immunoprecipitation and mass spectrometry of purified type XI collagen revealed a heterotrimeric molecular composition of α1(XI)α2(XI)α1(IIA) chains where the α1(IIA) chain is the IIA form of the α3(XI) chain. Since the N-propeptide of type XI collagen regulates type II collagen fibril diameter in cartilage, the retention of the exon 2-encoded IIA globular domain would structurally alter the N-propeptide of type XI collagen. This

  6. Expression of abnormal von Willebrand factor by endothelial cells from a patient with type IIA von Willebrand disease.

    PubMed Central

    Levene, R B; Booyse, F M; Chediak, J; Zimmerman, T S; Livingston, D M; Lynch, D C

    1987-01-01

    Studies were conducted to characterize the biosynthesis of von Willebrand factor (vWf) by cultured endothelial cells (EC) derived from the umbilical vein of a patient with type IIA von Willebrand disease. The patient's EC, compared with those from normal individuals, produced vWf that had decreased amounts of large multimers and an increase in rapidly migrating satellite species, features characteristic of plasma vWf from patients with type IIA von Willebrand disease. The type IIA EC did produce a full spectrum of vWf multimers in both cell lysates and postculture medium, although the relative amounts of the largest species were decreased. The large multimers were degraded in conjunction with the appearance of rapidly migrating satellites that contained approximately equal to 170-kDa proteolytic fragments, suggesting that this patient's functional defect is due to abnormal proteolysis and not to a primary failure of vWf subunit oligomerization. Moreover, the observed degradation appears to result from an abnormal vWf molecule and not elevated protease levels. These results suggest that this patient's von Willebrand disease phenotype is caused by increased proteolytic sensitivity of his vWf protein. Images PMID:3306682

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

    USDA-ARS?s Scientific Manuscript database

    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...

  8. 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.

  9. Different patterns of postprandial lipoprotein metabolism in normal, type IIa, type III, and type IV hyperlipoproteinemic individuals. Effects of treatment with cholestyramine and gemfibrozil.

    PubMed Central

    Weintraub, M S; Eisenberg, S; Breslow, J L

    1987-01-01

    To study exogenous fat metabolism, we used the vitamin A-fat loading test, which specifically labels intestinally derived lipoproteins with retinyl palmitate (RP). Postprandial RP concentrations were followed in total plasma, and chylomicron (Sf greater than 1,000) and nonchylomicron (Sf less than 1,000) fractions. In normal subjects postprandial lipoproteins were present for more than 14 h, and chylomicron levels correlated inversely with lipoprotein lipase activity and fasting high density lipoprotein (HDL) cholesterol levels and nonchylomicron levels correlated inversely with hepatic triglyceride lipase activity. The main abnormality in type IV patients was a 5.6-fold increase in the chylomicron fraction, whereas in type III patients it was a 6.4-fold increase in nonchylomicrons. Type IIa patients had abnormally low chylomicron fractions. In type IV patients gemfibrozil decreased, whereas in type IIa patients cholestyramine increased the chylomicron fraction 66 and 88%, respectively. This study demonstrates an unexpectedly large magnitude and long duration of postprandial lipemia in normal subjects and patients. These particles are potentially atherogenic, and their role in human atherosclerosis warrants further study. PMID:3470306

  10. Hearing loss in the RBF/DnJ mouse, a proposed animal model of Usher syndrome type IIa.

    PubMed

    Pieke-Dahl, S; Ohlemiller, K K; McGee, J; Walsh, E J; Kimberling, W J

    1997-10-01

    The Usher syndromes (US) are a group of inherited disorders that feature autosomal recessive neurosensory hearing loss or deafness with retinitis pigmentosa (RP). Moderate to severe non-progressive high frequency hearing loss with RP and normal vestibular function describes Usher syndrome type IIa, which has been localized to 1q41. Severe retinal degeneration in the inbred mouse strain RBF/DnJ is caused by rd3, a recessive gene located on mouse chromosome 1 distal to akp1 in a region which is orthologous to human 1q32-q42. We evaluated rd3 as a candidate for orthology with USH2A by first reducing and refining the relatively broad region in which rd3 is thought to reside. DNA of offspring from an RBF/DnJ x MOLF/Ei backcross was genotyped with PCR markers closely flanking the predicted location of rd3. Our haplotype analysis re-positioned rd3 to a 3.6 cM region between markers D1Mit273 (cen) and D1Mit209 (tel), consistent with the expected position of an USH2A murine orthologue. Consequently, rd3 is a positional candidate for Usher type IIa. Next we assessed the rd3/rd3 audiological phenotype to see how closely it paralleled that of Usher IIa. Audiological evaluation of mice at various ages revealed evidence of high frequency progressive hearing loss, previously unreported in the RBF/DnJ strain. However, this newly discovered hearing deficit was observed to be inherited independently of rd3, establishing that a completely different gene is responsible.

  11. Behavior of crystal defects in synthetic type-IIa single-crystalline diamond at high temperatures under normal pressure

    NASA Astrophysics Data System (ADS)

    Tatsumi, Natsuo; Tamasaku, Kenji; Ito, Toshimichi; Sumiya, Hitoshi

    2017-01-01

    The behavior of dislocation lines (DLs) and stacking faults (SFs) in synthetic type-IIa single-crystalline diamond at high temperatures under normal pressure has been investigated. After annealing the diamond at 1500 °C for 60 min in pure N2 atmosphere, straight DLs were bent to converge to fewer curved dislocation bundles, so that some of the stacking faults were extinct while new DLs appeared at the edges of the removed SFs. These results indicate that SFs in the diamond examined belong to the Shockley type, and that the Shockley partials changed to a perfect dislocation. From this result, the following generation mechanism has been proposed for SFs in diamond. On one hand, because [112] dislocations in the (111) growth sector are contained in the slip plane labelled as (1 ̅ 1 ̅ 1), one perfect dislocation tends to be split into two Shockley partials and a SF when an appropriate stress is applied. On the other hand, the angle between the {111} slip plane and the direction of bundled dislocations in the (001) growth sector is as high as 54.7°, so that a perfect dislocation can hardly slip into partial dislocations. Thus, SFs exist only in the (111) growth sector of type IIa diamond.

  12. Influence of fast and slow alkali myosin light chain isoforms on the kinetics of stretch-induced force transients of fast-twitch type IIA fibres of rat.

    PubMed

    Andruchov, Oleg; Galler, Stefan

    2008-03-01

    This study contributes to understand the physiological role of slow myosin light chain isoforms in fast-twitch type IIA fibres of skeletal muscle. These isoforms are often attached to the myosin necks of rat type IIA fibres, whereby the slow alkali myosin light chain isoform MLC1s is much more frequent and abundant than the slow regulatory myosin light chain isoform MLC2s. In the present study, single-skinned rat type IIA fibres were maximally Ca(2+) activated and subjected to stepwise stretches for causing a perturbation of myosin head pulling cycles. From the time course of the resulting force transients, myosin head kinetics was deduced. Fibres containing MLC1s exhibited slower kinetics independently of the presence or absence of MLC2s. At the maximal MLC1s concentration of about 75%, the slowing was about 40%. The slowing effect of MLC1s is possibly due to differences in the myosin heavy chain binding sites of the fast and slow alkali MLC isoforms, which changes the rigidity of the myosin neck. Compared with the impact of myosin heavy chain isoforms in various fast-twitch fibre types, the influence of MLC1s on myosin head kinetics of type IIA fibres is much smaller. In conclusion, the physiological role of fast and slow MLC isoforms in type IIA fibres is a fine-tuning of the myosin head kinetics.

  13. Comparison of tension band wiring and precontoured locking compression plate fixation in Mayo type IIA olecranon fractures.

    PubMed

    Schliemann, Benedikt; Raschke, Michael J; Groene, Philipp; Weimann, André; Wähnert, Dirk; Lenschow, Simon; Kösters, Clemens

    2014-03-01

    Aim of the present study was to compare the clinical and radiographic outcome of tension band wiring and precontoured locking compression plate fixation in patients treated surgically for an isolated olecranon fractures type IIA according to the Mayo classification. Of 26 patients presenting with an isolated Mayo type IIA olecranon fracture, 13 underwent fixation with a precontoured locking compression plate (group A), 13 patients were treated with tension band wiring (group B). At a mean follow-up of 43 months, patients were clinically and radiographically re-examined using the DASH score, the Mayo Elbow Performance score (MEPS) and anteroposterior and lateral radiographs. The mean DASH score was 14 points in group A and 12.5 points in group B. Regarding the MEPS, 92% of the patients in group A achieved a good to excellent results in comparison to 77% in group B. No significant differences between the two groups could be detected regarding the clinical and radiographic outcome. Implant-related irritations requiring hardware removal occurred more frequently in group B (12 vs. 7). Procedure and implant related costs were significantly higher in group A. Tension band wiring is still a preferable surgical method to treat simple isolated olecranon fractures. The patient must be informed that in all likelihood implant removal will be required once the fracture has healed. Fixation with precontoured locking compression plates does not provide better functional and radiographic outcome but is more expensive than tension band wiring.

  14. The Elusive Third Subunit IIa of the Bacterial B-Type Oxidases: The Enzyme from the Hyperthermophile Aquifex aeolicus

    PubMed Central

    Prunetti, Laurence; Brugna, Myriam; Lebrun, Régine; Giudici-Orticoni, Marie-Thérèse; Guiral, Marianne

    2011-01-01

    The reduction of molecular oxygen to water is catalyzed by complicated membrane-bound metallo-enzymes containing variable numbers of subunits, called cytochrome c oxidases or quinol oxidases. We previously described the cytochrome c oxidase II from the hyperthermophilic bacterium Aquifex aeolicus as a ba3-type two-subunit (subunits I and II) enzyme and showed that it is included in a supercomplex involved in the sulfide-oxygen respiration pathway. It belongs to the B-family of the heme-copper oxidases, enzymes that are far less studied than the ones from family A. Here, we describe the presence in this enzyme of an additional transmembrane helix “subunit IIa”, which is composed of 41 amino acid residues with a measured molecular mass of 5105 Da. Moreover, we show that subunit II, as expected, is in fact longer than the originally annotated protein (from the genome) and contains a transmembrane domain. Using Aquifex aeolicus genomic sequence analyses, N-terminal sequencing, peptide mass fingerprinting and mass spectrometry analysis on entire subunits, we conclude that the B-type enzyme from this bacterium is a three-subunit complex. It is composed of subunit I (encoded by coxA2) of 59000 Da, subunit II (encoded by coxB2) of 16700 Da and subunit IIa which contain 12, 1 and 1 transmembrane helices respectively. A structural model indicates that the structural organization of the complex strongly resembles that of the ba3 cytochrome c oxidase from the bacterium Thermus thermophilus, the IIa helical subunit being structurally the lacking N-terminal transmembrane helix of subunit II present in the A-type oxidases. Analysis of the genomic context of genes encoding oxidases indicates that this third subunit is present in many of the bacterial oxidases from B-family, enzymes that have been described as two-subunit complexes. PMID:21738733

  15. 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.

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

    PubMed

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

    2008-10-01

    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.

  17. One-point functions of non-SUSY operators at arbitrary genus in a matrix model for type IIA superstrings

    NASA Astrophysics Data System (ADS)

    Kuroki, Tsunehide; Sugino, Fumihiko

    2017-06-01

    In the previous paper, the authors pointed out correspondence between a supersymmetric double-well matrix model and two-dimensional type IIA superstring theory on a Ramond-Ramond background from the viewpoint of symmetry and spectrum. This was confirmed by agreement between planar correlation functions in the matrix model and tree-level amplitudes in the superstring theory. In order to investigate the correspondence further, in this paper we compute correlation functions to all order of genus expansion in the double scaling limit of the matrix model. One-point functions of operators protected by supersymmetry terminate at some finite order, whereas those of unprotected operators yield non-Borel summable series. The behavior of the latter is characteristic in string perturbation series, providing further evidence that the matrix model describes a string theory. Moreover, instanton corrections to the planar one-point functions are also computed, and universal logarithmic scaling behavior is found for non-supersymmetric operators.

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

    PubMed

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

    2015-08-07

    We describe three analytic classes of infinitely many AdS(d) supersymmetric solutions of massive IIA supergravity, for d=7,5,4. The three classes are related by simple universal maps. For example, the AdS(7)×M(3) solutions (where M(3) is topologically S(3)) are mapped to AdS(5)×Σ(2)×M(3)', where Σ(2) is a Riemann surface of genus g≥2 and the metric on M(3)' is obtained by distorting M(3) in a certain way. The solutions can have localized D6 or O6 sources, as well as an arbitrary number of D8-branes. The AdS(7) 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 AdS(4) solutions have numerical "attractor" generalizations that might be useful for flux compactification purposes.

  19. Native defect properties and p -type doping efficiency in group-IIA doped wurtzite AlN

    NASA Astrophysics Data System (ADS)

    Zhang, Yong; Liu, Wen; Niu, Hanben

    2008-01-01

    Using the first-principles full-potential linearized augmented plane-wave (FPLAPW) method based on density functional theory (DFT), we have investigated the native defect properties and p -type doping efficiency in AlN doped with group-IIA elements such as Be, Mg, and Ca. It is shown that nitrogen vacancies (VN) have low formation energies and introduce deep donor levels in wurtzite AlN, while in zinc blende AlN and GaN, these levels are reported to be shallow. The calculated acceptor levels γ(0/-) for substitutional Be (BeAl) , Mg (MgAl) , and Ca (CaAl) are 0.48, 0.58, and 0.95eV , respectively. In p -type AlN, Be interstitials (Bei) , which act as donors, have low formation energies, making them a likely compensating center in the case of acceptor doping. Whereas, when N-rich growth conditions are applied, Bei are energetically not favorable. It is found that p -type doping efficiency of substitutional Be, Mg, and Ca impurities in w-AlN is affected by atomic size and electronegativity of dopants. Among the three dopants, Be may be the best candidate for p -type w-AlN . N-rich growth conditions help us to increase the concentration of BeAl , MgAl , and CaAl .

  20. One-loop corrections to type IIA string theory in AdS 4 × CP 3

    NASA Astrophysics Data System (ADS)

    Bandres, Miguel A.; Lipstein, Arthur E.

    2010-04-01

    We study various methods for computing the one-loop correction to the energy of classical solutions to type IIA string theory in AdS 4 × CP 3. This involves computing the spectrum of fluctuations and then adding up the fluctuation frequencies. We focus on two classical solutions with support in CP 3: a rotating point-particle and a circular spinning string with two angular momenta equal to J. For each of these solutions, we compute the spectrum of fluctuations using two techniques, known as the algebraic curve approach and the world-sheet approach. If we use the same prescription for adding fluctuation frequencies that was used for type IIB string theory in AdS 5 × S 5, then we find that the world-sheet spectrum gives convergent one-loop corrections but the algebraic curve spectrum gives divergent ones. On the other hand, we find a new summation prescription which gives finite results when applied to both the algebraic curve and world-sheet spectra. Naively, this gives three predictions for the one-loop correction to the spinning string energy (one from the algebraic curve and two from the world-sheet), however we find that in the - J limit (where J = J sqrt {2{π^2}λ } ), the J^{ - 2n} terms in all three cases agree. We therefore obtain a unique prediction for the one-loop correction to the spinning string energy.

  1. Molecular characterization of Activin Receptor Type IIA and its expression during gonadal maturation and growth stages in rohu carp.

    PubMed

    Patnaik, Siddhi; Mohanty, Mausumee; Bit, Amrita; Sahoo, Lakshman; Das, Sachidananda; Jayasankar, Pallipuram; Das, Paramananda

    2017-01-01

    Activin receptor type IIA (ActRIIA), a transmembrane serine/threonine kinase receptor is an important regulator of physiological traits, viz., reproduction and body growth in vertebrates including teleosts. However, existing knowledge of its role in regulating fish physiology is limited. To address this, we have cloned and characterized the ActRIIA cDNA of Labeo rohita (rohu), an economically important fish species of the Indian subcontinent. Comparative expression profiling of the receptor gene at various reproductive and growth stages supports to its role in promoting oocyte maturation, spermatogenesis and skeletal muscle development via interaction with multiple ligands of transforming growth factor-β (TGF-β) family. The full-length cDNA of rohu ActRIIA was found to be of 1587bp length encoding 528 amino acids. The three-dimensional structure of the intracellular kinase domain of rohu ActRIIA has also been predicted. Phylogenetic relationship studies showed that the gene is evolutionarily conserved across the vertebrate lineage implicating that the functioning of the receptor is more or less similar in vertebrates. Taken together, these findings could be an initial step towards the use of ActRIIA as a potential candidate gene marker for understanding the complex regulatory mechanism of fish reproduction and growth.

  2. Six1 homeoprotein drives myofiber type IIA specialization in soleus muscle.

    PubMed

    Sakakibara, Iori; Wurmser, Maud; Dos Santos, Matthieu; Santolini, Marc; Ducommun, Serge; Davaze, Romain; Guernec, Anthony; Sakamoto, Kei; Maire, Pascal

    2016-01-01

    Adult skeletal muscles are composed of slow and fast myofiber subtypes which each express selective genes required for their specific contractile and metabolic activity. Six homeoproteins are transcription factors regulating muscle cell fate through activation of myogenic regulatory factors and driving fast-type gene expression during embryogenesis. We show here that Six1 protein accumulates more robustly in the nuclei of adult fast-type muscles than in adult slow-type muscles, this specific enrichment takes place during perinatal growth. Deletion of Six1 in soleus impaired fast-type myofiber specialization during perinatal development, resulting in a slow phenotype and a complete lack of Myosin heavy chain 2A (MyHCIIA) expression. Global transcriptomic analysis of wild-type and Six1 mutant myofibers identified the gene networks controlled by Six1 in adult soleus muscle. This analysis showed that Six1 is required for the expression of numerous genes encoding fast-type sarcomeric proteins, glycolytic enzymes and controlling intracellular calcium homeostasis. Parvalbumin, a key player of calcium buffering, in particular, is a direct target of Six1 in the adult myofiber. This analysis revealed that Six1 controls distinct aspects of adult muscle physiology in vivo, and acts as a main determinant of fast-fiber type acquisition and maintenance.

  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.

  4. Genomic Structure and Identification of Novel Mutations in Usherin, the Gene Responsible for Usher Syndrome Type IIa

    PubMed Central

    Weston, M. D.; Eudy, J. D.; Fujita, S.; Yao, S.-F.; Usami, S.; Cremers, C.; Greenburg, J.; Ramesar, R.; Martini, A.; Moller, C.; Smith, R. J.; Sumegi, J.; Kimberling, William J.

    2000-01-01

    Usher syndrome type IIa (USHIIa) is an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa. This disorder maps to human chromosome 1q41. Recently, mutations in USHIIa patients were identified in a novel gene isolated from this chromosomal region. The USH2A gene encodes a protein with a predicted molecular weight of 171.5 kD and possesses laminin epidermal growth factor as well as fibronectin type III domains. These domains are observed in other protein components of the basal lamina and extracellular matrixes; they may also be observed in cell-adhesion molecules. The intron/exon organization of the gene whose protein we name “Usherin” was determined by direct sequencing of PCR products and cloned genomic DNA with cDNA-specific primers. The gene is encoded by 21 exons and spans a minimum of 105 kb. A mutation search of 57 independent USHIIa probands was performed with a combination of direct sequencing and heteroduplex analysis of PCR-amplified exons. Fifteen new mutations were found. Of 114 independent USH2A alleles, 58 harbored probable pathologic mutations. Ten cases of USHIIa were true homozygotes and 10 were compound heterozygotes; 18 heterozygotes with only one identifiable mutation were observed. Sixty-five percent (38/58) of cases had at least one mutation, and 51% (58/114) of the total number of possible mutations were identified. The allele 2299delG (previously reported as 2314delG) was the most frequent mutant allele observed (16%; 31/192). Three new missense mutations (C319Y, N346H, and C419F) were discovered; all were restricted to the previously unreported laminin domain VI region of Usherin. The possible significance of this domain, known to be necessary for laminin network assembly, is discussed in the context of domain VI mutations from other proteins. PMID:10729113

  5. 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.

  6. Hyperactivity in 103P/Hartley 2: Chunks from the sub-surface in Type IIa jet regions

    NASA Astrophysics Data System (ADS)

    Belton, Michael J. S.

    2017-03-01

    We analyze the observed radial distribution of column densities of water-ice particulates embedded in the primary jet region (J1) of 103P's inner coma at altitudes between 439 and 1967 m (Protopapa et al., 2014, Icarus 238, 191-204) and determine the speed and acceleration of particles and their mass-flow within the filaments of the jet. This is done by applying a CO2 driven (Type IIa) jet model proposed by Belton (2010, Icarus 210, 881-897). The model utilizes water-ice particles dislodged in the source regions of the jet filaments and accelerated by CO2 to explain the radial distribution of water-ice particulates. We provide an explanation for the remarkably different radial distribution of refractory dust particles by hypothesizing that the majority of the dust originates directly from the nucleus surface in inter-filament regions of the jet complex and is accelerated by H2O. Our model provides a mass-flow of water from the J1 jet complex that is ∼40 times greater than the constant speed sublimation model discussed by Protopapa et al. but is still too small to explain the hyperactivity of the comet. Speeds in the flow are increased by a factor up to ∼20 over those found by Protopapa et al. To account for the hyperactivity, most of the mass dislodged in the filament source regions must be in weakly accelerated large chunks that achieve only low speeds en route to the region of observation. These chunks soon leave the filamentary jet structure due to the rotation of the nucleus and do not contribute to the column densities observed at higher altitudes in the jet filaments. Employing the results of Kelley et al. (2015. Icarus 262, 187-189)) on total cross-section and mass-flow in the coma we find that large chunks with the same bulk properties as the nucleus can increase the active fraction of the comet by two or three times. With the exception that the chunks do not need to be "nearly pure water ice", these results support the hypothesis that hyperactivity in

  7. Clinical characteristics and epilepsy outcomes following surgery caused by focal cortical dysplasia (type IIa) in 110 adult epileptic patients.

    PubMed

    Sun, Yuqiang; Wang, Xiaofeng; Che, Ningwei; Qin, Huamin; Liu, Shuping; Wu, Xinling; Wei, Minghai; Cheng, Huakun; Yin, Jian

    2017-05-01

    The aim of the present study was to investigate the effects of surgical intervention of focal cortical dysplasia (FCD) IIa on the outcome of epilepsy, and to evaluate the prognostic factors of seizure freedom. Patient data from epilepsy surgeries were retrospectively reviewed at the Second Affiliated Hospital of Dalian Medical University between 2007 and 2015. A total of 110 patients with a definite pathological diagnosis of FCD IIa were included. Moreover, the clinical characteristics, seizure outcome and quality of life in adults with FCD IIa were evaluated. The Engel seizure outcome achievements were class I in 72, class II in 20, class III in 11 and class IV in 7 patients. In addition, the Engel seizure outcome was relevant with the resection range of the lesions (P=0.028). The assessments of electrocorticography (ECoG) patterns and magnetic resonance imaging (MRI) are relevant to determining the extent of the resection, which may influence the surgery outcome (P=0.001 and P=0.023). Using multivariate regression analyses, the extent of resection, seizure frequency, preoperative ECoG and location of resection were the most important risk factors for seizure recurrence. The results of quality of life in epilepsy-10 scoring revealed that the quality of life improved significantly following surgery (P<0.01). Moreover, surgical intervention, EcoG, MRI positioning and complete resection helped to have improved seizure control, relief of anxiety and quality of life. All these observations strongly recommend an early consideration of epilepsy surgery in FCD IIa patients.

  8. From superstrings to M theory

    SciTech Connect

    Schwarz, John H.

    1999-07-01

    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. {copyright} {ital 1999 American Institute of Physics.}

  9. The construction of a yeast artificial chromosome (YAC) contig in the vicinity of the Usher syndrome type IIa (USH2A) gene in 1q41

    SciTech Connect

    Sumegi, Janos; Wang, Ji-Yi; Zhen, Dong-Kai

    1996-07-01

    The gene for Usher syndrome type II (USH2A), and autosomal recessive syndromic deafness, has been mapped to a region of 1q41 flanked proximally by D1S217 and distally by D1S439. Using sequence-tagged sites (STSs) within the region, a total of 21 yeast artificial chromosome (YAC) clones were isolated and ordered into a single contig that spans approximately 11.0 Mb. The order of microsatellite and STS markers in this region was established as D1S505-D1S425-DXS217-D1S556-D1S237-D1S474-EB1-KB6-AFM144XF2-KB1-KB4-D1S229-D1S490-D1S227-TGF{beta}2-D1S439. Analysis of newly positioned polymorphic markers in recombinant individuals in two Usher syndrome type IIa families has enabled us to identify DXS474 and AFM144XF2 as two flanking markers for the Usher type IIa locus. The physical distance between the two markers is 1.0 Mb. This region is covered by eight YACs from the CEPH library: 945f7, 867g9, 762a6, 919h3, 794b8, 785h4, 848b9, and 841g2. A long range physical map of the Usher type IIa critical region, using MluI, BssHII, NotI, EagI, and SacII, has been developed. 41 refs., 5 figs.

  10. Solution structure of carnobacteriocin B2 and implications for structure-activity relationships among type IIa bacteriocins from lactic acid bacteria.

    PubMed

    Wang, Y; Henz, M E; Gallagher, N L; Chai, S; Gibbs, A C; Yan, L Z; Stiles, M E; Wishart, D S; Vederas, J C

    1999-11-23

    Carnobacteriocin B2 (CbnB2), a type IIa bacteriocin, is a 48 residue antimicrobial peptide from the lactic acid bacterium Carnobacterium pisicola LV17B. Type IIa bacteriocins have a conserved YGNGVXC sequence near the N-terminus and usually contain a disulfide bridge. CbnB2 seemed to be unique in that its two cysteines (Cys9 and Cys14) could be isolated as free thiols [Quadri et al. (1994) J. Biol. Chem. 26, 12204-12211]. To establish the structural consequences of the presence or absence of a disulfide bridge and to investigate if the YGNGVXC sequence is a receptor-binding motif [Fleury et al. (1996) J. Biol. Chem. 271, 14421-14429], the three-dimensional solution structure of CbnB2 was determined by two-dimensional (1)H nuclear magnetic resonance (NMR) techniques. Mass spectroscopic and thiol modification experiments on CbnB2 and on model peptides, in conjunction with activity measurements, were used to verify the redox status of CbnB2. The results show that CbnB2 readily forms a disulfide bond and that this peptide has full antimicrobial activity. NMR results indicate that CbnB2 in trifluoroethanol (TFE) has a well-defined central helical structure (residues 18-39) but a disordered N terminus. Comparison of the CbnB2 structure with the refined solution structure of leucocin A (LeuA), another type IIa bacteriocin, indicates that the central helical structure is conserved between the two peptides despite differences in sequence but that the N-terminal structure (a proposed receptor binding site) is not. This is unexpected because LeuA and CbnB2 exhibit >66% sequence identity in the first 24 residues. This suggests that the N-terminus, which had been proposed [Fleury et al. (1996) J. Biol. Chem. 271, 14421-14429] to be a receptor binding site of type IIa bacteriocins, may not be directly involved and that recognition of the amphiphilic helical portion is the critical feature.

  11. BPS black hole horizons from massive IIA

    NASA Astrophysics Data System (ADS)

    Guarino, Adolfo

    2017-08-01

    The maximal four-dimensional supergravity with a dyonic ISO(7) gauging that arises from the reduction of massive IIA on a six-sphere has recently been shown to accommodate static BPS black holes with hyperbolic horizons. When restricted to the N=2 subsector that retains one vector multiplet and the universal hypermultiplet, the attractor mechanism was shown to fix both the vector charges and the scalar fields at the horizon to a unique configuration in terms of the gauging parameters. In order to assess the (non-)uniqueness of BPS black hole horizons from massive IIA, we extend the study of the attractor mechanism to other N=2 subsectors including additional matter multiplets. We note that, while extending the hypermultiplet sector does not modify the set of solutions to the attractor equations, the inclusion of additional vector multiplets results in new hyperbolic/spherical horizon configurations containing free parameters. The model with three vector multiplets and the universal hypermultiplet, which is the massive IIA analogue of the STU-model from M-theory, may play a relevant role in massive IIA holography.

  12. Properties of the Mutant Ser-460-Cys Implicate This Site in a Functionally Important Region of the Type Iia Na+/Pi Cotransporter Protein

    PubMed Central

    Lambert, Georg; Forster, Ian C.; Stange, Gerti; Biber, Jürg; Murer, Heini

    1999-01-01

    The substituted cysteine accessibility approach, combined with chemical modification using membrane-impermeant alkylating reagents, was used to identify functionally important structural elements of the rat type IIa Na+/Pi cotransporter protein. Single point mutants with different amino acids replaced by cysteines were made and the constructs expressed in Xenopus oocytes were tested for function by electrophysiology. Of the 15 mutants with substituted cysteines located at or near predicted membrane-spanning domains and associated linker regions, 6 displayed measurable transport function comparable to wild-type (WT) protein. Transport function of oocytes expressing WT protein was unchanged after exposure to the alkylating reagent 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA, 100 μM), which indicated that native cysteines were inaccessible. However, for one of the mutants (S460C) that showed kinetic properties comparable with the WT, alkylation led to a complete suppression of Pi transport. Alkylation in 100 mM Na+ by either cationic {[2-(trimethylammonium)ethyl] methanethiosulfonate bromide (MTSET), MTSEA} or anionic [sodium(2-sulfonatoethyl)methanethiosulfonate (MTSES)] reagents suppressed the Pi response equally well, whereas exposure to methanethiosulfonate (MTS) reagents in 0 mM Na+ resulted in protection from the MTS effect at depolarized potentials. This indicated that accessibility to site 460 was dependent on the conformational state of the empty carrier. The slippage current remained after alkylation. Moreover, after alkylation, phosphonoformic acid and saturating Pi suppressed the slippage current equally, which indicated that Pi binding could occur without cotransport. Pre–steady state relaxations were partially suppressed and their kinetics were significantly faster after alkylation; nevertheless, the remaining charge movement was Na+ dependent, consistent with an intact slippage pathway. Based on an alternating access model for type IIa Na

  13. 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.

  14. TLR2-dependent modulation of dendritic cells by LT-IIa-B5, a novel mucosal adjuvant derived from a type II heat-labile enterotoxin

    PubMed Central

    Lee, Chang Hoon; Masso-Welch, Patricia; Hajishengallis, George; Connell, Terry D.

    2011-01-01

    A host of human pathogens invades the body at mucosal surfaces. Yet, strong, protective mucosal immune responses directed against those pathogens routinely cannot be induced without the use of adjuvants. Although the strongest mucosal adjuvants are members of the family of HLTs, the inherent toxicities of HLT holotoxins preclude their clinical use. Herein, it is shown that LT-IIa-B5 enhances mucosal immune responses by modulating activities of DCs. i.n. immunization of mice with OVA in the presence of LT-IIa-B5 recruited DCs to the NALT and significantly increased uptake of OVA by those DCs. Furthermore, LT-IIa-B5 increased expression of CCR7 by DCs, which mediated enhanced migration of the cells from the NALT to the draining CLNs. LT-IIa-B5 also enhanced maturation of DCs, as revealed by increased surface expression of CD40, CD80, and CD86. Ag-specific CD4+ T cell proliferation was augmented in the CLNs of mice that had received i.n. LT-IIa-B5. Finally, when used as an i.n. adjuvant, LT-IIa-B5 dramatically increased the levels of OVA-specific salivary IgA and OVA-specific serum IgG. Strikingly, each of the activities induced by LT-IIa-B5 was strictly TLR2-dependent. The data strongly suggest that the immunomodulatory properties of LT-IIa-B5 depend on the productive modulation of mucosal DCs. Notably, this is the first report for any HLT to demonstrate in vivo the elicitation of strong, TLR2-dependent modulatory effects on DCs with respect to adjuvanticity. PMID:21791597

  15. 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.

  16. Effects of phosphonoformic acid and renagel on renal type IIa sodium-dependent phosphate cotransporter mRNA expression in hyperphosphatemia rats.

    PubMed

    Zeng, Ming; Wang, Xiaoyun; Wang, Xiaobing; Zhao, Xiufen

    2012-01-01

    To investigate the effects of phosphonoformic acid (PFA) and sevelamer hydrochloride (Renagel) on renal type IIa sodium-dependent phosphate cotransporter (NaPi-2) mRNA expression in hyperphosphatemia rats. Thirty rats were randomly divided into five groups based on the diet for 2 weeks after 5/6 nephrectomy (Nx): Nx + high-phosphate (HP; 1.2% P) diet; Nx + low-phosphate (LP; 0.2% P) diet; HP + PFA (injected with 0.15 g/kg PFA daily); HP + Saline (injected with the same amount of saline daily); and HP + Renagel (2%) group. Another 12 rats were sham operated and divided into Sham + HP and Sham + LP groups. Serum ionized calcium, phosphorus (P), and intact parathyroid hormone (iPTH) were measured on days 2, 7, and 14. Serum 1,25(OH)2D3 was measured on day 14 and NaPi-2 mRNA levels were assayed by RT-PCR. PFA decreased iPTH level but had no effect on NaPi-2 mRNA expression. Renagel decreased serum P and iPTH levels, but upregulated renal NaPi-2 mRNA expression. Both PFA and Renagel are effective drugs to decrease iPTH level and they might be potential candidates for treatment of clinical secondary hyperparathyroidism. Renagel can also decrease serum P and upregulate renal NaPi-2 mRNA expression.

  17. Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent phosphate co-transporter (Npt2a) gene.

    PubMed

    Ishiguro, Mariko; Yamamoto, Hironori; Masuda, Masashi; Kozai, Mina; Takei, Yuichiro; Tanaka, Sarasa; Sato, Tadatoshi; Segawa, Hiroko; Taketani, Yutaka; Arai, Hidekazu; Miyamoto, Ken-Ichi; Takeda, Eiji

    2010-03-15

    The type IIa renal sodium-dependent phosphate (Na/Pi) co-transporter Npt2a is implicated in the control of serum phosphate levels. It has been demonstrated previously that renal Npt2a protein and its mRNA expression are both up-regulated by the thyroid hormone T3 (3,3',5-tri-iodothyronine) in rats. However, it has never been established whether the induction was mediated by a direct effect of thyroid hormones on the Npt2a promoter. To address the role of Npt2a in T3-dependent regulation of phosphate homoeostasis and to identify the molecular mechanisms by which thyroid hormones modulate Npt2a gene expression, mice were rendered pharmacologically hypo- and hyper-thyroid. Hypothyroid mice showed low levels of serum phosphate and a marked decrease in renal Npt2a protein abundance. Importantly, we also showed that Npt2a-deficient mice had impaired serum phosphate responsiveness to T3 compared with wild-type mice. Promoter analysis with a luciferase assay revealed that the transcriptional activity of a reporter gene containing the Npt2a promoter and intron 1 was dependent upon TRs (thyroid hormone receptors) and specifically increased by T3 in renal cells. Deletion analysis and EMSAs (electrophoretic mobility-shift assays) determined that there were unique TREs (thyroid-hormone-responsive elements) within intron 1 of the Npt2a gene. These results suggest that Npt2a plays a critical role as a T3-target gene, to control phosphate homoeostasis, and that T3 transcriptionally activates the Npt2a gene via TRs in a renal cell-specific manner.

  18. Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (IIe865 to Thr).

    PubMed Central

    Iannuzzi, M C; Hidaka, N; Boehnke, M; Bruck, M E; Hanna, W T; Collins, F S; Ginsburg, D

    1991-01-01

    Reports of families with members affected with both von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia (HHT) suggest a possible relationship between these two disorders. vWD, the most common inherited bleeding disorder in humans, is due to either a quantitative or qualitative defect in von Willebrand factor (vWF). The gene for vWF has been cloned and mapped to chromosome 12 (12p12----12pter). HHT, an uncommon inherited bleeding disorder, is characterized by malformed, dilated, fragile blood vessels. The chromosomal location of the gene for HHT is unknown. We studied two families by RFLP analysis to determine whether there is a molecular basis for the association of vWD and HHT. Family A is affected with both type IIA vWD and HHT; family B is affected with HHT alone. Linkage of HHT to the vWF gene was not detected, and vWF was ruled out as a candidate gene for HHT. The vWF gene was found to be tightly linked to type IIA vWD in family A (lod score 3.61 at recombination fraction .00). By PCR and DNA sequence analysis of vWF exon 28, a single T----C transition resulting in the substitution of Thr for Ile865 was identified. This substitution is located immediately adjacent to two previously identified type IIA vWD mutations. Images Figure 3 Figure 4 PMID:1673047

  19. Improvement of the Pharmacokinetics and In Vivo Antibacterial Efficacy of a Novel Type IIa Topoisomerase Inhibitor by Formulation in Liposomes

    PubMed Central

    Newman, Joseph; Goteti, Kosalaram; Beaudoin, Marie-Eve; Harrison, Rane; Hopkins, Sussie; Agrawal, Nikunj; Rivin, Olga

    2013-01-01

    Several useful properties of liposome-based formulations of various existing antibacterial drugs have been reported. These properties include lower MICs, improved pharmacokinetics, lower toxicity, selective distribution to infected tissues, and enhanced in vivo efficacy. Here we report in vivo studies of a liposomal formulation of a member of a novel class of antibacterial type II topoisomerase inhibitors, others of which have progressed to early phases of clinical trials. The free (i.e., nonliposomal) compound has broad-spectrum MICs but suboptimal pharmacokinetics in rats and mice, characterized by a high volume of distribution and rapid clearance. The liposomal formulation of the compound had essentially unchanged MICs but greatly reduced volume of distribution and clearance in rats and mice. In an in vivo mouse model of Staphylococcus aureus infection of one thigh, the liposomal compound localized preferentially to the infected thigh, whereas the free compound showed no preference for the infected versus the uninfected thigh. Most importantly, the liposomal compound had enhanced efficacy at clearing the infection compared with the free compound. Delivery of this class of compounds as liposomal formulations may offer clinical advantages compared with free compounds. PMID:23877679

  20. Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach.

    PubMed

    Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

    2016-01-01

    Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r(2)) value of 0.6774, cross-validated correlation coefficient (q(2)) of 0.6157 and co-relation coefficient for external test set (pred_r(2)) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of -10.097 and -9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free

  1. Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

    PubMed Central

    Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

    2017-01-01

    Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free

  2. 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.

  3. 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.

  4. Dynamical symmetry enhancement near massive IIA horizons

    NASA Astrophysics Data System (ADS)

    Gran, U.; Gutowski, J.; Kayani, U.; Papadopoulos, G.

    2015-12-01

    We prove that Killing horizons in massive IIA supergravity preserve an even number of supersymmetries, and that their symmetry algebra contains an {sl}(2,{{R}}) subalgebra, confirming the conjecture of Gran et al (2013 J. High Energy Phys. JHEP11(2013)104). We also prove a new class of Lichnerowicz-type theorems for connections of the spin bundle whose holonomy is contained in a general linear group.

  5. Neutrino mass from M theory SO(10)

    NASA Astrophysics Data System (ADS)

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

    2016-11-01

    We study the origin of neutrino mass from SO(10) arising from M Theory compactified on a G 2-manifold. This is linked to the problem of the breaking of the extra U(1) gauge group, in the SU(5) × U(1) subgroup of SO(10), which we show can achieved via a (generalised) Kolda-Martin mechanism. The resulting neutrino masses arise from a combination of the seesaw mechanism and induced R-parity breaking contributions. The rather complicated neutrino mass matrix is analysed for one neutrino family and it is shown how phenomenologically acceptable neutrino masses can emerge.

  6. 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.

  7. Identification of the mouse and rat orthologs of the gene mutated in Usher syndrome type IIA and the cellular source of USH2A mRNA in retina, a target tissue of the disease.

    PubMed

    Huang, Dali; Eudy, James D; Uzvolgyi, Eva; Davis, Jack R; Talmadge, Catherine B; Pretto, Dalyir; Weston, Michael D; Lehman, Janae E; Zhou, Ming; Seemayer, Thomas A; Ahmad, Iqbal; Kimberling, William J; Sumegi, Janos

    2002-08-01

    Usher syndrome type IIA (MIM: 27601) is an autosomal recessive disorder characterized by moderate to severe congenital deafness and progressive retinitis pigmentosa. We recently identified the human Usher syndrome type IIA gene (USH2A) on chromosome 1q41, which encodes a protein possessing 10 laminin epidermal growth factor and four fibronectin type 3 domains, both commonly observed in extracellular matrix proteins. To gain insight into the pathogenesis of Usher syndrome type IIA, we isolated and characterized the murine (Ush2a) and rat (rat Ush2a) orthologs of human USH2A. We mapped mouse Ush2a by fluorescence in situ hybridization to mouse chromosome 1 in the region syntenic to human chromosome 1q41. Rat Ush2a has been localized by radiation hybrid mapping to rat chromosome 13 between d13rat49 and d13rat76. The mouse and rat genes, similar to human USH2A, are expressed primarily in retina and cochlea. Mouse Ush2a encodes a 161-kDa protein that shows 68% identity and 9% similarity to the human USH2A protein. Rat Ush2a encodes a 167-kDa protein with 64% identity and 10% similarity to the human protein and 81% identity and 5% similarity to the mouse USH2A protein. The predicted amino acid sequence of the mouse and rat proteins, like their human counterpart, contains a leader sequence, an amino-terminal globular domain, 10 laminin epidermal growth factor domains, and four carboxy-terminal fibronectin type III motifs. With in situ hybridization, we compared the cellular expression of the USH2A gene in rat, mouse, and human retinas. USH2A mRNA in the adult rat, mouse, and human is expressed in the cells of the outer nuclear layer of the retina, one of the target tissues of the disease. In the developing rat retina, Ush2a mRNA expression appears in the neuroepithelium at embryonic day 17.

  8. Myosin IIA dependent retrograde flow drives 3D cell migration.

    PubMed

    Shih, Wenting; Yamada, Soichiro

    2010-04-21

    Epithelial cell migration is an essential part of embryogenesis and tissue regeneration, yet their migration is least understood. Using our three-dimensional (3D) motility analysis, migrating epithelial cells formed an atypical polarized cell shape with the nucleus leading the cell front and a contractile cell rear. Migrating epithelial cells exerted traction forces to deform both the anterior and posterior extracellular matrix toward the cell body. The cell leading edge exhibited a myosin II-dependent retrograde flow with the magnitude and direction consistent with surrounding network deformation. Interestingly, on a two-dimensional substrate, myosin IIA-deficient cells migrated faster than wild-type cells, but in a 3D gel, these myosin IIA-deficient cells were unpolarized and immobile. In contrast, the migration rates of myosin IIB-deficient cells were similar to wild-type cells. Therefore, myosin IIA, not myosin IIB, is required for 3D epithelial cell migration.

  9. Membranes for topological M-theory

    NASA Astrophysics Data System (ADS)

    Bao, Ling; Bengtsson, Viktor; Cederwall, Martin; Nilsson, Bengt E. W.

    2006-01-01

    We formulate a theory of topological membranes on manifolds with G2 holonomy. The BRST charges of the theories are the superspace Killing vectors (the generators of global supersymmetry) on the background with reduced holonomy G2⊂Spin(7). In the absence of spinning formulations of supermembranes, the starting point is an N = 2 target space supersymmetric membrane in seven euclidean dimensions. The reduction of the holonomy group implies a twisting of the rotations in the tangent bundle of the branes with ``R-symmetry'' rotations in the normal bundle, in contrast to the ordinary spinning formulation of topological strings, where twisting is performed with internal U(1) currents of the N = (2,2) superconformal algebra. The double dimensional reduction on a circle of the topological membrane gives the strings of the topological A-model (a by-product of this reduction is a Green-Schwarz formulation of topological strings). We conclude that the action is BRST-exact modulo topological terms and fermionic equations of motion. We discuss the rôle of topological membranes in topological M-theory and the relation of our work to recent work by Hitchin and by Dijkgraaf et al.

  10. SO(10) Heterotic M-Theory Vacua

    NASA Astrophysics Data System (ADS)

    Garavuso, Richard S.

    2004-08-01

    This talk adapts the available formalism to study a class of heterotic M-theory vacua with SO(10) grand unification group. Compactification to four dimensions with {N}=1 supersymmetry is achieved on a torus fibered Calabi-Yau 3-fold Z=X/τX with first homotopy group π1(Z)=Z2. Here X is an elliptically fibered Calabi-Yau 3-fold which admits two global sections and τX is a freely acting involution on X. The vacua in this class have net number of three generations of chiral fermions in the observable sector and may contain M5-branes in the bulk space which wrap holomorphic curves in Z. Vacua with nonvanishing and vanishing instanton charges in the observable sector are considered. The latter case corresponds to potentially viable matter Yukawa couplings. Since π1(Z)=Z2, the grand unification group can be broken with Z2 Wilson lines. The motivation is to use the above formalism to extend realistic free-fermionic models to the nonperturbative regime. The correspondence between these models and Z2×Z2 orbifold compactification of the weakly coupled 10-dimensional heterotic string identifies associated Calabi-Yau 3-folds which possess the structure of the above Z and X. A nonperturbative extension of the top quark Yukawa coupling is discussed.

  11. 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.

  12. 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.

  13. 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.

  14. Structure of the S100A4/myosin-IIA complex.

    PubMed

    Ramagopal, Udupi A; Dulyaninova, Natalya G; Varney, Kristen M; Wilder, Paul T; Nallamsetty, Sridevi; Brenowitz, Michael; Weber, David J; Almo, Steven C; Bresnick, Anne R

    2013-11-20

    S100A4, a member of the S100 family of Ca2+-binding proteins, modulates the motility of both non-transformed and cancer cells by regulating the localization and stability of cellular protrusions. Biochemical studies have demonstrated that S100A4 binds to the C-terminal end of the myosin-IIA heavy chain coiled-coil and disassembles myosin-IIA filaments; however, the mechanism by which S100A4 mediates myosin-IIA depolymerization is not well understood. We determined the X-ray crystal structure of the S100A4Δ8C/MIIA(1908-1923) peptide complex, which showed an asymmetric binding mode for the myosin-IIA peptide across the S100A4 dimer interface. This asymmetric binding mode was confirmed in NMR studies using a spin-labeled myosin-IIA peptide. In addition, our NMR data indicate that S100A4Δ8C binds the MIIA(1908-1923) peptide in an orientation very similar to that observed for wild-type S100A4. Studies of complex formation using a longer, dimeric myosin-IIA construct demonstrated that S100A4 binding dissociates the two myosin-IIA polypeptide chains to form a complex composed of one S100A4 dimer and a single myosin-IIA polypeptide chain. This interaction is mediated, in part, by the instability of the region of the myosin-IIA coiled-coil encompassing the S100A4 binding site. The structure of the S100A4/MIIA(1908-1923) peptide complex has revealed the overall architecture of this assembly and the detailed atomic interactions that mediate S100A4 binding to the myosin-IIA heavy chain. These structural studies support the idea that residues 1908-1923 of the myosin-IIA chain heavy represent a core sequence for the S100A4/myosin-IIA complex. In addition, biophysical studies suggest that structural fluctuations within the myosin-IIA coiled-coil may facilitate S100A4 docking onto a single myosin-IIA polypeptide chain.

  15. 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.

  16. 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 Uq(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 Funq (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.

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

    PubMed

    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.

  18. 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

  19. 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.

  20. Real borcherds superalgebras and M-theory

    NASA Astrophysics Data System (ADS)

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

    2003-04-01

    The correspondence between del Pezzo surfaces and field theory models is extended to other real forms, in particular to those compatible with supersymmetry.Specifically, all theories of the Magic triangle that reduce to the pure supergravities in four dimensions correspond to singular real del Pezzo surfaces and the same is true for the Magic square of N=2 SUGRAS. A real del Pezzo surface is the invariant set under an antilinear involution of a complex one. This conjugation induces an involution of the Picard group that preserves the anticanonical class and the intersection form. The known non-split U-duality algebras are embedded into Borcherds superalgebras defined by their Cartan matrix (minus the intersection form) and fixed by the anti-involution. These data may be described by Tits-Satake bicoloured superdiagrams. As in the split case, oxidation results from blowing down disjoint real RP1's of self-intersection -1. The singular del Pezzo surfaces of interest are obtained by degenerating regular surfaces upon contraction of real curves of self-intersection -2. We use the finite classification of real simple singularities to exhibit the relevant normal surfaces. We also give a general construction of more magic triangles like a type I split magic triangle and prove their (approximate) symmetry with respect to their diagonal, this symmetry argument was announced in our previous paper for the split case.

  1. 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.

  2. Exceptional generalised geometry for massive IIA and consistent reductions

    NASA Astrophysics Data System (ADS)

    Cassani, Davide; de Felice, Oscar; Petrini, Michela; Strickland-Constable, Charles; Waldram, Daniel

    2016-08-01

    We develop an exceptional generalised geometry formalism for massive type IIA supergravity. In particular, we construct a deformation of the generalised Lie derivative, which generates the type IIA gauge transformations as modified by the Romans mass. We apply this new framework to consistent Kaluza-Klein reductions preserving maximal supersymmetry. We find a generalised parallelisation of the exceptional tangent bundle on S 6, and from this reproduce the consistent truncation ansatz and embedding tensor leading to dyonically gauged ISO(7) supergravity in four dimensions. We also discuss closely related hyperboloid reductions, yielding a dyonic ISO( p, 7 - p) gauging. Finally, while for vanishing Romans mass we find a generalised parallelisation on S d , d = 4 , 3 , 2, leading to a maximally supersymmetric reduction with gauge group SO( d + 1) (or larger), we provide evidence that an analogous reduction does not exist in the massive theory.

  3. Ligand trap for the Activin Type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease

    PubMed Central

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

    2016-01-01

    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 II A (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

  4. 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.

  5. 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

  6. Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease

    PubMed Central

    Sugatani, Toshifumi; Agapova, Olga A.; Fang, Yifu; Berman, Alycia G.; Wallace, Joseph M.; Malluche, Hartmut H.; Faugere, Marie-Claude; Smith, William; Sung, Victoria; Hruska, Keith A.

    2017-01-01

    Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr−/− high fat-fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr−/− high fat-fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A-enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin-A induced osteoclastogenesis. PMID:27666759

  7. String and M-theory cosmological solutions with Ramond forms

    NASA Astrophysics Data System (ADS)

    Lukas, André; Ovruta, Burt A.; Waldram, Daniel

    1997-02-01

    A general framework for studying a large class of cosmological solutions of the low-energy limit of type II string theory and of M-theory, with non-trivial Ramond form fields excited, is presented. The framework is applicable to space-times decomposable into a set of flat or, more generally, maximally symmetric spatial subspaces, with multiple non-trivial form fields spanning one or more of the subspaces. It is shown that the corresponding low-energy equations of motion are equivalent to those describing a particle moving in a moduli space consisting of the scale factors of the subspaces together with the dilaton. The choice of which form fields are excited controls the potential term in the particle equations. Two classes of exact solutions are given, those corresponding to exciting only a single form and those with multiple forms excited which correspond to Toda theories. Although typically these solutions begin or end in a curvature singularity, there is a subclass with positive spatial curvature which appears to be singularity free. Elements of this class are directly related to certain black p-brane solutions.

  8. Myosin IIA deficient cells migrate efficiently despite reduced traction forces at cell periphery.

    PubMed

    Jorrisch, Melissa H; Shih, Wenting; Yamada, Soichiro

    2013-04-15

    Cell motility is a cornerstone of embryogenesis, tissue remodeling and repair, and cancer cell invasion. It is generally thought that migrating cells grab and exert traction force onto the extracellular matrix in order to pull the cell body forward. While previous studies have shown that myosin II deficient cells migrate efficiently, whether these cells exert traction forces during cell migration in the absence of the major contractile machinery is currently unknown. Using an array of micron-sized pillars as a force sensor and shRNA specific to each myosin II isoform (A and B), we analyzed how myosin IIA and IIB individually regulate cell migration and traction force generation. Myosin IIA and IIB localized preferentially to the leading edge where traction force was greatest, and the trailing edge, respectively. When individual myosin II isoforms were depleted by shRNA, myosin IIA deficient cells lost actin stress fibers and focal adhesions, whereas myosin IIB deficient cells maintained similar actin organization and focal adhesions as wild-type cells. Interestingly, myosin IIA deficient cells migrated faster than wild-type or myosin IIB deficient cells on both a rigid surface and a pillar array, yet myosin IIA deficient cells exerted significantly less traction force at the leading edge than wild-type or myosin IIB deficient cells. These results suggest that, in the absence of myosin IIA mediated force-generating machinery, cells move with minimal traction forces at the cell periphery, thus demonstrating the remarkable ability of cells to adapt and migrate.

  9. (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.

  10. 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.

  11. 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

  12. Class IIa bacteriocins: diversity and new developments.

    PubMed

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

    2012-12-06

    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.

  13. 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.

  14. A ``periodic table'' for supersymmetric M-theory compactifications

    NASA Astrophysics Data System (ADS)

    Doran, Charles F.; Faux, Michael

    2003-07-01

    We develop a systematic method for classifying supersymmetric orbifold compactifications of M-theory. By restricting our attention to Abelian orbifolds with low order, in the special cases where elements do not include coordinate shifts, we construct a "periodic table" of such compactifications, organized according to the orbifolding group (order ⩽12) and dimension (up to 7). An intriguing connection between supersymmetric orbifolds and G2 structures is explored.

  15. Heterotic and M-theory Compactifications for String Phenomenology

    NASA Astrophysics Data System (ADS)

    Anderson, Lara B.

    2008-08-01

    In this thesis, we explore two approaches to string phenomenology. In the first half of the work, we investigate M-theory compactifications on spaces with co-dimension four, orbifold singularities. We construct M-theory on C^2/Z_N by coupling 11-dimensional supergravity to a seven-dimensional Yang-Mills theory located on the orbifold fixed-plane. The resulting action is supersymmetric to leading non-trivial order in the 11-dim Newton constant. We thereby reduce M-theory on a G2 orbifold with C^2/Z_N singularities, explicitly incorporating the additional gauge fields at the singularities. We derive the Kahler potential, gauge-kinetic function and superpotential for the resulting N=1 four-dimensional theory. Blowing-up of the orbifold is described by a Higgs effect and the results are consistent with the corresponding ones obtained for smooth G2 spaces. Further, we consider flux and Wilson lines on singular loci of the G2 space, and discuss the relation to N=4 SYM theory. In the second half, we develop an algorithmic framework for E8 x E8 heterotic compactifications with monad bundles. We begin by considering cyclic Calabi-Yau manifolds where we classify positive monad bundles, prove stability, and compute the complete particle spectrum for all bundles. Next, we generalize the construction to bundles on complete intersection Calabi-Yau manifolds. We show that the class of positive monad bundles, subject to the heterotic anomaly condition, is finite (~7000 models). We compute the particle spectrum for these models and develop new techniques for computing the cohomology of line bundles. There are no anti-generations of particles and the spectrum is manifestly moduli-dependent. We further study the slope-stability of positive monad bundles and develop a new method for proving stability of SU(n) vector bundles.

  16. Features of de Sitter Vacua in M-Theory

    SciTech Connect

    Hsu, Jonathan P.; Kallosh, Renata; Sivanandam, Navin; /Stanford U., Phys. Dept. /SLAC

    2005-11-09

    We compute the masses of all moduli in the unstable deSitter vacua arising in the toy model of cosmological M-theory flux compactifications on the G{sub 2} holonomy manifolds of [1]. The slow-roll parameters in the tachyonic directions are shown to be too large to be useful for conventional models of inflation. However, it appears that we can find fast roll regimes which could, under certain conditions, account for the current dark energy driven accelerated expansion of the universe.

  17. BPS states in M theory and twistorial constituents.

    PubMed

    Bandos, I A; de Azcárraga, J A; Izquierdo, J M; Lukierski, J

    2001-05-14

    We provide a complete algebraic description of Bogomol'nyi-Prasad-Sommerfield (BPS) states in M theory in terms of primary constituents that we call BPS preons. We argue that any BPS state preserving k of the 32 supersymmetries is a composite of (32-k) BPS preons. In particular, the BPS states corresponding to the basic M2 and M5 branes are composed of 16 BPS preons. By extending the M algebra to a generalized D = 11 conformal superalgebra osp(1/64) we relate the BPS preons with its fundamental representation, the D = 11 supertwistors.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. M-theory superstrata and the MSW string

    NASA Astrophysics Data System (ADS)

    Bena, Iosif; Martinec, Emil; Turton, David; Warner, Nicholas P.

    2017-06-01

    The low-energy description of wrapped M5 branes in compactifications of M-theory on a Calabi-Yau threefold times a circle is given by a conformal field theory studied by Maldacena, Strominger and Witten and known as the MSW CFT. Taking the threefold to be {T}_6 or K3× {T}^2 , we construct a map between a sub-sector of this CFT and a sub-sector of the D1-D5 CFT. We demonstrate this map by considering a set of D1-D5 CFT states that have smooth horizonless bulk duals, and explicitly constructing the supergravity solutions dual to the corresponding states of the MSW CFT. We thus obtain the largest known class of solutions dual to MSW CFT microstates, and demonstrate that five-dimensional ungauged supergravity admits much larger families of smooth horizonless solutions than previously known.

  3. 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.

  4. Superconformal field theories from M-theory crystal lattices

    NASA Astrophysics Data System (ADS)

    Lee, Sangmin

    2007-05-01

    We propose a brane configuration for the (2+1)d, N=2 superconformal theories (CFT3) arising from M2 branes probing toric Calabi-Yau 4-fold cones, using a T-duality transformation of M theory. We obtain intersections of M5-branes on a three-torus which form a 3d bipartite crystal lattice in a way similar to the 2d dimer models for CFT4. The fundamental fields of the CFT3 are M2-brane discs localized around the intersections, and the superpotential terms are identified with the atoms of the crystal. The model correctly reproduces the Bogomol’nyi-Prasad-Sommerfield (BPS) spectrum of mesons.

  5. A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells.

    PubMed

    Martín, Rubén; Cordova, Claudia; Gutiérrez, Beatriz; Hernández, Marita; Nieto, María L

    2017-01-01

    Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.

  6. A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells

    PubMed Central

    Martín, Rubén; Cordova, Claudia; Gutiérrez, Beatriz; Hernández, Marita; Nieto, María L.

    2017-01-01

    Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications. PMID:28249041

  7. Theory and phenomenology of μ in M theory

    NASA Astrophysics Data System (ADS)

    Samir Acharya, Bobby; Kane, Gordon; Kuflik, Eric; Lu, Ran

    2011-05-01

    We consider a solution to the μ-problem within M theory on a G 2-manifold. Our study is based upon the discrete symmetry proposed by Witten that forbids the μ-term and solves the doublet-triplet splitting problem. We point out that the symmetry must be broken by moduli stabilization, describing in detail how this can occur. The μ-term is generated via Kahler interactions after strong dynamics in the hidden sector generate a potential which stabilizes all moduli and breaks supersymmetry with m 3/2 ˜ 20-30 TeV. We show that μ is suppressed relative to the gravitino mass, by higher dimensional operators, μ ˜ 0 .1 m 3/2 ˜ 2-3 TeV. This necessarily gives a Higgsino component to the (mostly Wino) LSP, and a small but non-negligible LSP-nucleon scattering cross-section. The maximum spin-independent cross-sections are not within reach of the current XENON100 experiment, but are within reach of upcoming runs and upgrades.

  8. Hitchin’s equations and M-theory phenomenology

    NASA Astrophysics Data System (ADS)

    Pantev, Tony; Wijnholt, Martijn

    2011-07-01

    Phenomenological compactifications of M-theory involve seven-manifolds with G2 holonomy and various singularities. Here we study local geometries with such singularities, by thinking of them as compactifications of 7d supersymmetric Yang-Mills theory on a three-manifold Q3. We give a general discussion of compactifications of 7d Yang-Mills theory in terms of Higgs bundles on Q3. We show that they can be constructed using spectral covers, which are Lagrangian branes with a flat connection in the cotangent bundle T∗Q3. We explain the dictionary with ALE fibrations over Q3 and conjecture that these configurations have G2 holonomy. We further develop tools to study the low energy effective theory of such a model. We show that the naive massless spectrum is corrected by instanton effects. Taking the instanton effects into account, we find that the massless spectrum and many of the interactions can be computed with Morse theoretic methods.

  9. 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.

  10. 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.

  11. Diamond radiation detectors I. Detector properties for IIa diamond

    SciTech Connect

    Kania, D.R.

    1997-05-16

    The detector properties and carrier dynamics of type IIa diamonds are reasonably well understood. The trends in the electron and hole mobilities have been characterized as a function of temperature, impurity content, electric field and carrier density. The carrier lifetimes are coupled through the nitrogen impurity. This leaves us with typical samples with collection distances of 20 to 50 micrometers. The detailed dynamics of the carriers can be modeled using a rate equation analysis. Much progress has been made in understanding the detector properties of diamond, but continued progress has been limited by the geologic processes used to make the material, for example sample size and no synthesis control. CVD diamond promises to eliminate these restrictions.

  12. 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.

  13. Simultaneous induction of apoptosis and necroptosis by Tanshinone IIA in human hepatocellular carcinoma HepG2 cells

    PubMed Central

    Lin, C-Y; Chang, T-W; Hsieh, W-H; Hung, M-C; Lin, I-H; Lai, S-C; Tzeng, Y-J

    2016-01-01

    Tanshinone IIA (Tan IIA), a constituent of the traditional medicinal plant Salvia miltiorrhiza BUNGE, has been reported to possess anticancer activity through induction of apoptosis in many cancer cells. Surprisingly, the present study finds that Tan IIA simultaneously causes apoptosis and necroptosis in human hepatocellular carcinoma HepG2 cells. We further find that apoptosis can be converted to necroptosis by pan-caspase inhibitor Z-VAD-fmk, and the two death modes can be blocked by necroptotic inhibitor necrostatin-1. The underlying mechanisms are revealed by analysis of the signaling molecules using western blotting. In control cells, FLICE inhibitory protein in short form (FLIPS) is expressed in relatively high levels and binds to caspase 8 in ripoptosome, which supposedly sustains cell survival. However, in Tan IIA-treated cells, FLIPS is down-regulated and may thus cause homodimer formation of cleaved caspase 8, cleavage of receptor-interacting serine/threonine-protein kinases 1, 3 (RIP1, RIP3), and mixed-lineage kinase domain-like (MLKL), in turn leads to cell apoptosis. In parallel, Tan IIA causes necroptosis by forming a suggested necrosomal complex composed of RIP1/RIP3. Regarding the inhibitors, z-VAD-fmk diminishes the cleaved caspase 8, RIP1, RIP3, and MLKL induced by Tan IIA, and reconstructs the ripoptosome complex, which marks cells moving from apoptosis to necroptosis. Nec-1 recovers the Tan IIA down-regulated FLIPS, consequently causes FLIPS to form heterodimer with caspase 8 and thus block apoptosis. Meanwhile, cleaved forms of RIP1 and RIP3 were observed preventing necroptosis. Intriguingly, the cytotoxicity of tumor necrosis factor-related apoptosis-inducing ligand to HepG2 cells is enhanced by Tan IIA in a pilot study, which may be attributed to low FLIPS levels induced by Tan IIA. In short, Tan IIA simultaneously induces both Nec-1 inhibition and FLIPS regulation-mediated apoptosis/necroptosis, which has not been previously documented

  14. Knot invariants and M-theory: Hitchin equations, Chern-Simons actions, and surface operators

    NASA Astrophysics Data System (ADS)

    Dasgupta, Keshav; Errasti Díez, Verónica; Ramadevi, P.; Tatar, Radu

    2017-01-01

    Recently Witten introduced a type IIB brane construction with certain boundary conditions to study knot invariants and Khovanov homology. The essential ingredients used in his work are the topologically twisted N =4 Yang-Mills theory, localization equations and surface operators. In this paper we extend his construction in two possible ways. On one hand we show that a slight modification of Witten's brane construction could lead, using certain well-defined duality transformations, to the model used by Ooguri-Vafa to study knot invariants using gravity duals. On the other hand, we argue that both these constructions, of Witten and of Ooguri-Vafa, lead to two different seven-dimensional manifolds in M-theory from where the topological theories may appear from certain twisting of the G-flux action. The non-Abelian nature of the topological action may also be studied if we take the wrapped M2-brane states in the theory. We discuss explicit constructions of the seven-dimensional manifolds in M-theory, and show that both the localization equations and surface operators appear naturally from the Hamiltonian formalism of the theories. Knots and link invariants are then constructed using M2-brane states in both the models.

  15. Tanshinone IIA increases the bystander effect of herpes simplex virus thymidine kinase/ganciclovir gene therapy via enhanced gap junctional intercellular communication.

    PubMed

    Xiao, Jianyong; Zhang, Guangxian; Qiu, Pengxiang; Liu, Xijuan; Wu, Yingya; Du, Biaoyan; Li, Jiefen; Zhou, Jing; Li, Jingjing; Tan, Yuhui

    2013-01-01

    The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy.

  16. 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.

  17. Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells.

    PubMed

    Chen, Hung-Chen; Chen, Pei-Yi; Wu, Ming-Jiuan; Tai, Mi-Hsueh; Yen, Jui-Hung

    2016-01-01

    Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1α (HNF-1α), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management.

  18. Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells

    PubMed Central

    Wu, Ming-Jiuan; Tai, Mi-Hsueh; Yen, Jui-Hung

    2016-01-01

    Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1α (HNF-1α), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management. PMID:27617748

  19. Stringy corrections to a time-dependent background solution of string and M theory

    SciTech Connect

    Niz, Gustavo; Turok, Neil

    2007-06-15

    We consider one of the simplest time-dependent backgrounds in M theory, describing the shrinking away of the M-theory dimension with the other spatial dimensions static. As the M-theory dimension becomes small, the situation becomes well described by string theory in a singular cosmological background where the string coupling tends to zero but the {alpha}{sup '} corrections become large, near the cosmic singularity. We compute these {alpha}{sup '} corrections, both for the background and for linearized perturbations, in heterotic string theory, and show that they may be reproduced by a map from 11-dimensional M theory.

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

    PubMed

    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

    2015-07-07

    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.

  1. Inhibitory Effect of Tanshinone IIA on Rat Hepatic Stellate Cells

    PubMed Central

    Liu, Ya-Wei; Huang, Yi-Tsau

    2014-01-01

    Background Anti-inflammation via inhibition of NF-κB pathways in hepatic stellate cells (HSCs) is one therapeutic approach to hepatic fibrosis. Tanshinone IIA (C19H18O3, Tan IIA) is a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge, with reported anti-inflammatory activity. We tested whether Tan IIA could inhibit HSC activation. Materials and Methods The cell line of rat hepatic stellate cells (HSC-T6) was stimulated with lipopolysaccharide (LPS) (100 ng/ml). Cytotoxicity was assessed by MTT assay. HSC-T6 cells were pretreated with Tan IIA (1, 3 and 10 µM), then induced by LPS (100 ng/ml). NF-κB activity was evaluated by the luciferase reporter gene assay. Western blotting analysis was performed to measure NF-κB-p65, and phosphorylations of MAPKs (ERK, JNK, p38). Cell chemotaxis was assessed by both wound-healing assay and trans-well invasion assay. Quantitative real-time PCR was used to detect gene expression in HSC-T6 cells. Results All concentrations of drugs showed no cytotoxicity against HSC-T6 cells. LPS stimulated NF-κB luciferase activities, nuclear translocation of NF-κB-p65, and phosphorylations of ERK, JNK and p38, all of which were suppressed by Tan IIA. In addition, Tan IIA significantly inhibited LPS-induced HSCs chemotaxis, in both wound-healing and trans-well invasion assays. Moreover, Tan IIA attenuated LPS-induced mRNA expressions of CCL2, CCL3, CCL5, IL-1β, TNF-α, IL-6, ICAM-1, iNOS, and α-SMA in HSC-T6 cells. Conclusion Our results demonstrated that Tan IIA decreased LPS-induced HSC activation. PMID:25076488

  2. 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.

  3. GADD34 suppresses wound healing by upregulating expression of myosin IIA.

    PubMed

    Tanaka, Chie; Ito, Sachiko; Nishio, Naomi; Kodera, Yasuhiro; Sakurai, Hidetoshi; Suzuki, Haruhiko; Nakao, Akimasa; Isobe, Ken-Ichi

    2010-08-01

    Wound healing consists of sequential steps of tissue repair, and cell migration is particularly important. In order to analyze the potential function of growth arrest and DNA damage inducible protein 34 (GADD34) in tissue repair, we performed in vitro and in vivo wound healing experiments. In an in vitro scratch assay, GADD34 knockout (KO) mouse embryonic fibroblasts (MEFs) had higher migration rates than did wild type (WT) MEFs. Furthermore, the rate of wound closure was faster in GADD34 KO MEFs than in WT MEFs. Using in vivo punch biopsy assays, GADD34 KO mice had accelerated wound healing compared to WT mice. WT mice expressed higher amounts of myosin IIA in migrating macrophages and myofibroblasts than did GADD34 KO mice. These results indicate that GADD34 negatively regulates cell migration in wound healing via expression of myosin IIA.

  4. Myosin IIA Heavy Chain Phosphorylation Mediates Adhesion Maturation and Protrusion in Three Dimensions.

    PubMed

    Rai, Vandana; Thomas, Dustin G; Beach, Jordan R; Egelhoff, Thomas T

    2017-02-24

    Non-muscle myosin II (NMII) is a conserved force-producing cytoskeletal enzyme with important but poorly understood roles in cell migration. To investigate myosin heavy chain (MHC) phosphorylation roles in 3D migration, we expressed GFP-tagged NMIIA wild-type or mutant constructs in cells depleted of endogenous NMIIA protein. We find that individual mutation or double mutation of Ser-1916 or Ser-1943 to alanine potently blocks recruitment of GFP-NM-IIA filaments to leading edge protrusions in 2D, and this in turn blocks maturation of anterior focal adhesions. When placed in 3D collagen gels, cells expressing wild-type GFP MHC-IIA behave like parental cells, displaying robust and active formation and retraction of protrusions. However, cells depleted of NMIIA or cells expressing the mutant GFP MHC-IIA display severe defects in invasion and in stabilizing protrusions in 3D. These studies reveal an NMIIA-specific role in 3D invasion that requires competence for NMIIA phosphorylation at Ser-1916 and Ser-1943. In sum, these results demonstrate a critical and previously unrecognized role for NMIIA phosphorylation in 3D invasion.

  5. Remarks on non-BPS string amplitudes and their all order α' contact interactions in IIB, IIA

    DOE PAGES

    Hatefi, Ehsan

    2017-03-06

    Here, we explore the entire form of S-Matrix elements of a potential Cn–1 Ramond-Ramond (RR) form field, a tachyon and two transverse scalar fields on both world volume and transverse directions of type IIB and IIA superstring theories. Apart from VC–2VΦ0VΦ0VT0 the other scattering amplitude, namely VC–1VΦ–1VΦ0VT0 is also revealed. We then start to compare all singularity structures of symmetric and asymmetric analysis, generating all infinite singularity structures as well as all order α' contact interactions on the whole directions. This leads to deriving various new contact terms and several new restricted Bianchi identities in both type IIB and IIA.more » It is also shown that just some of the new couplings of type IIB (IIA) string theory can be re-verified in an Effective Field Theory (EFT) by pull-back of branes. To construct the rest of S-matrix elements one needs to first derive restricted world volume (or bulk) Bianchi identities and then discover new EFT couplings in both type IIB and IIA. Finally the presence of commutator of scalar fields inside the exponential of Wess-Zumino action for non-BPS branes has been confirmed as well.« less

  6. Remarks on non-BPS string amplitudes and their all order α' contact interactions in IIB, IIA

    NASA Astrophysics Data System (ADS)

    Hatefi, Ehsan

    2017-03-01

    We explore the entire form of S-Matrix elements of a potential C n-1 Ramond-Ramond (RR) form field, a tachyon and two transverse scalar fields on both world volume and transverse directions of type IIB and IIA superstring theories. Apart from < {V}_{C^{-2}}{V}_{φ^0}{V}_{φ^0}{V}_{T^0}\\rangle the other scattering amplitude, namely < {V}_{C^{-1}}{V}_{φ^{-1}}{V}_{φ^0}{V}_{T^0}\\rangle is also revealed. We then start to compare all singularity structures of symmetric and asymmetric analysis, generating all infinite singularity structures as well as all order α' contact interactions on the whole directions. This leads to deriving various new contact terms and several new restricted Bianchi identities in both type IIB and IIA. It is also shown that just some of the new couplings of type IIB (IIA) string theory can be re-verified in an Effective Field Theory (EFT) by pull-back of branes. To construct the rest of S-matrix elements one needs to first derive restricted world volume (or bulk) Bianchi identities and then discover new EFT couplings in both type IIB and IIA. Finally the presence of commutator of scalar fields inside the exponential of Wess-Zumino action for non-BPS branes has been confirmed as well.

  7. Nonmuscle myosin heavy chain IIA is a critical factor contributing to the efficiency of early infection of severe fever with thrombocytopenia syndrome virus.

    PubMed

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

    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.

  8. Exact M-Theory Solutions, Integrable Systems, and Superalgebras

    NASA Astrophysics Data System (ADS)

    D'Hoker, Eric

    2015-04-01

    In this paper, an overview is presented of the recent construction of fully back-reacted half-BPS solutions in 11-dimensional supergravity which correspond to near-horizon geometries of M2 branes ending on, or intersecting with, M5 and M5' branes along a self-dual string. These solutions have space-time manifold {AdS}_3 × S^3 × S^3 warped over a Riemann surface Σ, and are invariant under the exceptional Lie superalgebra D(2,1;γ) ⊕ D(2,1;γ), where γ is a real continuous parameter and |γ| is governed by the ratio of the number of M5 and M5' branes. The construction proceeds by mapping the reduced BPS equations onto an integrable field theory on Σ which is of the Liouville sine-Gordon type. Families of regular solutions are distinguished by the sign of γ, and include a two-parameter Janus solution for γ >0, and self-dual strings on M5 as well as asymptotically AdS_4/Z_2 solutions for γ <0.

  9. 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.

  10. On WZ and RR couplings of BPS branes and their all order α‧ corrections in IIB, IIA

    NASA Astrophysics Data System (ADS)

    Hatefi, Ehsan

    2017-03-01

    We compute all three and four point couplings of BPS Dp-branes for all different nonzero p-values on the entire world volume and transverse directions. We start finding out all four point function supersymmetric Wess-Zumino (WZ) actions of one closed string Ramond-Ramond (RR) field with two fermions, either with the same (IIB) or different chirality (IIA) as well as their all order α‧ corrections. The closed form of S-matrices of two closed string RR in both IIB, IIA, including their all order α‧ corrections have also been addressed. Our results confirm that, not only the structures of α‧ corrections but also their coefficients of IIB are quite different from their IIA ones. The S-matrix of an RR and two gauge (scalar) fields and their all order corrections in antisymmetric picture of RR have been carried out as well. Various remarks on the restricted Bianchi identities as well as all order α‧ corrections to all different supersymmetric WZ couplings in both type IIA and IIB superstring theory are also released. Lastly, different singularity structures as well as all order contact terms for all non-vanishing traces in type II have also been constructed.

  11. 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}

  12. 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.}

  13. AdS/CFT in string theory and M-theory

    NASA Astrophysics Data System (ADS)

    Gulotta, Daniel R.

    The AdS/CFT correspondence is a powerful tool that can help shed light on the relationship between geometry and field theory. The first part of this thesis will focus on the construction of theories dual to Type IIB string theory on AdS5 × Y5, where Y5 is a toric Sasaki-Einstein manifold. This thesis will introduce a consistency condition called ``proper ordering'' and demonstrate that it is equivalent to several other previously known consistency conditions. It will then give an efficient algorithm that produces a consistent field theory for any toric Sasaki-Einstein Y5. The second part of this thesis will examine the large-N limit of the Kapustin-Willett-Yaakov matrix model. This model computes the S3 partition function for a CFT dual to M-theory on AdS4 × Y7. One of the main results will be a formula that relates the distribution of eigenvalues in the matrix model to the distribution of holomorphic operators on the cone over Y7. A variety of examples are given to support this formula.

  14. Quantification of tear proteins and sPLA2-IIa alteration in patients with allergic conjunctivitis.

    PubMed

    Li, Kaijun; Liu, Xialin; Chen, Ziyan; Huang, Qiang; Wu, Kaili

    2010-10-14

    Allergic conjunctivitis (AC) has been reported to induce the instability of the tear film. The tear protein and the lipid layer play important roles in maintaining the tear film. The aim of this study was to quantify the alteration of the major tear protein components and a lipid related protein secretory type IIa phospholipase A2 (sPLA2-IIa) in tears of seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) patients. Twenty-one SAC and PAC patients and thirteen normal controls completed a symptom questionnaire and underwent regular ocular examination. SAC and PAC patients were diagnosed based on the clinical presentation and elevated serum IgE levels. Schirmer test paper was used to collect tear samples from SAC and PAC patients and normal controls. Soybean trypsin inhibitor (SBTI) was used as an internal standard to analyze tear samples in 15% SDS-PAGE gel. Total tear protein and its major components from the SAC and PAC patients and normal controls were quantified by band densitometry. The major tear protein bands were determined by MALDI-TOF/TOF spectrum analysis. Western blot was used to detect the content of sPLA2-IIa in tears of allergic conjunctivitis patients and normal controls. Schirmer test scores were more than 10 mm in all the SAC and PAC patients and control subjects. The tear film breakup time of SAC and PAC patients was much shorter than that of the normal controls. We obtained 15 bands of tear protein by one dimensional SDS-PAGE, in which 14 bands were determined by mass-spectrum analysis. The band densitometry analysis revealed that the total tear protein concentration was much higher in SAC and PAC patients than in normal controls (p<0.05). The quantity of tear protein band 4 (serum albumin precursor), band 6 (Ig gamma-2), band 9 (leukocyte elastase inhibitor) were also significantly higher in AC patients (p<0.05). Content of sPLA2-IIa, as shown by western blot, was much higher in AC patients than in controls. The

  15. Quantification of tear proteins and sPLA2-IIa alteration in patients with allergic conjunctivitis

    PubMed Central

    Li, Kaijun; Liu, Xialin; Chen, Ziyan; Huang, Qiang

    2010-01-01

    Purpose Allergic conjunctivitis (AC) has been reported to induce the instability of the tear film. The tear protein and the lipid layer play important roles in maintaining the tear film. The aim of this study was to quantify the alteration of the major tear protein components and a lipid related protein secretory type IIa phospholipase A2 (sPLA2-IIa) in tears of seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) patients. Methods Twenty-one SAC and PAC patients and thirteen normal controls completed a symptom questionnaire and underwent regular ocular examination. SAC and PAC patients were diagnosed based on the clinical presentation and elevated serum IgE levels. Schirmer test paper was used to collect tear samples from SAC and PAC patients and normal controls. Soybean trypsin inhibitor (SBTI) was used as an internal standard to analyze tear samples in 15% SDS–PAGE gel. Total tear protein and its major components from the SAC and PAC patients and normal controls were quantified by band densitometry. The major tear protein bands were determined by MALDI-TOF/TOF spectrum analysis. Western blot was used to detect the content of sPLA2-IIa in tears of allergic conjunctivitis patients and normal controls. Results Schirmer test scores were more than 10 mm in all the SAC and PAC patients and control subjects. The tear film breakup time of SAC and PAC patients was much shorter than that of the normal controls. We obtained 15 bands of tear protein by one dimensional SDS–PAGE, in which 14 bands were determined by mass-spectrum analysis. The band densitometry analysis revealed that the total tear protein concentration was much higher in SAC and PAC patients than in normal controls (p<0.05). The quantity of tear protein band 4 (serum albumin precursor), band 6 (Ig gamma-2), band 9 (leukocyte elastase inhibitor) were also significantly higher in AC patients (p<0.05). Content of sPLA2-IIa, as shown by western blot, was much higher in AC

  16. [Modern tendencies in the treatment of cervical cancer stage IB-IIA, prognostic factors--our and foreign experience].

    PubMed

    Ivanov, S; Batashki, I

    2008-01-01

    We tried to summarize our and foreign experience in the treatment of cervical cancer stage IB-IIA, as well as to examine and evaluate the prognostic factors in this field. We tried to summarize our and foreign experience for 10 years period /from 1998 till 2008/ as we examined 1250 patients with cervical cancer stage IB-IIA. According to our results and most of the authors the preferred method for treatment of cervical cancer stage IB-IIA is the radical hysterectomy with or without chemo-radiation therapy. In patients with bulky lymph nodes we performed radical hysterectomy with dyssection only of these nudes, as in this way we converted the patient into patient with micrometastases. We introduced postoperative radiotherapy with "small field "of radiation. In our study we examined the most important prognostic factors as LVSI, the depth of invasion, the parametrial invasion and the hystological type of tumor. When we summarized our and foreign experience in the field of radical hysterectomy with pelvic lymph nude dyssection in the treatment of cervical cancer stage IB-IIA we have produced an algorithm, which can be practically useful.

  17. H-IIA launch vehicle and its avionics system

    NASA Astrophysics Data System (ADS)

    Kawabe, Toshikazu

    1999-01-01

    In the beginning of the 21st century, we will start sending materials to the space station. Launches of lunar and planetary probes, and HOPE-X are also planned in addition to the launches of conventional satellites. The H-IIA is now being developed for the purpose of meeting various demands for flexibility and economy. This paper is to report about the system concept, design features and the development status of the H-IIA launch vehicle and its avionics system, which put emphasis on meeting various missions efficiently.

  18. Supersymmetric IIB background with AdS4 vacua from massive IIA supergravity

    NASA Astrophysics Data System (ADS)

    Pando Zayas, Leopoldo A.; Tsimpis, Dimitrios; Whiting, Catherine A.

    2017-08-01

    We present a new type IIB supergravity background of the warped form AdS4×M6 with dilaton, B -field and all Ramond-Ramond fluxes turned on. We obtain the solution by applying non-Abelian T-duality to a certain representative of a class of AdS4 backgrounds in massive IIA supergravity. By explicitly constructing the Killing spinor of the seed solution and using an argument involving Kosmann spinorial Lie derivative we demonstrate that the background is supersymmetric.

  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. Characterization of Class IIa Bacteriocin Resistance in Enterococcus faecium.

    PubMed

    Geldart, Kathryn; Kaznessis, Yiannis N

    2017-04-01

    Vancomycin-resistant enterococci, particularly resistant Enterococcus faecium, pose an escalating threat in nosocomial environments because of their innate resistance to many antibiotics, including vancomycin, a treatment of last resort. Many class IIa bacteriocins strongly target these enterococci and may offer a potential alternative for the management of this pathogen. However, E. faecium's resistance to these peptides remains relatively uncharacterized. Here, we explored the development of resistance of E. faecium to a cocktail of three class IIa bacteriocins: enterocin A, enterocin P, and hiracin JM79. We started by quantifying the frequency of resistance to these peptides in four clinical isolates of E. faecium We then investigated the levels of resistance of E. faecium 6E6 mutants as well as their fitness in different carbon sources. In order to elucidate the mechanism of resistance of E. faecium to class IIa bacteriocins, we completed whole-genome sequencing of resistant mutants and performed reverse transcription-quantitative PCR (qRT-PCR) of a suspected target mannose phosphotransferase (ManPTS). We then verified this ManPTS's role in bacteriocin susceptibility by showing that expression of the ManPTS in Lactococcus lactis results in susceptibility to the peptide cocktail. Based on the evidence found from these studies, we conclude that, in accord with other studies in E. faecalis and Listeria monocytogenes, resistance to class IIa bacteriocins in E. faecium 6E6 is likely caused by the disruption of a particular ManPTS, which we believe we have identified.

  1. 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

  2. 1/4-BPS M-theory bubbles with SO(3) × SO(4) symmetry

    NASA Astrophysics Data System (ADS)

    Kim, Hyojoong; Kiu Kim, Kyung; Kim, Nakwoo

    2007-08-01

    In this paper we generalize the work of Lin, Lunin and Maldacena on the classification of 1/2-BPS M-theory solutions to a specific class of 1/4-BPS configurations. We are interested in the solutions of 11 dimensional supergravity with SO(3) × SO(4) symmetry, and it is shown that such solutions are constructed over a one-parameter familiy of 4 dimensional almost Calabi-Yau spaces. Through analytic continuations we can obtain M-theory solutions having AdS2 × S3 or AdS3 × S2 factors. It is shown that our result is equivalent to the AdS solutions which have been recently reported as the near-horizon geometry of M2 or M5-branes wrapped on 2 or 4-cycles in Calabi-Yau threefolds. We also discuss the hierarchy of M-theory bubbles with different number of supersymmetries.

  3. 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

  4. Timelike duality, M'-theory and an exotic form of the Englert solution

    NASA Astrophysics Data System (ADS)

    Henneaux, Marc; Ranjbar, Arash

    2017-08-01

    Through timelike dualities, one can generate exotic versions of M-theory with different spacetime signatures. These are the M *-theory with signature (9 , 2 , -), the M'-theory, with signature (6 , 5 , +) and the theories with reversed signatures (1 , 10 , -), (2 , 9 , +) and (5 , 6 , -). In ( s, t, ±), s is the number of space directions, t the number of time directions, and ± refers to the sign of the kinetic term of the 3 form. The only irreducible pseudo-riemannian manifolds admitting absolute parallelism are, besides Lie groups, the seven-sphere S 7 ≡ SO(8) /SO(7) and its pseudo-riemannian version S 3,4 ≡ SO(4 , 4) /SO(3 , 4). [There is also the complexification SO(8,\\mathrmC)/SO(7,\\mathrmC) , but it is of dimension too high for our considerations.] The seven-sphere S 7 ≡ S 7,0 has been found to play an important role in 11-dimensional supergravity, both through the Freund-Rubin solution and the Englert solution that uses its remarkable parallelizability to turn on non trivial internal fluxes. The spacetime manifold is in both cases AdS 4 × S 7. We show that S 3,4 enjoys a similar role in M '-theory and construct the exotic form AdS 4 × S 3,4 of the Englert solution, with non zero internal fluxes turned on. There is no analogous solution in M ∗-theory.

  5. 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

    2014-02-03

    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.

  6. Management and outcomes of clinical stage IIA/B seminoma: Results from the National Cancer Data Base 1998-2012.

    PubMed

    Paly, Jonathan J; Lin, Chun Chieh; Gray, Phillip J; Hallemeier, Christopher L; Beard, Clair; Sineshaw, Helmneh; Jemal, Ahmedin; Efstathiou, Jason A

    Disease-specific survival for testicular seminoma approaches 100%, even for those with node-positive disease. We sought to describe modern practice patterns, survival outcomes, and factors associated with postoperative therapy for patients with clinical stage (CS) IIA/B disease. Data on patients diagnosed with CS IIA/B seminoma from 1998 to 2012 were extracted from the National Cancer Data Base. Demographic, clinical, treatment, and payer characteristics were evaluated using multivariate regression to identify factors associated with receipt of chemotherapy or radiation therapy (RT) within 6 months of orchiectomy. Five-year Kaplan-Meier overall survival (OS) by CS and treatment was calculated. A Cox proportional hazards regression for 5-year OS was performed. A total of 1885 patients were included; 38.5% received chemotherapy and 61.5% received RT. On multivariate analysis, factors associated with receipt of postorchiectomy RT rather than chemotherapy included CS IIA (odds ratio [OR], 3.04; P < .01) and community treatment setting (OR, 1.81-2.76; P < .01). Reduced likelihood of receiving RT was associated with Medicaid insurance (OR, 0.50; P < .01), more recent year of diagnosis (continuous OR, 0.93; P < .01), and primary pathologic tumor 3/4 stage (OR, 0.47; P < .01). On multivariate Cox regression, decreased 5-year OS was associated with receipt of chemotherapy in CS IIA patients (hazard ratio, 13.33; P < .01) but not in CS IIB patients (hazard ratio, 1.39; P = .45). For CS IIA, 5-year OS was 99.4% for orchiectomy and RT versus 91.2% for orchiectomy and chemotherapy (log-rank P < .01). For CS IIB, 5-year OS was 96.1% for orchiectomy and RT versus 92.8% for orchiectomy and chemotherapy (log-rank P = .08). Consistent with national guideline recommendations, our analysis supports preferred status for RT in CS IIA. In addition, these data also support use of RT for CS IIB. CS, treatment year, primary pathologic tumor stage, insurance, and facility type were

  7. IIA/IIB supergravity and ten-forms

    NASA Astrophysics Data System (ADS)

    Bergshoeff, E. A.; Hartong, J.; Howe, P. S.; Ortín, T.; Riccioni, F.

    2010-05-01

    We perform a careful investigation of which p-form fields can be introduced consistently with the supersymmetry algebra of IIA and/or IIB ten-dimensional supergravity. In particular the ten-forms, also known as “top-forms”, require a careful analysis since in this case, as we will show, closure of the supersymmetry algebra at the linear level does not imply closure at the non-linear level. Consequently, some of the (IIA and IIB) ten-form potentials introduced in earlier work of some of us are discarded. At the same time we show that new ten-form potentials, consistent with the full non-linear supersymmetry algebra can be introduced. We give a superspace explanation of our work. All of our results are precisely in line with the predictions of the E 11 algebra.

  8. Comparative Studies of Class IIa Bacteriocins of Lactic Acid Bacteria

    PubMed Central

    Eijsink, Vincent G. H.; Skeie, Marianne; Middelhoven, P. Hans; Brurberg, May Bente; Nes, Ingolf F.

    1998-01-01

    Four class IIa bacteriocins (pediocin PA-1, enterocin A, sakacin P, and curvacin A) were purified to homogeneity and tested for activity toward a variety of indicator strains. Pediocin PA-1 and enterocin A inhibited more strains and had generally lower MICs than sakacin P and curvacin A. The antagonistic activity of pediocin-PA1 and enterocin A was much more sensitive to reduction of disulfide bonds than the antagonistic activity of sakacin P and curvacin A, suggesting that an extra disulfide bond that is present in the former two may contribute to their high levels of activity. The food pathogen Listeria monocytogenes was among the most sensitive indicator strains for all four bacteriocins. Enterocin A was most effective in inhibiting Listeria, having MICs in the range of 0.1 to 1 ng/ml. Sakacin P had the interesting property of being very active toward Listeria but not having concomitant high levels of activity toward lactic acid bacteria. Strains producing class IIa bacteriocins displayed various degrees of resistance toward noncognate class IIa bacteriocins; for the sakacin P producer, it was shown that this resistance is correlated with the expression of immunity genes. It is hypothesized that variation in the presence and/or expression of such immunity genes accounts in part for the remarkably large variation in bacteriocin sensitivity displayed by lactic acid bacteria. PMID:9726871

  9. Human group IIA secretory phospholipase A2 induces neuronal cell death via apoptosis.

    PubMed

    Yagami, Tatsurou; Ueda, Keiichi; Asakura, Kenji; Hata, Satoshi; Kuroda, Takayuki; Sakaeda, Toshiyuki; Takasu, Nobuo; Tanaka, Kazushige; Gemba, Takefumi; Hori, Yozo

    2002-01-01

    Expression of group IIA secretory phospholipase A2 (sPLA2-IIA) is documented in the cerebral cortex (CTX) after ischemia, suggesting that sPLA2-IIA is associated with neurodegeneration. However, how sPLA2-IIA is involved in the neurodegeneration remains obscure. To clarify the pathologic role of sPLA2-IIA, we examined its neurotoxicity in rats that had the middle cerebral artery occluded and in primary cultures of cortical neurons. After occlusion, sPLA2 activity was increased in the CTX. An sPLA2 inhibitor, indoxam, significantly ameliorated not only the elevated activity of the sPLA2 but also the neurodegeneration in the CTX. The neuroprotective effect of indoxam was observed even when it was administered after occlusion. In primary cultures, sPLA2-IIA caused marked neuronal cell death. Morphologic and ultrastructural characteristics of neuronal cell death by sPLA2-IIA were apoptotic, as evidenced by condensed chromatin and fragmented DNA. Before apoptosis, sPLA2-IIA liberated arachidonic acid (AA) and generated prostaglandin D2 (PGD2), an AA metabolite, from neurons. Indoxam significantly suppressed not only AA release, but also PGD2 generation. Indoxam prevented neurons from sPLA2-IIA-induced neuronal cell death. The neuroprotective effect of indoxam was observed even when it was administered after sPLA2-IIA treatment. Furthermore, a cyclooxygenase-2 inhibitor significantly prevented neurons from sPLA2-IIA-induced PGD2 generation and neuronal cell death. In conclusion, sPLA2-IIA induces neuronal cell death via apoptosis, which might be associated with AA metabolites, especially PGD2. Furthermore, sPLA2 contributes to neurodegeneration in the ischemic brain, highlighting the therapeutic potential of sPLA2-IIA inhibitors for stroke.

  10. 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.

  11. 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.

  12. 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. Copyright © 2016 the American Physiological Society.

  13. 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

  14. 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

  15. Tanshinone IIA attenuates renal fibrosis and inflammation via altering expression of TGF-β/Smad and NF-κB signaling pathway in 5/6 nephrectomized rats.

    PubMed

    Wang, Dong-Tao; Huang, Ren-Hua; Cheng, Xin; Zhang, Zhi-Hua; Yang, Ya-Jun; Lin, Xin

    2015-05-01

    In traditional Chinese medicine, Tanshinone IIA is used to treat chronic kidney disease (CKD). However, its biological activity and mechanism of action in renal fibrosis and inflammation are not fully identified. The current study was conducted to determine the effects of Tanshinone IIA treatment on CKD by assessing potential modulation of the TGF-β/Smad and NF-κB signaling pathway. CKD was produced in rats by 5/6 nephrectomy. They were then divided into the following groups: control (sham operation); CKD (5/6 nephrectomy); 5/6 nephrectomy+Tanshinone IIA (10mg/kg in average, once a day for 16 weeks). Serum and urine samples were obtained from animals in each group, and serum creatinine (Scr), blood urea nitrogen (BUN) levels and 24h urinary protein excretion were measured. Tissue samples from the kidney were used for morphometric studies (Masson's trichrome). The expression of fibronectin protein and collagen types I, III, IV, and TGF-β, TNF-α, CXCL-1, MCP-1, RANTES mRNA were evaluated using immunohistochemistry and RT-PCR analysis; the TGF-β/Smad and NF-κB signaling pathway was detected by immunohistochemistry and Western blot analysis. The following effects were observed in CKD rats treated with Tanshinone IIA: (1) marked improvements in Scr, and 24h urine protein excretion; (2) significant reductions in protein and mRNA levels of fibronectin, collagen III, and collagen IV and TNF-α, MCP-1, and CXCL-1; (3) significantly inhibited the TGF-β/Smad and NF-κB signaling activation. These results suggest that Tanshinone IIA suppresses renal fibrosis and inflammation via altering expression of TGF-β/Smad and NF-κB pathway in the remnant kidney, thus supporting the potential of Tanshinone IIA as a new therapeutic agent for slowing the progression of CKD. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. G 2-structures and quantization of non-geometric M-theory backgrounds

    NASA Astrophysics Data System (ADS)

    Kupriyanov, Vladislav G.; Szabo, Richard J.

    2017-02-01

    We describe the quantization of a four-dimensional locally non-geometric M-theory background dual to a twisted three-torus by deriving a phase space star product for deformation quantization of quasi-Poisson brackets related to the nonassociative algebra of octonions. The construction is based on a choice of G 2-structure which defines a nonassociative deformation of the addition law on the seven-dimensional vector space of Fourier momenta. We demonstrate explicitly that this star product reduces to that of the three-dimensional parabolic constant R-flux model in the contraction of M-theory to string theory, and use it to derive quantum phase space uncertainty relations as well as triproducts for the nonassociative geometry of the four-dimensional configuration space. By extending the G 2-structure to a Spin(7)-structure, we propose a 3-algebra structure on the full eight-dimensional M2-brane phase space which reduces to the quasi-Poisson algebra after imposing a particular gauge constraint, and whose deformation quantisation simultaneously encompasses both the phase space star products and the configuration space triproducts. We demonstrate how these structures naturally fit in with previous occurences of 3-algebras in M-theory.

  17. SU(N) Transitions in M-Theory on Calabi-Yau Fourfolds and Background Fluxes

    NASA Astrophysics Data System (ADS)

    Jockers, Hans; Katz, Sheldon; Morrison, David R.; Plesser, M. Ronen

    2017-04-01

    We study M-theory on a Calabi-Yau fourfold with a smooth surface S of A N-1 singularities. The resulting three-dimensional theory has a N=2 SU( N) gauge theory sector, which we obtain from a twisted dimensional reduction of a seven-dimensional N=1 SU( N) gauge theory on the surface S. A variant of the Vafa-Witten equations governs the moduli space of the gauge theory, which—for a trivial SU( N) principal bundle over S—admits a Coulomb and a Higgs branch. In M-theory these two gauge theory branches arise from a resolution and a deformation to smooth Calabi-Yau fourfolds, respectively. We find that the deformed Calabi-Yau fourfold associated to the Higgs branch requires for consistency a non-trivial four-form background flux in M-theory. The flat directions of the flux-induced superpotential are in agreement with the gauge theory prediction for the moduli space of the Higgs branch. We illustrate our findings with explicit examples that realize the Coulomb and Higgs phase transition in Calabi-Yau fourfolds embedded in weighted projective spaces. We generalize and enlarge this class of examples to Calabi-Yau fourfolds embedded in toric varieties with an A N-1 singularity in codimension two.

  18. Inhibitory Effect of Orientin on Secretory Group IIA Phospholipase A2.

    PubMed

    Bae, Jong-Sup

    2015-08-01

    It is well known that the expression level of secretory group IIA phospholipase A2 (sPLA2-IIA) is elevated in inflammatory diseases and lipopolysaccharide (LPS) upregulates the expression of sPLA2-IIA in human umbilical vein endothelial cells (HUVECs). Orientin, a C-glycosyl flavonoid, is known to have anxiolytic, anti-oxidative, and anti-inflammatory activity. Here, orientin was examined for its effects on the expression and activity of sPLA2-IIA in HUVECs and mouse. Prior treatment of cells or mouse with orientin inhibited LPS-induced expression and activity of sPLA2-IIA. And orientin suppressed the activation of cytosolic phospholipase A2 (cPLA2) and extracellular signal-regulated kinase (ERK) 1/2 by LPS. Therefore, these results suggest that orientin may inhibit LPS-mediated expression of sPLA2-IIA by suppression of cPLA2 and ERK 1/2.

  19. Tanshinone IIA improves functional recovery in spinal cord injury-induced lower urinary tract dysfunction

    PubMed Central

    Yang, Yong-dong; Yu, Xing; Wang, Xiu-mei; Mu, Xiao-hong; He, Feng

    2017-01-01

    Tanshinone IIA, extracted from Salvia miltiorrhiza Bunge, exerts neuroprotective effects through its anti-inflammatory, anti-oxidative and anti-apoptotic properties. This study intravenously injected tanshinone IIA 20 mg/kg into rat models of spinal cord injury for 7 consecutive days. Results showed that tanshinone IIA could reduce the inflammation, edema as well as compensatory thickening of the bladder tissue, improve urodynamic parameters, attenuate secondary injury, and promote spinal cord regeneration. The number of hypertrophic and apoptotic dorsal root ganglion (L6–S1) cells was less after treatment with tanshinone IIA. The effects of tanshinone IIA were similar to intravenous injection of 30 mg/kg methylprednisolone. These findings suggested that tanshinone IIA improved functional recovery after spinal cord injury-induced lower urinary tract dysfunction by remodeling the spinal pathway involved in lower urinary tract control. PMID:28400810

  20. Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria.

    PubMed

    Jiang, Haiyang; Zhao, Lei; Dong, Xiaoshen; He, Anning; Zheng, Caiwei; Johansson, Magnus; Karlsson, Anna; Zheng, Xinyu

    2015-09-01

    Heterologous expression of the Drosophila melanogaster multi-substrate deoxyribonucleoside kinase (Dm-dNK) increases the sensitivity of cancer cells to several cytotoxic nucleoside analogs. Thus, it may be used as a suicide gene in combined gene/chemotherapy treatment of cancer. To further characterize this potential suicide gene, we constructed two retroviral vectors that enabled the expression of Dm-dNK in cancer cells. One vector harbored the wild‑type enzyme that localized to the nucleus. The other vector harbored a mitochondrial localized mutant enzyme that was constructed by deleting the nuclear localization signal and fusing it to a mitochondrial import signal of cytochrome c oxidase. A thymidine kinase-deficient osteosarcoma cell line was transduced with the recombinant viruses. The sensitivity and bystander cell killing in the presence of pyrimidine nucleoside analogs (E)-5-(2-bromovinyl)‑2'‑deoxyuridine and 1-β-D-arabinofuranosylthymine were investigated. Tanshinone IIA is a constituent of Danshen; a traditional Chinese medicine used in the treatment of cardiovascular diseases. This study also looked at the influence of Tanshinone IIA on the bystander effect and the underlying mechanisms. We showed that sensitivity of the osteosarcoma cell line to the nucleoside analogs and the efficiency of bystander cell killing were independent of the subcellular localization of Dm-dNK. The enhanced effect of tanshinone IIA on the bystander effect was related to the increased expression of Cx43 and Cx26.

  1. Flux compactification of M-theory on compact manifolds with spin(7) holonomy

    NASA Astrophysics Data System (ADS)

    Constantin, Dragos Eugeniu

    2005-11-01

    At the leading order, M-theory admits minimal supersymmetric compactifications if the internal manifold has exceptional holonomy. The inclusion of non-vanishing fluxes in M-theory and string theory compactifications induce a superpotential in the lower dimensional theory, which depends on the fluxes. In this work, we check the conjectured form of this superpotential in the case of warped M-theory compactifications on Spin (7) holonomy manifolds. We perform a Kaluza-Klein reduction of the eleven-dimensional supersymmetry transformation for the gravitino and we find by direct comparison the superpotential expression. We check the conjecture for the heterotic string compactified on a Calabi-Yau three-fold as well. The conjecture can be checked indirectly by inspecting the scalar potential obtained after the compactification of M-theory on Spin (7) holonomy manifolds with non-vanishing fluxes. The scalar potential can be written in terms of the superpotential and we show that this potential stabilizes all the moduli fields describing deformations of the metric except for the radial modulus. All the above analyses require the knowledge of the minimal supergravity action in three dimensions. Therefore we calculate the most general causal N = 1 three-dimensional, gauge invariant action coupled to matter in superspace and derive its component form using Ectoplasmic integration theory. We also show that the three-dimensional theory which results from the compactification is in agreement with the more general supergravity construction. The compactification procedure takes into account higher order quantum correction terms in the low energy effective action. We analyze the properties of these terms on a Spin (7) background. We derive a perturbative set of solutions which emerges from a warped compactification on a Spin (7) holonomy manifold with non-vanishing flux for the M-theory field strength and we show that in general the Ricci flatness of the internal manifold is lost

  2. 4D superfield reduction of 5D orbifold SUGRA and heterotic M-theory

    NASA Astrophysics Data System (ADS)

    Paccetti Correia, Filipe; Schmidt, Michael G.; Tavartkiladze, Zurab

    2006-09-01

    We present a detailed study of the reduction to 4D of 5D supergravity compactified on the S/Z orbifold. For this purpose we develop and employ a recently proposed N=1 conformal superfield description of the 5D supergravity couplings to Abelian vector and hypermultiplets. In particular, we obtain a unique relation of the "radion" to chiral superfields as in global 5D SUSY and we can embed the universal hypermultiplet into this formalism. In our approach, it is transparent how the superconformal structure of the effective 4D actions is inherited from the one of the original 5D supergravity. We consider both ungauged and gauged 5D supergravities. This includes compactifications in unwarped geometries, generalizations of the supersymmetric Randall-Sundrum (RS) model as well as 5D heterotic M-theory. In the unwarped case, after obtaining the effective Kähler potentials and superpotentials, we demonstrate that the tree-level 4D potentials have flat and/or tachyonic directions. One-loop corrections to the Kähler potential and gaugino condensation are presented as suitable tools for moduli stabilization to be discussed in subsequent work. Turning to the RS-like models, we obtain a master formula for the Kähler potential for an arbitrary number of vector and hyper moduli, which we evaluate exactly for special cases. Finally, we formulate the superfield description of 5D heterotic M-theory and obtain its effective 4D description for the universal ( h=1) case, in the presence of an arbitrary number of bulk 5-branes. We present, as a check of our expressions, time-dependent solutions of 4D heterotic M-theory, which uplift to 5D solutions generalizing the ones recently found in [W. Chen, Z.-W. Chong, G.W. Gibbons, H. Lü, C.N. Pope, Hořava-Witten stability: Eppur si muove, Nucl. Phys. B 732 (2006) 118, hep-th/0502077].

  3. Effects of homoeologous wheat starch synthase IIa genes on starch properties.

    PubMed

    Shimbata, Tomoya; Ai, Yongfeng; Fujita, Masaya; Inokuma, Takayuki; Vrinten, Patricia; Sunohara, Ai; Saito, Mika; Takiya, Toshiyuki; Jane, Jay-lin; Nakamura, Toshiki

    2012-12-05

    Near-isogenic lines (NILs) of the eight haplotypes of starch synthase IIa (SSIIa) were used to analyze the effects of SSIIa gene dosage on branch chain length, gelatinization, pasting, retrogradation, and enzymatic hydrolysis of starches. Compared to wild-type, the amylopectin of lines missing one or more active SSIIa enzymes had increases in the proportion of short branch chains (DP6-10) and decreases in midlength chains (DP11-24), and the size of these differences depended on the dosage of active SSIIa enzymes. Of the three loci, SSIIa-A1 had the smallest contribution to amylopectin structure and SSIIa-B1 the largest. The different effects of the three SSIIa enzymes on starch properties were also seen in gelatinization, retrogradation, pasting, and enzymatic hydrolysis properties. Such differences in starch properties might be useful in influencing the texture and shelf life of food products.

  4. 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.

  5. 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.

  6. 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.

  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. Current algebra formulation of M-theory based on E11 Kac-Moody algebra

    NASA Astrophysics Data System (ADS)

    Sugawara, Hirotaka

    2017-02-01

    Quantum M-theory is formulated using the current algebra technique. The current algebra is based on a Kac-Moody algebra rather than usual finite dimensional Lie algebra. Specifically, I study the E11 Kac-Moody algebra that was shown recently1-5 to contain all the ingredients of M-theory. Both the internal symmetry and the external Lorentz symmetry can be realized inside E11, so that, by constructing the current algebra of E11, I obtain both internal gauge theory and gravity theory. The energy-momentum tensor is constructed as the bilinear form of the currents, yielding a system of quantum equations of motion of the currents/fields. Supersymmetry is incorporated in a natural way. The so-called “field-current identity” is built in and, for example, the gravitino field is itself a conserved supercurrent. One unanticipated outcome is that the quantum gravity equation is not identical to the one obtained from the Einstein-Hilbert action.

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

    USDA-ARS?s Scientific Manuscript database

    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 ...

  10. 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... Standards for Methane in Metal and Nonmetal Mines Equipment § 57.22311 Electrical cables (II-A mines). Only jacketed electrical cables accepted or approved by MSHA as flame resistant shall be used to supply power to...

  11. 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... Standards for Methane in Metal and Nonmetal Mines Equipment § 57.22311 Electrical cables (II-A mines). Only jacketed electrical cables accepted or approved by MSHA as flame resistant shall be used to supply power to...

  12. 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... Standards for Methane in Metal and Nonmetal Mines Equipment § 57.22311 Electrical cables (II-A mines). Only jacketed electrical cables accepted or approved by MSHA as flame resistant shall be used to supply power to...

  13. 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... Standards for Methane in Metal and Nonmetal Mines Equipment § 57.22311 Electrical cables (II-A mines). Only jacketed electrical cables accepted or approved by MSHA as flame resistant shall be used to supply power to...

  14. 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... Standards for Methane in Metal and Nonmetal Mines Equipment § 57.22311 Electrical cables (II-A mines). Only jacketed electrical cables accepted or approved by MSHA as flame resistant shall be used to supply power to...

  15. 30 CFR 57.22312 - Distribution boxes (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 Distribution boxes (II-A and V-A mines). 57... MINES Safety Standards for Methane in Metal and Nonmetal Mines Equipment § 57.22312 Distribution boxes (II-A and V-A mines). Distribution boxes containing short circuit protection for trailing cables...

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

    PubMed Central

    2015-01-01

    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

  17. Tanshinone IIA Protects Endothelial Cells from H2O2-Induced Injuries via PXR Activation.

    PubMed

    Zhu, Haiyan; Chen, Zhiwu; Ma, Zengchun; Tan, Hongling; Xiao, Chengrong; Tang, Xianglin; Zhang, Boli; Wang, Yuguang; Gao, Yue

    2017-02-06

    Tanshinone IIA (Tan IIA) is a pharmacologically active substance extracted from the rhizome of Salvia miltiorrhiza Bunge (also known as the Chinese herb Danshen), and is widely used to treat atherosclerosis. The pregnane X receptor (PXR) is a nuclear receptor that is a key regulator of xenobiotic and endobiotic detoxification. Tan IIA is an efficacious PXR agonist that has a potential protective effect on endothelial injuries induced by xenobiotics and endobiotics via PXR activation. Previously numerous studies have demonstrated the possible effects of Tan IIA on human umbilical vein endothelial cells, but the further mechanism for its exerts the protective effect is not well established. To study the protective effects of Tan IIA against hydrogen peroxide (H2O2) in human umbilical vein endothelial cells (HUVECs), we pretreated cells with or without different concentrations of Tan IIA for 24 h, then exposed the cells to 400 μM H2O2 for another 3 h. Therefore, our data strongly suggests that Tan IIA may lead to increased regeneration of glutathione (GSH) from the glutathione disulfide (GSSG) produced during the GSH peroxidase-catalyzed decomposition of H2O2 in HUVECs, and the PXR plays a significant role in this process. Tan IIA may also exert protective effects against H2O2-induced apoptosis through the mitochondrial apoptosis pathway associated with the participation of PXR. Tan IIA protected HUVECs from inflammatory mediators triggered by H2O2 via PXR activation. In conclusion, Tan IIA protected HUVECs against H2O2-induced cell injury through PXR-dependent mechanisms.

  18. 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).

  19. Qualitative detection of class IIa bacteriocinogenic lactic acid bacteria from traditional Chinese fermented food using a YGNGV-motif-based assay.

    PubMed

    Liu, Wenli; Zhang, Lanwei; Yi, Huaxi; Shi, John; Xue, Chaohui; Li, Hongbo; Jiao, Yuehua; Shigwedha, Nditange; Du, Ming; Han, Xue

    2014-05-01

    In the present study, a YGNGV-motif-based assay was developed and applied. Given that there is an increasing demand for natural preservatives, we set out to obtain lactic acid bacteria (LAB) that produce bacteriocins against Gram-positive and Gram-negative bacteria. We here isolated 123 LAB strains from 5 types of traditional Chinese fermented food and screened them for the production of bacteriocins using the agar well diffusion assay (AWDA). Then, to acquire LAB producing class IIa bacteriocins, we used a YGNGV-motif-based assay that was based on 14 degenerate primers matching all class IIa bacteriocin-encoding genes currently deposited in NCBI. Eight of the LAB strains identified by AWDA could inhibit Gram-positive and Gram-negative bacteria; 5 of these were YGNGV-amplicon positive. Among these 5 isolates, amplicons from 2 strains (Y31 and Y33) matched class IIa bacteriocin genes. Strain Y31 demonstrated the highest inhibitory activity and the best match to a class IIa bacteriocin gene in NCBI, and was identified as Enterococcus faecium. The bacteriocin from Enterococcus avium Y33 was 100% identical to enterocin P. Both of these strains produced bacteriocins with strong antimicrobial activity against Listeria monocytogenes, Escherichia coli, and Bacillus subtilis, hence these bacteriocins hold promise as potential bio-preservatives in the food industry. These findings also indicated that the YGNGV-motif-based assay used in this study could identify novel class IIa bacteriocinogenic LAB, rapidly and specifically, saving time and labour by by-passing multiple separation and purification steps.

  20. Sakurai Prize: Why the Higgs Boson data implies an M-theory world

    NASA Astrophysics Data System (ADS)

    Kane, Gordon

    2017-01-01

    Compactifying 11D M-theory on a 7D G2 manifold automatically gives a supersymmetric 4D relativistic quantum field theory. The supersymmetry is softly broken by gluino condensation of the largest gauge group hidden sector, which runs fastest. The resulting gravitino mass is about 40 TeV, and the scalar masses and trilinears of the soft breaking Lagrangian have similar values. All solutions having electroweak symmetry breaking are in the two doublet decoupling region. The coefficient λ of the effective Higgs potential is calculable and determines Mh/MZ. Using the most recent match and run methods, and running down to the TeV scale gives Mh = 126 GeV, and decay BR within a few per cent of the SM Higgs. This was reported in summer 2011, before LHC data, though the result does not depend on any adjustable parameters so it would be unchanged whenever it was reported.

  1. 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.

  2. 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.

  3. Tanshinone II-A: new perspectives for old remedies.

    PubMed

    Xu, Suowen; Liu, Peiqing

    2013-02-01

    Tanshinone II-A (TSN) is the most abundant diterpene quinone isolated from Danshen (Salvia miltiorrhiza), which has been used in treating cardiovascular diseases for more than 2000 years in China. Interest in its versatile protective effects in cardiovascular, metabolic, neurodegenerative diseases, and cancers has been growing over the last decade. TSN is a multi-target drug, whose molecular targets include transcription factors, scavenger receptors, ion channels, kinases, pro- and anti-apoptotic proteins, growth factors, inflammatory mediators, microRNA, and others. More recently, enhanced or synergistic effects can be observed when TSN is used in combination therapy with cardioprotective and anti-cancer drugs. These combination therapy regimens may open new therapeutic avenues for the treatment of various kinds of human diseases.

  4. Involvement of Oxidative Pathways in Cytokine-induced Secretory Phospholipase A2-IIA in Astrocytes

    PubMed Central

    Jensen, Michael D.; Sheng, Wenwen; Simonyi, Agnes; Johnson, Gary S.; Sun, Albert Y.; Sun, Grace Y.

    2009-01-01

    Recent studies have suggested the involvement of secretory phospholipase A2-IIA (sPLA2-IIA) in neuroinflammatory diseases. Although sPLA2-IIA is transcriptionally induced through the NF-κB pathway by pro-inflammatory cytokines, whether this induction pathway is affected by other intracellular signaling pathways has not been investigated in detail. In this study, we demonstrated the induction of sPLA2-IIA mRNA and protein expression in astrocytes by cytokines and detected the protein in the culture medium after stimulation. We further investigated the effects of oxidative pathways and botanical antioxidants on the induction pathway and observed that IL-1β-induced sPLA2-IIA mRNA expression in astrocytes is dependent on ERK1/2 and PI-3 kinase, but not p38 MAPK. In addition to apocynin, a known NADPH oxidase inhibitor, botanical antioxidants, such as resveratrol and epigallocatechin gallate, also inhibited IL-1β-induced sPLA2-IIA mRNA expression. These compounds also suppressed IL-1β-induced ERK1/2 activation and translocation of the NADPH oxidase subunit p67 phox from cytosol to membrane fraction. Taken together, these results support the involvement of reactive oxygen species from NADPH oxidase in cytokine induction of sPLA2-IIA in astrocytes and promote the use of botanical antioxidants as protective agents for inhibition of inflammatory responses in these cells. PMID:19375465

  5. Tanshinone IIA Protects Against Folic Acid-Induced Acute Kidney Injury.

    PubMed

    Jiang, Chunming; Zhu, Wei; Shao, Qiuyuan; Yan, Xiang; Jin, Bo; Zhang, Miao; Xu, Biao

    2016-01-01

    Tanshinone IIA is a diterpene extracted from Salvia miltiorrhiza, a popular and safe herb medicine that has been widely used in China and other Asian countries. Previous studies have demonstrated the pleiotropic effects of Tanshinone IIA on many disease treatments via its antitoxicity, anti-inflammation, anti-oxidative stress, as well as antifibrosis activities. However, its effect on acute kidney injury (AKI) has not been fully investigated. Here, we show for the first time that systemic administration of Tanshinone IIA can lead to improved kidney function in folic acid-induced kidney injury mice. In the acute phase of AKI, Tanshinone IIA attenuated renal tubular epithelial injury, as determined by histologic changes and the detection of Neutrophil gelatinase-associated lipocalin (NGAL) in the kidney and urine. Additionally, Tanshinone IIA treatment resulted in elevated proliferating cell nuclear antigen (PCNA) expression and decreased inflammatory cells infiltration as well as chemokine expression, suggesting that Tanshinone IIA promoted renal repair following AKI and inhibited local inflammatory response in the injured kidney. This led to decreased long-term fibrosis in the injured kidney, characterized by less accumulation of fibronectin and collagen I in tubulointerstitium. Taken together, these results suggest that Tanshinone IIA may represent a potential approach for AKI treatment.

  6. 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

  7. The effect of tanshinone IIA on the cardiovascular system in ovine fetus in utero.

    PubMed

    Mao, Caiping; Zhang, Yifan; Zhang, Yuying; Cao, Li; Shao, Huan; Wang, Liping; Zhu, Liyan; Xu, Zhice

    2009-01-01

    This was the first study to determine the effect of tanshinone IIA (an active ingredient in herb Danshen) on fetuses in utero under unstressed condition. Tanshinone IIA or 0.9% NaCl as control was intravenously (i.v.) administrated into pregnant ewes. Both maternal and fetal blood were analyzed for PO(2), PCO(2), SO(2)%, hemoglobin, hemotecrit, glucose, lactic acid, Na(+), K(+), and Cl(-) concentrations. Maternal and fetal heart functions were assessed by examining cardiac enzymes and cardiovascular responses. The results showed that tanshinone IIA did not alter the blood values in ewes and fetuses. Cardiac enzyme activities related to the heart remained unchanged. In cardiovascular experiments, no alternation in maternal blood pressure by tanshinone IIA was observed. However, fetal systolic pressure was slightly and significantly increased following i.v. tanshinone IIA into the mothers, while fetal diastolic pressure, mean arterial pressure, and heart rate were not changed. The results demonstrated that tanshinone IIA used during the last third of gestation did not cause the biochemical changes related to cardiac functions in both maternal and fetal sheep. Fetal oxygen metabolism remained stable in utero, providing new information for clinical use of the herb in pregnancy. That tanshinone IIA increased fetal systolic pressure may open new opportunities to study the herb in fetal medicine.

  8. Nucleotide sequence analysis and DNA hybridization studies of the ant(4')-IIa gene from Pseudomonas aeruginosa.

    PubMed Central

    Shaw, K J; Munayyer, H; Rather, P N; Hare, R S; Miller, G H

    1993-01-01

    The ant(4')-IIa gene was previously cloned from Pseudomonas aeruginosa on a 1.6-kb DNA fragment (G. A. Jacoby, M. J. Blaser, P. Santanam, H. Hächler, F. H. Kayser, R. S. Hare, and G. H. Miller, Antimicrob. Agents Chemother. 34:2381-2386, 1990). In the current study, the ant(4')-IIa gene was localized by gamma-delta mutagenesis. A region of approximately 600 nucleotides which contained the ant(4')-IIa gene was identified, and DNA sequence analysis revealed two overlapping open reading frames (ORFs) within this region. Northern (RNA) blot analysis demonstrated expression of both ORFs in P. aeruginosa; therefore, site-directed mutagenesis was used to identify the ORF which encodes the ant(4')-IIa gene. No homology was found between ant(4')-IIa and ant(4')-Ia DNA sequences. Hybridization experiments confirmed that the ant(4')-Ia probe hybridized only to gram-positive presumptive ANT(4')-I strains and that the ant(4')-IIa probe hybridized only to gram-negative strains presumed to carry ANT(4')-II. Seven gram-negative strains which had been classified as having ANT(4')-II resistance profiles did not hybridize with probes for either ant(4')-Ia or ant(4')-IIa, suggesting that at least one additional ant(4') gene may exist. The predicted amino-terminal sequences of the ANT(4')-Ia and ANT(4')-IIa proteins showed significant sequence similarity between residues 38 and 63 of the ANT(4')-Ia protein and residues 26 and 51 of the ANT(4')-IIa protein. PMID:8494365

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

    PubMed

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

    2016-03-01

    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). 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. 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. In summary, the results of this study provide evidence that cell-free TopoIIA DNA may be a potential biomarker for BC.

  10. Molecular determinants of bacterial sensitivity and resistance to mammalian Group IIA phospholipase A2.

    PubMed

    Weiss, Jerrold P

    2015-11-01

    Group IIA secretory phospholipase A2 (sPLA(2)-IIA) of mammalian species is unique among the many structurally and functionally related mammalian sPLA(2) in their high net positive charge and potent (nM) antibacterial activity. Toward the Gram-positive bacteria tested thus far, the global cationic properties of sPLA(2)-IIA are necessary for optimal binding to intact bacteria and penetration of the multi-layered thick cell wall, but not for the degradation of membrane phospholipids that is essential for bacterial killing. Various Gram-positive bacterial species can differ as much as 1000-fold in sPLA(2)-IIA sensitivity despite similar intrinsic enzymatic activity of sPLA(2)-IIA toward the membrane phospholipids of various bacteria. d-alanylation of wall- and lipo-teichoic acids in Staphylococcus aureus and sortase function in Streptococcus pyogenes increase bacterial resistance to sPLA(2)-IIA by up to 100-fold apparently by affecting translocation of bound sPLA(2)-IIA to the cell membrane. Action of the sPLA(2)-IIA and other related sPLA(2) against Gram-negative bacteria is more dependent on cationic properties of the enzyme near the amino-terminus of the protein and collaboration with other host defense proteins that produce alterations of the unique Gram-negative bacterial outer membrane that normally represents a barrier to sPLA(2)-IIA action. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.

  11. Identification of structural determinants for inhibition strength and specificity of wheat xylanase inhibitors TAXI-IA and TAXI-IIA.

    PubMed

    Pollet, Annick; Sansen, Stefaan; Raedschelders, Gert; Gebruers, Kurt; Rabijns, Anja; Delcour, Jan A; Courtin, Christophe M

    2009-07-01

    Triticum aestivum xylanase inhibitor (TAXI)-type inhibitors are active against microbial xylanases from glycoside hydrolase family 11, but the inhibition strength and the specificity towards different xylanases differ between TAXI isoforms. Mutational and biochemical analyses of TAXI-I, TAXI-IIA and Bacillus subtilis xylanase A showed that inhibition strength and specificity depend on the identity of only a few key residues of inhibitor and xylanase [Fierens K et al. (2005) FEBS J 272, 5872-5882; Raedschelders G et al. (2005) Biochem Biophys Res Commun335, 512-522; Sorensen JF & Sibbesen O (2006) Protein Eng Des Sel 19, 205-210; Bourgois TM et al. (2007) J Biotechnol 130, 95-105]. Crystallographic analysis of the structures of TAXI-IA and TAXI-IIA in complex with glycoside hydrolase family 11 B. subtilis xylanase A now provides a substantial explanation for these observations and a detailed insight into the structural determinants for inhibition strength and specificity. Structures of the xylanaseinhibitor complexes show that inhibition is established by loop interactions with active-site residues and substrate-mimicking contacts in the binding subsites. The interaction of residues Leu292 of TAXI-IA and Pro294 of TAXI-IIA with the -2 glycon subsite of the xylanase is shown to be critical for both inhibition strength and specificity. Also, detailed analysis of the interaction interfaces of the complexes illustrates that the inhibition strength of TAXI is related to the presence of an aspartate or asparagine residue adjacent to the acid/base catalyst of the xylanase, and therefore to the pH optimum of the xylanase. The lower the pH optimum of the xylanase, the stronger will be the interaction between enzyme and inhibitor, and the stronger the resulting inhibition.

  12. 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.

  13. Flowing with eight supersymmetries in M-theory and F-theory

    NASA Astrophysics Data System (ADS)

    Gowdigere, Chethan N.; Warner, Nicholas P.

    2003-12-01

    We consider holographic RG flow solutions with eight supersymmetries and study the geometry transverse to the brane. For both M2-branes and for D3-branes in F-theory this leads to an eight-manifold with only a four-form flux. In both settings there is a natural four-dimensional hyper-Kahler slice that appears on the Coulomb branch. In the IIB theory this hyper-Kahler manifold encodes the Seiberg-Witten coupling over the Coulomb branch of a U(1) probe theory. We focus primarily upon a new flow solution in M-theory. This solution is first obtained using gauged supergravity and then lifted to eleven dimensions. In this new solution, the brane probes have an Eguchi-Hanson moduli space with the M2-branes spread over the non-trivial 2-sphere. It is also shown that the new solution is valid for a class of orbifold theories. We discuss how the hyper-Kahler structure on the slice extends to some form of G-structure in the eight-manifold, and describe how this can be computed.

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

    NASA Astrophysics Data System (ADS)

    Sepehri, Alireza; Pincak, Richard

    2016-10-01

    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.

  15. 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.

  16. $$ \\mathcal{N} $$ = 2 supersymmetric Janus solutions and flows: From gauged supergravity to M theory

    DOE PAGES

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

    2016-05-02

    In this study, we investigate a family of SU(3)×U(1)×U(1)-invariant holographic flows and Janus solutions obtained from gaugedmore » $$ \\mathcal{N} $$ = 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.« less

  17. $ \\mathcal{N} $ = 2 supersymmetric Janus solutions and flows: From gauged supergravity to M theory

    SciTech Connect

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

    2016-05-02

    In this study, we investigate a family of SU(3)×U(1)×U(1)-invariant holographic flows and Janus solutions obtained from gauged $ \\mathcal{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.

  18. On the duality between perturbative heterotic orbifolds and M-theory on T4/ ZN

    NASA Astrophysics Data System (ADS)

    Kaplunovsky, V.; Sonnenschein, J.; Theisen, S.; Yankielowicz, S.

    2000-12-01

    The heterotic E8× E8 string compactified on an orbifold T 4/ ZN has gauge group G× G' with (massless) states in its twisted sectors which are charged under both gauge group factors. In the dual M-theory on (T 4/ ZN)⊗(S 1/ Z2) the two group factors are separated in the eleventh direction and the G and G' gauge fields are confined to the two boundary planes, respectively. We present a scenario which allows for a resolution of this apparent paradox and assigns all massless matter multiplets locally to the different six-dimensional boundary fixed planes. The resolution consists of diagonal mixing between the gauge groups which live on the connecting seven-planes (6d and the eleventh dimension) and one of the gauge group factors. We present evidence supporting this mixing by considering gauge couplings and verify local anomaly cancellation. We also discuss open problems which arise in the presence of U1 factors.

  19. The CDF Run IIa Silicon Detector and Its Upgrade RunIIb

    SciTech Connect

    Cigdem Issever

    2003-12-19

    The CDF RunIIa silicon detector made the transition from commissioning to data taking. CDF's online and offline tracking algorithms, the performance of Layer 00 and the RunIIb silicon upgrade project are covered in this article.

  20. 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

  1. 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.

  2. Precipitation of kidney myosin IIA and IIB by freezing.

    PubMed

    Dias, Decivaldo dos Santos; da Cruz, Grabriel Costa Nunes; de Sousa, Marcelo Valle; Coelho, Milton Vieira

    2011-03-01

    Actomyosin precipitation is a critical step in the purification of myosins. In this work, the objective was to precipitate rat kidney actomyosin and isolate myosin by freezing and thawing the soluble fraction. Kidney was homogenized in imidazole buffer, centrifuged at 45000 g for 30 min, and the supernatant was frozen at -20°C for 48 h. The supernatant was thawed at 4°C, centrifuged at 45000 g for 30 min and the precipitate washed twice with imidazole buffer pH 7.0 (with and without Triton X-100, respectively). The resulting precipitate presented a polypeptide profile in SDS/PAGE characteristic of actomyosin and expressed Mg- and K/EDTA-ATPase activity. The actomyosin complex was solubilized with ATP and Mg, and the main polypeptide, p200, was purified in a DEAE-Sepharose column. p200 was marked with anti-myosin II, co-sedimented with F-actin in the absence, but not in the presence, of ATP and was identified by MS/MS with a high Mascot score for myosin IIA. The analysis identified peptides exclusive of myosin IIB, but detected no peptides exclusive of myosin IIC.

  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

    2016-05-12

    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.

  4. Correlation between sPLA2-IIA and phosgene-induced rat acute lung injury.

    PubMed

    Chen, Hong-li; Hai, Chun-xu; Liang, Xin; Zhang, Xiao-di; Liu, Riu; Qin, Xu-jun

    2009-02-01

    Secreted phospholipase A(2) of group IIA (sPLA(2)-IIA) has been involved in a variety of inflammatory diseases, including acute lung injury. However, the specific role of sPLA(2)-IIA in phosgene-induced acute lung injury remains unidentified. The aim of the present study was to investigate the correlation between sPLA(2)-IIA activity and the severity of phosgene-induced acute lung injury. Adult male rats were randomly exposed to either normal room air (control group) or a concentration of 400 ppm phosgene (phosgene-exposed group) for there are 5 phosgene-exposed groups altogether. For the time points of 1, 3, 6, 12 and 24 h post-exposure, one phosgene-exposed group was sacrificed at each time point. The severity of acute lung injury was assessed by Pa(O2)/F(IO2) ratio, wet-to-dry lung-weight ratio, and bronchoalveolar lavage (BAL) fluid protein concentration. sPLA(2)-IIA activity in BAL fluid markedly increased between 1 h and 12 h after phosgene exposure, and reached its highest level at 6 h. Moreover, the trend of this elevation correlated well with the severity of lung injury. These results indicate that sPLA(2)-IIA probably participates in phosgene-induced acute lung injury.

  5. 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

  6. Tanshinone IIA inhibits osteoclast differentiation through down-regulation of c-Fos and NFATc1.

    PubMed

    Kwak, Han Bok; Yang, Daum; Ha, Hyunil; Lee, Jong Ho; Kim, Ha Neui; Woo, Eun Ran; Lee, Seungbok; Kim, Hong Hee; Lee, Zang Hee

    2006-06-30

    Bone is a dynamic tissue that is regulated by the activity of bone-resorbing osteoclasts and bone-forming osteoblasts. Excessive osteoclast formation causes diseases such as osteoporosis and rheumatoid arthritis. Natural substances may be useful as therapeutic drugs to prevent many diseases in humans because they avoid the many side effects of treatment with chemical compounds. Here we show that tanshinone IIA isolated from Salvia miltiorrhiza Bunge inhibits the receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclast differentiation of osteoclast precursors. Tanshinone IIA suppressed the expression levels of c-Fos and NFATc1 induced by RANKL. However, retrovirus-mediated overexpression of c-Fos induced the expression of NFATc1 despite the presence of tanshinone IIA and reversed the inhibitory effect of tanshinone IIA on osteoclast differentiation. Also, the introduction of osteoclast precursors with the NFATc1 retrovirus led to osteoclast differentiation in the presence of tanshinone IIA. Our results suggest that tanshinone IIA may have a role as a therapeutic drug in the treatment of bone disease such as osteoporosis.

  7. 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.

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

    PubMed Central

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

    2013-01-01

    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

  9. Born-Infeld action and Chern-Simons term from Kaluza-Klein monopole in M-theory

    NASA Astrophysics Data System (ADS)

    Imamura, Yosuke

    1997-11-01

    We investigate the zero modes of the Kaluza-Klein monopole in M-theory and show that the Born-Infeld action and the Chern-Simons term of a D6-brane are reproduced to quadratic order in the field strength of the U(1) field on the brane.

  10. 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.

  11. GPM's H-IIA Launch Vehicle No.23, First stage VOS

    NASA Image and Video Library

    2017-09-27

    GPM's launch vehicle, the H-IIA No.23, first stage VOS (Vehicle On Stand). GPM is a joint mission between NASA and the Japan Aerospace Exploration Agency (JAXA). The Core Observatory will link data from a constellation of current and planned satellites to produce next-generation global measurements of rainfall and snowfall from space. The GPM mission is the first coordinated international satellite network to provide near real-time observations of rain and snow every three hours anywhere on the globe. The GPM Core Observatory anchors this network by providing observations on all types of precipitation. The observatory's data acts as the measuring stick by which partner observations can be combined into a unified data set. The data will be used by scientists to study climate change, freshwater resources, floods and droughts, and hurricane formation and tracking. Credit: Mitsubishi Heavy Industries NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

  12. Interaction of low molecular weight group IIA phospholipase A2 with apoptotic human T cells: role of heparan sulfate proteoglycans.

    PubMed

    Boilard, Eric; Bourgoin, Sylvain G; Bernatchez, Chantale; Poubelle, Patrice E; Surette, Marc E

    2003-06-01

    Human group IIA phospholipase A2 (hIIA PLA2) is a 14 kDa secreted enzyme associated with inflammatory diseases. A newly discovered property of hIIA PLA2 is the binding affinity for the heparan sulfate proteoglycan (HSPG) glypican-1. In this study, the binding of hIIA PLA2 to apoptotic human T cells was investigated. Little or no exogenous hIIA PLA2 bound to CD3-activated T cells but significant binding was measured on activated T cells induced to undergo apoptosis by anti-CD95. Binding to early apoptotic T cells was greater than to late apoptotic cells. The addition of heparin and the hydrolysis of HSPG by heparinase III only partially inhibited hIIA PLA2 binding to apoptotic cells, suggesting an interaction with both HSPG and other binding protein(s). Two low molecular weight HSPG were coimmunoprecipitated with hIIA PLA2 from apoptotic T cells, but not from living cells. Treatment of CD95-stimulated T cells with hIIA PLA2 resulted in the release of arachidonic acid but not oleic acid from cells and this release was blocked by heparin and heparinase III. Altogether, these results suggest a role for hIIA PLA2 in the release of arachidonic acid from apoptotic cells through interactions with HSPG and its potential implication in the progression of inflammatory diseases.

  13. Tanshinone IIA exerts protective effects in a LCA-induced cholestatic liver model associated with participation of pregnane X receptor.

    PubMed

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

    2015-04-22

    Tanshinone IIA (Tan IIA) is one of the main natural active ingredients purified from Salvia miltiorrhiza radix, which has long been used in clinical practice in China to treat diseases including liver fibrosis, Alzheimer׳s disease, and cardiovascular diseases. Tan IIA has hepatoprotective properties, and is an efficacious PXR agonist. Our study was designed to observe the function and mechanism of the hepatoprotective properties of Tan IIA. HepG2 cells were used to investigate the vitrol effects of Tan IIA on PXR and CYP3A4. Gut-formed LCA is hepatotoxic, and has been implicated in the pathogenesis of cholestatic diseases. To further investigate the hepatoprotective mechanisms of Tan IIA against LCA-induced cholestasis in vivo, we choose the normal mice and siRNA-treated mice. The in vitro study demonstrated that the effect of Tan IIA on CYP3A4 was mediated by transactivation of PXR in a dose- and time-dependent manner. The in vivo experiments using PXR siRNA revealed that Tan IIA could protect against LCA-induced hepatotoxicity and cholestasis in a dose-dependent manner. These effects were partially caused by the upregulation of PXR, as well as Cyp3a11, Cyp3a13, and Mdr1, which are the enzymes responsible for LCA metabolism. This is the first report showing that the hepatoprotective effects of Tan IIA are partly mediated by PXR.

  14. Tanshinone IIA induces intrinsic apoptosis in osteosarcoma cells both in vivo and in vitro associated with mitochondrial dysfunction

    PubMed Central

    Huang, Sheng-Teng; Huang, Chao-Chun; Huang, Wen-Liang; Lin, Tsu-Kung; Liao, Pei-Lin; Wang, Pei-Wen; Liou, Chia-Wei; Chuang, Jiin-Haur

    2017-01-01

    Tanshinone IIA (Tan IIA), a phytochemical derived from the roots of Salvia miltiorrhiza, has been shown to inhibit growth and induce apoptosis in various cancer cells. The association of its inhibitory effect on the primary malignant bone tumor, osteosarcoma, with mitochondrial dysfunction remains unclear. This study aimed to investigate the anti-proliferative effects of Tan IIA on human osteosarcoma 143B cells both in vitro and in vivo. Administration of Tan IIA to NOD-SCID mice implanted with 143B cells led to significant inhibition of tumor development. The inhibition of proliferation, migration, and invasion was observed in 143B cells treated with Tan IIA. The tumor proliferation markers, Ki67 and PCNA, were suppressed and apoptosis by TUNEL assay was activated respectively. Apoptosis in the Tan IIA-treated 143B cells and xerograft mice was associated with the activation of caspase cascade via the modulation of Bcl-2 family. The CD31 was inhibited in Tan IIA-treated xenografts to indicate anti-neovasculization. Tan IIA administration resulted in a significant decrease in the mitochondrial fusion proteins, Mfn1/2 and Opa1, as well as an increase in the fission protein Drp1. We concluded that mitochondrial dysfunction associated with dynamic change was involved in apoptosis and anti-angiogenesis elicited by Tan IIA. PMID:28106052

  15. Preoperatively Assessable Clinical and Pathological Risk Factors for Parametrial Involvement in Surgically Treated FIGO Stage IB-IIA Cervical Cancer.

    PubMed

    Canaz, Emel; Ozyurek, Eser Sefik; Erdem, Baki; Aldikactioglu Talmac, Merve; Yildiz Ozaydin, Ipek; Akbayir, Ozgur; Numanoglu, Ceyhun; Ulker, Volkan

    2017-06-14

    Determining the risk factors associated with parametrial involvement (PMI) is of paramount importance to decrease the multimodality treatment in early-stage cervical cancer. We investigated the preoperatively assessable clinical and pathological risk factors associated with PMI in surgically treated stage IB1-IIA2 cervical cancer. A retrospective cohort study of women underwent Querleu-Morrow type C hysterectomy for cervical cancer stage IB1-IIA2 from 2001 to 2015. All patients underwent clinical staging examination under anesthesia by the same gynecological oncologists during the study period. Evaluated variables were age, menopausal status, body mass index, smoking status, FIGO (International Federation of Obstetrics and Gynecology) stage, clinically measured maximal tumor diameter, clinical presentation (exophytic or endophytic tumor), histological type, tumor grade, lymphovascular space invasion, clinical and pathological vaginal invasion, and uterine body involvement. Endophytic clinical presentation was defined for ulcerative tumors and barrel-shaped morphology. Two-dimensional transvaginal ultrasonography was used to measure tumor dimensions. Of 127 eligible women, 37 (29.1%) had PMI. On univariate analysis, endophytic clinical presentation (P = 0.01), larger tumor size (P < 0.001), lymphovascular space invasion (P < 0.001), pathological vaginal invasion (P = 0.001), and uterine body involvement (P < 0.001) were significantly different among the groups with and without PMI. In multivariate analysis endophytic clinical presentation (odds ratio, 11.34; 95% confidence interval, 1.34-95.85; P = 0.02) and larger tumor size (odds ratio, 32.31; 95% confidence interval, 2.46-423.83; P = 0.008) were the independent risk factors for PMI. Threshold of 31 mm in tumor size predicted PMI with 71% sensitivity and 75% specificity. We identified 18 patients with tumor size of more than 30 mm and endophytic presentation; 14 (77.7%) of these had PMI. Endophytic clinical

  16. Q-I/IIA-OS formula for predicting left atrial pressure in mitral stenosis

    PubMed Central

    Yiğitbaşi, Ömer; Nalbantgil, İstemi; Birand, Ahmet; Terek, Ahmet

    1970-01-01

    The relation of the phonocardiographic time intervals (Q-I) and (IIA-OS) and the use of two formulas (Q-I, IIA-OS difference versus their ratio) for estimation of left atrial pressure were investigated in 70 cases of pure mitral stenosis. It was noted that, in cases with normal blood pressure and pluse rate, there was a fair correlation of the two intervals to left atrial pressure. In our studies the best correlation was obtained by using the ratio of these two intervals (Q-I)/(IIA-OS). These results indicate that it is possible to use a new formula and equation that are dependable for phonocardiographic evaluation of left atrial pressure. PMID:5433316

  17. Non-Muscle Myosin IIA Differentially Regulates Intestinal Epithelial Cell Restitution and Matrix Invasion

    PubMed Central

    Babbin, Brian A.; Koch, Stefan; Bachar, Moshe; Conti, Mary-Anne; Parkos, Charles A.; Adelstein, Robert S.; Nusrat, Asma; Ivanov, Andrei I.

    2009-01-01

    Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin II motor. However, the role of myosin II in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Pharmacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of β1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SK-CO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression. PMID:19147824

  18. Myosin IIA-related Actomyosin Contractility Mediates Oxidative Stress-induced Neuronal Apoptosis.

    PubMed

    Wang, Yan; Xu, Yingqiong; Liu, Qian; Zhang, Yuanyuan; Gao, Zhen; Yin, Mingzhu; Jiang, Nan; Cao, Guosheng; Yu, Boyang; Cao, Zhengyu; Kou, Junping

    2017-01-01

    Oxidative stress-induced neuronal apoptosis plays an important role in the progression of central nervous system (CNS) diseases. In our study, when neuronal cells were exposed to hydrogen peroxide (H2O2), an exogenous oxidant, cell apoptosis was observed with typical morphological changes including membrane blebbing, neurite retraction and cell contraction. The actomyosin system is considered to be responsible for the morphological changes, but how exactly it regulates oxidative stress-induced neuronal apoptosis and the distinctive functions of different myosin II isoforms remain unclear. We demonstrate that myosin IIA was required for neuronal contraction, while myosin IIB was required for neuronal outgrowth in normal conditions. During H2O2-induced neuronal apoptosis, myosin IIA, rather than IIB, interacted with actin filaments to generate contractile forces that lead to morphological changes. Moreover, myosin IIA knockout using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9) reduced H2O2-induced neuronal apoptosis and the associated morphological changes. We further demonstrate that caspase-3/Rho-associated kinase 1 (ROCK1) dependent phosphorylation of myosin light chain (MLC) was required for the formation of the myosin IIA-actin complex. Meanwhile, either inhibition of myosin II ATPase with blebbistatin or knockdown of myosin IIA with siRNA reversely attenuated caspase-3 activation, suggesting a positive feedback loop during oxidative stress-induced apoptosis. Based on our observation, myosin IIA-actin complex contributes to actomyosin contractility and is associated with the positive feedback loop of caspase-3/ROCK1/MLC pathway. This study unravels the biochemical and mechanistic mechanisms during oxidative stress-induced neuronal apoptosis and may be applicable for the development of therapies for CNS diseases.

  19. Myosin IIA-related Actomyosin Contractility Mediates Oxidative Stress-induced Neuronal Apoptosis

    PubMed Central

    Wang, Yan; Xu, Yingqiong; Liu, Qian; Zhang, Yuanyuan; Gao, Zhen; Yin, Mingzhu; Jiang, Nan; Cao, Guosheng; Yu, Boyang; Cao, Zhengyu; Kou, Junping

    2017-01-01

    Oxidative stress-induced neuronal apoptosis plays an important role in the progression of central nervous system (CNS) diseases. In our study, when neuronal cells were exposed to hydrogen peroxide (H2O2), an exogenous oxidant, cell apoptosis was observed with typical morphological changes including membrane blebbing, neurite retraction and cell contraction. The actomyosin system is considered to be responsible for the morphological changes, but how exactly it regulates oxidative stress-induced neuronal apoptosis and the distinctive functions of different myosin II isoforms remain unclear. We demonstrate that myosin IIA was required for neuronal contraction, while myosin IIB was required for neuronal outgrowth in normal conditions. During H2O2-induced neuronal apoptosis, myosin IIA, rather than IIB, interacted with actin filaments to generate contractile forces that lead to morphological changes. Moreover, myosin IIA knockout using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9) reduced H2O2-induced neuronal apoptosis and the associated morphological changes. We further demonstrate that caspase-3/Rho-associated kinase 1 (ROCK1) dependent phosphorylation of myosin light chain (MLC) was required for the formation of the myosin IIA-actin complex. Meanwhile, either inhibition of myosin II ATPase with blebbistatin or knockdown of myosin IIA with siRNA reversely attenuated caspase-3 activation, suggesting a positive feedback loop during oxidative stress-induced apoptosis. Based on our observation, myosin IIA-actin complex contributes to actomyosin contractility and is associated with the positive feedback loop of caspase-3/ROCK1/MLC pathway. This study unravels the biochemical and mechanistic mechanisms during oxidative stress-induced neuronal apoptosis and may be applicable for the development of therapies for CNS diseases. PMID:28352215

  20. [Effects of Tanshinone IIa on cytokines and platelets in immune vasculitis and its mechanism].

    PubMed

    Li, Xiao-Jing; Zhou, Min; Li, Xiao-Hui; Xu, You-Hua; Liu, Hong; Yang, Mo

    2009-02-01

    The objective of this study was to investigate the effect of Tanshinone IIa on IL-1beta, IL-6 and TNF-alpha cytokines in immune vasculitis and platelets, as well as their relationship. The model of immune vasculitis of rabbits were established by intravenous injection of bovine serum albumin twice. Experiment was divided into 4 groups: control group, model group, tanshinone IIa-treated group and aspirin-treated group. The platelet count, platelet aggregation of peripheral blood were determined. The levels of serum IL-1beta, IL-6, TNF-alpha were detected by ELISA. The pathological changes of immune vasculitis were analyzed by hematoxylin & eosin staining, elastic fibers staining and electron microscopy. The results showed that the levels of IL-1beta and TNF-alpha in model group were significantly higher than those in normal group (p < 0.05), while the level of IL-6 was not significantly different between various groups. The serum level of IL-1beta was correlated with platelet number, while serum levels IL-1beta and TNF-alpha were both correlated with the platelet aggregation. The treatment with tanshinone IIa could significantly decrease the serum levels of IL-1beta, TNF-alpha and platelet number, and the efficacy of tanshinone IIa was same as aspirin. The tanshinone IIa and aspirin both could alleviate the vessels damage in patients with immune vasculitis. It is concluded that the tanshinone IIa may diminish the inflammation damage of vessels in patients with immune vasculitis through the inhibition of cytokines and platelets.

  1. The miniaturised Mössbauer spectrometer MIMOS IIA: Increased sensitivity and new capability for elemental analysis

    NASA Astrophysics Data System (ADS)

    Blumers, M.; Bernhardt, B.; Lechner, P.; Klingelhöfer, G.; d'Uston, C.; Soltau, H.; Strüder, L.; Eckhardt, R.; Brückner, J.; Henkel, H.; Lopez, J. G.; Maul, J.

    2010-12-01

    The Miniaturised Mössbauer Spectrometers MIMOS II on board the two Mars Exploration Rovers (MER) have now been collecting valuable scientific data for more than five years. Mössbauer Spectrometers are part of two future missions: Phobos Grunt (Russian Space Agency) and a joint ESA—NASA Rover in 2018. The new advanced MIMOS IIA instrument described in this paper uses Silicon Drift Detectors (SDD) allowing also X-ray fluorescence chemical analysis (XRF) simultaneously to Mössbauer acquisitions. This paper highlights the features and technological improvements of the new spectrometer MIMOS IIA.

  2. 30 CFR 57.22301 - Atmospheric monitoring systems (I-A, II-A, and V-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Atmospheric monitoring systems (I-A, II-A, and... Atmospheric monitoring systems (I-A, II-A, and V-A mines). (a) An atmospheric monitoring system shall be... explosion-proof. (b) Atmospheric monitoring systems shall— (1) Give warnings on the surface and...

  3. 30 CFR 57.22301 - Atmospheric monitoring systems (I-A, II-A, and V-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Atmospheric monitoring systems (I-A, II-A, and... Atmospheric monitoring systems (I-A, II-A, and V-A mines). (a) An atmospheric monitoring system shall be... explosion-proof. (b) Atmospheric monitoring systems shall— (1) Give warnings on the surface and...

  4. 30 CFR 57.22301 - Atmospheric monitoring systems (I-A, II-A, and V-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Atmospheric monitoring systems (I-A, II-A, and... Atmospheric monitoring systems (I-A, II-A, and V-A mines). (a) An atmospheric monitoring system shall be... explosion-proof. (b) Atmospheric monitoring systems shall— (1) Give warnings on the surface and...

  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.

  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. Tanshinone IIA Exhibits Anticonvulsant Activity in Zebrafish and Mouse Seizure Models

    PubMed Central

    2013-01-01

    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

  8. Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2

    PubMed Central

    Jayathilaka, Nimanthi; Gaffney, Kevin J.; Dey, Raja; Jarusiewicz, Jamie A.; Noridomi, Kaori; Philips, Michael A.; Lei, Xiao; He, Ju; Ye, Jun; Gao, Tao; Petasis, Nicos A.; Chen, Lin

    2012-01-01

    Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA.Weused X-ray crystallography and 19F NMRto show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development. PMID:22396528

  9. Bulky “Gatekeeper” Residue Changes the Cosubstrate Specificity of Aminoglycoside 2″-Phosphotransferase IIa

    PubMed Central

    Bhattacharya, Monolekha; Toth, Marta; Smith, Clyde A.

    2013-01-01

    The aminoglycoside 2″-phosphotransferases APH(2″)-IIa and APH(2″)-IVa can utilize ATP and GTP as cosubstrates, since both enzymes possess overlapping but discrete structural templates for ATP and GTP binding. APH(2″)-IIIa uses GTP exclusively, because its ATP-binding template is blocked by a bulky tyrosine “gatekeeper” residue. Replacement of the “gatekeeper” residues M85 and F95 in APH(2″)-IIa and APH(2″)-IVa, respectively, by tyrosine does not significantly change the antibiotic susceptibility profiles produced by the enzymes. In APH(2″)-IIa, M85Y substitution results in an ∼10-fold decrease in the Km value of GTP and an ∼320-fold increase in the Km value of ATP. In APH(2″)-IVa, F95Y substitution results in a modest decrease in the Km values of both GTP and ATP. Structural analysis indicates that in the APH(2″)-IIa M85Y mutant, tyrosine blocks access of ATP to the correct position in the binding site, while the larger nucleoside triphosphate (NTP)-binding pocket of the APH(2″)-IVa F95Y mutant allows the tyrosine to move away, thus giving access to the ATP-binding template. PMID:23716051

  10. Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach.

    PubMed

    Hsu, Kai-Cheng; Liu, Chang-Yi; Lin, Tony Eight; Hsieh, Jui-Hua; Sung, Tzu-Ying; Tseng, Hui-Ju; Yang, Jinn-Moon; Huang, Wei-Jan

    2017-06-12

    Histone deacetylases (HDAC) contain eighteen isoforms that can be divided into four classes. Of these isoform enzymes, class IIa (containing HDAC4, 5, 7 and 9) target unique substrates, some of which are client proteins associated with epigenetic control. Class IIa HDACs are reportedly associated with some neuronal disorders, making HDACs therapeutic targets for treating neurodegenerative diseases. Additionally, some reported HDAC inhibitors contain hydroxamate moiety that chelates with zinc ion to become the cofactor of HDAC enzymes. However, the hydroxamate functional group is shown to cause undesirable effects and has poor pharmacokinetic profile. This study used in silico virtual screening methodology to identify several nonhydroxamate compounds, obtained from National Cancer Institute database, which potentially inhibited HDAC4. Comparisons of the enzyme inhibitory activity against a panel of HDAC isoforms revealed these compounds had strong inhibitory activity against class IIa HDACs, but weak inhibitory activity against class I HDACs. Further analysis revealed that a single residue affects the cavity size between class I and class IIa HDACs, thus contributing to the selectivity of HDAC inhibitors discovered in this study. The discovery of these inhibitors presents the possibility of developing new therapeutic treatments that can circumvent the problems seen in traditional hydroxamate-based drugs.

  11. 30 CFR 57.22304 - Approved equipment (II-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Approved equipment (II-A mines). 57.22304 Section 57.22304 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...

  12. 30 CFR 57.22304 - Approved equipment (II-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Approved equipment (II-A mines). 57.22304 Section 57.22304 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...

  13. 30 CFR 57.22304 - Approved equipment (II-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Approved equipment (II-A mines). 57.22304 Section 57.22304 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...

  14. 30 CFR 57.22304 - Approved equipment (II-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Approved equipment (II-A mines). 57.22304 Section 57.22304 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...

  15. 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

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

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 57.22307 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 Methane in Metal and Nonmetal Mines Equipment § 57.22307 Methane monitors (II-A mines)....

  17. 30 CFR 57.22304 - Approved equipment (II-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Section 57.22304 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 Methane in Metal and Nonmetal Mines Equipment § 57.22304 Approved equipment (II-A mines)....

  18. Production and immunogenicity of Actinobacillus pleuropneumoniae ApxIIA protein in transgenic rice callus.

    PubMed

    Kim, Mi-Young; Kim, Tae-Geum; Yang, Moon-Sik

    2017-04-01

    Actinobacillus pleuropneumoniae is a major etiological agent that is responsible for swine pleuropneumonia, a highly contagious respiratory infection that causes severe economic losses in the swine production industry. ApxIIA is one of the virulence factors in A. pleuropneumoniae and has been considered as a candidate for developing a vaccine against the bacterial infection. A gene encoding an ApxIIA fragment (amino acids 439-801) was modified based on a plant-optimized codon and constructed into a plant expression vector under the control of a promoter and the 3' UTR of the rice amylase 3D gene. The plant expression vector was introduced into rice embryogenic callus (Oryza sativa L. cv. Dongjin) via particle bombardment-mediated transformation. The integration and transcription of the ApxIIA439-801 gene were confirmed by using genomic DNA PCR amplification and Northern blot analysis, respectively. The synthesis of ApxIIA439-801 antigen protein in transgenic rice callus was confirmed by western blot analysis. The concentration of antigen protein in lyophilized samples of transgenic rice callus was 250 μg/g. Immunizing mice with protein extracts from transgenic plants intranasally elicited secretory IgA. These results demonstrate the feasibility of using a transgenic plant to elicit immune responses against A. pleuropneumoniae. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Job Training Partnership Act PY '91 Title II-A Program Review.

    ERIC Educational Resources Information Center

    McDaniel, Sue; Riley, Dee Ann

    Management information system (MIS) data about women's participation in Missouri's job training system funded under Title II-A of the Job Training Partnership Act (JTPA) in program year 1992 were analyzed. Analysis of data from Missouri's 15 service delivery areas (SDAs) established the following: 75% of the state's 4,598 female JTPA participants…

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 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 Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22230 Weekly testing (II-A mines). (a...

  1. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 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 Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22230 Weekly testing (II-A mines). (a...

  2. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 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 Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22230 Weekly testing (II-A mines). (a...

  3. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 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 Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22230 Weekly testing (II-A mines). (a...

  4. 30 CFR 57.22230 - Weekly testing (II-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 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 Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22230 Weekly testing (II-A mines). (a...

  5. Purification and characterization of a phospholipase A2-IIA from common stingray (Dasyatis pastinaca) intestine.

    PubMed

    Ben Bacha, Abir; Daihan, Sooad K; Moubayed, Nadine M S; Mejdoub, Hafedh

    2013-06-01

    A phospholipase A2 belonging to IIA group secretory PLA2 was isolated and purified to homogeneity from the intestine of common stingray (Dasyatis pastinaca) using acidic treatment (pH 1.5) and ammonium sulphate precipitation methods combined with single-column ion-exchange chromatography. The purified enzyme was found to be a glycosylated monomeric protein with a molecular mass of about 14 kDa. The stingray sPLA2-IIA had optimum activity at 45 degrees C, unlike known mammalian PLA2-IIAs, which show optimum activity at 37 degrees C. The purified enzyme exhibited a specific activity of 290 U/mg at optimal conditions (pH 9.5 and 45 degrees C) in the presence of 6 mM NaDC and 8 mM CaCl2 with egg yolk as substrate. The NH2-terminal sequence of the enzyme and some protein fragments obtained from its tryptic digestion were also determined. All sequences obtained were similar to those of sPLA2-IIA. The enzyme also showed good stability in the presence of organic solvents, acidic and alkaline pH media and high temperature conditions. Thus, the purified enzyme exhibited a number of unique and promising properties, making it a potential possible candidate for future applications in the treatment of phospholipid-rich industrial effluents and synthesis of useful preparations for the food production and processing industry.

  6. [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.

  7. Tanshinone IIA protects rabbits against LPS-induced disseminated intravascular coagulation (DIC).

    PubMed

    Wu, Liang-Cai; Lin, Xi; Sun, Hao

    2012-10-01

    To evaluate the effects of tanshinone IIA (Tan IIA), a lipophilic diterpene from the Chinese herb Salvia miltiorrhiza, on lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) in rabbits. LPS-induced DIC model was made in adult male New Zealand rabbits by continuous intravenous infusion of LPS (0.5 mg/kg) via marginal ear vein for 6 h. The animals were simultaneously administered with Tan IIA (1, 3 and 10 mg/kg) or heparin (500 000 IU/kg) through continuous infusion via the contralateral marginal ear vein for 6 h. Before and 2 and 6 h after the start of LPS infusion, blood samples were taken for biochemical analyses. Continuous infusion of LPS into the rabbits gradually impaired the hemostatic parameters, damaged renal and liver functions, increased the plasma TNF-α level, and led to a high mortality rate (80%). Treatment of the rabbits with Tan IIA dose-dependently attenuated the increase in activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrin-fibrinogen degradation products (FDP); ameliorated the decrease in plasma levels of fibrinogen and platelets; and reversed the decline in activity of protein C and antithrombin III. Meanwhile, the treatment significantly suppressed the increase in the plasma levels of aminotransferase, creatinine and TNF-α, and led to much lower mortality (46.7% and 26.7% for the medium- and high-dose groups). Treatment of the rabbits with the high dose of heparin also effectively improved the hemostatic parameters, ameliorated liver and renal injuries, and reduced the plasma level of TNF-α, and significantly reduced the mortality (33.3%). Tan IIA exerts a protective effect against DIC in rabbits.

  8. Concurrent chemoradiotherapy with nedaplatin in patients with stage IIA to IVA cervical carcinoma.

    PubMed

    Fujioka, Toru; Yasuoka, Toshiaki; Koizumi, Masae; Tanaka, Hiroki; Hashimoto, Hisashi; Nabeta, Motoo; Koizumi, Koji; Matsubara, Yuko; Hamada, Katsuyuki; Matsubara, Keiichi; Katayama, Tomihiro; Nawa, Akihiro

    2013-01-01

    The present study aimed to evaluate the efficacy and toxicities of nadaplatin-based concurrent chemoradiotherapy (CCRT) in patients with stage IIA to IVA cervical carcinoma. Patients with an International Federation of Gynecology and Obstetrics (FIGO) stage IIA to IVA cervical carcinoma were treated with nadaplatin-based CCRT, using high-dose rate intracavitary brachytherapy (HDR-ICBT) or radiotherapy (RT) alone, in patients with FIGO stage IIA to IVA cervical carcinoma. CCRT with nedaplatin (80 mg/m(2)) was administered on Days 1 and 29. The records of 17 women treated either with nadaplatin-based CCRT using HSR-ICBT (n=8) or RT alone (n=9), for stage IIA to IVA cervical carcinoma were retrospectively reviewed. The activity and toxicity were compared in the two treatment groups. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. The 5-year overall survival rates in the CCRT and RT groups were 68.6 and 77.8%, respectively. The median OS of the CCRT and RT groups was 38.5 and 27.3 months, respectively. There was no significant difference in either PFS (P=0.618) or OS (P= 0.231). The most common grade 3-4 or higher toxicities in the CCRT groups were leuko-/neutropenia (37.5%). The frequency of acute grade 3-4 toxicity was higher in the CCRT compared to the RT group. However, no statistically significant difference was observed. Nedaplatin-based CCRT was safely performed. Although the prognosis of patients with FIGO stage IIA to IVA cervical carcinoma was not significantly improved, fewer distant relapses were observed in this treatment. Consequently, nedaplatin-based CCRT may be considered as a potential alternative to cisplatin-based CCRT in this patient population.

  9. 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

  10. Plasma secretory phospholipase A2-IIa as a potential biomarker for lung cancer in patients with solitary pulmonary nodules

    PubMed Central

    2011-01-01

    Background Five-year survival for lung cancer has remained at 16% over last several decades largely due to the fact that over 50% of patients are diagnosed with locally-advanced or metastatic disease. Diagnosis at an earlier and potentially curable stage is crucial. Solitary pulmonary nodules (SPNs) are common, but the difficulty lies in the determination of which SPN is malignant. Currently, there is no convenient and reliable biomarker effective for early diagnosis. Secretory phospholipase A2-IIa (sPLA2-IIa) is secreted into the circulation by cancer cells and may allow for an early detection of lung cancer. Methods Plasma samples from healthy donors, patients with only benign SPN, and patients with lung cancer were analyzed. Expression of sPLA2-IIa protein in lung cancer tissues was also determined. Results We found that the levels of plasma sPLA2-IIa were significantly elevated in lung cancer patients. The receiver operating characteristic curve analysis, comparing lung cancer patients to patients with benign nodules, revealed an optimum cutoff value for plasma sPLA2-IIa of 2.4 ng/ml to predict an early stage cancer with 48% sensitivity and 86% specificity and up to 67% sensitivity for T2 stage lung cancer. Combined sPLA2-IIa, CEA, and Cyfra21.1 tests increased the sensitivity for lung cancer prediction. High level of plasma sPLA2-IIa was associated with a decreased overall cancer survival. sPLA2-IIa was overexpressed in almost all non-small cell lung cancer and in the majority of small cell lung cancer by immunohistochemistry analysis. Conclusion Our finding strongly suggests that plasma sPLA2-IIa is a potential lung biomarker to distinguish benign nodules from lung cancer and to aid lung cancer diagnosis in patients with SPNs. PMID:22151235

  11. The prevention and treatment effects of tanshinone IIA on oestrogen/androgen-induced benign prostatic hyperplasia in rats.

    PubMed

    Wang, Chao; Du, Xiaoling; Yang, Rui; Liu, Jie; Xu, Da; Shi, Jiandang; Chen, Linfeng; Shao, Rui; Fan, Guanwei; Gao, Xiumei; Tian, Guo; Zhu, Yan; Zhang, Ju

    2015-01-01

    Benign prostatic hyperplasia (BPH) is one of the major diseases of the urinary system in elderly men. Tanshinone IIA (Tan IIA) is the active ingredient extracted from the traditional Chinese medicine Salvia, and it has effects of anti-oxidation, anti-inflammation, vascular smooth muscle relaxation and tumour growth inhibition. The present study aimed to investigate the therapeutic potential of Tan IIA in the prevention and treatment of BPH. In a rat model of oestradiol/testosterone-induced BPH, Tan IIA inhibited the increase in the thickness of the peri-glandular smooth muscle layer, suppressed the expression of proliferating cell nuclear antigen (PCNA) in both prostate epithelial cells and stromal cells, downregulated the expression of androgen receptor (AR), oestrogen receptor α (ERα), cyclin B1 (CCNB1) and cyclin D1 (CCND1), and effectively prevented the development of the disorder. In vitro, Tan IIA inhibited the proliferation of human prostate stromal cell line WPMY-1 and epithelial cell line RWPE-1 in a dose- and time-dependent manner. In WPMY-1 cells, Tan IIA treatment arrested the cell cycle at the G2/M phase and downregulated the expression of CCNB1. However, in RWPE-1 cells, Tan IIA treatment arrested cell cycle at the G0/G1 phase and reduced the expression of CCND1. Tan IIA also reduced the expression of ERα and AR in WPMY-1 and RWPE-1 cells. These results suggest that Tan IIA can inhibit the growth of prostate stromal and epithelial cells both in vivo and in vitro by a mechanism that may involve arresting the cell cycle and downregulating ERα and AR expression.

  12. Comparison of the carbohydrate-binding specificities of cholera toxin and Escherichia coli heat-labile enterotoxins LTh-I, LT-IIa, and LT-IIb.

    PubMed Central

    Fukuta, S; Magnani, J L; Twiddy, E M; Holmes, R K; Ginsburg, V

    1988-01-01

    The heat-labile enterotoxins of Vibrio cholerae and Escherichia coli are related in structure and function. They are oligomers consisting of A and B polypeptide subunits. They bind to gangliosides, and they activate adenylate cyclase. The toxins form two antigenically distinct groups; members of each group cross-react but are not necessarily identical. Serogroup I includes cholera toxin (CT) and type I heat-labile enterotoxin (LT-I) of E. coli. LTh-I and LTp-I are antigenic variants of LT-I produced by strains of E. coli from humans and pigs, respectively. Serogroup II contains the type II heat-labile enterotoxin (LT-II) of E. coli. Two antigenic variants designated LT-IIa and LT-IIb have been described. The binding of CT, LTh-I, LT-IIa, and LT-IIb to gangliosides was analyzed by immunostaining thin-layer chromatograms and by solid-phase radioimmunoassay. The four toxins have different glycolipid-binding specificities. LTh-I and CT bind strongly to ganglioside GM1 and less strongly to ganglioside GD1b. However, LTh-I, unlike CT, also binds weakly to GM2 and asialo GM1. LTh-I, like CT, probably binds to the terminal sugar sequence Gal beta 1-3GalNAc beta 1-4(NeuAc alpha 2-3)Gal . . ., where GalNAc is N-acetylgalactosamine and NeuAc is N-acetylneuraminic acid. LT-IIa probably binds to the same sugar sequence to which CT and LTh-I bind, with the additional contribution to binding of a second NeuAc as in GD1b and GD2. Also, LT-IIa must bind the Gal beta 1-3GalNAc . . . sequence in such a way that its binding is relatively unaffected by attachment of NeuAc to the terminal galactose residue as in GD1a, GT1b, and GQ1b. LT-IIb probably binds to the terminal sugar sequence NeuAc alpha 2-3Gal beta 1-4GalNAc . . ., as it binds to gangliosides GD1a and GT1b but not to GM1. Images PMID:3290106

  13. Essential amino acids of starch synthase IIa differentiate amylopectin structure and starch quality between japonica and indica rice varieties.

    PubMed

    Nakamura, Yasunori; Francisco, Perigio B; Hosaka, Yuko; Sato, Aya; Sawada, Takayuki; Kubo, Akiko; Fujita, Naoko

    2005-05-01

    Four amino acids were variable between the 'active' indica-type and 'inactive' japonica-type soluble starch synthase IIa (SSIIa) of rice plants; Glu-88 and Gly-604 in SSIIa of indica-cultivars IR36 and Kasalath were replaced by Asp-88 and Ser-604, respectively, in both japonica cultivars Nipponbare and Kinmaze SSIIa, whereas Val-737 and Leu-781 in indica SSIIa were replaced by Met-737 in cv. Nipponbare and Phe-781 in cv. Kinmaze SSIIa, respectively. The SSIIa gene fragments shuffling experiments revealed that Val-737 and Leu-781 are essential not only for the optimal SSIIa activity, but also for the capacity to synthesize indica-type amylopectin. Surprisingly, however, a combination of Phe-781 and Gly-604 could restore about 44% of the SSIIa activity provided that Val-737 was conserved. The introduction of the 'active' indica-type SSIIa gene enabled the japonica-type cv. Kinmaze to synthesize indica-type amylopectin. The starch in the transformed japonica rice plants exhibited gelatinization-resistant properties that are characteristic of indica-rice starch. Transformed lines expressing different levels of the IR36 SSIIa protein produced a variety of starches with amylopectin chain-length distribution patterns that correlated well with their onset temperatures of gelatinization. The present study confirmed that the SSIIa activity determines the type of amylopectin structure of rice starch to be either the typical indica-type or japonica-type, by playing a specific role in the synthesis of the long B(1) chains by elongating short A and B(1) chains, notwithstanding the presence of functional two additional SSII genes, a single SSI gene, two SSIII genes, and two SSIV genes in rice plants.

  14. Decreased pretreatment lymphocyte/monocyte ratio is associated with poor prognosis in stage Ib1–IIa cervical cancer patients who undergo radical surgery

    PubMed Central

    Chen, Liang; Zhang, Fang; Sheng, Xiu-gui; Zhang, Shi-qian

    2015-01-01

    Background Recently, pretreatment monocyte counts and the lymphocyte/monocyte ratio (LMR) have been proven to be significantly associated with the clinical outcomes of several types of cancer. In this study, we analyzed the prognostic significance of the LMR in stage Ib1–IIa cervical cancer patients who underwent a radical operation. Methods A total of 485 patients with stage Ib1–IIa cervical cancer were included in this retrospective study. We evaluated the prognostic values of the absolute lymphocyte count, absolute monocyte count, and LMR by applying receiver operating characteristic curves. Kaplan–Meier curves and multivariate Cox proportional analyses were used to determine the recurrence-free survival (RFS) and overall survival (OS). Results The area under the curve was 0.640 for the RFS and 0.647 for the OS using the LMR. In the univariate analysis, an elevated preoperative LMR was significantly associated with an increased RFS (hazard ratio [HR], 0.373; 95% confidence interval [CI]: 0.247–0.563; P<0.001), and this result remained significant in the multivariate analysis (HR, 0.439; 95% CI: 0.279–0.693; P<0.001). In the univariate analysis, an elevated LMR was also significantly associated with an increased OS (HR, 0.381; 95% CI: 0.233–0.622; P<0.001), and the significance persisted in the multivariate analysis (HR, 0.417; 95% CI: 0.244–0.714; P=0.001). Conclusion A decreased pretreatment LMR is associated with a poor prognosis in stage Ib1–IIa cervical cancer patients who undergo a radical operation. A prospective study is warranted for further validation of our findings. PMID:26089685

  15. Brane cosmology in the Horava-Witten heterotic M-theory on S{sup 1}/Z{sub 2}

    SciTech Connect

    Wu, Qiang; Gong, Yungui; Wang, Anzhong E-mail: gongyg@cqupt.edu.cn

    2009-06-01

    We study the radion stability and radion mass in the framework of the Horava-Witten (HW) heterotic M-Theory on S{sup 1}/Z{sub 2}, and find that the radion is stable and its mass can be of the order of GeV. The gravity is localized on the visible brane, and the spectrum of the gravitational Kaluza-Klein (KK) modes is discrete and can have a mass gap of TeV. The corrections to the 4D Newtonian potential from the higher order gravitational KK modes are exponentially suppressed. Applying such a setup to cosmology, we find the generalized Friedmann-like equations on each of the two orbifold branes.

  16. 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.

  17. 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.

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

    NASA Astrophysics Data System (ADS)

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

    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.

  19. Drug-target networks for Tanshinone IIA identified by data mining.

    PubMed

    Chen, Shao-Jun

    2015-10-01

    Tanshinone IIA is a pharmacologically active compound isolated from Danshen (Salvia miltiorrhiza), a traditional Chinese herbal medicine for the management of cardiac diseases and other disorders. But its underlying molecular mechanisms of action are still unclear. The present investigation utilized a data mining approach based on network pharmacology to uncover the potential protein targets of Tanshinone IIA. Network pharmacology, an integrated multidisciplinary study, incorporates systems biology, network analysis, connectivity, redundancy, and pleiotropy, providing powerful new tools and insights into elucidating the fine details of drug-target interactions. In the present study, two separate drug-target networks for Tanshinone IIA were constructed using the Agilent Literature Search (ALS) and STITCH (search tool for interactions of chemicals) methods. Analysis of the ALS-constructed network revealed a target network with a scale-free topology and five top nodes (protein targets) corresponding to Fos, Jun, Src, phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and mitogen-activated protein kinase kinase 1 (MAP2K1), whereas analysis of the STITCH-constructed network revealed three top nodes corresponding to cytochrome P450 3A4 (CYP3A4), cytochrome P450 A1 (CYP1A1), and nuclear factor kappa B1 (NFκB1). The discrepancies were probably due to the differences in the divergent computer mining tools and databases employed by the two methods. However, it is conceivable that all eight proteins mediate important biological functions of Tanshinone IIA, contributing to its overall drug-target network. In conclusion, the current results may assist in developing a comprehensive understanding of the molecular mechanisms and signaling pathways of in a simple, compact, and visual manner. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  20. Ligand promiscuity through the eyes of the aminoglycoside N3 acetyltransferase IIa

    PubMed Central

    Norris, Adrianne L; Serpersu, Engin H

    2013-01-01

    Aminoglycoside-modifying enzymes (AGMEs) are expressed in many pathogenic bacteria and cause resistance to aminoglycoside (AG) antibiotics. Remarkably, the substrate promiscuity of AGMEs is quite variable. The molecular basis for such ligand promiscuity is largely unknown as there is not an obvious link between amino acid sequence or structure and the antibiotic profiles of AGMEs. To address this issue, this article presents the first kinetic and thermodynamic characterization of one of the least promiscuous AGMEs, the AG N3 acetyltransferase-IIa (AAC-IIa) and its comparison to two highly promiscuous AGMEs, the AG N3-acetyltransferase-IIIb (AAC-IIIb) and the AG phosphotransferase(3′)-IIIa (APH). Despite having similar antibiotic selectivities, AAC-IIIb and APH catalyze different reactions and share no homology to one another. AAC-IIa and AAC-IIIb catalyze the same reaction and are very similar in both amino acid sequence and structure. However, they demonstrate strong differences in their substrate profiles and kinetic and thermodynamic properties. AAC-IIa and APH are also polar opposites in terms of ligand promiscuity but share no sequence or apparent structural homology. However, they both are highly dynamic and may even contain disordered segments and both adopt well-defined conformations when AGs are bound. Contrary to this AAC-IIIb maintains a well-defined structure even in apo form. Data presented herein suggest that the antibiotic promiscuity of AGMEs may be determined neither by the flexibility of the protein nor the size of the active site cavity alone but strongly modulated or controlled by the effects of the cosubstrate on the dynamic and thermodynamic properties of the enzyme. PMID:23640799

  1. 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,...

  2. 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,...

  3. 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,...

  4. 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,...

  5. 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,...

  6. 30 CFR 57.22103 - Open flames (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 Open flames (I-A, II-A, III, and V-A mines). 57... Open flames (I-A, II-A, III, and V-A mines). Open flames shall not be permitted underground except for... I-A mine. When using open flames in other than fresh air, or in places where methane may enter the...

  7. 30 CFR 57.22103 - Open flames (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 Open flames (I-A, II-A, III, and V-A mines). 57... Open flames (I-A, II-A, III, and V-A mines). Open flames shall not be permitted underground except for... I-A mine. When using open flames in other than fresh air, or in places where methane may enter the...

  8. 30 CFR 57.22103 - Open flames (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 Open flames (I-A, II-A, III, and V-A mines). 57... Open flames (I-A, II-A, III, and V-A mines). Open flames shall not be permitted underground except for... I-A mine. When using open flames in other than fresh air, or in places where methane may enter the...

  9. 30 CFR 57.22103 - Open flames (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 Open flames (I-A, II-A, III, and V-A mines). 57... Open flames (I-A, II-A, III, and V-A mines). Open flames shall not be permitted underground except for... I-A mine. When using open flames in other than fresh air, or in places where methane may enter the...

  10. 30 CFR 57.22103 - Open flames (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 Open flames (I-A, II-A, III, and V-A mines). 57... Open flames (I-A, II-A, III, and V-A mines). Open flames shall not be permitted underground except for... I-A mine. When using open flames in other than fresh air, or in places where methane may enter the...

  11. Development of innovative pediocin PA-1 by DNA shuffling among class IIa bacteriocins.

    PubMed

    Tominaga, Tatsuya; Hatakeyama, Yoshinori

    2007-08-01

    Pediocin PA-1 is a member of the class IIa bacteriocins, which show antimicrobial effects against lactic acid bacteria. To develop an improved version of pediocin PA-1, reciprocal chimeras between pediocin PA-1 and enterocin A, another class IIa bacteriocin, were constructed. Chimera EP, which consisted of the C-terminal half of pediocin PA-1 fused to the N-terminal half of enterocin A, showed increased activity against a strain of Leuconostoc lactis isolated from a sour-spoiled dairy product. To develop an even more effective version of this chimera, a DNA-shuffling library was constructed, wherein four specific regions within the N-terminal half of pediocin PA-1 were shuffled with the corresponding sequences from 10 other class IIa bacteriocins. Activity screening indicated that 63 out of 280 shuffled mutants had antimicrobial activity. A colony overlay activity assay showed that one of the mutants (designated B1) produced a >7.8-mm growth inhibition circle on L. lactis, whereas the parent pediocin PA-1 did not produce any circle. Furthermore, the active shuffled mutants showed increased activity against various species of Lactobacillus, Pediococcus, and Carnobacterium. Sequence analysis revealed that the active mutants had novel N-terminal sequences; in active mutant B1, for example, the parental pediocin PA-1 sequence (KYYGNGVTCGKHSC) was changed to TKYYGNGVSCTKSGC. These new and improved DNA-shuffled bacteriocins could prove useful as food additives for inhibiting sour spoilage of dairy products.

  12. Roles and Targets of Class I and IIa Histone Deacetylases in Cardiac Hypertrophy

    PubMed Central

    Kee, Hae Jin; Kook, Hyun

    2011-01-01

    Cardiac hypertrophy occurs in association with heart diseases and ultimately results in cardiac dysfunction and heart failure. Histone deacetylases (HDACs) are post-translational modifying enzymes that can deacetylate histones and non-histone proteins. Research with HDAC inhibitors has provided evidence that the class I HDACs are pro-hypertrophic. Among the class I HDACs, HDAC2 is activated by hypertrophic stresses in association with the induction of heat shock protein 70. Activated HDAC2 triggers hypertrophy by inhibiting the signal cascades of either Krüppel like factor 4 (KLF4) or inositol polyphosphate-5-phosphatase f (Inpp5f). Thus, modulators of HDAC2 enzymes, such as selective HDAC inhibitors, are considered to be an important target for heart diseases, especially for preventing cardiac hypertrophy. In contrast, class IIa HDACs have been shown to repress cardiac hypertrophy by inhibiting cardiac-specific transcription factors such as myocyte enhancer factor 2 (MEF2), GATA4, and NFAT in the heart. Studies of class IIa HDACs have shown that the underlying mechanism is regulated by nucleo-cytoplasm shuttling in response to a variety of stress signals. In this review, we focus on the class I and IIa HDACs that play critical roles in mediating cardiac hypertrophy and discuss the non-histone targets of HDACs in heart disease. PMID:21151616

  13. Regulation of amantadine hydrochloride binding with IIA subdomain of human serum albumin by fatty acid chains.

    PubMed

    Yang, Feng; Lee, Philbert; Ma, Zhiyuan; Ma, Li; Yang, Guoping; Wu, Xiaoyang; Liang, Hong

    2013-01-01

    Human serum albumin (HSA) is a major protein component of blood plasma that has been exploited to bind and transport a wide variety of endogenous and exogenous organic compounds. Although anionic drugs readily associate with the IIA subdomain of HSA, most cationic drugs poorly associate with HSA at this subdomain. In this study, we propose to improve the association between cationic drugs and HSA by modifying HSA with fatty acid chains. For our experiments, we tested amantadine hydrochloride, a cationic drug with antiviral and antiparkinsonian effects. Our results suggest that extensive myristoylation of HSA can help stabilize the interaction between amantadine and HSA in vitro. Our X-ray crystallography data further elucidate the structural basis of this regulation. Additionally, our crystallography data suggest that anionic drugs, with a functional carboxylate group, may enhance the association between amantadine and HSA by a mechanism similar to myristoylation. Ultimately, our results provide critical structural insight into this novel association between cationic drugs and the HSA IIA subdomain, raising the tempting possibility to fully exploit the unique binding capacity of HSA's IIA subdomain to achieve simultaneous delivery of anionic and cationic drugs.

  14. Src-dependent Tyrosine Phosphorylation of Non-muscle Myosin Heavy Chain-IIA Restricts Listeria monocytogenes Cellular Infection*

    PubMed Central

    Almeida, Maria Teresa; Mesquita, Francisco S.; Cruz, Rui; Osório, Hugo; Custódio, Rafael; Brito, Cláudia; Vingadassalom, Didier; Martins, Mariana; Leong, John M.; Holden, David W.; Cabanes, Didier; Sousa, Sandra

    2015-01-01

    Bacterial pathogens often interfere with host tyrosine phosphorylation cascades to control host responses and cause infection. Given the role of tyrosine phosphorylation events in different human infections and our previous results showing the activation of the tyrosine kinase Src upon incubation of cells with Listeria monocytogenes, we searched for novel host proteins undergoing tyrosine phosphorylation upon L. monocytogenes infection. We identify the heavy chain of the non-muscle myosin IIA (NMHC-IIA) as being phosphorylated in a specific tyrosine residue in response to L. monocytogenes infection. We characterize this novel post-translational modification event and show that, upon L. monocytogenes infection, Src phosphorylates NMHC-IIA in a previously uncharacterized tyrosine residue (Tyr-158) located in its motor domain near the ATP-binding site. In addition, we found that other intracellular and extracellular bacterial pathogens trigger NMHC-IIA tyrosine phosphorylation. We demonstrate that NMHC-IIA limits intracellular levels of L. monocytogenes, and this is dependent on the phosphorylation of Tyr-158. Our data suggest a novel mechanism of regulation of NMHC-IIA activity relying on the phosphorylation of Tyr-158 by Src. PMID:25635050

  15. Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β

    PubMed Central

    Jiang, Chunming; Zhu, Wei; Yan, Xiang; Shao, Qiuyuan; Xu, Biao; Zhang, Miao; Gong, Rujun

    2016-01-01

    Acute kidney injury (AKI) remains challenging for clinical practice and poses a risk of developing progressive chronic kidney disease (CKD) with no definitive treatment available yet. Tanshinone IIA, an active ingredient of Chinese herbal Salvia miltiorrhiza, has been widely used in Asia for the remarkable organoprotective activities. Its effect on established AKI, however, remains unknown. In mice with folic acid-induced AKI, delayed treatment with Tanshinone IIA, commenced early or late after injury, diminished renal expression of kidney injury markers, reduced apoptosis and improved kidney dysfunction, concomitant with mitigated histologic signs of AKI to CKD transition, including interstitial fibrosis and tubular atrophy, and with an ameliorated inflammatory infiltration in tubulointerstitium and a favored M2-skewed macrophage polarization. Mechanistically, Tanshinone IIA blunted glycogen synthase kinase (GSK)3β overactivity and hyperactivation of its downstream mitogen-activated protein kinases that are centrally implicated in renal fibrogenesis and inflammation. Inhibition of GSK3β is likely a key mechanism mediating the therapeutic activity of Tanshinone IIA, because sodium nitroprusside, a GSK3β activator, largely offset its renoprotective effect. In confirmatory studies, rescue treatment with Tanshinone IIA likewise ameliorated ischemia/reperfusion-induced kidney destruction in mice. Our data suggest that Tanshinone IIA represents a valuable treatment that improves post-AKI kidney salvage via targeting GSK3β. PMID:27857162

  16. Fludarabine resistance mediated by aminoglycoside-3'-phosphotransferase-IIa and the structurally related eukaryotic cAMP-dependent protein kinase.

    PubMed

    Sánchez-Carrera, Dámaso; Bravo-Navas, Sara; Cabezón, Elena; Arechaga, Ignacio; Cabezas, Matilde; Yáñez, Lucrecia; Pipaón, Carlos

    2017-04-03

    While working with G418-resistant stably transfected cells, we realized the neomycin resistance gene (NeoR), which encodes the aminoglycoside-3'-phosphotransferase-IIa [APH(3')-IIa], also confers resistance to the nucleoside analog fludarabine. Fludarabine is a cytostatic drug widely used in the treatment of hematologic and solid tumors as well as in the conditioning of patients before transplantation of hematopoietic progenitors. We present evidence that NeoR-transfected cells do not incorporate fludarabine, thus avoiding DNA damage caused by the drug, evidenced by a lack of FANCD2 monoubiquitination and impaired apoptosis. A screening of other nucleoside analogs revealed that APH(3')-IIa only protects against ATP purine analogs. Moreover, APH(3')-IIa ATPase activity is inhibited by fludarabine monophosphate, suggesting that APH(3')-IIa blocks fludarabine incorporation into DNA by dephosphorylating its active fludarabine triphosphate form. Furthermore, overexpression of the catalytic subunit of the eukaryotic kinase PKA, which is structurally related to APHs, also provides resistance to fludarabine, anticipating its putative utility as a response marker to the drug. Our results preclude the use of Neo marker plasmids in the study of purine analogs and unveils a new resistance mechanism against these chemotherapeuticals.-Sánchez-Carrera, D., Bravo-Navas, S., Cabezón, E., Arechaga, I., Cabezas, M., Yáñez, L., Pipaón, C. Fludarabine resistance mediated by aminoglycoside-3'-phosphotransferase-IIa and the structurally related eukaryotic cAMP-dependent protein kinase.

  17. Anti-bactericidal properties of stingray Dasyatis pastinaca groups V, IIA, and IB phospholipases A2: a comparative study.

    PubMed

    Bacha, Abir Ben

    2014-10-01

    Group IIA secreted phospholipase A2 (group IIA sPLA2) is known to display potent Gram-positive bactericidal activity in vitro and in vivo. We have analyzed the bactericidal activity of the full set of native stingray and dromedary groups V, IIA, and IB sPLA2s on several Gram-positive and Gram-negative strains. The rank order potency among both marine and mammal sPLA2s against Gram-positive bacteria is group IIA > V > IB, whereas Gram-negative bacteria exhibited a much higher resistance. There is a synergic action of the sPLA2 with lysozyme when added to the bacteria culture prior to sPLA2.The bactericidal efficiency of groups V and IIA sPLA2s was shown to be dependent upon the presence of calcium ions and to a less extent Mg(2+) ions and then a correlation could be made to its hydrolytic activity of membrane phospholipids. Importantly, we showed that stingray and dromedary groups V, IIA, and IB sPLA2s present no cytotoxicity after their incubation with MDA-MB-231cells. stingray groups V and IIA sPLA2s, like mammal ones, may be considered as future therapeutic agents against bacterial infections.

  18. Effects of Statins and Xuezhikang on the Expression of Secretory Phospholipase A2, Group IIA in Rat Vascular Smooth Muscle Cells.

    PubMed

    Xie, Qiang; Zhang, Dan

    2017-02-07

    Atherosclerosis is a multifactorial vascular disease characterized by formation of inflammatory lesions. Secretory phospholipase A2, group IIA (sPLA2-IIA) is involved in this process and plays a critical role. However, the exact role of sPLA2-IIA in cardiovascular inflammation is more complicated and remains unclear. Furthermore, both statins and Xuezhikang (XZK) are widely used in the prevention and treatment of cardiovascular disease risk because of their pleiotropic effects on the cardiovascular system. However, their effects on sPLA2-IIA are still controversial. We investigated the regulation of sPLA2-IIA by rat thoracic aorta smooth muscle cells (VSMCs) in culture. Cells were first incubated with IL-1β alone to induce expression of sPLA2-IIA and then treated with several concentrations of statins or XZK for different times in the absence or presence of IL-1β. We tested the expression of sPLA2-IIA, including sPLA2-IIA mRNA, protein, as well as activity. We found that statins or IL-1β increase the expression of sPLA2-IIA in VSMCs and the effect is based on a synergetic relationship between them. However, for the first time, we observed that XZK effectively reduces sPLA2-IIA expression in IL-1β-treated VSMCs. Our findings may shine a new light on the clinical use of XZK and statins in the prevention and treatment of atherosclerosis-related thrombosis.

  19. Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases.

    PubMed

    Miles, Timothy J; Barfoot, Christopher; Brooks, Gerald; Brown, Pamela; Chen, Dongzhao; Dabbs, Steven; Davies, David T; Downie, David L; Eyrisch, Susanne; Giordano, Ilaria; Gwynn, Michael N; Hennessy, Alan; Hoover, Jennifer; Huang, Jianzhong; Jones, Graham; Markwell, Roger; Rittenhouse, Stephen; Xiang, Hong; Pearson, Neil

    2011-12-15

    As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.

  20. Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases.

    PubMed

    Miles, Timothy J; Axten, Jeffrey M; Barfoot, Christopher; Brooks, Gerald; Brown, Pamela; Chen, Dongzhao; Dabbs, Steven; Davies, David T; Downie, David L; Eyrisch, Susanne; Gallagher, Timothy; Giordano, Ilaria; Gwynn, Michael N; Hennessy, Alan; Hoover, Jennifer; Huang, Jianzhong; Jones, Graham; Markwell, Roger; Miller, William H; Minthorn, Elizabeth A; Rittenhouse, Stephen; Seefeld, Mark; Pearson, Neil

    2011-12-15

    We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.

  1. The effects of Tanshinone IIA on blood-brain barrier and brain edema after transient middle cerebral artery occlusion in rats.

    PubMed

    Tang, Chao; Xue, Hongli; Bai, Changlin; Fu, Rong; Wu, Anhua

    2010-12-01

    Disruption of blood-brain barrier (BBB) and edema formation play a key role in the development of neurological dysfunction after cerebral ischemia. In this study, the effects of Tanshinone IIA (Tan IIA), one of the active ingredients of Salvia miltiorrhiza root, on the BBB and brain edema after transient middle cerebral artery occlusion in rats were examined. Our study demonstrated that Tan IIA reduced brain infarct area, water content in the ischemic hemisphere. Furthermore, Tan IIA significantly decreased BBB permeability to Evans blue, suppressed the expression of intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), inhibited the degradation of tight junction proteins zonula occludens-1 (ZO-1) and Occludin. These results demonstrated that Tan IIA was effective for attenuating the extent of brain edema formation in response to ischemia injury in rats, partly by Tan IIA's protective effect on the BBB. Our results may have implications in the treatment of brain edema in cerebral ischemia.

  2. Defoliation induces fructan 1-exohydrolase II in Witloof chicory roots. Cloning and purification of two isoforms, fructan 1-exohydrolase IIa and fructan 1-exohydrolase IIb. Mass fingerprint of the fructan 1-exohydrolase II enzymes.

    PubMed

    Van den Ende, W; Michiels, A; Van Wonterghem, D; Clerens, S P; De Roover, J; Van Laere, A J

    2001-07-01

    The cloning of two highly homologous chicory (Cichorium intybus var. foliosum cv Flash) fructan 1-exohydrolase cDNAs (1-FEH IIa and 1-FEH IIb) is described. Both isoenzymes could be purified from forced chicory roots as well as from the etiolated "Belgian endive" leaves where the 1-FEH IIa isoform is present in higher concentrations. Full-length cDNAs were obtained by a combination of reverse transcriptase-polymerase chain reaction (PCR), PCR and 5'- and 3'-rapid amplification of cDNA ends using primers based on N-terminal and conserved amino acid sequences. 1-FEH IIa and 1-FEH IIb cDNA-derived amino acid sequences are most homologous to a new group of plant glycosyl hydrolases harboring cell wall-type enzymes with acid isoelectric points. Unlike the observed expression profiles of chicory 1-FEH I, northern analysis revealed that 1-FEH II is expressed when young chicory plants are defoliated, suggesting that this enzyme can be induced at any developmental stage when large energy supplies are necessary (regrowth after defoliation).

  3. Purification, amino acid sequence and characterization of the class IIa bacteriocin weissellin A, produced by Weissella paramesenteroides DX.

    PubMed

    Papagianni, Maria; Papamichael, Emmanuel M

    2011-06-01

    Weissella paramesenteroides DX has been shown to produce a 4450-Da class IIa bacteriocin, weissellin A, composed of 43 amino acids with the sequence KNYGNGVYCNKHKCSVDWATFSANIANNSVAMAGLTGGNAGN. The bacteriocin shares 68% similarity with leucocin C from Leuconostoc mesenteroides. Computational analyses predict that the bacteriocin is a hydrophobic molecule with a beta-sheet type conformation. Weissellin A exhibited various levels of activity against all gram-positive bacteria tested, but was not active against Salmonella enterica Enteritidis. The antimicrobial activity was not associated with target-cell lysis. The bacteriocin retained activity after exposure to 121°C for 60 min or to -20°C for 6months, and to pH 2.0-10.0. It was not sensitive to trypsin, α-chymotrypsin, pepsin and papain, but was inactivated by proteinase K. At a dissolved oxygen concentration of 50%, weissellin A was produced with growth-associated kinetics. The properties of weissellin A make this bacteriocin a potentially suitable agent for food and feed preservation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. 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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. On Simon's two-stage design for single-arm phase IIA cancer clinical trials under beta-binomial distribution.

    PubMed

    Liu, Junfeng; Lin, Yong; Shih, Weichung Joe

    2010-05-10

    Simon (Control. Clin. Trials 1989; 10:1-10)'s two-stage design has been broadly applied to single-arm phase IIA cancer clinical trials in order to minimize either the expected or the maximum sample size under the null hypothesis of drug inefficacy, i.e. when the pre-specified amount of improvement in response rate (RR) is not expected to be observed. This paper studies a realistic scenario where the standard and experimental treatment RRs follow two continuous distributions (e.g. beta distribution) rather than two single values. The binomial probabilities in Simon's (Control. Clin. Trials 1989; 10:1-10) design are replaced by prior predictive Beta-binomial probabilities that are the ratios of two beta functions and domain-restricted RRs involve incomplete beta functions to induce the null hypothesis acceptance probability. We illustrate that Beta-binomial mixture model based two-stage design retains certain desirable properties for hypothesis testing purpose. However, numerical results show that such designs may not exist under certain hypothesis and error rate (type I and II) setups within maximal sample size approximately 130. Furthermore, we give theoretical conditions for asymptotic two-stage design non-existence (sample size goes to infinity) in order to improve the efficiency of design search and to avoid needless searching.

  6. Alanine scan of α-conotoxin RegIIA reveals a selective α3β4 nicotinic acetylcholine receptor antagonist.

    PubMed

    Kompella, Shiva N; Hung, Andrew; Clark, Richard J; Marí, Frank; Adams, David J

    2015-01-09

    Activation of the α3β4 nicotinic acetylcholine receptor (nAChR) subtype has recently been implicated in the pathophysiology of various conditions, including development and progression of lung cancer and in nicotine addiction. As selective α3β4 nAChR antagonists, α-conotoxins are valuable tools to evaluate the functional roles of this receptor subtype. We previously reported the discovery of a new α4/7-conotoxin, RegIIA. RegIIA was isolated from Conus regius and inhibits acetylcholine (ACh)-evoked currents mediated by α3β4, α3β2, and α7 nAChR subtypes. The current study used alanine scanning mutagenesis to understand the selectivity profile of RegIIA at the α3β4 nAChR subtype. [N11A] and [N12A] RegIIA analogs exhibited 3-fold more selectivity for the α3β4 than the α3β2 nAChR subtype. We also report synthesis of [N11A,N12A]RegIIA, a selective α3β4 nAChR antagonist (IC50 of 370 nM) that could potentially be used in the treatment of lung cancer and nicotine addiction. Molecular dynamics simulations of RegIIA and [N11A,N12A]RegIIA bound to α3β4 and α3β2 suggest that destabilization of toxin contacts with residues at the principal and complementary faces of α3β2 (α3-Tyr(92), Ser(149), Tyr(189), Cys(192), and Tyr(196); β2-Trp(57), Arg(81), and Phe(119)) may form the molecular basis for the selectivity shift.

  7. Influence of Tanshinone IIA on apoptosis of human esophageal carcinoma Eca‐109 cells and its molecular mechanism

    PubMed Central

    He, Hang; Han, Qianqian; Wang, Baiyan; Zhu, Yanqin

    2017-01-01

    Background Previous studies have shown that Tanshinone (Tan) IIA exerts obvious antitumor efficacy; however, its molecular mechanism remains unclear. This study was conducted to identify the influence of Tan IIA on Eca‐109 cell apoptosis, explore its molecular mechanism, and provide a theoretical basis for clinical application. Methods Eca‐109 cells were cultured in vitro and treated with different concentrations of Tan IIA. Morphologic changes were viewed under inverted fluorescence microscope with dual acridine orange/ethidium bromide staining assay. Methyl‐thiazolyl‐tetrazolium and Annexin V propidium iodide assays were respectively used to measure cell viability and apoptosis rate. The protein and messenger (m)RNA expression of binding immunoglobulin protein (BIP), mitochondrial cytochrome c (CytC), and caspase‐9 were detected by Western blot and quantitative real‐time PCR, respectively. Results Cell viability decreased and the apoptosis rate significantly increased with increasing concentrations of Tan IIA (0, 20, 40, 60 μg/mL), which indicated that Tan IIA inhibited the proliferation and induced the apoptosis of Eca‐109 cells in a dose‐dependent manner. Eca‐109 cells treated with 60 μg/mLTan IIA showed typical morphological changes of apoptosis under the inverted microscope. Moreover, compared with the negative control group, protein and mRNA expression of BIP decreased significantly (P < 0.05), whereas protein and mRNA expression of CytC and caspase‐9 increased significantly (P < 0.05). Conclusion Tan IIA can induce apoptosis in human esophageal carcinoma Eca‐109 cells by regulating BIP, CytC, and caspase‐9 expression. Endoplasmic reticulum stress and mitochondrial‐dependent may be involved in Tan IIA‐induced Eca‐109 cell apoptosis. PMID:28407361

  8. Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in breast cancer.

    PubMed

    Wang, Weiwei; Zhang, Hangxiao; Wang, Xumin; Patterson, Jordan; Winter, Philip; Graham, Kathryn; Ghosh, Sunita; Lee, John C; Katsetos, Christos D; Mackey, John R; Tuszynski, Jack A; Wong, Gane Ka-Shu; Ludueña, Richard F

    2017-05-01

    Tubulin is the target for very widely used anti-tumor drugs, including Vinca alkaloids, taxanes, and epothilones, which are an important component of chemotherapy in breast cancer and other malignancies. Paclitaxel and other tubulin-targeting drugs bind to the β subunit of tubulin, which is a heterodimer of α and β subunits. β-Tubulin exists in the form of multiple isotypes, which are differentially expressed in normal and neoplastic cells and differ in their ability to bind to drugs. Among them, the βIII isotype is overexpressed in many aggressive and metastatic cancers and may serve as a prognostic marker in certain types of cancer. The underpinning mechanisms accounting for the overexpression of this isotype in cancer cells are unclear. To better understand the role of β-tubulin isotypes in cancer, we analyzed over 1000 clones from 90 breast cancer patients, sequencing their β-tubulin isotypes, in search of novel mutations. We have elucidated two putative emerging molecular subgroups of invasive breast cancer, each of which involve mutations in the βI-, βIIA-, or βIVB isotypes of tubulin that increase their structural, and possibly functional, resemblance to the βIII isotype. A unifying feature of the first of the two subgroups is the mutation of the highly reactive C239 residue of βI- or βIVB-tubulin to L239, R239, Y239, or P239, culminating in probable conversion of these isotypes from ROS-sensitive to ROS-resistant species. In the second subgroup, βI, βIIA, and βIVB have up to seven mutations to the corresponding residues in βIII-tubulin. Given that βIII-tubulin has emerged as a pro-survival factor, overexpression of this isotype may confer survival advantages to certain cancer cell types. In this mini-review, we bring attention to a novel mechanism by which cancer cells may undergo adaptive mutational changes involving alternate β-tubulin isotypes to make them acquire some of the pro-survival properties of βIII-tubulin. These "hybrid

  9. Skeletal muscle fibre types in the dog.

    PubMed Central

    Latorre, R; Gil, F; Vázquez, J M; Moreno, F; Mascarello, F; Ramirez, G

    1993-01-01

    Using a variety of histochemical methods we have investigated the mATPase reaction of skeletal muscle fibres in the dog. Types I, IIA, IIDog (peculiar to the dog) and IIC fibres were identified. The results reveal that the interpretation of the fibre type composition depends on the methods used. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8226288

  10. Energetics, molecular electronic structure, and spectroscopy of forming Group IIA dihalide complexes

    NASA Astrophysics Data System (ADS)

    Devore, T. C.; Gole, J. L.

    1999-02-01

    Multiple-collision relaxed (helium) chemiluminescence and laser-induced fluorescent spectroscopy have been used to demonstrate the highly efficient collisional stabilization of electronically excited Group IIA dihalide collision complexes formed in M (Ca,Sr)+X 2 (XY) (Cl 2, Br 2, ICl, IBr, I 2) reactive encounters. The first discrete emission spectra for the CaCl 2, CaBr 2, SrCl 2, SrBr 2, and SrICl dihalides are observed and evaluated; however, the low-pressure `continuous' chemiluminescent emission observed for forming barium dihalide (BaX 2) complexes is quenched under these experimental conditions. The reactions of the Group IIA metals with molecular fluorine do not readily produce the corresponding dihalide. While the lowest-lying observed dihalide visible transition is, as predicted, found to result in an extended progression in a dihalide complex bending mode (SrCl 2), the observed progression suggests the presence of a residual halogen (Cl-Cl) bond. Two higher-lying transitions are dominated by a vibrational mode structure corresponding to progressions in the symmetric stretching mode or, for nominally forbidden electronic transitions, odd quanta of the asymmetric stretching mode. Some evidence for sequence structure associated with the dihalide bending mode is also obtained. These observations are consistent with complex formation as it is coupled with a modified valence electron structure (correlation diagram) associated with the highly ionic nature of the dihalides. The bonding in the Group IIA dihalides (and their complexes), whose atomization energies are more than twice the metal monohalide bond energy, strongly influences the evaluation of energetics and the determination of monohalide bond energies from chemiluminescent processes. Discrepancies between those bond strengths determined by mass spectrometry and chemiluminescence are discussed with a focus on energy partitioning in dihalide complex formation and its influence on chemical vapor

  11. 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.

  12. The Crystal Structures of Substrate and Nucleotide Complexes of Enterococcus faecium Aminoglycoside-2′′-Phosphotransferase-IIa [APH(2′′)-IIa] Provide Insights into Substrate Selectivity in the APH(2′′) Subfamily▿ ‡

    PubMed Central

    Young, Paul G.; Walanj, Rupa; Lakshmi, Vendula; Byrnes, Laura J.; Metcalf, Peter; Baker, Edward N.; Vakulenko, Sergei B.; Smith, Clyde A.

    2009-01-01

    Aminoglycoside-2′′-phosphotransferase-IIa [APH(2′′)-IIa] is one of a number of homologous bacterial enzymes responsible for the deactivation of the aminoglycoside family of antibiotics and is thus a major component in bacterial resistance to these compounds. APH(2′′)-IIa produces resistance to several clinically important aminoglycosides (including kanamycin and gentamicin) in both gram-positive and gram-negative bacteria, most notably in Enterococcus species. We have determined the structures of two complexes of APH(2′′)-IIa, the binary gentamicin complex and a ternary complex containing adenosine-5′-(β,γ-methylene)triphosphate (AMPPCP) and streptomycin. This is the first crystal structure of a member of the APH(2′′) family of aminoglycoside phosphotransferases. The structure of the gentamicin-APH(2′′)-IIa complex was solved by multiwavelength anomalous diffraction methods from a single selenomethionine-substituted crystal and was refined to a crystallographic R factor of 0.210 (Rfree, 0.271) at a resolution of 2.5 Å. The structure of the AMPPCP-streptomycin complex was solved by molecular replacement using the gentamicin-APH(2′′)-IIa complex as the starting model. The enzyme has a two-domain structure with the substrate binding site located in a cleft in the C-terminal domain. Gentamicin binding is facilitated by a number of conserved acidic residues lining the binding cleft, with the A and B rings of the substrate forming the majority of the interactions. The inhibitor streptomycin, although binding in the same pocket as gentamicin, is orientated such that no potential phosphorylation sites are adjacent to the catalytic aspartate residue. The binding of gentamicin and streptomycin provides structural insights into the substrate selectivity of the APH(2′′) subfamily of aminoglycoside phosphotransferases, specifically, the selectivity between the 4,6-disubstituted and the 4,5-disubstituted aminoglycosides. PMID:19429619

  13. Tanshinone IIA inhibits the growth of pancreatic cancer BxPC‑3 cells by decreasing protein expression of TCTP, MCL‑1 and Bcl‑xL.

    PubMed

    Huang, Cheng-Yen; Chiu, Tsung-Lang; Kuo, Shou-Jen; Chien, Su-Yu; Chen, Dar-Ren; Su, Chin-Cheng

    2013-03-01

    Pancreatic cancer remains a challenging disease worldwide. Tanshinone IIA (Tan‑IIA) is one of the active constituents of Danshen (Radix Salviae miltiorrhizae). Tan‑IIA has been hypothesized to inhibit numerous human cancer cells by various molecular mechanisms. However, the efficacy and molecular mechanism of Tan‑IIA action in pancreatic cancer has not been well studied. In the present study, the cytotoxicity of Tan‑IIA in human pancreatic cancer BxPC‑3 cells was evaluated by MTT assay. Cell cycle analysis of BxPC‑3 cells treated with Tan‑IIA was performed by flow cytometry (FACS). Protein expression levels of TCTP, Mcl‑1, Bcl‑xL, Bax and Caspase‑3 in BxPC‑3 cells were measured by western blot analysis. The results revealed that Tan‑IIA inhibited BxPC‑3 cells in a time‑ and dose‑dependent manner. FACS analysis demonstrated that Tan‑IIA increases the rate of sub‑G1 phase. BxPC‑3 cells treated with Tan‑IIA were identified to upregulate protein expression of Bax and Caspase‑3 and downregulate expression of TCTP, Mcl‑1 and Bcl‑xL. These results indicate that Tan‑IIA may inhibit BxPC‑3 human pancreatic cancer cells through the induction of apoptosis by decreasing protein expression of TCTP, Mcl‑1 and Bcl‑xL and increasing Bax expression in vitro. The chemotherapeutic potential of Tan‑IIA for human pancreatic cancer warrants further study.

  14. Immunological study of an attenuated Salmonella Typhimurium expressing ApxIA, ApxIIA, ApxIIIA and OmpA of Actinobacillus pleuropneumoniae in a mouse model.

    PubMed

    Hur, Jin; Eo, Seong Kug; Park, Sang-Youel; Choi, Yoonyoung; Lee, John Hwa

    2016-01-01

    Salmonella Typhimurium strain expressing the Actinobacillus pleuropneumoniae antigens, ApxIA, ApxIIA, ApxIIIA and OmpA, was previously constructed as a vaccine candidate for porcine pleuropneumonia. This strain was a live attenuated (∆lon∆cpxR∆asd)Salmonella as a delivery host and contained a vector containing asd. An immunological study of lymphocyte proliferation, T-lymphocyte subsets and cytokines in the splenocytes of a mouse model was carried out after stimulation with the candidate Salmonella Typhimurium by intranasal inoculation. The splenic lymphocyte proliferation and the levels of IL-4, IL-6 and IL-12 of the inoculated mice were significantly increased, and the T- and B-cell populations were also elevated. Collectively, the candidate may efficiently induce the Th1- and Th2-type immune responses.

  15. An adhesome comprising laminin, dystroglycan and myosin IIA is required during notochord development in Xenopus laevis.

    PubMed

    Buisson, Nicolas; Sirour, Cathy; Moreau, Nicole; Denker, Elsa; Le Bouffant, Ronan; Goullancourt, Aline; Darribère, Thierry; Bello, Valérie

    2014-12-01

    Dystroglycan (Dg) is a transmembrane receptor for laminin that must be expressed at the right time and place in order to be involved in notochord morphogenesis. The function of Dg was examined in Xenopus laevis embryos by knockdown of Dg and overexpression and replacement of the endogenous Dg with a mutated form of the protein. This analysis revealed that Dg is required for correct laminin assembly, for cell polarization during mediolateral intercalation and for proper differentiation of vacuoles. Using mutations in the cytoplasmic domain, we identified two sites that are involved in cell polarization and are required for mediolateral cell intercalation, and a site that is required for vacuolation. Furthermore, using a proteomic analysis, the cytoskeletal non-muscle myosin IIA has been identified for the first time as a molecular link between the Dg-cytoplasmic domain and cortical actin. The data allowed us to identify the adhesome laminin-Dg-myosin IIA as being required to maintain the cortical actin cytoskeleton network during vacuolation, which is crucial to maintain the shape of notochordal cells.

  16. Myosin IIA is critical for organelle distribution and F-actin organization in megakaryocytes and platelets.

    PubMed

    Pertuy, Fabien; Eckly, Anita; Weber, Josiane; Proamer, Fabienne; Rinckel, Jean-Yves; Lanza, François; Gachet, Christian; Léon, Catherine

    2014-02-20

    During proplatelet formation, a relatively homogeneous content of organelles is transported from the megakaryocyte (MK) to the nascent platelets along microtubule tracks. We found that platelets from Myh9(-/-) mice and a MYH9-RD patient were heterogeneous in their organelle content (granules and mitochondria). In addition, Myh9(-/-) MKs have an abnormal cytoplasmic clustering of organelles, suggesting that the platelet defect originates in the MKs. Myosin is not involved in the latest stage of organelle traffic along microtubular tracks in the proplatelet shafts as shown by confocal observations of proplatelet buds. By contrast, it is required for the earlier distribution of organelles within the large MK preplatelet fragments shed into the sinusoid circulation before terminal proplatelet remodeling. We show here that F-actin is abnormally clustered in the cytoplasm of Myh9(-/-) MKs and actin polymerization is impaired in platelets. Myosin IIA is required for normal granule motility and positioning within MKs, mechanisms that may be dependent on organelle traveling and tethering onto F-actin cytoskeleton tracks. Altogether, our results indicate that the distribution of organelles within platelets critically depends on a homogeneous organelle distribution within MKs and preplatelet fragments, which requires myosin IIA.

  17. 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.

  18. 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

  19. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages.

    PubMed

    Guerriero, Jennifer L; Sotayo, Alaba; Ponichtera, Holly E; Castrillon, Jessica A; Pourzia, Alexandra L; Schad, Sara; Johnson, Shawn F; Carrasco, Ruben D; Lazo, Suzan; Bronson, Roderick T; Davis, Scott P; Lobera, Mercedes; Nolan, Michael A; Letai, Anthony

    2017-03-16

    Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

  20. 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.

  1. 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

  2. Myosin-IIA regulates leukemia engraftment and brain infiltration in a mouse model of acute lymphoblastic leukemia

    PubMed Central

    Wigton, Eric J.; Thompson, Scott B.; Long, Robert A.; Jacobelli, Jordan

    2016-01-01

    Leukemia dissemination (the spread of leukemia cells from the bone marrow) and relapse are associated with poor prognosis. Often, relapse occurs in peripheral organs, such as the CNS, which acts as a sanctuary site for leukemia cells to escape anti-cancer treatments. Similar to normal leukocyte migration, leukemia dissemination entails migration of cells from the blood circulation into tissues by extravasation. To extravasate, leukemia cells cross through vascular endothelial walls via a process called transendothelial migration, which requires cytoskeletal remodeling. However, the specific molecular players in leukemia extravasation are not fully known. We examined the role of myosin-IIA a cytoskeletal class II myosin motor protein, in leukemia progression and dissemination into the CNS by use of a mouse model of Bcr-Abl-driven B cell acute lymphoblastic leukemia. Small hairpin RNA-mediated depletion of myosin-IIA did not affect apoptosis or the growth rate of B cell acute lymphoblastic leukemia cells. However, in an in vivo leukemia transfer model, myosin-IIA depletion slowed leukemia progression and prolonged survival, in part, by reducing the ability of B cell acute lymphoblastic leukemia cells to engraft efficiently. Finally, myosin-IIA inhibition, either by small hairpin RNA depletion or chemical inhibition by blebbistatin, drastically reduced CNS infiltration of leukemia cells. The effects on leukemia cell entry into tissues were mostly a result of the requirement for myosin-IIA to enable leukemia cells to complete the transendothelial migration process during extravasation. Overall, our data implicate myosin-IIA as a key mediator of leukemia cell migration, making it a promising target to inhibit leukemia dissemination in vivo and potentially reduce leukemia relapses. PMID:26792819

  3. The saxitoxin/tetrodotoxin binding site on cloned rat brain IIa Na channels is in the transmembrane electric field.

    PubMed Central

    Satin, J.; Limberis, J. T.; Kyle, J. W.; Rogart, R. B.; Fozzard, H. A.

    1994-01-01

    The rat brain IIa (BrIIa) Na channel alpha-subunit and the brain beta 1 subunit were coexpressed in Xenopus oocytes, and peak whole-oocyte Na current (INa) was measured at a test potential of -10 mV. Hyperpolarization of the holding potential resulted in an increased affinity of STX and TTX rested-state block of BrIIa Na channels. The apparent half-block concentration (ED50) for STX of BrIIa current decreased with hyperpolarizing holding potentials (Vhold). At Vhold of -100 mV, the ED50 was 2.1 +/- 0.4 nM, and the affinity increased to a ED50 of 1.2 +/- 0.2 nM with Vhold of -140 mV. In the absence of toxin, the peak current amplitude was the same for all potentials negative to -90 mV, demonstrating that all of the channels were in a closed conformation and maximally available to open in this range of holding potentials. The Woodhull model (1973) was used to describe the increase of the STX ED50 as a function of holding potential. The equivalent electrical distance of block (delta) by STX was 0.18 from the extracellular milieu when the valence of STX was fixed to +2. Analysis of the holding potential dependence of TTX block yielded a similar delta when the valence of TTX was fixed to +1. We conclude that the guanidinium toxin site is located partially within the transmembrane electric field. Previous site-directed mutagenesis studies demonstrated that an isoform-specific phenylalanine in the BrIIa channel is critical for high affinity toxin block. Therefore, we propose that amino acids at positions corresponding to this Phe in the BrIIa channel, which lie in the outer vestibule of the channel adjacent to the pore entrance,are partially in the transmembrane potential drop. PMID:7811911

  4. The saxitoxin/tetrodotoxin binding site on cloned rat brain IIa Na channels is in the transmembrane electric field.

    PubMed

    Satin, J; Limberis, J T; Kyle, J W; Rogart, R B; Fozzard, H A

    1994-09-01

    The rat brain IIa (BrIIa) Na channel alpha-subunit and the brain beta 1 subunit were coexpressed in Xenopus oocytes, and peak whole-oocyte Na current (INa) was measured at a test potential of -10 mV. Hyperpolarization of the holding potential resulted in an increased affinity of STX and TTX rested-state block of BrIIa Na channels. The apparent half-block concentration (ED50) for STX of BrIIa current decreased with hyperpolarizing holding potentials (Vhold). At Vhold of -100 mV, the ED50 was 2.1 +/- 0.4 nM, and the affinity increased to a ED50 of 1.2 +/- 0.2 nM with Vhold of -140 mV. In the absence of toxin, the peak current amplitude was the same for all potentials negative to -90 mV, demonstrating that all of the channels were in a closed conformation and maximally available to open in this range of holding potentials. The Woodhull model (1973) was used to describe the increase of the STX ED50 as a function of holding potential. The equivalent electrical distance of block (delta) by STX was 0.18 from the extracellular milieu when the valence of STX was fixed to +2. Analysis of the holding potential dependence of TTX block yielded a similar delta when the valence of TTX was fixed to +1. We conclude that the guanidinium toxin site is located partially within the transmembrane electric field. Previous site-directed mutagenesis studies demonstrated that an isoform-specific phenylalanine in the BrIIa channel is critical for high affinity toxin block. Therefore, we propose that amino acids at positions corresponding to this Phe in the BrIIa channel, which lie in the outer vestibule of the channel adjacent to the pore entrance,are partially in the transmembrane potential drop.

  5. 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.

  6. 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

  7. Keratin 5-Cre-driven excision of nonmuscle myosin IIA in early embryo trophectoderm leads to placenta defects and embryonic lethality.

    PubMed

    Crish, James; Conti, Mary Anne; Sakai, Takao; Adelstein, Robert S; Egelhoff, Thomas T

    2013-10-01

    In studies initially focused on roles of nonmuscle myosin IIA (NMIIA) in the developing mouse epidermis, we have discovered that a previously described cytokeratin 5 (K5)-Cre gene construct is expressed in early embryo development. Mice carrying floxed alleles of the nonmuscle myosin II heavy chain gene (NMHC IIA(flox/flox)) were crossed with the K5-Cre line. The progeny of newborn pups did not show a Mendelian genotype distribution, suggesting embryonic lethality. Analysis of post-implantation conceptuses from embryonic day (E)9.5 to E13.5 revealed poorly developed embryos and defective placentas, with significantly reduced labyrinth surface area and blood vessel vascularization. These results suggested the novel possibility that the bovine K5 promoter-driven Cre-recombinase was active early in trophoblast-lineage cells that give rise to the placenta. To test this possibility, K5-Cre transgenic mice were crossed with the mT/mG reporter mouse in which activation of GFP expression indicates Cre transgene expression. We observed activation of K5-Cre-driven GFP expression in the ectoplacental cone, in the extraembryonic ectoderm, and in trophoblast giant cells in the E6.5 embryo. In addition, we observed GFP expression at E11.5 to E13.5 in both the labyrinth of the placenta and the yolk sac. NMIIA expression was detected in these same cell types in normal embryos, as well as in E13.5 yolk sac and labyrinth. These findings taken together suggest that NMHC IIA may play critical roles in the early trophoblast-derived ectoplacental cone and extraembryonic ectoderm, as well as in the yolk sac and labyrinth tissues that form later. Our findings are consistent with phenotypes of constitutive NMIIA knockout mice made earlier, that displayed labyrinth and yolk sac-specific defects, but our findings extend those observations by suggesting possible NMIIA roles in trophoblast lineages as well. These results furthermore demonstrate that K5-Cre gene constructs, previously reported

  8. 30 CFR 57.22204 - Main fan operation and inspection (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 Main fan operation and inspection (I-A, II-A... Main fan operation and inspection (I-A, II-A, III, and V-A mines). Main fans shall be— (a) Provided with a pressure-recording system; and (b) Inspected daily while operating if persons are underground...

  9. 30 CFR 57.22204 - Main fan operation and inspection (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 Main fan operation and inspection (I-A, II-A... Main fan operation and inspection (I-A, II-A, III, and V-A mines). Main fans shall be— (a) Provided with a pressure-recording system; and (b) Inspected daily while operating if persons are underground...

  10. 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

  11. 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

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

    PubMed

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

    2015-03-21

    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

  13. 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

  14. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease.

    PubMed

    Coleman, Robert; Aksnes, Anne-Kirsti; Naume, Bjørn; Garcia, Camilo; Jerusalem, Guy; Piccart, Martine; Vobecky, Nancy; Thuresson, Marcus; Flamen, Patrick

    2014-06-01

    Radium-223 dichloride (radium-223) mimics calcium and emits high-energy, short-range alpha-particles resulting in an antitumor effect on bone metastases. This open-label, phase IIa nonrandomized study investigated safety and short-term efficacy of radium-223 in breast cancer patients with bone-dominant disease. Twenty-three advanced breast cancer patients with progressive bone-dominant disease, and no longer candidates for further endocrine therapy, were to receive radium-223 (50 kBq/kg IV) every 4 weeks for 4 cycles. The coprimary end points were change in urinary N-telopeptide of type 1 (uNTX-1) and serum bone alkaline phosphatase (bALP) after 16 weeks of treatment. Exploratory end points included sequential (18)F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) to assess metabolic changes in osteoblastic bone metastases. Safety data were collected for all patients. Radium-223 significantly reduced uNTX-1 and bALP from baseline to end of treatment. Median uNTX-1 change was -10.1 nmol bone collagen equivalents/mmol creatinine (-32.8 %; P = 0.0124); median bALP change was -16.7 ng/mL (-42.0 %; P = 0.0045). Twenty of twenty-three patients had FDG PET/CT identifying 155 hypermetabolic osteoblastic bone lesions at baseline: 50 lesions showed metabolic decrease (≥25 % reduction of maximum standardized uptake value from baseline) after 2 radium-223 injections [32.3 % metabolic response rate (mRR) at week 9], persisting after the treatment period (41.5 % mRR at week 17). Radium-223 was safe and well tolerated. Radium-223 targets areas of increased bone metabolism and shows biological activity in advanced breast cancer patients with bone-dominant disease.

  15. A non-enzymatic function of Golgi glycosyltransferases: Mediation of Golgi fragmentation by interaction with non-muscle myosin IIA

    PubMed Central

    Petrosyan, Armen; Cheng, Pi-Wan

    2013-01-01

    The Golgi apparatus undergoes morphological changes under stress or malignant transformation, but the precise mechanisms are not known. We recently showed that non-muscle myosin IIA (NMIIA) binds to the cytoplasmic tail of Core 2 N-acetylglucosaminyltransferase mucus-type (C2GnT-M) and transports it to the endoplasmic reticulum for recycling. Here, we report that Golgi fragmentation induced by brefeldin A (BFA) or coatomer protein (β-COP) knockdown (KD) in Panc1-bC2GnT-M (c-Myc) cells is accompanied by the increased association of NMIIA with C2GnT-M and its degradation by proteasomes. Golgi fragmentation is prevented by inhibition or KD of NMIIA. Using multiple approaches, we have shown that the speed of BFA-induced Golgi fragmentation is positively correlated with the levels of this enzyme in the Golgi. The observation is reproduced in LNCaP cells which express high levels of two endogenous glycosyltransferases—C2GnT-L and β-galactoside α2,3 sialyltransferase 1. NMIIA is found to form complexes with these two enzymes but not Golgi matrix proteins. The KD of both enzymes or the prevention of Golgi glycosyltransferases from exiting endoplasmic reticulum reduced Golgi-associated NMIIA and decreased the BFA-induced fragmentation. Interestingly, the fragmented Golgi detected in colon cancer HT-29 cells can be restored to a compact morphology after inhibition or KD of NMIIA. The Golgi disorganization induced by the microtubule or actin destructive agent is NMIIA-independent and does not affect the levels of glycosyltransferases. We conclude that NMIIA interacts with Golgi residential but not matrix proteins, and this interaction is responsible for Golgi fragmentation induced by β-COP KD or BFA treatment. This is a novel non-enzymatic function of Golgi glycosyltransferases. PMID:23396488

  16. The Karyopherin Kap122p/Pdr6p Imports Both Subunits of the Transcription Factor Iia into the Nucleus

    PubMed Central

    Titov, Anton A.; Blobel, Günter

    1999-01-01

    We discovered a nuclear import pathway mediated by the product of the previously identified Saccharomyces cerevisiae gene PDR6 (pleiotropic drug resistance). This gene product functions as a karyopherin (Kap) for nuclear import. Consistent with previously proposed nomenclature, we have renamed this gene KAP122. Kap122p was localized both to the cytoplasm and the nucleus. As a prominent import substrate of Kap122p, we identified the complex of the large and small subunit (Toa1p and Toa2p, respectively) of the general transcription factor IIA (TFIIA). Recombinant GST-Kap122p formed a complex with recombinant His6-Toa1p/Toa2p. In wild-type cells, Toa1p and Toa2p were localized to the nucleus. Consistent with Kap122p being the principal Kap for import of the Toa1p–Toa2p complex, we found that deletion of KAP122 results in increased cytoplasmic localization of both Toa1p and Toa2p. Deletion of KAP122 is not lethal, although deletion of TOA1 and TOA2 is. Together these data suggest that Kap122p is the major Kap for the import of Toa1p–Toa2p into the nucleus. Like other substrate–Kap complexes, the Toa1p/Toa2p/Kap122p complex isolated from yeast cytosol or reconstituted from recombinant proteins, was dissociated by RanGTP but not RanGDP. Kap122p bound to nucleoporins, specifically, to the peptide repeat–containing fragments of Nup1p and Nup2p. PMID:10525531

  17. U2 toggles iteratively between the stem IIa and stem IIc conformations to promote pre-mRNA splicing.

    PubMed

    Hilliker, Angela K; Mefford, Melissa A; Staley, Jonathan P

    2007-04-01

    To ligate exons in pre-messenger RNA (pre-mRNA) splicing, the spliceosome must reposition the substrate after cleaving the 5' splice site. Because spliceosomal small nuclear RNAs (snRNAs) bind the substrate, snRNA structures may rearrange to reposition the substrate. However, such rearrangements have remained undefined. Although U2 stem IIc inhibits binding of U2 snRNP to pre-mRNA during assembly, we found that weakening U2 stem IIc suppressed a mutation in prp16, a DExD/H box ATPase that promotes splicing after 5' splice site cleavage. The prp16 mutation was also suppressed by mutations flanking stem IIc, suggesting that Prp16p facilitates a switch from stem IIc to the mutually exclusive U2 stem IIa, which activates binding of U2 to pre-mRNA during assembly. Providing evidence that stem IIa switches back to stem IIc before exon ligation, disrupting stem IIa suppressed 3' splice site mutations, and disrupting stem IIc impaired exon ligation. Disrupting stem IIc also exacerbated the 5' splice site cleavage defects of certain substrate mutations, suggesting a parallel role for stem IIc at both catalytic stages. We propose that U2, much like the ribosome, toggles between two conformations--a closed stem IIc conformation that promotes catalysis and an open stem IIa conformation that promotes substrate binding and release.

  18. 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…

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

    USDA-ARS?s Scientific Manuscript database

    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....

  20. 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

  1. Statewide Analysis of the Ohio Thirteen-Week Follow-up Survey of Title IIA JTP Clients.

    ERIC Educational Resources Information Center

    Hotchkiss, Lawrence; Smythe, John

    Data from a sample of adult participants in JTP Ohio under Title IIA of the Job Training Partnership Act (JTPA) were analyzed. Respondents were surveyed after completion of 13 weeks of JTP training. Five outcome variables were studied: weeks worked, employment status during week 13, earnings in week 13, welfare status during week 13, and school…

  2. 30 CFR 57.22206 - Main ventilation failure (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22206..., tests for methane shall be conducted in affected active workings until normal air flow has resumed. (b... less than 1.0 percent methane. Persons other than examiners shall not reenter a Subcategory II-A...

  3. 30 CFR 57.22212 - Air flow (I-C, II-A, and V-A mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 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,...

  4. 30 CFR 57.22206 - Main ventilation failure (I-A, II-A, III, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22206..., tests for methane shall be conducted in affected active workings until normal air flow has resumed. (b... less than 1.0 percent methane. Persons other than examiners shall not reenter a Subcategory II-A...

  5. 30 CFR 57.22212 - Air flow (I-C, II-A, and V-A mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 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,...

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

    PubMed

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

    2015-09-15

    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 (A(Nkx)/A(Nkx)) are born at the expected ratio with normal hearts, but consistently develop an invasive squamous cell carcinoma (SCC) of the tongue (32/32 A(Nkx)/A(Nkx)) 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 A(Nkx)/A(Nkx) 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.

  7. 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…

  8. 30 CFR 57.22212 - Air flow (I-C, II-A, and V-A mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 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, smoke...

  9. 30 CFR 57.22212 - Air flow (I-C, II-A, and V-A mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 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, smoke...

  10. 30 CFR 57.22212 - Air flow (I-C, II-A, and V-A mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 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, smoke...

  11. Implementation of Title I and Title II-A Program Initiatives: Results from 2013-14. NCEE 2017-4014

    ERIC Educational Resources Information Center

    Troppe, Patricia; Milanowski, Anthony T.; Heid, Camilla; Gill, Brian; Ross, Christine

    2017-01-01

    This report describes the implementation of policies and initiatives supported by Title I and Title II-A of the federal Elementary and Secondary Education Act (ESEA) during the 2013-14 school year. Title I is one of the U.S. Department of Education's largest programs, accounting for $15 billion in the 2016 federal budget. Historically, Title I has…

  12. 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.

  13. Mutant APH(2″)-IIa Enzymes with Increased Activity against Amikacin and Isepamicin▿

    PubMed Central

    Toth, Marta; Frase, Hilary; Chow, Joseph W.; Smith, Clyde; Vakulenko, Sergei B.

    2010-01-01

    Directed evolution by random PCR mutagenesis of the gene for the aminoglycoside 2″-IIa phosphotransferase generated R92H/D268N and N196D/D268N mutant enzymes, resulting in elevated levels of resistance to amikacin and isepamicin but not to other aminoglycoside antibiotics. Increases in the activities of the mutant phosphotransferases for isepamicin are the result of decreases in Km values, while improved catalytic efficiency for amikacin is the result of both a decrease in Km values and an increase in turnover of the antibiotic. Enzymes with R92H, D268N, and D268N single amino acid substitutions did not result in elevated MICs for aminoglycosides. PMID:20145089

  14. 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.

  15. Structural characterization of the PTS IIA and IIB proteins associated with pneumococcal fucose utilization.

    PubMed

    Higgins, Melanie A; Hamilton, Aileen M; Boraston, Alisdair B

    2017-05-01

    Streptococcus pneumoniae harbors a significant number of transporters, including phosphotransferase (PTS) systems, allowing the bacterium to utilize a number of different carbohydrates for metabolic and other purposes. The genes encoding for one PTS transport system in particular (EII(fuc) ) are found within a fucose utilization operon in S. pneumoniae TIGR4. Here, we report the three-dimensional structures of IIA(fuc) and IIB(fuc) providing evidence that this PTS system belongs to the EII(man) family. Additionally, the predicted metabolic pathway for this distinctive fucose utilization system suggests that EII(fuc) transports the H-disaccharide blood group antigen, which would represent a novel PTS transporter specificity. Proteins 2017; 85:963-968. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  16. Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer's Disease Phase IIa and Expanded Access Trials.

    PubMed

    Nelson, Thomas J; Sun, Miao-Kun; Lim, Chol; Sen, Abhik; Khan, Tapan; Chirila, Florin V; Alkon, Daniel L

    2017-01-01

    Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus -1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

  17. The crystal structure of aminoglycoside-3'-phosphotransferase-IIa, an enzyme responsible for antibiotic resistance.

    PubMed

    Nurizzo, Didier; Shewry, Steven C; Perlin, Michael H; Brown, Scott A; Dholakia, Jaydev N; Fuchs, Roy L; Deva, Taru; Baker, Edward N; Smith, Clyde A

    2003-03-21

    A major factor in the emergence of antibiotic resistance is the existence of enzymes that chemically modify common antibiotics. The genes for these enzymes are commonly carried on mobile genetic elements, facilitating their spread. One such class of enzymes is the aminoglycoside phosphotransferase (APH) family, which uses ATP-mediated phosphate transfer to chemically modify and inactivate aminoglycoside antibiotics such as streptomycin and kanamycin. As part of a program to define the molecular basis for aminoglycoside recognition and inactivation by such enzymes, we have determined the high resolution (2.1A) crystal structure of aminoglycoside-3'-phosphotransferase-IIa (APH(3')-IIa) in complex with kanamycin. The structure was solved by molecular replacement using multiple models derived from the related aminoglycoside-3'-phosphotransferase-III enzyme (APH(3')-III), and refined to an R factor of 0.206 (R(free) 0.238). The bound kanamycin molecule is very well defined and occupies a highly negatively charged cleft formed by the C-terminal domain of the enzyme. Adjacent to this is the binding site for ATP, which can be modeled on the basis of nucleotide complexes of APH(3')-III; only one change is apparent with a loop, residues 28-34, in a position where it could fold over an incoming nucleotide. The three rings of the kanamycin occupy distinct sub-pockets in which a highly acidic loop, residues 151-166, and the C-terminal residues 260-264 play important parts in recognition. The A ring, the site of phosphoryl transfer, is adjacent to the catalytic base Asp190. These results give new information on the basis of aminoglycoside recognition, and on the relationship between this phosphotransferase family and the protein kinases.

  18. Ginsenoside Rg1 Protects against Oxidative Stress-induced Neuronal Apoptosis through Myosin IIA-actin Related Cytoskeletal Reorganization

    PubMed Central

    Wang, Yan; Liu, Qian; Xu, Yingqiong; Zhang, Yuanyuan; Lv, Yanni; Tan, Yisha; Jiang, Nan; Cao, Guosheng; Ma, Xiaonan; Wang, Jingrong; Cao, Zhengyu; Yu, Boyang; Kou, Junping

    2016-01-01

    Oxidative stress-induced cytoskeletal dysfunction of neurons has been implicated as a crucial cause of cell apoptosis or death in the central nervous system (CNS) diseases, such as neurodegenerative and psychiatric diseases. The application of neuroprotectants rescuing the neurons from cytoskeletal damage and apoptosis can be a potential treatment for these CNS diseases. Ginsenoside Rg1 (Rg1), one of the major active components of ginseng, has been reported possessing notable neuroprotective activities. However, there is rare report about its effect on cytoskeleton and its undergoing mechanism. The current study is to reveal the regulatory effects of Rg1 on cytoskeletal and morphological lesion in oxidative stress-induced neuronal apoptosis. The results demonstrated that pre-treatment with Rg1 (0.1-10 μM) attenuated hydrogen peroxide (H2O2)-induced neuronal apoptosis and oxidative stress through reducing the intracellular reactive oxygen species (ROS) production and methane dicarboxylic aldehyde (MDA) level. The Rg1 treatment also abolished H2O2-induced morphological changes, including cell rounding, membrane blebbing, neurite retraction and nuclei condensation, which were generated by myosin IIA-actin interaction. These effects were mediated via the down-regulation of caspase-3, ROCK1 (Rho-associated kinase1) activation and myosin light chain (MLC, Ser-19) phosphorylation. Furthermore, inhibiting myosin II activity with blebbistatin partly blocked the neuroprotective effects of Rg1. The computer-aided homology modelling revealed that Rg1 preferentially positioned in the actin binding cleft of myosin IIA and might block the binding of myosin IIA to actin filaments. Accordingly, the neuroprotective mechanism of Rg1 is related to the activity that inhibits myosin IIA-actin interaction and the caspase-3/ROCK1/MLC signaling pathway. These findings put some insights into the unique neuroprotective properties of Rg1 associated with the regulation of myosin IIA

  19. 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

  20. Non-associativity in non-geometric string and M-theory backgrounds, the algebra of octonions, and missing momentum modes

    SciTech Connect

    Günaydin, Murat; Lüst, Dieter; Malek, Emanuel

    2016-11-07

    We propose a non-associative phase space algebra for M-theory backgrounds with locally non-geometric fluxes based on the non-associative algebra of octonions. Our proposal is based on the observation that the non-associative algebra of the non-geometric R-flux background in string theory can be obtained by a proper contraction of the simple Malcev algebra generated by imaginary octonions. Furthermore, by studying a toy model of a four-dimensional locally non-geometric M-theory background which is dual to a twisted torus, we show that the non-geometric background is “missing” a momentum mode. The resulting seven-dimensional phase space can thus be naturally identified with the imaginary octonions. This allows us to interpret the full uncontracted algebra of imaginary octonions as the uplift of the string theory R-flux algebra to M-theory, with the contraction parameter playing the role of the string coupling constant gs.

  1. Non-associativity in non-geometric string and M-theory backgrounds, the algebra of octonions, and missing momentum modes

    DOE PAGES

    Günaydin, Murat; Lüst, Dieter; Malek, Emanuel

    2016-11-07

    We propose a non-associative phase space algebra for M-theory backgrounds with locally non-geometric fluxes based on the non-associative algebra of octonions. Our proposal is based on the observation that the non-associative algebra of the non-geometric R-flux background in string theory can be obtained by a proper contraction of the simple Malcev algebra generated by imaginary octonions. Furthermore, by studying a toy model of a four-dimensional locally non-geometric M-theory background which is dual to a twisted torus, we show that the non-geometric background is “missing” a momentum mode. The resulting seven-dimensional phase space can thus be naturally identified with the imaginarymore » octonions. This allows us to interpret the full uncontracted algebra of imaginary octonions as the uplift of the string theory R-flux algebra to M-theory, with the contraction parameter playing the role of the string coupling constant gs.« less

  2. Stage IIA and IIB testicular seminoma treated post-orchiectomy with radiation therapy versus other approaches: a population-based analysis of 241 patients

    PubMed Central

    Ahmed, Kamran A.; Wilder, Richard B.

    2015-01-01

    Objectives To evaluate post-orchiectomy utilization of radiation therapy (RT) versus other management approaches in stage IIA and IIB testicular seminoma patients. Materials and Methods Two hundred and forty-one patients with stage IIA and IIB testicular seminoma were identified between 1988 and 2003 using the Surveillance, Epidemiology, and End Results (SEER) database. Results Median follow-up was 10 years. Patients with stage IIA disease underwent RT more frequently than those with stage IIB disease (72% vs. 46%, respectively; P<0.001). There was no significant change in RT utilization for stage IIA or IIB disease between 1988 and 2003 (P = 0.89). Conclusions Between 1988 and 2003, stage IIA patients underwent RT more often than stage IIB patients in the United States. There was no significant change in RT utilization for stage IIA or IIB disease during this time period. Based on reports describing excellent progression-free survival with cisplatin-based chemotherapy, this approach has increased in popularity since 2003 and may eventually become the most popular treatment approach for both stage IIA and IIB testicular seminoma. PMID:25928512

  3. Stage IIA and IIB testicular seminoma treated postorchiectomy with radiation therapy versus other approaches: a population-based analysis of 241 patients.

    PubMed

    Ahmed, Kamran A; Wilder, Richard B

    2015-01-01

    To evaluate post-orchiectomy utilization of radiation therapy (RT) versus other management approaches in stage IIA and IIB testicular seminoma patients. Two hundred and forty-one patients with stage IIA and IIB testicular seminoma were identified between 1988 and 2003 using the Surveillance, Epidemiology, and End Results (SEER) database. Median follow-up was 10 years. Patients with stage IIA disease underwent RT more frequently than those with stage IIB disease (72 % vs. 46 %, respectively; P < 0.001). There was no significant change in RT utilization for stage IIA or IIB disease between 1988 and 2003 (P = 0.89). Between 1988 and 2003, stage IIA patients underwent RT more often than stage IIB patients in the United States. There was no significant change in RT utilization for stage IIA or IIB disease during this time period. Based on reports describing excellent progression-free survival with cisplatin-based chemotherapy, this approach has increased in popularity since 2003 and may eventually become the most popular treatment approach for both stage IIA and IIB testicular seminoma.

  4. Direct vasorelaxation by a novel phytoestrogen tanshinone IIA is mediated by nongenomic action of estrogen receptor through endothelial nitric oxide synthase activation and calcium mobilization.

    PubMed

    Fan, Guanwei; Zhu, Yan; Guo, Hao; Wang, Xiaoying; Wang, Hong; Gao, Xiumei

    2011-03-01

    Salvia miltiorrhiza (Danshen) has been widely used in China and other Asian countries for treating various cardiovascular diseases resulting from its ability to improve coronary microcirculation and increase coronary blood flow. Tanshinone IIA (Tan IIA), the major active lipophilic ingredient responsible for the beneficial actions of Salvia miltiorrhiza, has been shown to induce vasodilation in coronary arteries. Because our recent study identified Tan IIA as a new member of the phytoestrogens, we hypothesized that its action might be mediated by estrogen receptor (ER) in vascular endothelial cells. The aim of the present study was to assess whether cardiovascular protection exerted by Tan IIA is mediated by the ER signal pathway and whether the genomic or nongenomic action of ER is involved within arteries and vascular endothelial cells. The effect of Tan IIA on blood vessels was investigated by vascular ring assay using endothelium-intact and endothelium-denuded rat aortas. Similar to estrogen, Tan IIA caused an nitric oxide- and endothelium-dependent relaxation, which was blocked by ER antagonist ICI 182,780. Primary cardiac microvascular endothelial cells were used as a model to study the cellular and molecular mechanisms of Tan IIA-induced vasorelaxation. We demonstrate that Tan IIA is capable of activating the estrogen receptor signal pathway, leading to increased endothelial nitric oxide synthase gene expression, nitric oxide production, ERK1/2 phosphorylation, and Ca mobilization. Collectively, these effects contribute to Tan IIA's vasodilative activity effects of y ER antagonist Cnt of cardiovascular diseases. Our findings support a continued effort in discovering and developing novel phytoestrogens as an alternative hormone replacement therapy for safer and more effective treatment of cardiovascular diseases.

  5. Crosstalk between Beclin-1-dependent autophagy and caspase-dependent apoptosis induced by tanshinone IIA in human osteosarcoma MG-63 cells

    PubMed Central

    Ma, Kun; Zhang, Chuan; Huang, Man-Yu; Guo, Yan-Xing; Hu, Guo-Qiang

    2016-01-01

    The aim of the present study was to ascertain whether or not autophagy is induced by tanshinone IIA (TanIIA), and to explore the crosstalk between autophagy and apoptosis in regards to the antitumor effects of TanIIA on MG-63 cells and the potential mechanism. MG-63 cells were cultured in vitro with various concentrations of TanIIA (0, 2.5, 5, 10 and 20 mg/l) for 0, 24, 48 and 72 h, respectively. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT assay was used to evaluate the inhibition of the proliferation of osteosarcoma MG-63 cells by TanIIA or in the presence/absence of chloroquine (CQ). Autophagic vacuoles and characteristic autophagosomes were observed by transmission electron microscopy (TEM). TanIIA-induced autophagy in MG-63 cells was confirmed by GFP-LC3 punctate fluorescence. The expression levels of apoptosis-related proteins caspase-3, caspase-8, caspase-9 and cleaved-PARP and autophagy-related proteins LC3II/LC3I and Beclin-1 were detected by western blotting. FITC-Annexin V/propidium iodide (PI) staining, flow cytometry and Hoechst 33258 staining were used to analyze the apoptotic rate. Fluorescence intensity of reactive oxygen species (ROS) was examined under a fluorescence microscope using an analysis software system. Cell proliferation was obviously inhibited by TanIIA in a dose- and time-dependent manner. Generation of autophagy was triggered by TanIIA (0–20 mg/l) treatment, and in a Beclin-1-dependent manner. Compared with the control group, the apoptosis ratio following treatment with 2.5 mg/l TanIIA failed to achieve statistical significance. Expression of caspase-3, -8 and -9, and cleaved-PARP in the other groups was gradually enhanced in dose-dependent manner. Our analysis also suggested that the influence of autophagy on TanIIA cytotoxicity had a phase effect; with low-dose drugs and shorter treatment periods, autophagy functioned as a damage repair mechanism. In conrast, when the cells were treated with higher doses of TanIIA

  6. Elevated Type II Secretory Phospholipase A2 Increases the Risk of Early Atherosclerosis in Patients with Newly Diagnosed Metabolic Syndrome

    PubMed Central

    Sun, Chang-Qing; Zhong, Chun-Yan; Sun, Wei-Wei; Xiao, Hua; Zhu, Ping; Lin, Yi-Zhang; Zhang, Chen-Liang; Gao, Hao; Song, Zhi-Yuan

    2016-01-01

    A critical association between type II secretory phospholipase A2 (sPLA2-IIa) and established atherosclerotic cardiovascular disease has been demonstrated. However, the contribution of sPLA2-IIa to early atherosclerosis remains unknown. This study investigated the association between early-stage atherosclerosis and sPLA2-IIa in metabolic syndrome (MetS) patients. One hundred and thirty-six MetS patients and 120 age- and gender-matched subjects without MetS were included. Serum sPLA2-IIa protein levels and activity were measured using commercial kits. Circulating endothelial activation molecules (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin), and carotid intima-media thickness (cIMT), were measured as parameters of vascular endothelial dysfunction and early atherosclerosis. MetS patients exhibited significantly higher sPLA2-IIa protein and activity levels than the controls. Both correlated positively with fasting blood glucose and waist circumference in MetS patients. Additionally, MetS patients exhibited strikingly higher levels of endothelial activation molecules and increased cIMT than controls. These levels correlated positively with serum sPLA2-IIa protein levels and activity. Moreover, multivariate analysis showed that high sPLA2-IIa protein and activity levels were independent risk factors of early atherosclerosis in MetS patients. This study demonstrates an independent association between early-stage atherosclerosis and increased levels of sPLA2-IIa, implying that increased sPLA2-IIa may predict early-stage atherosclerosis in MetS patients. PMID:27941821

  7. 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

  8. 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.

  9. Hemofiltration during cardiopulmonary bypass: the effect on anti-Xa and anti-IIa heparin activity.

    PubMed

    Despotis, G J; Levine, V; Filos, K S; Joiner-Maier, D; Joist, J H

    1997-03-01

    Previous studies have demonstrated that heparin concentrations during cardiopulmonary bypass (CPB) may vary considerably, which may be related to variability in redistribution, cellular and plasma protein binding, and clearance of heparin. The purpose of this study was to determine whether hemofiltration removes lower molecular weight fractions of heparin from plasma and thus contributes to variability of blood levels of heparin. Twenty patients undergoing cardiac surgery with CPB were enrolled in this study after informed consent was obtained. The study was subdivided into two phases. The first 10 patients were enrolled in Phase I, which was designed to determine whether hemofiltration removes lower molecular weight fractions of heparin from blood. Blood specimens obtained from the inflow line and outflow lines of the hemofiltration unit were used to measure complete blood counts (CBC) and plasma heparin activity by anti-Xa and anti-IIa assays. Phase II was designed to evaluate the effect of hemofiltration on circulating plasma heparin activity. In Phase II, blood specimens were obtained from 10 patients via the arterial cannula of the extracorporeal circuit prior to and after hemofiltration for measurements of CBCs, anti-Xa plasma heparin, as well as whole blood heparin concentration using an automated protamine titration assay (Hepcon instrument, Medtronic Inc., Parker, CO). Ultrafiltrate and reservoir volumes were measured in both phases of the study. Hemofiltration did not remove lower (anti-Xa measurable) molecular weight heparin, but it resulted in a considerable increase in heparin activity in the outflow line, as measured by both anti-Xa and anti-IIa assays. The plasma anti-Xa heparin activity obtained after hemofiltration (5 +/- 1.8 U/mL) was substantially (P = 0.003) greater than heparin activity obtained prior to hemofiltration (3.9 +/- 1.7 U/mL). The increase in heparin activity with hemofiltration was directly related to ultrafiltrate volume (r = 0

  10. 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.

  11. Hydrogen adsorption on Be, Mg, Ca and Sr doped graphenes: The role of the dopant in the IIA main group

    NASA Astrophysics Data System (ADS)

    Luo, Huijuan; Li, Hejun; Fu, Qiangang

    2017-02-01

    Hydrogen (H2) adsorption on the IIA elements doped double-vacancy graphenes (BeG, MgG, CaG and SrG) was studied by using dispersion-corrected density functional theory calculations. Through investigation of different numbers of hydrogen dockings from two directions, it is found that 1H2/BeG, 1H2/MgG, 8H2/CaG and 8H2/SrG are the most stable adsorption configurations for Be, Mg, Ca and Sr doped graphenes, respectively. Atomic radius, electronegativity and ionization potential of the IIA dopant contribute to the dominating adsorption mechanism under specific H2 concentration. The study would facilitate exploration of high performance graphene-related supports for hydrogen storage.

  12. Purification and characterization of a novel class IIa bacteriocin, piscicocin CS526, from surimi-associated Carnobacterium piscicola CS526.

    PubMed

    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 degrees 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 approximately 4,430 Da.

  13. 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

  14. Molecular Basis for Differential Sensitivity of α-Conotoxin RegIIA at Rat and Human Neuronal Nicotinic Acetylcholine Receptors.

    PubMed

    Kompella, Shiva N; Cuny, Hartmut; Hung, Andrew; Adams, David J

    2015-12-01

    α-Conotoxins, as nicotinic acetylcholine receptor (nAChR) antagonists, are powerful tools for dissecting biologic processes and guiding drug development. The α3β2 and α3β4 nAChR subtypes are expressed in the central and peripheral nervous systems and play a critical role in various pathophysiological conditions ranging from nicotine addiction to the development and progression of lung cancer. Here we used the α4/7-conotoxin RegIIA, a disulfide-bonded peptide from the venom of Conus regius, and its analog [N11A,N12A]RegIIA to probe the specific pharmacological properties of rat and human nAChR subtypes. nAChR subtypes were heterologously expressed in Xenopus oocytes and two-electrode voltage clamp recordings used to investigate the effects of the peptides on nAChR activity. RegIIA potently inhibited currents evoked by acetylcholine (ACh) at rat α3β2 (IC50 = 10.7 nM), whereas a 70-fold lower potency was observed at human α3β2 nAChR (IC50 = 704.1 nM). Conversely, there were no species-specific differences in sensitivity to RegIIA at the α3β4 nAChR. Receptor mutagenesis and molecular dynamics studies revealed that this difference can be attributed primarily to a single amino acid change: Glu198 on the rat α3 subunit corresponding to a proline on the human subunit. These findings reveal a novel species- and subunit-specific receptor-antagonist interaction. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  15. Enzymatic properties of stingray Dasyatis pastinaca group V, IIA and IB phospholipases A(2): a comparative study.

    PubMed

    Ben Bacha, Abir; Abid, Islem; Horchani, Habib; Mejdoub, Hafedh

    2013-11-01

    In the present study, we have purified the group V phospholipase from the heart of cartilaginous fish stingray Dasyatis pastinaca and compared its biochemical properties with group IIA (sPLA2-IIA) and IB (sPLA2-IB) phospholipases previously purified from pancreas and intestine, respectively. Group V phospholipase (sPLA2-V) was purified to homogeneity by heat treatment, ammonium sulphate precipitation and RP-HPLC. The N-terminal sequence of the purified sPLA2-V exhibits a high degree of homology with those of mammal. The enzyme was found to be monomeric with a molecular mass estimation of 14 kDa. The specific activity of the purified enzyme, measured at pH 8 and 37 °C was 52 U/mg. Like sPLA2-IB and sPLA2-IIA, the sPLA2-V is found to be stable between pH 3 and 11 after 30 min of incubation. The purified sPLA2-V retained 65% of its activity after 10 min of incubation at 70 °C and it absolutely requires Ca(2+) for enzymatic activity. In addition it displayed high tolerance to organic solvents. Kinetic parameters Kmapp, kcat and the deduced catalytic efficiency (kcat/Kmapp) of the purified group-V, -IB and -IIA PLA2s were determined using phosphatidylethanolamine (PE), phosphatidylcholine (PC) or phosphatidylserine (PS) as substrate. The three enzymes hydrolyze the zwiterionic PE and PC substrates more efficiently than anionic PS substrate.

  16. 30 CFR 57.22228 - Preshift examination (I-A, I-C, 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 Preshift examination (I-A, I-C, II-A, III, and V-A mines). 57.22228 Section 57.22228 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION... Preshift examination (I-A, I-C, II-A, III, and V-A mines). (a) Preshift examinations shall be conducted...

  17. 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, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). 57.22222 Section 57.22222 Mineral Resources MINE SAFETY AND HEALTH....22222 Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). Brattice cloth and...

  18. 30 CFR 57.22228 - Preshift examination (I-A, I-C, 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 Preshift examination (I-A, I-C, II-A, III, and V-A mines). 57.22228 Section 57.22228 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION... Preshift examination (I-A, I-C, II-A, III, and V-A mines). (a) Preshift examinations shall be conducted...

  19. 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, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). 57.22222 Section 57.22222 Mineral Resources MINE SAFETY AND HEALTH....22222 Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). Brattice cloth and...

  20. 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, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). 57.22222 Section 57.22222 Mineral Resources MINE SAFETY AND HEALTH....22222 Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). Brattice cloth and...

  1. 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

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). 57.22222 Section 57.22222 Mineral Resources MINE SAFETY AND HEALTH....22222 Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). Brattice cloth and...

  2. 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, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). 57.22222 Section 57.22222 Mineral Resources MINE SAFETY AND HEALTH....22222 Ventilation materials (I-A, I-B, I-C, II-A, III, V-A, and V-B mines). Brattice cloth and...

  3. 30 CFR 57.22220 - Air passing unsealed areas (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 Air passing unsealed areas (I-A, II-A, III, and V-A mines). 57.22220 Section 57.22220 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION... passing unsealed areas (I-A, II-A, III, and V-A mines). Air that has passed by or through...

  4. 30 CFR 57.22215 - Separation of intake and return air (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 Separation of intake and return air (I-A, II-A... Separation of intake and return air (I-A, II-A, III, and V-A mines). Main intake and return air currents... for separation of air currents. Such wall or partition shall be constructed of reinforced concrete or...

  5. 30 CFR 57.22215 - Separation of intake and return air (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 Separation of intake and return air (I-A, II-A... Separation of intake and return air (I-A, II-A, III, and V-A mines). Main intake and return air currents... for separation of air currents. Such wall or partition shall be constructed of reinforced concrete or...

  6. 30 CFR 57.22215 - Separation of intake and return air (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 Separation of intake and return air (I-A, II-A... Separation of intake and return air (I-A, II-A, III, and V-A mines). Main intake and return air currents... for separation of air currents. Such wall or partition shall be constructed of reinforced concrete or...

  7. 30 CFR 57.22215 - Separation of intake and return air (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 Separation of intake and return air (I-A, II-A... Separation of intake and return air (I-A, II-A, III, and V-A mines). Main intake and return air currents... for separation of air currents. Such wall or partition shall be constructed of reinforced concrete or...

  8. 30 CFR 57.22215 - Separation of intake and return air (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 Separation of intake and return air (I-A, II-A... Separation of intake and return air (I-A, II-A, III, and V-A mines). Main intake and return air currents... for separation of air currents. Such wall or partition shall be constructed of reinforced concrete or...

  9. 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

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Actions at 1.0 percent methane (I-C, II-A, II-B... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22235 Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in...

  10. 30 CFR 57.22232 - Actions at 0.5 percent methane (I-B, II-A, II-B, IV, V-B, and VI mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Actions at 0.5 percent methane (I-B, II-A, II-B...-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22232 Actions at 0.5 percent methane (I-B, II-A, II-B, IV, V-B, and VI mines). If methane reaches...

  11. 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

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Actions at 1.0 percent methane (I-C, II-A, II-B... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22235 Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in...

  12. 30 CFR 57.22232 - Actions at 0.5 percent methane (I-B, II-A, II-B, IV, V-B, and VI mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Actions at 0.5 percent methane (I-B, II-A, II-B...-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22232 Actions at 0.5 percent methane (I-B, II-A, II-B, IV, V-B, and VI mines). If methane reaches...

  13. 30 CFR 57.22235 - Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Actions at 1.0 percent methane (I-C, II-A, II-B... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22235 Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in the...

  14. 30 CFR 57.22235 - Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Actions at 1.0 percent methane (I-C, II-A, II-B... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22235 Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in the...

  15. 30 CFR 57.22235 - Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Actions at 1.0 percent methane (I-C, II-A, II-B... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22235 Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in the...

  16. sPLA2 -IIA Overexpression in Mice Epidermis Depletes Hair Follicle Stem Cells and Induces Differentiation Mediated Through Enhanced JNK/c-Jun Activation.

    PubMed

    Sarate, Rahul M; Chovatiya, Gopal L; Ravi, Vagisha; Khade, Bharat; Gupta, Sanjay; Waghmare, Sanjeev K

    2016-09-01

    Secretory phospholipase A2 Group-IIA (sPLA2 -IIA) catalyzes the hydrolysis of the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. sPLA2 -IIA is deregulated in various cancers; however, its role in hair follicle stem cell (HFSC) regulation is obscure. Here we report a transgenic mice overexpressing sPLA2 -IIA (K14-sPLA2 -IIA) showed depletion of HFSC pool. This was accompanied with increased differentiation, loss of ortho-parakeratotic organization and enlargement of sebaceous gland, infundibulum and junctional zone. The colony forming efficiency of keratinocytes was significantly reduced. Microarray profiling of HFSCs revealed enhanced level of epithelial mitogens and transcription factors, c-Jun and FosB that may be involved in proliferation and differentiation. Moreover, K14-sPLA2 -IIA keratinocytes showed enhanced activation of EGFR and JNK1/2 that led to c-Jun activation, which co-related with enhanced differentiation. Further, depletion of stem cells in bulge is associated with high levels of chromatin silencing mark, H3K27me3 and low levels of an activator mark, H3K9ac suggestive of alteration in gene expression contributing toward stem cells differentiation. Our results, first time uncovered that overexpression of sPLA2 -IIA lead to depletion of HFSCs and differentiation associated with altered histone modification. Thus involvement of sPLA2 -IIA in stem cells regulation and disease pathogenesis suggest its prospective clinical implications. Stem Cells 2016;34:2407-2417.

  17. 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.

  18. Phylogenetic relationship and geographic distribution of multiple human T-cell lymphotropic virus type II subtypes.

    PubMed Central

    Switzer, W M; Pieniazek, D; Swanson, P; Samdal, H H; Soriano, V; Khabbaz, R F; Kaplan, J E; Lal, R B; Heneine, W

    1995-01-01

    The current env-based subtyping of human T-cell lymphotropic virus type II (HTLV-II) identifies only two heterogenetic groups, HTLV-IIa and HTLV-IIb. To better understand the genetic diversity and phylogeny of HTLV-II, we examined the most divergent genomic region of HTLV-II, the long terminal repeat, by using restriction fragment length polymorphism (RFLP) and sequence analysis. Long terminal repeat sequences were amplified from peripheral blood mononuclear cells by PCR and digested with seven restriction endonucleases that differentiated HTLV-II into five HTLV-IIa (IIa0 to IIa4) and six HTLV-IIb (IIb0 to IIb5) restriction types, with HTLV-IIa0 and HTLV-IIb0 being prototypes for the MoT and NRA isolates, respectively. We examined 169 HTLV-II-infected samples, including 123 from blood donors and intravenous drug users (IDU) from the Americas, 16 from IDU from Europe, and 30 from Amerindians. Of the 169 samples, 109 (64.5%) were categorized as HTLV-IIa and 60 (35.5%) were categorized as HTLV-IIb. The predominant restriction types seen among the U.S. blood donors and U.S. IDU were IIa0 (68.7%) and IIb4 (10.4%). Four Spanish and seven Italian samples were IIb4, while five Norwegian samples were IIa2. Twelve Guaymi and all ten Seminole samples were single restriction types (IIb1 and IIb5, respectively), whereas the two Navajo and six Pueblo samples had a mixture of restriction types IIa0, IIa4, and IIb5. Of the HTLV-IIb restriction types observed in the U.S. non-Indians, 42.8% appear to have originated from the North Amerindian (IIb5), while 57.2% were similar to the European IIb4 restriction type. Sequences of 15 selected HTLV-II samples were determined and phylogenetically compared with 7 previously published HTLV-II LTR sequences. The derived topologies revealed three HTLV-IIa phylogroups (A-I to A-III) and four HTLV-IIb phylogroups (B-I to B-IV). Furthermore, the HTLV-IIa phylogroups appear to have evolved from the HTLV-IIb phylogroups. In the HTLV-IIa cluster, a

  19. 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

  20. 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

  1. 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

    2014-10-02

    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.

  2. 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.

  3. Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis.

    PubMed

    Moran, Corey S; Seto, Sai-Wang; Krishna, Smriti M; Sharma, Surabhi; Jose, Roby J; Biros, Erik; Wang, Yutang; Morton, Susan K; Golledge, Jonathan

    2017-02-21

    Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE(-/-) mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm.

  4. Functional differences in Leuconostoc sensitive and resistant strains to mesenterocin 52A, a class IIa bacteriocin.

    PubMed

    Jasniewski, Jordane; Cailliez-Grimal, Catherine; Younsi, Mohamed; Millière, Jean-Bernard; Revol-Junelles, Anne-Marie

    2008-12-01

    Mesenterocin 52A (Mes 52A) is a class IIa bacteriocin produced by Leuconostoc mesenteroides ssp. mesenteroides FR52. The interaction of Mes 52A with bacterial membranes of sensitive, resistant and insensitive Leuconostoc strains has been investigated. The degree of insertion of Mes 52A on the phospholipid bilayer was studied by fluorescence anisotropy measurements using two probes, 1-(4-trimethylammonium)-6-phenyl-1,3,5-hexatriene (TMA-DPH) and DPH, located at different positions in the membrane, and the consequence for K(+) efflux and proton motive force was analyzed. Mes 52A caused an increase in the fluorescence of TMA-DPH and DPH in the membrane of the sensitive strain L. mesenteroides ssp. mesenteroides LMA 7, indicating that Mes 52A inserts into the cytoplasmic membrane of this sensitive strain. This insertion leads to K(+) efflux, without perturbation of DeltapH and a weak modification of DeltaPsi, and is consistent with pore formation. With the high-level resistant strain L. mesenteroides ssp. mesenteroides LMA 7AR, or with the insensitive strain Leuconostoc citreum CIP 103405, no modification of TMA-DPH or DPH anisotropy occurred, even in the presence of high Mes 52A levels. The membrane potential was not modified and no K(+) efflux was detected. There is a clear correlation between the physico-chemical characteristics of the membrane, the degree of Mes 52A penetration, the mechanism of action and the resistance or insensitivity characteristic of the target strains.

  5. Supersymmetry of IIA warped flux AdS and flat backgrounds

    NASA Astrophysics Data System (ADS)

    Beck, S.; Gutowski, J.; Papadopoulos, G.

    2015-09-01

    We identify the fractions of supersymmetry preserved by the most general warped flux AdS and flat backgrounds in both massive and standard IIA supergravities. We find that AdS n × w M 10 - n preserve {2}^{[n/2]}k for n ≤ 4 and {2}^{[n/2]+1}k for 4 < n ≤ 7 supersymmetries, k ∈ ℕ >0. In addition we show that, for suitably restricted fields and M 10 - n , the killing spinors of AdS backgrounds are given in terms of the zero modes of Dirac like operators on M 10 - n . This generalizes the Lichnerowicz theorem for connections whose holonomy is included in a general linear group. We also adapt our results to ℝ 1, n - 1 × w M 10 - n backgrounds which underpin flux compactifications to ℝ 1, n - 1 and show that these preserve {2}^{[n/2]}k for 2

  6. Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA

    PubMed Central

    Catera, Rosa; Hatzi, Katerina; Yan, Xiao-Jie; Zhang, Lu; Wang, Xiao Bo; Fales, Henry M.; Allen, Steven L.; Kolitz, Jonathan E.; Rai, Kanti R.; Chiorazzi, Nicholas

    2008-01-01

    Leukemic B lymphocytes of a large group of unrelated chronic lymphocytic leukemia (CLL) patients express an unmutated heavy chain immunoglobulin variable (V) region encoded by IGHV1-69, IGHD3-16, and IGHJ3 with nearly identical heavy and light chain complementarity-determining region 3 sequences. The likelihood that these patients developed CLL clones with identical antibody V regions randomly is highly improbable and suggests selection by a common antigen. Monoclonal antibodies (mAbs) from this stereotypic subset strongly bind cytoplasmic structures in HEp-2 cells. Therefore, HEp-2 cell extracts were immunoprecipitated with recombinant stereotypic subset-specific CLL mAbs, revealing a major protein band at approximately 225 kDa that was identified by mass spectrometry as nonmuscle myosin heavy chain IIA (MYHIIA). Reactivity of the stereotypic mAbs with MYHIIA was confirmed by Western blot and immunofluorescence colocalization with anti-MYHIIA antibody. Treatments that alter MYHIIA amounts and cytoplasmic localization resulted in a corresponding change in binding to these mAbs. The appearance of MYHIIA on the surface of cells undergoing stress or apoptosis suggests that CLL mAb may generally bind molecules exposed as a consequence of these events. Binding of CLL mAb to MYHIIA could promote the development, survival, and expansion of these leukemic cells. PMID:18812466

  7. Sodium tanshinone IIA sulfonate attenuates radiation-induced fibrosis damage in cardiac fibroblasts.

    PubMed

    Gu, Jing; Li, Hai-Long; Wu, Hong-Yan; Gu, Mei; Li, Ying-Dong; Wang, Xiao-Gang; Ming, Hai-Xia; Dong, Xiao-Li; Liu, Kai

    2014-01-01

    The main pathological change in radiation-induced heart disease is fibrosis. Emerging evidence has indicated that sodium tanshinone IIA sulfonate (STS) was used for treating fibrosis diseases. The present study was undertaken to characterize the effect of STS on radiation-induced cardiac fibrosis (RICF) on cultured cardiac fibroblasts (CFs). CFs were irradiated with 1 or 2 Gy X-rays, and the expression of TGF-β1 and collagen I (Col-1) increased, indicating that low-dose X-rays promoted fibrosis damage effect. The fibrosis damage was accompanied by morphologic changes in the endoplasmic reticulum (ER), as well as an increase in the expression of the ER stress-related molecules, GRP78 and CHOP. Administration of STS reduced ROS production and decreased the expression of Col-1, TGF-β1, p-Smad2/3, GRP78, and CHOP in irradiated CFs, thus weakening the radiation-induced fibrosis damage and ER stress. Radiation-induced fibrosis damage was observed on a cellular level. The involvement of ER stress in radiation-induced fibrosis damage was demonstrated for the first time. STS attenuated the fibrosis damage effect in CFs and this effect may be related to its antioxidant action, and also related to its inhibition of ER stress and TGF-β1-Smad pathway. These results suggest that STS shows a good prospect in clinical prevention and treatment of RICF.

  8. SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion

    PubMed Central

    Fan, Xueping; Yang, Hongying; Kumar, Sudhir; Tumelty, Kathleen E.; Pisarek-Horowitz, Anna; Sharma, Richa; Chan, Stefanie; Tyminski, Edyta; Shamashkin, Michael; Belghasem, Mostafa; Henderson, Joel M.; Coyle, Anthony J.; Berasi, Stephen P.

    2016-01-01

    The repulsive guidance cue SLIT2 and its receptor ROBO2 are required for kidney development and podocyte foot process structure, but the SLIT2/ROBO2 signaling mechanism regulating podocyte function is not known. Here we report that a potentially novel signaling pathway consisting of SLIT/ROBO Rho GTPase activating protein 1 (SRGAP1) and nonmuscle myosin IIA (NMIIA) regulates podocyte adhesion downstream of ROBO2. We found that the myosin II regulatory light chain (MRLC), a subunit of NMIIA, interacts directly with SRGAP1 and forms a complex with ROBO2/SRGAP1/NMIIA in the presence of SLIT2. Immunostaining demonstrated that SRGAP1 is a podocyte protein and is colocalized with ROBO2 on the basal surface of podocytes. In addition, SLIT2 stimulation inhibits NMIIA activity, decreases focal adhesion formation, and reduces podocyte attachment to collagen. In vivo studies further showed that podocyte-specific knockout of Robo2 protects mice from hypertension-induced podocyte detachment and albuminuria and also partially rescues the podocyte-loss phenotype in Myh9 knockout mice. Thus, we have identified SLIT2/ROBO2/SRGAP1/NMIIA as a potentially novel signaling pathway in kidney podocytes, which may play a role in regulating podocyte adhesion and attachment. Our findings also suggest that SLIT2/ROBO2 signaling might be a therapeutic target for kidney diseases associated with podocyte detachment and loss. PMID:27882344

  9. Autologous Myoblast Transplantation for Oculopharyngeal Muscular Dystrophy: a Phase I/Iia Clinical Study

    PubMed Central

    Périé, Sophie; Trollet, Capucine; Mouly, Vincent; Vanneaux, Valérie; Mamchaoui, Kamel; Bouazza, Belaïd; Marolleau, Jean Pierre; Laforêt, Pascal; Chapon, Françoise; Eymard, Bruno; Butler-Browne, Gillian; Larghero, Jérome; St Guily, Jean Lacau

    2014-01-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblast transplantation and the surgical procedure were assessed by videoendoscopy in addition to physical examinations. Potential therapeutic benefit was also assessed through videoendoscopy and videofluoroscopy of swallowing, quality of life score, dysphagia grade, and a drink test. Patients were injected with a median of 178 million myoblasts following myotomy. Short and long-term (2 years) safety and tolerability were observed in all the patients, with no adverse effects. There was an improvement in the quality of life score for all 12 patients, and no functional degradation in swallowing was observed for 10 patients. A cell dose-dependant improvement in swallowing was even observed in this study. This trial supports the hypothesis that a local injection of autologous myoblasts in the pharyngeal muscles is a safe and efficient procedure for OPMD patients. PMID:23831596

  10. Detection of Listeria monocytogenes with short peptide fragments from class IIa bacteriocins as recognition elements.

    PubMed

    Azmi, Sarfuddin; Jiang, Keren; Stiles, Michael; Thundat, Thomas; Kaur, Kamaljit

    2015-03-09

    We employed a direct peptide-bacteria binding assay to screen peptide fragments for high and specific binding to Listeria monocytogenes. Peptides were screened from a peptide array library synthesized on cellulose membrane. Twenty four peptide fragments (each a 14-mer) were derived from three potent anti-listerial peptides, Leucocin A, Pediocin PA1, and Curvacin A, that belong to class IIa bacteriocins. Fragment Leu10 (GEAFSAGVHRLANG), derived from the C-terminal region of Leucocin A, displayed the highest binding among all of the library fragments toward several pathogenic Gram-positive bacteria, including L. monocytogenes, Enterococcus faecalis, and Staphylococcus aureus. The specific binding of Leu10 to L. monocytogenes was further validated using microcantilever (MCL) experiments. Microcantilevers coated with gold were functionalized with peptides by chemical conjugation using a cysteamine linker to yield a peptide density of ∼4.8×10(-3) μmol/cm2 for different peptide fragments. Leu10 (14-mer) functionalized MCL was able to detect Listeria with same sensitivity as that of Leucocin A (37-mer) functionalized MCL, validating the use of short peptide fragments in bacterial detection platforms. Fragment Leu10 folded into a helical conformation in solution, like that of native Leucocin A, suggesting that both Leu10 and Leucocin A may employ a similar mechanism for binding target bacteria. The results show that peptide-conjugated microcantilevers can function as highly sensitive platforms for Listeria detection and hold potential to be developed as biosensors for pathogenic bacteria.

  11. Nisin and class IIa bacteriocin resistance among Listeria and other foodborne pathogens and spoilage bacteria.

    PubMed

    Kaur, Gurpreet; Malik, Ravinder Kumar; Mishra, Santosh Kumar; Singh, Tejinder Pal; Bhardwaj, Arun; Singroha, Garima; Vij, Shilpa; Kumar, Naresh

    2011-06-01

    Food safety has been an important issue globally due to increasing foodborne diseases and change in food habits. To inactivate foodborne pathogens, various novel technologies such as biopreservation systems have been studied. Bacteriocins are ribosomally synthesized peptides or proteins with antimicrobial activity produced by different groups of bacteria, but the bacteriocins produced by many lactic acid bacteria offer potential applications in food preservation. The use of bacteriocins in the food industry can help reduce the addition of chemical preservatives as well as the intensity of heat treatments, resulting in foods that are more naturally preserved. However, the development of highly tolerant and/or resistant strains may decrease the efficiency of bacteriocins as biopreservatives. Several mechanisms of bacteriocin resistance development have been proposed among various foodborne pathogens. The acquiring of resistance to bacteriocins can significantly affect physiological activity profile of bacteria, alter cell-envelope lipid composition, and also modify the antibiotic susceptibility/resistance profile of bacteria. This article presents a brief review on the scientific research about the various possible mechanisms involved in the development of resistance to nisin and Class IIa bacteriocins among the foodborne pathogens.

  12. Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis

    PubMed Central

    Moran, Corey S.; Seto, Sai-Wang; Krishna, Smriti M.; Sharma, Surabhi; Jose, Roby J.; Biros, Erik; Wang, Yutang; Morton, Susan K.; Golledge, Jonathan

    2017-01-01

    Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE−/−) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE−/− mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm. PMID:28220880

  13. 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

  14. Tanshinone IIA suppresses gastric cancer cell proliferation and migration by downregulation of FOXM1

    PubMed Central

    Yu, Jiao; Wang, Xiaoxia; Li, Yuhua; Tang, Bin

    2017-01-01

    Tanshinone IIA (TSN) exhibits a variety of anticancer effects. However, whether it inhibits gastric cancer (GC) cell proliferation and migration and the mechanism remain unclear. In the present study, different concentrations of TSN were co-incubated with SGC-7901 cells. The pcDNA-FOXM1 or FOXM1-siRNA plasmid was transfected into cells before treatment with 5 µg/l TSN. The proliferation and migration abilities of the SGC-7901 cells were tested by MTT and wound healing assays. Western blotting was used to investigate the expression levels of P21, Ki-67, PCNA, MMP-2, MMP-9 and FOXM1. We found that compared with the control, the proliferation and migration abilities of the SGC-7901 cells were decreased after incubation with different concentrations of TSN in a dose-dependent manner (p<0.01). Moreover, the expression levels of Ki-67, PCAN, MMP-2, MMP-9 and FOXM1 were decreased, and P21 was increased in the TSN-treated SGC-7901 cells (p<0.01). In addition, downregulation of FOXM1 by FOXM1-siRNA had the same effect as TSN on SGC-7901 cells, and overexpression of FOXM1 partly abrogated TSN-mediated inhibition of SGC-7901 cell proliferation and migration. These results suggested that TSN inhibits SGC-7901 cell proliferation and migration by downregulation of FOXM1. PMID:28184921

  15. Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration.

    PubMed

    Morin, Nicole A; Oakes, Patrick W; Hyun, Young-Min; Lee, Dooyoung; Chin, Y Eugene; Chin, Eugene Y; King, Michael R; Springer, Timothy A; Shimaoka, Motomu; Tang, Jay X; Reichner, Jonathan S; Kim, Minsoo

    2008-01-21

    Precise spatial and temporal regulation of cell adhesion and de-adhesion is critical for dynamic lymphocyte migration. Although a great deal of information has been learned about integrin lymphocyte function-associated antigen (LFA)-1 adhesion, the mechanism that regulates efficient LFA-1 de-adhesion from intercellular adhesion molecule (ICAM)-1 during T lymphocyte migration is unknown. Here, we show that nonmuscle myosin heavy chain IIA (MyH9) is recruited to LFA-1 at the uropod of migrating T lymphocytes, and inhibition of the association of MyH9 with LFA-1 results in extreme uropod elongation, defective tail detachment, and decreased lymphocyte migration on ICAM-1, without affecting LFA-1 activation by chemokine CXCL-12. This defect was reversed by a small molecule antagonist that inhibits both LFA-1 affinity and avidity regulation, but not by an antagonist that inhibits only affinity regulation. Total internal reflection fluorescence microscopy of the contact zone between migrating T lymphocytes and ICAM-1 substrate revealed that inactive LFA-1 is selectively localized to the posterior of polarized T lymphocytes, whereas active LFA-1 is localized to their anterior. Thus, during T lymphocyte migration, uropodal adhesion depends on LFA-1 avidity, where MyH9 serves as a key mechanical link between LFA-1 and the cytoskeleton that is critical for LFA-1 de-adhesion.

  16. Tanshinone IIA ameliorates apoptosis of cardiomyocytes induced by endoplasmic reticulum stress

    PubMed Central

    Feng, Jun; Li, Shusheng

    2016-01-01

    The fat-soluble diterpenoids tanshinone IIA (TSA) is the major active element of Danshen, which has widespread cardioprotective effect. However, the mechanism of its beneficial effect on cardiomyocytes has not been fully investigated. Here, we aim to demonstrate that TSA ameliorates apoptosis of cardiomyocytes activated by endoplasmic reticulum stress (ERS). Primary cultures of neonatal rat cardiomyocytes are used, in which ERS-mediated apoptosis is induced by tunicamycin (Tm). Apoptosis of cardiomyocytes are detected by Hoechst staining and caspase 3 activity analysis. Protein expression of ERS markers are detected by Western blot, and level of miroRNA-133 (miR-133) is detected by real-time polymerase chain reaction. Tm treatment significantly triggers the apoptosis and ERS of cardiomyocytes. TSA dramatically ameliorates apoptosis and ERS of cardiomyocytes induced by Tm. Interestingly, level of miR-133 is reduced by Tm treatment, which is reversed by TSA. The cardioprotective effect of TSA on apoptosis and ERS of cardiomyocytes is blocked by anti-miR-133. These results suggest that TSA protects cardiomyocytes through ameliorated ERS-mediated apoptosis, which may be resulted from upregulation of miR-133. PMID:27465140

  17. 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

  18. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study.

    PubMed

    Périé, Sophie; Trollet, Capucine; Mouly, Vincent; Vanneaux, Valérie; Mamchaoui, Kamel; Bouazza, Belaïd; Marolleau, Jean Pierre; Laforêt, Pascal; Chapon, Françoise; Eymard, Bruno; Butler-Browne, Gillian; Larghero, Jérome; St Guily, Jean Lacau

    2014-01-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblast transplantation and the surgical procedure were assessed by videoendoscopy in addition to physical examinations. Potential therapeutic benefit was also assessed through videoendoscopy and videofluoroscopy of swallowing, quality of life score, dysphagia grade, and a drink test. Patients were injected with a median of 178 million myoblasts following myotomy. Short and long-term (2 years) safety and tolerability were observed in all the patients, with no adverse effects. There was an improvement in the quality of life score for all 12 patients, and no functional degradation in swallowing was observed for 10 patients. A cell dose-dependant improvement in swallowing was even observed in this study. This trial supports the hypothesis that a local injection of autologous myoblasts in the pharyngeal muscles is a safe and efficient procedure for OPMD patients.

  19. Spectroscopic and molecular modeling evidence of clozapine binding to human serum albumin at subdomain IIA

    NASA Astrophysics Data System (ADS)

    Wu, Xinhu; Liu, Jianjun; Wang, Qiang; Xue, Weiwei; Yao, Xiaojun; Zhang, Yan; Jin, Jing

    2011-09-01

    Various spectroscopy and molecular docking methods were used to examine the binding of Clozapine (CLZ) to human serum albumin (HSA) in this paper. By monitoring the intrinsic fluorescence of single Trp214 residue and performing Dansylamide (DNSA) displacement measurement, the specific binding of CLZ in the vicinity of Sudlow's Site I of HSA has been clarified. An apparent distance of 27.3 Å between the Trp214 and CLZ was obtained via fluorescence resonance energy transfer (FRET) method. In addition, the changes in the secondary structure of HSA after its complexation with CLZ ligand were studied with CD spectroscopy, which indicate that CLZ does not has remarkable effect on the structure of the protein. Moreover, thermal denaturation experiment shows that the HSA-CLZ complexes are conformationally more stable. Finally, the binding details between CLZ and HSA were further confirmed by molecular docking studies, which revealed that CLZ was bound at subdomain IIA through multiple interactions, such as hydrophobic effect, van der Waals forces and hydrogen bonding.

  20. Spectroscopic and molecular modeling evidence of clozapine binding to human serum albumin at subdomain IIA.

    PubMed

    Wu, Xinhu; Liu, Jianjun; Wang, Qiang; Xue, Weiwei; Yao, Xiaojun; Zhang, Yan; Jin, Jing

    2011-09-01

    Various spectroscopy and molecular docking methods were used to examine the binding of Clozapine (CLZ) to human serum albumin (HSA) in this paper. By monitoring the intrinsic fluorescence of single Trp214 residue and performing Dansylamide (DNSA) displacement measurement, the specific binding of CLZ in the vicinity of Sudlow's Site I of HSA has been clarified. An apparent distance of 27.3 Å between the Trp214 and CLZ was obtained via fluorescence resonance energy transfer (FRET) method. In addition, the changes in the secondary structure of HSA after its complexation with CLZ ligand were studied with CD spectroscopy, which indicate that CLZ does not has remarkable effect on the structure of the protein. Moreover, thermal denaturation experiment shows that the HSA-CLZ complexes are conformationally more stable. Finally, the binding details between CLZ and HSA were further confirmed by molecular docking studies, which revealed that CLZ was bound at subdomain IIA through multiple interactions, such as hydrophobic effect, van der Waals forces and hydrogen bonding.

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

    PubMed

    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.

  2. 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

  3. 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.

  4. Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

    PubMed Central

    2012-01-01

    Background Activation of microglia, the primary component of the innate immune response in the brain, is a hallmark of neuroinflammation in neurodegenerative disorders, including Alzheimer’s disease (AD) and other pathological conditions such as stroke or CNS infection. In response to a variety of insults, microglial cells produce high levels of inflammatory cytokines that are often involved in neuronal injury, and play an important role in the recognition, engulfment, and clearance of apoptotic cells and/or invading microbes. Secreted phospholipase A2-IIA (sPLA2-IIA), an enzyme that interacts with cells involved in the systemic immune/inflammatory response, has been found up-regulated in the cerebrospinal fluid and brain of AD patients. However, despite several approaches, its functions in mediating CNS inflammation remain unknown. In the present study, the role of sPLA2-IIA was examined by investigating its direct effects on microglial cells. Methods Primary and immortalized microglial cells were stimulated by sPLA2-IIA in order to characterize the cytokine-like actions of the phospholipase. The hallmarks of activated microglia analyzed include: mitogenic response, phagocytic capabilities and induction of inflammatory mediators. In addition, we studied several of the potential molecular mechanisms involved in those events. Results The direct exposure of microglial cells to sPLA2-IIA stimulated, in a time- and dose-dependent manner, their phagocytic and proliferative capabilities. sPLA2-IIA also triggered the synthesis of the inflammatory proteins COX-2 and TNFα. In addition, EGFR phosphorylation and shedding of the membrane-anchored heparin-binding EGF-like growth factor (pro-HB-EGF) ectodomain, as well as a rapid activation/phosphorylation of the classical survival proteins ERK, P70S6K and rS6 were induced upon sPLA2-IIA treatment. We further demonstrated that the presence of an EGFR inhibitor (AG1478), a matrix metalloproteinase inhibitor (GM6001), an ADAM

  5. Genetic characterisation and heterologous expression of leucocin C, a class IIa bacteriocin from Leuconostoc carnosum 4010.

    PubMed

    Wan, Xing; Li, Ruiqing; Saris, Per E J; Takala, Timo M

    2013-04-01

    Leuconostoc carnosum 4010 is a protective culture for meat products. It kills the foodborne pathogen Listeria monocytogenes by producing two class IIa (pediocin-like) bacteriocins, leucocin A and leucocin C. The genes for leucocin A production have previously been characterised from Leuconostoc gelidum UAL 187, whereas no genetic studies about leucocin C has been published. Here, we characterised the genes for the production of leucocins A and C in L. carnosum 4010. In this strain, leucocin A and leucocin C operons were localised in different plasmids. Unlike in L. gelidum, leucocin A operon in L. carnosum 4010 only contained the structural and the immunity genes lcaAB without transporter genes lcaECD. On the contrary, leucocin C cluster included two intact operons. Novel genes lecCI encode the leucocin C precursor and the 97-aa immunity protein LecI, respectively. LecI shares 48 % homology with the immunity proteins of sakacin P and listeriocin. Another leucocin C operon lecXTS, encoding an ABC transporter and an accessory protein, was 97 % identical with the leucocin A transporter operon lcaECD of L. gelidum. For heterologous expression of leucocin C in Lactococcus lactis, the mature part of the lecC gene was fused with the signal sequence of usp45 in the secretion vector pLEB690. L. lactis secreted leucocin C efficiently, as shown by large halos on lawns of L. monocytogenes and Leuconostoc mesenteroides indicators. The function of LecI was then demonstrated by expressing the gene lecI in L. monocytogenes. LecI-producing Listeria was less sensitive to leucocin C than the vector strain, thus corroborating the immunity function of LecI.

  6. 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

  7. Reduction of atrial fibrillation by Tanshinone IIA in chronic heart failure.

    PubMed

    He, Zhifeng; Sun, Changzheng; Xu, Yi; Cheng, Dezhi

    2016-12-01

    The aim of the present study was to confirm the effect of Tanshinone IIA (TAN) on the prevention of AF in chronic heart failure (CHF), and to elucidate the underlying electrophysiological mechanisms for the antiarrhythmic effects of TAN at the level of the atrium in an experimental model of CHF. In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1μm) and isoproterenol (1μm) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of TAN (10μm) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. TAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, TAN application moderately increased interatrial conduction time. TAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to prolongations of atrial post-repolarization refractoriness and a moderate increase in interatrial conduction time. Copyright © 2016. Published by Elsevier Masson SAS.

  8. Binding of methacycline to human serum albumin at subdomain IIA using multispectroscopic and molecular modeling methods.

    PubMed

    Dong, Chengyu; Lu, Ningning; Liu, Ying

    2013-01-01

    This study was designed to examine the interaction of methacyline (METC) with human serum albumin (HSA) by multispectroscopy and a molecular modeling method under simulative physiological conditions. The quenching mechanism was suggested to be static quenching based on fluorescence and ultraviolet-visible (UV-Vis) spectroscopy. According to the Vant' Hoff equation, the values of enthalpy (∆H) and entropy change (∆S) were calculated to be -95.29 kJ/mol and -218.13 J/mol/K, indicating that the main driving force of the interaction between HSA and METC were hydrogen bonds and van der Waals's forces. By performing displacement measurements, the specific binding of METC in the vicinity of Sudlow's site I of HSA was clarified. An apparent distance of 3.05 nm between Trp214 and METC was obtained via the fluorescence resonance energy transfer (FRET) method. Furthermore, the binding details between METC and HSA were further confirmed by molecular docking studies, which revealed that METC was bound at subdomain IIA through multiple interactions, such as hydrophobic effect, polar forces, hydrogen bonding, etc. The results of three-dimensional fluorescence and Fourier transform infrared (FTIR) spectroscopy showed that METC caused conformational and some microenvironmental changes in HSA and reduced the α-helix significantly in the range of 52.3-40.4% in HSA secondary structure. Moreover, the coexistence of metal ions such as Ca(2+), Al(3+), Fe(3+), Zn(2+), Cu(2+), Cr(3+) and Cd(2+) can decrease the binding constants of METC-HSA.

  9. 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.

  10. Effects of escins Ia, Ib, IIa, and IIb from horse chestnuts on gastric emptying in mice.

    PubMed

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

    1999-03-05

    Inhibitory effects of the saponin fraction and its principal constituents, escins Ia, Ib, IIa, and IIb, from horse chestnuts on gastric emptying were investigated in mice loaded with a non-nutrient or nutrient meal. The saponin fraction and escins Ia-IIb inhibited gastric emptying of a 1.5% carboxymethyl cellulose sodium salt (CMC-Na) meal by 11.1-54.2% (12.5-200 mg/kg). Escins Ia-IIb (50 mg/kg) also inhibited gastric emptying of a 40% glucose meal by 21.1-23.5% except for escin Ia, a milk meal by 18.4-33.1%, and a 30% ethanol meal by 13.5-15.9%. The effects of escins Ia-IIb on gastric emptying of the CMC-Na meal were attenuated by pretreatment with streptozotocin (100 mg/kg, i.v.), capsaicin (75 mg/kg in total, s.c.), or insulin (1 U/kg, s.c.). The effect of insulin was reduced by glucose (2 g/kg, i.v.) which can directly nourish the brain, but not by fructose (2 g/kg, i.v.) which cannot be utilized by the brain. The effects of escins Ia-IIb (50 mg/kg) were overridden in 60% ethanol-loaded mice, in which the central nervous system was suppressed by ethanol. These results suggest that capsaicin-sensitive sensory nerves and central nervous system partly participate in the effects of escins Ia-IIb.

  11. 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

  12. The Development of IIA Method and the Application on the 1661 Luermen event

    NASA Astrophysics Data System (ADS)

    Wu, T. R.; Wu, H.; Hu, S. K.; Tsai, Y. L.

    2016-12-01

    In 1661, Chinese navy led by General Koxinga at the end of Ming Dynasty had a naval battle against the Netherlands. This battle was not only the first official sea warfare that China confronted the Western world, but also the only naval battle won by Chinese Navy so far. This case was significant because it altered the fate of Taiwan until today. Ace of the critical points that General Zheng won the battle was entering Lakjemuyse bay unexpected. Luermen bay was and is an extremely shallow bay with a 2.1m maximum water depth during the high tide, which was not possible for a fleet of 20,000 marines to cross. Hence, no defense was deployed from the Netherlands side. However, plenty of historical literatures mentioned a strange phenomenon that helped Chinese warships entered the Luermen bay, the rise of water level. In this study, we will discuss the possible causes that might rise the water level, e.g. Tsunami, storm surge, and high tide. We analyzed it based on the knowledge of hydrodynamics. We performed the newly developed Impact Intensify Analysis (IIA) for finding the potential tsunami sources, and the COMCOT tsunami model was adopted for the nonlinear scenario simulations, associated with the high resolution bathymetry data. Both earthquake and mudslide tsunamis were inspected. Other than that, we also collected the information of tide and weather for identifying the effects from high tide and storm surge. After the thorough study, a scenario that satisfies most of the descriptions in the historical literatures will be presented. The results will explain the cause of mysterious event that changed the destiny of Taiwan.

  13. Tanshinone IIA attenuates seawater aspiration-induced lung injury by inhibiting macrophage migration inhibitory factor.

    PubMed

    Zhang, Yong; Zhang, Bo; Xu, Dun-Quan; Li, Wang-Ping; Xu, Min; Li, Jia-Huan; Xie, Xiao-Yan; Fan, Qi-Xin; Liu, Wei; Mu, De-Guang; Dong, Hai-Ying; Wang, Yan-Xia; Nan, Yan-Dong; Li, Zhi-Chao; Jin, Fa-Guang

    2011-01-01

    Inflammation takes responsibility for the seawater aspiration-induced lung injury. Tanshinone IIA (TIIA) can protect lipopolysaccharide-induced lung injury in mice through the inhibition of inflammation, but it is not reported whether TIIA have a protective effect on lung injury induced by seawater aspiration. Macrophage migration inhibitory factor (MIF) plays an important role in acute lung injury. In this study, we observed the effect of TIIA on the seawater aspiration-induced lung injury and the role of MIF in it. Seawater was aspirated into trachea of rats to make the lung injury model. TIIA was administered to investigate its beneficial effect on seawater-induced acute lung injury. The results showed that seawater aspiration led to hyoxemia, pulmonary edema, neutrophil infiltration, and lung histopathologic changes, with the elevated MIF expression in the lung tissues and plasma. However, these changes were attenuated by TIIA. In macrophage cells we also demonstrated that TIIA could inhibit MIF expression, nuclear factor κB (NF-κB) activity and release of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) induced by seawater. Besides, pretreatment with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), the MIF antagonist, elevated NF-κB and cytokines induced by seawater were also reduced markedly. Furthermore, rMIF treatment alone increased the phosphorylation level of NF-κB and release of cytokines, which was almost abolished by TIIA. Taken together, our results suggested that TIIA exert a protective effect on the seawater aspiration-induced lung injury partly through downregulation of MIF and the subsequent NF-κB activity, as well as expression of IL-6 and TNF-α.

  14. Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease.

    PubMed

    Domingo, Pere; Muñiz-Diaz, Eduardo; Baraldès, Maria A; Arilla, Marina; Barquet, Nicolau; Pericas, Roser; Juárez, Cándido; Madoz, Pedro; Vázquez, Guillermo

    2002-01-01

    In vitro studies have shown that the neutrophil Fc gamma receptor IIA (FcgammaRIIA) polymorphism influences the phagocytic capacity of neutrophils and the removal of encapsulated bacteria from the bloodstream. In particular, the R/R131 allotype is associated with less phagocytic activity. We performed a case-control study to determine the influence of the FcgammaRIIA polymorphism (R/R131, R/H131, H/H131) on the risk and outcome of meningococcal disease. The polymorphisms were measured in 130 patients with microbiologically proven meningococcal disease diagnosed from 1987 to 1998 (cases) and 260 asymptomatic sex-matched blood donors (controls). Clinical manifestations and complications of meningococcal disease were recorded, and a prognostic score (based on age, hemorrhagic diathesis, neurologic signs, and the absence of preadmission antibiotic) therapy was calculated. The distributions of FcgammaRIIA allotypes were similar in cases and controls. However, among patients with meningococcal infection, fulminant meningococcal disease (odds ratio [OR] = 3.9; 95% confidence interval [CI]: 1.0 to 16; P = 0.04) and meningococcemia without meningitis (OR = 3.0; 95% CI: 1.4 to 7.8; P = 0.004) were more common in those with the FcgammaRIIA-R/R131 allotype. Complications were also significantly more frequent in these patients. Of the 42 patients with the R/R131 allotype, 31 (74%) had an adverse prognostic score, compared with 7% (4 of 59) of those with the R/H131 allotype and 3% (1 of 29) of those with the H/H131 allotype (P <0.0001). The FcgammaRIIA-R/R131 allotype is associated with more severe forms of meningococcal disease.

  15. Sugary Endosperm is Modulated by Starch Branching Enzyme IIa in Rice (Oryza sativa L.).

    PubMed

    Lee, Yunjoo; Choi, Min-Seon; Lee, Gileung; Jang, Su; Yoon, Mi-Ra; Kim, Backki; Piao, Rihua; Woo, Mi-Ok; Chin, Joong Hyoun; Koh, Hee-Jong

    2017-12-01

    Starch biosynthesis is one of the most important pathways that determine both grain quality and yield in rice (Oryza sativa L.). Sugary endosperm, sugary-1 (sug-1), is a mutant trait for starch biosynthesis. Rice plants carrying sug-1 produce grains that accumulate water-soluble carbohydrates instead of starch, even after maturity. Although this trait enhances the diversity of grain quality, sugary endosperm rice has hardly been commercialized due to the severely wrinkled grains and subsequent problems in milling. This study was conducted to identify the genes responsible for the sug-h phenotype through a map-based cloning technology. We induced a mild sugary mutant, sugary-h (sug-h) through the chemical mutagenesis on the Korean japonica cultivar Hwacheong. Grains of the sug-h mutant were translucent and amber-colored, and the endosperm appeared less wrinkled than sug-1, whereas the soluble sugar content was fairly high. These characteristics confer greater marketability to the sug-h mutant. Genetic analyses indicated that the sug-h mutant phenotype was controlled by a complementary interaction of two recessive genes, Isoamylase1 (OsISA1), which was reported previously, and Starch branching enzyme IIa (OsBEIIa), which was newly identified in this study. Complementation tests indicated that OsBEIIa regulated the properties of sugary endosperm. Complementary interactions between the starch biosynthesis genes OsISA1 and OsBEIIa determine the mild sugary endosperm mutant, sugary-h, in rice. Our finding may facilitate the breeding of sugaryendosperm rice for commercial benefit.

  16. Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone IIA discoidal and spherical biomimetic high density lipoproteins.

    PubMed

    Zhang, Wenli; He, Hongliang; Liu, Jianping; Wang, Ji; Zhang, Suyang; Zhang, Shuangshuang; Wu, Zimei

    2013-01-01

    High density lipoproteins (HDL) have been successfully reconstructed to deliver a large number of lipophilic drugs. Here, discoidal and spherical recombinant HDL loaded with cardiovascular drug tanshinone IIA (TA) were constructed (TA-d-rHDL and TA-s-rHDL), respectively. And next their in vitro physiochemical and biomimetic properties were characterized. Furthermore, pharmacokinetics, atherosclerotic lesions targeting effects and antiatherogenic efficacies were elaborately performed and compared in atherosclerotic New Zealand White (NZW) rabbits. In vitro characterizations results showed that both TA-d-rHDL and TA-s-rHDL had nano-size diameter, high entrapment efficiency (EE) and drug-loading capacity (DL). Additionally, similar to their native counterparts, TA-d-rHDL maintained remodeling behaviors induced by lecithin cholesterol acyltransferase (LCAT), and TA leaked during remodeling behaviors. Pharmacokinetic studies manifested that both TA-d-rHDL and TA-s-rHDL markedly improved pharmacokinetic behaviors of TA in vivo. Ex vivo imaging demonstrated that both d-rHDL and s-rHDL bound more avidly to atherosclerotic lesions than to normal vessel walls, and s-rHDL had better targeting effect than d-rHDL. Pharmacodynamic tests illustrated that both TA-d-rHDL and TA-s-rHDL had much stronger antiatherogenic efficacies than conventional TA nanostructured lipid carriers (TA-NLC), TA liposomes (TA-L) and commercially available preparation Sulfotanshinone Sodium Injection (SSI). Moreover, TA-s-rHDL had more potent antiatherogenic efficacies than TA-d-rHDL. Collectively our studies indicated that rHDL could be exploited as potential delivery vehicles of TA targeting atherosclerotic lesions as well as synergistically improving efficacies, especially for s-rHDL. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. High ω-3:ω-6 fatty acids ratio increases fatty acid binding protein 4 and extracellular secretory phospholipase A2IIa in human ectopic endometrial cells

    PubMed Central

    Khanaki, Korosh; Sadeghi, Mohammad Reza; Akhondi, Mohammad Mehdi; Darabi, Masoud; Mehdizadeh, Amir; Shabani, Mahdi; Rahimipour, Ali; Nouri, Mohammad

    2014-01-01

    Background: Endometriosis, a common chronic inflammatory disorder, is defined by the atypical growth of endometrium- like tissue outside of the uterus. Secretory phospholipase A2 group IIa (sPLA2-IIa) and fatty acid binding protein4 (FABP4) play several important roles in the inflammatory diseases. Objective: Due to reported potential anti-inflammatory effects of ω-3 and ω-6 fatty acids, the purpose of the present study was to investigate the effects of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) on fatty acid binding protein 4 and extracellular secretory phospholipase A2IIa in cultured endometrial cells. Materials and Methods: Ectopic and eutopic endometrial tissues obtained from 15 women were snap frozen. After thawing and tissue digestion, primary mixed stromal and endometrial epithelial cell culture was performed for 8 days in culture mediums supplemented with normal and high ratios of ω-3 and ω-6 PUFA. sPLA2-IIa in the culture medium and FABP4 level was determined using enzyme immuno assay (EIA) technique. Results: Within ectopic endometrial cells group, the level of cellular FABP4 and extracellular sPLA2-IIa were remarkably increased under high ω-3 PUFA exposure compared with control condition (p=0.014 and p=0.04 respectively). Conclusion: ω-3 PUFAs may increase the level of cellular FABP4 and extracellular sPLA2-IIa in ectopic endometrial cells, since sPLAIIa and FABP4 may affect endometriosis via several mechanisms, more relevant studies are encouraged to know the potential effect of increased cellular FABP4 and extracellular sPLA2-IIa on endometriosis. PMID:25709631

  18. Tanshinone IIA inhibits TNF-α-mediated induction of VCAM-1 but not ICAM-1 through the regulation of GATA-6 and IRF-1.

    PubMed

    Nizamutdinova, Irina Tsoy; Kim, Young Min; Jin, Hana; Son, Kun Ho; Lee, Jae Heun; Chang, Ki Churl; Kim, Hye Jung

    2012-12-01

    The goal of this study was to investigate the differential effect of tanshinone IIA on the induction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by TNF-α and the possible molecular mechanisms by which it regulates ICAM-1 and VCAM-1 expression differentially. Stimulation of human umbilical vein endothelial cells (HUVEC) with TNF-α increased ICAM-1 and VCAM-1 expressions, and the pretreatment with tanshinone IIA concentration dependently inhibited VCAM-1 expression but not ICAM-1 expression. In previous study, PI3K/Akt, PKC and Jak/STAT-3 pathways were involved in the TNF-α-mediated induction of VCAM-1 but not ICAM-1. Thus, we examined the effect of tanshinone IIA on TNF-α-mediated activations of PI3K/Akt, PKC and Jak/STAT-3 pathways. Tanshinone IIA efficiently inhibited the phosphorylations of Akt, PKC and STAT-3 by TNF-α. Moreover, we determined the effect of tanshinone IIA on IRF-1 or GATAs induction and binding activity to VCAM-1 promoter since the upstream promoter region of VCAM-1 but not ICAM-1 contains IRF-1 and GATA binding motifs. Western blot analysis and ChIP assay showed that tanshinone IIA efficiently inhibited TNF-α-increased nuclear level of IRF-1 and GATA-6 and their binding affinity to VCAM-1 promoter region. Taken together, tanshinone IIA selectively inhibits TNF-α-mediated expression of VCAM-1 but not ICAM-1 through modulation of PI3/Akt, PKC and Jak/STAT-3 pathway as well as IRF-1 and GATA-6 binding activity.

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

    PubMed

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

    2016-01-01

    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. 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. 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%). 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 screening bacterial infections. Both biomarkers either alone or in

  20. Crystal structure of human secretory phospholipase A2-IIA complex with the potent indolizine inhibitor 120-1032.

    PubMed

    Kitadokoro, K; Hagishita, S; Sato, T; Ohtani, M; Miki, K

    1998-04-01

    Phospholipase A2 is a key enzyme in a number of physiologically important cellular processes including inflammation and transmembrane signaling. Human secretory phospholipase A2-IIA is present at high concentrations in synovial fluid of patients with rheumatoid arthritis and in the plasma of patients with septic shock. Inhibitors of this enzyme have been suggested to be therapeutically useful non-steroidal anti-inflammatory drugs. The crystal structure of human secretory phospholipase A2-IIA bound to a novel potent indolizine inhibitor (120-1032) has been determined. The complex crystallizes in the space group P3121, with cell dimensions of a = b = 75.8 A and c = 51.3 A. The model was refined to an R-factor of 0. 183 for the intensity data collected to a resolution of 2.2 A. It was revealed that the inhibitor is located near the active site and bound to the calcium ion. Although the binding mode of the 120-1032 inhibitor to human secretory phospholipase A2-IIA is similar to that previously determined for an indole inhibitor LY311299, the specific interactions between the enzyme and the inhibitor in the present complex include the oxycarboxylate group which was introduced in this inhibitor. The oxycarboxylate group in 120-1032 is coordinated to the calcium ion and included in the water-mediated hydrogen bonding to the catalytic Asp49. In addition, the ethyl group in 120-1032 gains hydrophobic contacts with the cavity wall of the hydrophobic channel of the enzyme.

  1. 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.

  2. Tanshinone IIA protects against acetaminophen-induced hepatotoxicity via activating the Nrf2 pathway.

    PubMed

    Wang, Wenwen; Guan, Cuiwen; Sun, Xiaozhe; Zhao, Zhongxiang; Li, Jia; Fu, Xinlu; Qiu, Yuwen; Huang, Min; Jin, Jing; Huang, Zhiying

    2016-06-01

    Tanshinone IIA (Tan), the main active component of Salvia miltiorrhiza, has been demonstrated to have antioxidant activity. Acetaminophen (APAP), a widely used antipyretic and analgesic, can cause severe hepatotoxicity and liver failure when taken overdose. Oxidative stress has been reported to be involved in APAP-induced liver failure. This study aimed to investigate the effect of Tan on APAP-induced hepatotoxicity and the underlying mechanisms involved. C57BL/6J mice were divided into six groups: (1) control, (2) APAP group, (3) APAP+Tan (30mg/kg) group, (4) Tan (30mg/kg) group, (5) APAP+Tan (10mg/kg) group, (6) Tan (10mg/kg) group. Mice in group 3 and 5 were pre-treated with specified dose of Tan by gavage and subsequently injected with an overdose of APAP intraperitoneally (i.p., 300mg/kg). The effect of Tan on Nrf2 pathway was investigated in HepG2 cells and mice. Plasma aspartate transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), liver glutathione (GSH), glutathione transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) levels were determined after mice were sacrificed. Lipid peroxidation and histological examination were performed. The effect of Tan on the Nrf2 pathway was detected by western blotting and qRT-PCR. Tan pretreatment reduced APAP-induced liver injury. Tan was able to activate Nrf2 and increase the expression levels of Nrf2 target genes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1 (HO-1), in a dose-dependent manner in HepG2 cells. Consistent with our observations in HepG2 cells, Tan increased nuclear Nrf2 accumulation and upregulated mRNA and protein levels of the Nrf2 target genes GCLC, NQO1 and HO-1 in C57BL/6J mice compared with mice treated with APAP alone. Our results demonstrate that Tan pretreatment could protect the liver from APAP-induced hepatic injury by activating the Nrf2 pathway. Tan may

  3. Adjuvant therapy after primary surgery for stage I-IIA carcinoma of the cervix.

    PubMed

    Thomas, G M

    1996-01-01

    Radical hysterectomy and bilateral pelvic lymph node dissection is commonly used as a primary management option for treatment of stage IB/IIA carcinoma of the cervix. Overall cure rates approach 85%. However, a spectrum of relapse risk exists, depending on the presence or absence of primary tumor and nodal-related prognostic factors. Known factors include number and location of lymph nodes; size of primary, deep invasion in the cervix; capillary lymphatic space involvement; occult parametrial involvement; and positive or close surgical margins. Biologic determinants have yet to be identified. No systematic analysis has examined various combinations of prognostic factors to precisely define associated levels of risk and to predict the sites of relapse. Decreased local control and survival rates in some high-risk subgroups, usually those with nodal positivity, has led to the exploration of adjuvant therapies. Compiled data from retrospective series have defined the overall patterns of failure. Seventy-two percent of those relapsing have a component of pelvic failure, while 42% experience relapse in the pelvis alone. Fifty-eight percent have a component of distant failure but only 28% have distant disease alone. Adjuvant treatment options include pelvic radiotherapy, extended-field radiotherapy, chemoradiotherapy, and chemotherapy. Trials of adjuvant chemotherapy are too few to evaluate the use of available agents. Pelvic radiotherapy has been shown to reduce the relapse risk when surgical margins are close or positive. It also reduces the risk of pelvic relapse and improves the relapse-free interval but has no apparent impact on overall survival in the groups that have been selected for treatment. The apparent lack of benefit may relate to the choice of patients with nodal involvement who, despite high risk of pelvic failure, most likely have a predominant pattern of distant failure. Maximization of the survival benefit of pelvic radiotherapy requires the

  4. 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

  5. Glucose-specific enzyme IIA has unique binding partners in the vibrio cholerae biofilm.

    PubMed

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

    2012-11-06

    Glucose-specific enzyme IIA (EIIA(Glc)) 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 EIIA(Glc) activates transcription of the genes required for Vibrio cholerae biofilm formation. While EIIA(Glc) modulates the function of many proteins through a direct interaction, none of the known regulatory binding partners of EIIA(Glc) activates biofilm formation. Therefore, we used tandem affinity purification (TAP) to compare binding partners of EIIA(Glc) in both planktonic and biofilm cells. A surprising number of novel EIIA(Glc) binding partners were identified predominantly under one condition or the other. Studies of planktonic cells revealed established partners of EIIA(Glc), 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 EIIA(Glc). Further studies revealed that MshH inhibits biofilm formation. This function was independent of the Carbon storage regulator (Csr) pathway and dependent on EIIA(Glc). To explore the existence of multiprotein complexes centered on EIIA(Glc), we also affinity purified the binding partners of adenylate cyclase from biofilm cells. In addition to EIIA(Glc), this analysis yielded many of the same proteins that copurified with EIIA(Glc). We hypothesize that EIIA(Glc) serves as a hub for multiprotein complexes and furthermore that these complexes may provide a mechanism for competitive and cooperative interactions between binding partners. EIIA(Glc) is a global regulator of microbial physiology that acts through direct interactions with other proteins. This work represents the first demonstration that the protein partners of EIIA(Glc) are distinct in the microbial biofilm. Furthermore, it provides the first evidence that EIIA(Glc) may exist in multiprotein complexes with

  6. Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability.

    PubMed

    Murray, Rebecca D; Holthouser, Kristine; Clark, Barbara J; Salyer, Sarah A; Barati, Michelle T; Khundmiri, Syed J; Lederer, Eleanor D

    2013-04-15

    The acute inhibitory effects of parathyroid hormone (PTH) on proximal tubule Na(+)-K(+)-ATPase (Na-K) and sodium-dependent phosphate (NaPi) transport have been extensively studied, while little is known about the chronic effects of PTH. Patients with primary hyperparathyroidism, a condition characterized by chronic elevations in PTH, exhibit persistent hypophosphatemia but not significant evidence of salt wasting. We postulate that chronic PTH stimulation results in differential desensitization of PTH responses. To address this hypothesis, we compared the effects of chronic PTH stimulation on Na-P(i) cotransporter (Npt2a) expression and Na-K activity and expression in Sprague Dawley rats, transgenic mice featuring parathyroid-specific cyclin D1 overexpression (PTH-D1), and proximal tubule cell culture models. We demonstrated a progressive decrease in brush-border membrane (BBM) expression of Npt2a from rats treated with PTH for 6 h or 4 days, while Na-K expression and activity in the basolateral membranes (BLM) exhibited an initial decrease followed by recovery to control levels by 4 days. Npt2a protein expression in PTH-D1 mice was decreased relative to control animals, whereas levels of Na-K, NHERF-1, and PTH receptor remained unchanged. In PTH-D1 mice, NpT2a mRNA expression was reduced by 50% relative to control mice. In opossum kidney proximal tubule cells, PTH decreased Npt2a mRNA levels. Both actinomycin D and cycloheximide treatment prevented the PTH-mediated decrease in Npt2a mRNA, suggesting that the PTH response requires transcription and translation. These findings suggest that responses to chronic PTH exposure are selectively regulated at a posttranscriptional level. The persistence of the phosphaturic response to PTH occurs through posttranscriptional mechanisms.

  7. Urethral duplication II-A Y type with rectal urethra: ASTRA approach and tunica vaginalis flap for first stage repair.

    PubMed

    Macedo, Antonio; Rondon, Atila; Bacelar, Herick; Ottoni, Sergio; Liguori, Riberto; Garrone, Gilmar; Ortiz, Valdemar

    2012-01-01

    Urethral duplication is a rare congenital anomaly affecting mainly boys. Generally, the duplication develops on the sagittal plane; the accessory urethra may run dorsally or ventrally to the orthotopic one. We present a patient with urethral duplication in which the orthotopic urethra was patent in the penile segment but atresic in the bulbar and prostatic segment. The patient had urinary flow from the rectum and the ectopic urethra could be well identified by anal examination. Age at surgery was 13 months. The procedure consisted of an ASTRA (anterior sagittal trans-ano-rectal) approach for dividing the urethra and rectum and was successful to move the urethra up to the perineal area. The rectum was reconstructed and the patient placed into a lithotomy position. A urethral catheter inserted in the penile urethra oriented us were the atresic urethra in bulbar area started. The scrotum was opened in the middle and the distance between the two urethral stumps proximal and distal defined the extension of no urethral tissue that consisted of 5 cm. We opened the right scrotal space and a tunica vaginalis flap was obtained and attached to the bulbar tissue for a two-stage urethroplasty strategy. Patient had a nice healing and the tunica vaginalis was nicely incorporated to the adjacent tissue, having the two urethral stumps well delineated. ASTRA approach in combination with a two-stage urethroplasty with tunica vaginalis dorsal flap proved to be an excellent combination for a rare case of urethral Y duplication having the main urethra into the rectum.

  8. Class IIa Histone Deacetylases and Myocyte Enhancer Factor 2 Proteins Regulate the Mesenchymal-to-Epithelial Transition of Somatic Cell Reprogramming*

    PubMed Central

    Zhuang, Qiang; Qing, Xiaobing; Ying, Yue; Wu, Haitao; Benda, Christina; Lin, Jiao; Huang, Zhijian; Liu, Longqi; Xu, Yan; Bao, Xichen; Qin, Baoming; Pei, Duanqing; Esteban, Miguel A.

    2013-01-01

    Class IIa histone deacetylases (HDACs) and myocyte enhancer factor 2 (MEF2) proteins compose a signaling module that orchestrates lineage specification during embryogenesis. We show here that this module also regulates the generation of mouse induced pluripotent stem cells by defined transcription factors. Class IIa HDACs and MEF2 proteins rise steadily during fibroblast reprogramming to induced pluripotent stem cells. MEF2 proteins tend to block the process by inducing the expression of Tgfβ cytokines, which impairs the necessary phase of mesenchymal-to-epithelial transition (MET). Conversely, class IIa HDACs endeavor to suppress the activity of MEF2 proteins, thus enhancing the MET and colony formation efficiency. Our work highlights an unexpected role for a developmental axis in somatic cell reprogramming and provides new insight into how the MET is regulated in this context. PMID:23467414

  9. Primary Zonal High Intensity Focused Ultrasound for Prostate Cancer: Results of a Prospective Phase IIa Feasibility Study.

    PubMed

    Van Velthoven, Roland; Aoun, Fouad; Limani, Ksenija; Narahari, Krishna; Lemort, Marc; Peltier, Alexandre

    2014-01-01

    To present the results of a prospective phase IIa study assessing the role of primary zonal High Intensity Focused Ultrasound (HIFU) for prostate cancer treatment. 31 consecutive patients with unilateral organ confined prostate cancer primarily treated by zonal HIFU (from February 2007 to June 2011) were recruited into a single centre prospective phase IIa feasibility study. Complications were prospectively recorded and graded according to the Clavien-Dindo score. Postoperatively, patients were followed with serial serum PSA determinations and digital rectal examinations. An individual PSA nadir was identified in each patient. Followup also included whole gland biopsies performed in the event of a PSA rising>2.0 ng/mL above nadir value (Phoenix criteria). At a median followup of 38 months, biochemical recurrence free survival was 100%, 89%, and 82.7% at 1, 2, and 3 years, respectively, with overall and cancer specific survival of 100%. The procedure was safe and well tolerated with no major adverse events. All patients were continent at their last followup and 55.2% (16/29) had erectile function sufficient for penetration. Primary zonal HIFU is a valid focal therapy strategy, safe and feasible in day to day practice with good promising results [corrected].

  10. The superfast human extraocular myosin is kinetically distinct from the fast skeletal IIa, IIb, and IId isoforms.

    PubMed

    Bloemink, Marieke J; Deacon, John C; Resnicow, Daniel I; Leinwand, Leslie A; Geeves, Michael A

    2013-09-20

    Humans express five distinct myosin isoforms in the sarcomeres of adult striated muscle (fast IIa, IId, the slow/cardiac isoform I/β, the cardiac specific isoform α, and the specialized extraocular muscle isoform). An additional isoform, IIb, is present in the genome but is not normally expressed in healthy human muscles. Muscle fibers expressing each isoform have distinct characteristics including shortening velocity. Defining the properties of the isoforms in detail has been limited by the availability of pure samples of the individual proteins. Here we study purified recombinant human myosin motor domains expressed in mouse C2C12 muscle cells. The results of kinetic analysis show that among the closely related adult skeletal isoforms, the affinity of ADP for actin·myosin (K(AD)) is the characteristic that most readily distinguishes the isoforms. The three fast muscle myosins have K(AD) values of 118, 80, and 55 μM for IId, IIa, and IIb, respectively, which follows the speed in motility assays from fastest to slowest. Extraocular muscle is unusually fast with a far weaker K(AD) = 352 μM. Sequence comparisons and homology modeling of the structures identify a few key areas of sequence that may define the differences between the isoforms, including a region of the upper 50-kDa domain important in signaling between the nucleotide pocket and the actin-binding site.

  11. Determination of sodium tanshinone IIA sulfonate in plasma by liquid chromatography-electrospray ionisation-tandem mass spectrometry.

    PubMed

    Hao, Haiping; Wang, Guangji; Cui, Nan; Li, Jing; Ding, Zuoqi

    2007-11-01

    Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIa, an important lipophilic component contained in Salvia miltiorrhizae. A simple, sensitive and robust quantification method for STS based on LC-ESI-MS/MS was developed and validated, and has been successfully applied to the pharmacokinetic study. Liquid-liquid extraction was used for extracting STS from biological samples, with a satisfactory recovery exceeding 75% at all test concentrations. Isocratic mobile phase consisted of 75% acetonitrile and 25% water containing 0.005% ammonia acetate (pH 3). Good retention and baseline separation for STS and the selected internal standard, diclofenac sodium, were obtained on a Shim-pack VP-ODS analytical column under this condition. The method was linear in the concentration range of 1-500 ng/mL. The intra- and inter-day precisions (RSD%) were within 9.0%. The deviation of the assay accuracies was within +/-10.0%. STS was proved to be stable during all sample storing, preparation and analytic procedures. With a lower limit of quantitation at 1 ng/mL, this method has been proved to be sensitive enough for the pharmacokinetic study of STS. The plasma profile of STS followed a single intravenous dosing was well fitted to a three compartmental model.

  12. Antigenic polymorphism of human very late activation protein-2 (platelet glycoprotein Ia-IIa). Platelet alloantigen Hca.

    PubMed Central

    Woods, V L; Pischel, K D; Avery, E D; Bluestein, H G

    1989-01-01

    We have found evidence for a human alloantigenic system on the very late activation protein -2 (VLA-2) heterodimer (platelet GPIa/IIa). Sera from two patients with systemic lupus erythematosus (SLE) contained antibodies that immunoprecipitated surface molecules from platelets and fibroblasts that comigrated on SDS-PAGE and two-dimensional O'Farrell gels with platelet GPIa (VLA-alpha2 chain) and platelet GPIIa (VLA-beta chain). These SLE antibodies were alloreactive as they precipitated VLA molecules from only 5 of 22 normal donors' platelets and did not react with the lupus patients' own platelets, despite the expression of apparently normal amounts of VLA on the donors' cells. Two-dimensional O'Farrell analysis demonstrated no differences in the molecular weight or isoelectric point of GPIa and GPIIa obtained from platelets of alloantibody reactive or unreactive donors. Sequential immunoprecipitation experiments with VLA chain-specific monoclonal antibodies, and the pattern of immunoprecipitation of several different VLA heterodimers demonstrated that the alloantibody-reactive determinant was present on the VLA-2 heterodimer, and not other VLA molecules. Thus, these SLE sera demonstrate a previously unrecognized antigenic polymorphism of the VLA-2 (platelet GPIa/IIa) heterodimer, platelet alloantigen Hca. Images PMID:2646323

  13. TCR-driven transendothelial migration of human effector memory CD4 T cells involves Vav, Rac, and myosin IIA.

    PubMed

    Manes, Thomas D; Pober, Jordan S

    2013-04-01

    Human effector memory (EM) CD4 T cells may be recruited from the blood into a site of inflammation in response either to inflammatory chemokines displayed on or specific Ag presented by venular endothelial cells (ECs), designated as chemokine-driven or TCR-driven transendothelial migration (TEM), respectively. We have previously described differences in the morphological appearance of transmigrating T cells as well as in the molecules that mediate T cell-EC interactions distinguishing these two pathways. In this study, we report that TCR-driven TEM requires ZAP-70-dependent activation of a pathway involving Vav, Rac, and myosin IIA. Chemokine-driven TEM also uses ZAP-70, albeit in a quantitatively and spatially different manner of activation, and is independent of Vav, Rac, and mysosin IIA, depending instead on an as-yet unidentified GTP exchange factor that activates Cdc42. The differential use of small Rho family GTPases to activate the cytoskeleton is consistent with the morphological differences observed in T cells that undergo TEM in response to these distinct recruitment signals.

  14. Enhancement of solubility and dissolution rate of cryptotanshinone, tanshinone I and tanshinone IIA extracted from Salvia miltiorrhiza.

    PubMed

    Yu, Hang; Subedi, Robhash Kusam; Nepal, Pushp R; Kim, Yoon G; Choi, Hoo-Kyun

    2012-08-01

    Cryptotanshinone, tanshinone I and tanshinone IIA are three major components in the extract of Salvia miltiorrhiza with pharmacological significance. However, their effective utilization is limited due to poor water solubility and bioavailability. Solid dispersion (SD) of the extract of Salvia miltiorrhiza was prepared to enhance solubility and dissolution of the three major components. Various carriers were screened for SD preparation by conventional solvent method. Dissolution of the components from selected SD systems was compared with commercial tablets of the extract from Salvia miltiorrhiza. The solubility of three components viz., cryptotanshinone, tanshinone I and tanshinone IIA, after forming SD with either of povidone K-30 (PVP K-30) or poloxamer 407, exhibited enhanced solubility in pH 6.8 buffer. Dissolution test revealed that the amount of three components released was higher from SD tablets as compared to the commercial tablets. Pharmacokinetic profile was evaluated using cryptotanshinone as a representative compound. AUC of cryptotanshinone was significantly increased when administered as a solid dispersion.

  15. Tanshinone IIA and Baicalin inhibiting the formation of benzo[a]pyrene and benzo[a]pyrene induced cytotoxicity: correlation with scavenging free radical.

    PubMed

    Wang, Shixiang; Zang, Weijin; Yang, Yang; Zhang, Qian; Zhao, Ming; Gao, Zhijuan; Li, Gangcheng; Meng, Qingnai; Liu, Qinshe; Zheng, Xiaohui

    2013-09-01

    Benzo[a]pyrene (BaP), a ubiquitous environmental pollutant, is formed by incomplete combustion of organic materials, and causes oxidative damage to cells and tissues due to reactive oxygen species (ROS). The purpose of this study is to investigate the inhibition of Tanshinone IIA and Baicalin on the formation of BaP as well as the cytotoxicity in human umbilical vein endothelial cells (HUVECs) induced by BaP. The results showed that BaP formations in mainstream smoke were inhibited by 21μg/cigarette of Tanshinone IIA with a 12.8% decrease, and by 60μg/cigarette of Baicalin with an 11.1% decrease, respectively. Tanshinone IIA could protect HUVECs from the damage caused by BaP in a dose-dependent manner from 7.5 to 30μg/ml. 6μg/ml Baicalin significantly increased the cell survival rate from 47.37% to 84.21% compared with BaP-treated cells. Both Tanshinone IIA and Baicalin markedly attenuated the increase of LDH release, enhanced the activity of SOD and GPx and inhibited the generation of MDA in BaP-damaged HUVECs in vitro. In vivo exploration showed that the two compounds were capable of enhancing the activity of SOD and inhibiting generation of MDA in mainstream smoke-damaged in mice. Superoxide anion radical and hydroxyl radical were obviously inhibited by Tanshinone IIA and Baicalin. These data demonstrate an inhibition of Tanshinone IIA and Baicalin on the formation of BaP and the cytotoxicity on HUVECs related to free Radical induced by BaP.

  16. The novel kasugamycin 2'-N-acetyltransferase gene aac(2')-IIa, carried by the IncP island, confers kasugamycin resistance to rice-pathogenic bacteria.

    PubMed

    Yoshii, Atsushi; Moriyama, Hiromitsu; Fukuhara, Toshiyuki

    2012-08-01

    Kasugamycin (KSM), a unique aminoglycoside antibiotic, has been used in agriculture for many years to control not only rice blast caused by the fungus Magnaporthe grisea but also rice bacterial grain and seedling rot or rice bacterial brown stripe caused by Burkholderia glumae or Acidovorax avenae subsp. avenae, respectively. Since both bacterial pathogens are seed-borne and cause serious injury to rice seedlings, the emergence of KSM-resistant B. glumae and A. avenae isolates highlights the urgent need to understand the mechanism of resistance to KSM. Here, we identified a novel gene, aac(2')-IIa, encoding a KSM 2'-N-acetyltransferase from both KSM-resistant pathogens but not from KSM-sensitive bacteria. AAC(2')-IIa inactivates KSM, although it reveals no cross-resistance to other aminoglycosides. The aac(2')-IIa gene from B. glumae strain 5091 was identified within the IncP genomic island inserted into the bacterial chromosome, indicating the acquisition of this gene by horizontal gene transfer. Although excision activity of the IncP island and conjugational gene transfer was not detected under the conditions tested, circular intermediates containing the aac(2')-IIa gene were detected. These results indicate that the aac(2')-IIa gene had been integrated into the IncP island of a donor bacterial species. Molecular detection of the aac(2')-IIa gene could distinguish whether isolates are resistant or susceptible to KSM. This may contribute to the production of uninfected rice seeds and lead to the effective control of these pathogens by KSM.

  17. 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

  18. High expression of TGF-β1 in the vaginal incisional margin predicts poor prognosis in patients with stage Ib-IIa cervical squamous cell carcinoma.

    PubMed

    Fan, Dong-Mei; Wang, Xin-Jun; He, Tao; Wang, Yan; Zhou, Dan; Kong, Guo-Qiang; Jiang, Tao; Zhang, Mei-Mei

    2012-04-01

    This study evaluated the relationship between altered cytoplasmic expression of TGF-β1 in tissues of the vaginal incisional margin and vaginal cancer recurrence in patients with stage Ib-IIa cervical squamous cell carcinoma (CSCC). This paper also discusses the prognostic value of TGF-β1 expression at these locations. We found that TGF-β1 expression in the vaginal margin had a close association with vaginal recurrence of stage Ib-IIa CSCC and was an independent prognostic marker of this disease.

  19. Genetic variants of human T-lymphotrophic virus type II in American Indian groups.

    PubMed

    Biggar, R J; Taylor, M E; Neel, J V; Hjelle, B; Levine, P H; Black, F L; Shaw, G M; Sharp, P M; Hahn, B H

    1996-02-01

    The human T-lymphotropic virus type II (HTLV-II) is found in many New World Indian groups in North and South America and may have entered the New World from Asia with the earliest migration of ancestral Amerindians over 15,000 years ago. To characterize the phylogenetic relationships of HTLV-II strains infecting geographically diverse Indian populations, we used polymerase chain reaction to amplify HTLV-II sequences from lymphocytes of seropositive Amerindians from Brazil (Kraho, Kayapo, and Kaxuyana), Panama (Guaymi), and the United States (the Navajo and Pueblo tribes of the southwestern states and the Seminoles of Florida). Sequence analysis of a 780-base pair fragment (located between the env gene and the second exons of tax/rex) revealed that Amerindian viruses clustered in the same two genetic subtypes (IIa and IIb) previously identified for viruses from intravenous drug users. Most infected North and Central American Indians had subtype IIb, while HTLV-II infected members of three remote Amazonian tribes clustered as a distinct group within subtype IIa. These findings suggest that the ancestral Amerindians migrating to the New World brought at least two genetic subtypes, IIa and IIb. Because HTLV-II strains from Amazonian Indians form a distinct group within subtype HTLV-IIa, these Brazilian tribes are unlikely to be the source of IIa viruses in North American drug users. Finally, the near identity of viral sequences from geographically diverse populations indicate that HTLV-II is a very ancient virus of man.

  20. Magnetic Resonance Imaging as a Valuable Tool for Predicting Parametrial Invasion in Stage IB1 to IIA2 Cervical Cancer.

    PubMed

    Kim, Miseon; Suh, Dong Hoon; Kim, Kidong; Lee, Hak Jong; Kim, Yong Beom; No, Jae Hong

    2017-02-01

    The aims of study were to determine the predictive value of preoperative magnetic resonance imaging (MRI) for parametrial invasion (PMI) and to develop a predictive model for PMI in patients with stage IB1 to IIA2 cervical cancer. We retrospectively analyzed patients with stage IB1 to IIA2 cervical cancer (n = 215) who underwent radical hysterectomy between 2003 and 2014. The presence of PMI from postoperative pathological reports and its association with preoperative MRI findings were evaluated. We developed a predictive model for PMI using independent predictive factors identified by logistic regression and estimated its predictive performance. Thirty patients (14.0%) had PMI from postoperative pathological reports. Among the preoperative MRI findings, a greater tumor diameter (4.2 vs 2.0 cm; P < 0.001), a larger tumor volume (92.6 vs 12.7 cm; P < 0.001), the presence of PMI (53.3% vs 8.6%; P < 0.001), and upper vaginal involvement (73.3% vs 22.7%; P < 0.001) were significantly associated with PMI. Multivariate analysis identified tumor volume (odds ratio, 7.0; 95% confidence interval, 2.63-18.53; P < 0.001) and PMI (odds ratio, 6.1; 95% confidence interval, 2.31-15.97; P < 0.001) from preoperative MRI findings as independent predictive factors for PMI. Our predictive model demonstrates that the presence of PMI or a tumor volume of greater than 18.0 cm has a higher sensitivity (86.7% vs 53.3%) and lower specificity (74.6% vs 91.4%) than the presence of PMI alone. Specifically, the model's negative predictive value was superior to that of PMI only (97.2% vs 92.3%). In the low-risk group, defined as preoperative MRI findings suggesting no PMI and a tumor volume of 18.0 cm or less, the proportion of false negative cases was just 2.8%. When tumor volume with findings suggesting that PMI is considered, preoperative MRI is useful in excluding PMI. A predictive model based on preoperative MRI findings seems to be valuable in identifying potential candidates for less

  1. Elongated phytoglycogen chain length in transgenic rice endosperm expressing active starch synthase IIa affects the altered solubility and crystallinity of the storage α-glucan

    PubMed Central

    Fujita, Naoko; Toyosawa, Yoshiko; Utsumi, Yoshinori

    2012-01-01

    The relationship between the solubility, crystallinity, and length of the unit chains of plant storage α-glucan was investigated by manipulating the chain length of α-glucans accumulated in a rice mutant. Transgenic lines were produced by introducing a cDNA for starch synthase IIa (SSIIa) from an indica cultivar (SSIIa I, coding for active SSIIa) into an isoamylase1 (ISA1)-deficient mutant (isa1) that was derived from a japonica cultivar (bearing inactive SSIIa proteins). The water-soluble fraction accounted for >95% of the total α-glucan in the isa1 mutant, whereas it was only 35–70% in the transgenic SSIIa I /isa1 lines. Thus, the α-glucans from the SSIIa I /isa1 lines were fractionated into soluble and insoluble fractions prior to the following characterizations. X-ray diffraction analysis revealed a weak B-type crystallinity for the α-glucans of the insoluble fraction, while no crystallinity was confirmed for α-glucans in isa1. Concerning the degree of polymerization (DP) ≤30, the chain lengths of these α-glucans differed significantly in the order of SSIIa I /isa1 insoluble > SSIIa I /isa1 soluble > α-glucans in isa1. The amount of long chains with DP ≥33 was higher in the insoluble fraction α-glucans than in the other two α-glucans. No difference was observed in the chain length distributions of the β-amylase limit dextrins among these α-glucans. These results suggest that in the SSIIa I /isa1 transgenic lines, the unit chains of α-glucans were elongated by SSIIaI, whereas the expression of SSIIaI did not affect the branch positions. Thus, the observed insolubility and crystallinity of the insoluble fraction can be attributed to the elongated length of the outer chains due to SSIIaI. PMID:23048127

  2. On fractional quantum Hall solitons and Chern-Simons quiver gauge theories

    NASA Astrophysics Data System (ADS)

    Belhaj, Adil

    2012-05-01

    We investigate a class of hierarchical multiple layers of fractional quantum Hall soliton (FQHS) systems from Chern-Simons quivers embedded in M-theory on the cotangent on a two-dimensional complex toric variety V2, which is dual to type IIA superstring on a three-dimensional complex manifold CP1 × V2 fibered over a real line {R}. Based on M-theory/type IIA duality, FQHS systems can be derived from wrapped D4-branes on 2-cycles in CP1 × V2 type IIA geometry. In this realization, the magnetic source can be identified with gauge fields obtained from the decomposition of the R-R 3-form on a generic combination of 2-cycles. Using type IIA D-brane flux data, we compute the filling factors for models relying on CP2 and the zeroth Hirzebruch surface.

  3. Nitric oxide determines mesodermic differentiation of mouse embryonic stem cells by activating class IIa histone deacetylases: potential therapeutic implications in a mouse model of hindlimb ischemia.

    PubMed

    Spallotta, Francesco; Rosati, Jessica; Straino, Stefania; Nanni, Simona; Grasselli, Annalisa; Ambrosino, Valeria; Rotili, Dante; Valente, Sergio; Farsetti, Antonella; Mai, Antonello; Capogrossi, Maurizio C; Gaetano, Carlo; Illi, Barbara

    2010-03-31

    In human endothelial cells, nitric oxide (NO) results in class IIa histone deacetylases (HDACs) activation and marked histone deacetylation. It is unknown whether similar epigenetic events occur in embryonic stem cells (ESC) exposed to NO and how this treatment could influence ESC therapeutic potential during tissue regeneration.This study reports that the NO-dependent class IIa HDACs subcellular localization and activity decreases the global acetylation level of H3 histones in ESC and that this phenomenon is associated with the inhibition of Oct4, Nanog, and KLF4 expression. Further, a NO-induced formation of macromolecular complexes including HDAC3, 4, 7, and protein phosphatase 2A (PP2A) have been detected. These processes correlated with the expression of the mesodermal-specific protein brachyury (Bry) and the appearance of several vascular and skeletal muscle differentiation markers. These events were abolished by the class IIa-specific inhibitor MC1568 and by HDAC4 or HDAC7 short interfering RNA (siRNA). The ability of NO to induce mesodermic/cardiovascular gene expression prompted us to evaluate the regenerative potential of these cells in a mouse model of hindlimb ischemia. We found that NO-treated ESCs injected into the cardiac left ventricle selectively localized in the ischemic hindlimb and contributed to the regeneration of muscular and vascular structures. These findings establish a key role for NO and class IIa HDACs modulation in ESC mesodermal commitment and enhanced regenerative potential in vivo.

  4. 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…

  5. Genetic and antigenic characteristics of ApxIIA and ApxIIIA from Actinobacillus pleuropneumoniae serovars 2, 3, 4, 6, 8 and 15.

    PubMed

    To, Ho; Nagai, Shinya; Iwata, Akira; Koyama, Tomohiro; Oshima, Atsushi; Tsutsumi, Nobuyuki

    2016-07-01

    Apx toxins produced by Actinobacillus pleuropneumoniae are essential components of new generation vaccines. In this study, apxIIA and apxIIIA genes of serovars 2, 3, 4, 6, 8 and 15 were cloned and sequenced. Amino acid sequences of ApxIIA proteins of serovars 2, 3, 4, 6, 8 and 15 were almost identical to those of serovars 1, 5, 7, 9 and 11-13. Immunoblot analysis showed that rApxIIA from serovars 2 and 15 reacts strongly with sera from animals infected with various serovars. Sequence analysis revealed that ApxIIIA proteins has two variants, one in strains of serovar 2 and the other in strains of serovars 3, 4, 6, 8 and 15. A mouse cross-protection study showed that mice actively immunized with rApxIIIA/2 or rApxIIIA/15 are protected against challenge with A. pleuropneumoniae strains of serovars 3, 4, 6, 8, 15, and 2 expressing ApxIII/15 and ApxIII/2, respectively. Similarly, mice passively immunized with rabbit anti-rApxIIIA/2 or anti-rApxIIIA/15 sera were found to be protected against challenge with strains of serovars 2 and 15. Our study revealed antigenic and sequence similarities within ApxIIA and ApxIIIA proteins, which may help in the development of effective vaccines against disease caused by A. pleuropneumoniae. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

  6. 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 air...

  7. 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 air...

  8. 30 CFR 57.22232 - Actions at 0.5 percent methane (I-B, II-A, II-B, IV, V-B, and VI mines).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... percent in the mine atmosphere, ventilation changes shall be made to reduce the level of methane. Until... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Actions at 0.5 percent methane (I-B, II-A, II-B...-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57...

  9. 30 CFR 57.22232 - Actions at 0.5 percent methane (I-B, II-A, II-B, IV, V-B, and VI mines).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... percent in the mine atmosphere, ventilation changes shall be made to reduce the level of methane. Until... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Actions at 0.5 percent methane (I-B, II-A, II-B...-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57...

  10. 30 CFR 57.22232 - Actions at 0.5 percent methane (I-B, II-A, II-B, IV, V-B, and VI mines).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... percent in the mine atmosphere, ventilation changes shall be made to reduce the level of methane. Until... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Actions at 0.5 percent methane (I-B, II-A, II-B...-UNDERGROUND METAL AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57...

  11. Implementation of Title I and Title II-A Program Initiatives: Results from 2013-14. Executive Summary. NCEE 2017-4015

    ERIC Educational Resources Information Center

    Troppe, Patricia; Milanowski, Anthony T.; Heid, Camilla; Gill, Brian; Ross, Christine

    2017-01-01

    This report describes the implementation of policies and initiatives supported by Title I and Title II-A of the federal Elementary and Secondary Education Act (ESEA) during the 2013-14 school year. Title I is one of the U.S. Department of Education's largest programs, accounting for $15 billion in the 2016 federal budget. Historically, Title I has…

  12. Activated T cell trans-endothelial migration relies on myosin-IIA contractility for squeezing the cell nucleus through endothelial cell barriers.

    PubMed

    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.

  13. Targeted delivery of tanshinone IIA-conjugated mPEG-PLGA-PLL-cRGD nanoparticles to hepatocellular carcinoma.

    PubMed

    Wang, Yan; Song, Daqian; Costanza, Frankie; Ji, Guang; Fan, Zhongze; Cai, Jianfeng; Li, Qi

    2014-11-01

    Tanshinone IIA (TSIIA) is an active constituent of the traditional Chinese medicinal plant Salvia miltiorrhiza that is known to have anti-tumor properties. In order to increase the selectivity of TSIIA's anti-tumor activity, the current study evaluated the tumor-targeting efficacy of TSIIA incorporated into nanoparticles (NPs). TSIIA was loaded into mPEG-PLGA-PLL-cRGD (methoxy polyethylene glycol, polylactic-co-glycolic acid, poly-L-lysine, cyclic arginine-glycine-aspartic acid) nanoparticles (TNPs) and used to treat hepatocellular carcinoma in vitro and in vivo. Our data demonstrate that TNPs were stable and had an even size distribution as well as an extended TSIIA releasing time, and improved tumor-targeting activity. As a novel drug carrier system, TNPs significantly inhibited the development of liver cancer both in vitro and in vivo, proving to be a novel promising targeted treatment for liver cancer.

  14. 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.

  15. An interplay between TATA box-binding protein and transcription factors IIE and IIA modulates DNA binding and transcription.

    PubMed

    Yokomori, K; Verrijzer, C P; Tjian, R

    1998-06-09

    The basal transcription factor IIE (TFIIE) is thought to be one of the last factors to be assembled into a preinitiation complex (PIC) at eukaryotic promoters after RNA polymerase II and TFIIF have been incorporated. It was shown that a primary function of TFIIE is to recruit and cooperate with TFIIH in promoter melting. Here, we show that the large subunit of TFIIE (E56) can directly stimulate TBP binding to the promoter in the absence of other basal factors. The zinc-finger domain of E56, required for transcriptional activity, is critical for this function. In addition, the small subunit of TFIIE (E34) directly contacts DNA and TFIIA and thus providing a second mechanism for TFIIE to help binding of a TBP/IIA complex to the promoter, the first critical step in the PIC assembly. These studies suggest an alternative PIC assembly pathway in which TFIIE affects both TBP and TFIIH functions during initiation of RNA synthesis.

  16. 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.

  17. Inhibition of coagulation proteases Xa and IIa decreases ischemia-reperfusion injuries in a preclinical renal transplantation model.

    PubMed

    Tillet, Solenne; Giraud, Sébastien; Kerforne, Thomas; Saint-Yves, Thibaut; Joffrion, Sandrine; Goujon, Jean-Michel; Cau, Jerôme; Mauco, Gérard; Petitou, Maurice; Hauet, Thierry

    2016-12-01

    Coagulation is an important pathway in the pathophysiology of ischemia-reperfusion injuries. In particular, deceased after circulatory death (DCD) donors undergo a no-flow period, a strong activator of coagulation. Hence, therapies influencing the coagulation cascade must be developed. We evaluated the effect of a new highly specific and effective anti-Xa/IIa molecule, with an integrated innovative antidote site (EP217609), in a porcine preclinical model mimicking injuries observed in DCD donor kidney transplantation. Kidneys were clamped for 60 minutes (warm ischemia), then flushed and preserved for 24 hours at 4°C in University of Wisconsin (UW) solution (supplemented or not). EP217609-supplemented UW solution (UW-EP), compared with unfractionated heparin-supplemented UW solution (UW-UFH) or UW alone (UW). A mechanistic investigation was conducted in vitro: addition of EP217609 to endothelial cells during hypoxia at 4°C in the UW solution inhibited thrombin generation during reoxygenation at 37°C in human plasma and reduced tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 messenger RNA cell expressions. In vivo, function recovery was markedly improved in the UW-EP group. Interestingly, levels of thrombin-antithrombin complexes (reflecting thrombin generation) were reduced 60 minutes after reperfusion in the UW-EP group. In addition, 3 months after transplantation, lower fibrosis, epithelial-mesenchymal transition, inflammation, and leukocyte infiltration were observed. Using this new dual anticoagulant, anti-Xa/IIa activity during kidney flush and preservation is protected by reducing thrombin generation at revascularization, improving early function recovery, and decreasing chronic lesions. Such an easy-to-deploy clinical strategy could improve marginal graft outcome.

  18. Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer’s Disease Phase IIa and Expanded Access Trials

    PubMed Central

    Nelson, Thomas J.; Sun, Miao-Kun; Lim, Chol; Sen, Abhik; Khan, Tapan; Chirila, Florin V.; Alkon, Daniel L.

    2017-01-01

    Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer’s disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus –1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD. PMID:28482641

  19. Application of phenol red as a marker ligand for bilirubin binding site at subdomain IIA on human serum albumin.

    PubMed

    Sochacka, Jolanta

    2015-10-01

    The drug-bilirubin interaction for all drugs administered especially to infants with hyperbilirubinemia should be evaluated for their ability to displace bilirubin and vice versa. In order to examine whether phenol red (PhRed) can be used as a marker for bilirubin binding site located in subdomain IIA the interaction between PhRed and human serum albumin (HSA) in buffer solution or in normal and pathological sera solutions with different HSA:bilirubin molar ratio was investigated using absorption/absorption difference spectroscopy and molecular docking method. Six sulfonamides representing the binding site in the subdomain IIA and known to influence the binding of bilirubin were used for the PhRed displacement studies. The absorption spectra for PhRed completely bound to HSA showed significant differences in the spectral characteristic relative to the spectral profile of free PhRed. The intensity of the peak originating from the bivalent anionic form of dye was strongly reduced and the maximum peak position was red-shifted by 12 nm. The binding constant (K) of the bivalent anionic form of PhRed, calculated from absorbance data, was 1.61 · 10(4) L mol(-1). The variations of the absorption and absorption difference spectra of PhRed in the presence of HSA-bilirubin complex were indicative of the inhibition of PhRed binding process by bilirubin. Binding of PhRed carried out in the presence of sulfonamides showed that drugs and PhRed have a common site which also involves bilirubin. In agreement with the results of the spectroscopic analysis and molecular docking it was concluded that PhRed may be applied as a marker in the study of the binding of drugs to high-affinity bilirubin binding site.

  20. High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer.

    PubMed

    Ketola, Kirsi; Viitala, Miro; Kohonen, Pekka; Fey, Vidal; Culig, Zoran; Kallioniemi, Olli; Iljin, Kristiina

    2016-03-30

    Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer cells. The effect of compounds on cell viability was compared in androgen ablated LNCaP prostate cancer cells and in LNCaP cells grown in presence of androgens as well as in two non-malignant prostate epithelial cells (RWPE-1 and EP156T). Validation experiments of cancer specific anti-proliferative compounds indicated pinosylvin methyl ether (PSME) and tanshinone IIA as potent inhibitors of androgen ablated LNCaP cell proliferation. PSME is a stilbene compound with no previously described anti-neoplastic activity whereas tanshinone IIA is currently used in cardiovascular disorders and proposed as a cancer drug. To gain insights into growth inhibitory mechanisms in CRPC, genome-wide gene expression analysis was performed in PSME- and tanshinone IIA-exposed cells. Both compounds altered the expression of genes involved in cell cycle and steroid and cholesterol biosynthesis in androgen ablated LNCaP cells. Decrease in androgen signalling was confirmed by reduced expression of androgen receptor and prostate specific antigen in PSME- or tanshinone IIA-exposed cells. Taken together, this systematic screen identified a novel anti-proliferative agent, PSME, for CRPC. Moreover, our screen confirmed tanshinone IIA as well as several other compounds as potential prostate cancer growth inhibitors also in androgen ablated prostate cancer cells. These results provide valuable starting points for preclinical and clinical studies for CRPC treatment.

  1. Protective effect of tanshinone IIA against cardiac hypertrophy in spontaneously hypertensive rats through inhibiting the Cys-C/Wnt signaling pathway.

    PubMed

    Feng, Jun; Chen, Hua-Wen; Pi, Li-Juan; Wang, Jin; Zhan, Da-Qian

    2017-02-07

    The study aimed to investigate the protective effect of tanshinone IIA against cardiac hypertrophy in spontaneously hypertensive rats (SHRs) through the Cys-C/Wnt signaling pathway. Thirty SHRs were randomly divided into cardiac hypertrophy, low- and high-dose tanshinone IIA groups. Ten Wistar-Kyoto rats were selected as control group. The systolic blood pressure (SBP), heart weight (HW), left ventricular weight (LVW) and body weight (BW) of all rats were recorded. HE staining and qRT-PCR were applied to observe the morphology of myocardial tissue and mRNA expressions of COL1A1 and COL3A1. ELISA and Western blotting were used to measure the serum asymmetric dimethylarginine (ADMA), nitric oxide (NO) and cardiac troponin I (cTnI) levels, and the expressions of the Cys-C/Wnt signaling pathway-related proteins, eNOS and Nox4. Compared with the cardiac hypertrophy group, the SBP, HW/BW, LVW/BW, swelling degree of myocardial cells, COL1A1 and COL3A1 mRNA expressions, serum cTnI and ADMA levels, and the Cys-C/Wnt signaling pathway-related proteins and Nox4 expressions in the low- and high-dose tanshinone IIA groups were decreased, but the endothelial NO synthase (eNOS), phosphorylated eNOS (Ser1177) and NO expressions were increased. No significant difference was found between the low- and high-dose tanshinone IIA groups. Our study indicated a protective effect of tanshinone IIA against cardiac hypertrophy in SHRs through inhibiting the Cys-C/Wnt signaling pathway.

  2. 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

  3. 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

    2015-04-15

    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.

  4. Protein kinase D1 mediates class IIa histone deacetylase phosphorylation and nuclear extrusion in intestinal epithelial cells: role in mitogenic signaling

    PubMed Central

    Sinnett-Smith, James; Ni, Yang; Wang, Jia; Ming, Ming; Young, Steven H.

    2014-01-01

    We examined whether class IIa histone deacetylases (HDACs) play a role in mitogenic signaling mediated by protein kinase D1 (PKD1) in IEC-18 intestinal epithelial cells. Our results show that class IIa HDAC4, HDAC5, and HDAC7 are prominently expressed in these cells. Stimulation with ANG II, a potent mitogen for IEC-18 cells, induced a striking increase in phosphorylation of HDAC4 at Ser246 and Ser632, HDAC5 at Ser259 and Ser498, and HDAC7 at Ser155. Treatment with the PKD family inhibitors kb NB 142-70 and CRT0066101 or small interfering RNA-mediated knockdown of PKD1 prevented ANG II-induced phosphorylation of HDAC4, HDAC5, and HDAC7. A variety of PKD1 activators in IEC-18 cells, including vasopressin, lysophosphatidic acid, and phorbol esters, also induced HDAC4, HDAC5, and HDAC7 phosphorylation. Using endogenously and ectopically expressed HDAC5, we show that PKD1-mediated phosphorylation of HDAC5 induces its nuclear extrusion into the cytoplasm. In contrast, HDAC5 with Ser259 and Ser498 mutated to Ala was localized to the nucleus in unstimulated and stimulated cells. Treatment of IEC-18 cells with specific inhibitors of class IIa HDACs, including MC1568 and TMP269, prevented cell cycle progression, DNA synthesis, and proliferation induced in response to G protein-coupled receptor/PKD1 activation. The PKD1-class IIa HDAC axis also functions in intestinal epithelial cells in vivo, since an increase in phosphorylation of HDAC4/5 and HDAC7 was demonstrated in lysates of crypt cells from PKD1 transgenic mice compared with matched nontransgenic littermates. Collectively, our results reveal a PKD1-class IIa HDAC axis in intestinal epithelial cells leading to mitogenic signaling. PMID:24647541

  5. High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer

    PubMed Central

    Ketola, Kirsi; Viitala, Miro; Kohonen, Pekka; Fey, Vidal; Culig, Zoran; Kallioniemi, Olli; Iljin, Kristiina

    2016-01-01

    Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer cells. The effect of compounds on cell viability was compared in androgen ablated LNCaP prostate cancer cells and in LNCaP cells grown in presence of androgens as well as in two non-malignant prostate epithelial cells (RWPE-1 and EP156T). Validation experiments of cancer specific anti-proliferative compounds indicated pinosylvin methyl ether (PSME) and tanshinone IIA as potent inhibitors of androgen ablated LNCaP cell proliferation. PSME is a stilbene compound with no previously described anti-neoplastic activity whereas tanshinone IIA is currently used in cardiovascular disorders and proposed as a cancer drug. To gain insights into growth inhibitory mechanisms in CRPC, genome-wide gene expression analysis was performed in PSME- and tanshinone IIA-exposed cells. Both compounds altered the expression of genes involved in cell cycle and steroid and cholesterol biosynthesis in androgen ablated LNCaP cells. Decrease in androgen signalling was confirmed by reduced expression of androgen receptor and prostate specific antigen in PSME- or tanshinone IIA-exposed cells. Taken together, this systematic screen identified a novel anti-proliferative agent, PSME, for CRPC. Moreover, our screen confirmed tanshinone IIA as well as several other compounds as potential prostate cancer growth inhibitors also in androgen ablated prostate cancer cells. These results provide valuable starting points for preclinical and clinical studies for CRPC treatment. PMID:27891324

  6. The correlation of Salvia miltiorrhiza extract-induced regulation of osteoclastogenesis with the amount of components tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone.

    PubMed

    Kim, Hae-Kyung; Woo, Eun-Rhan; Lee, Hae-Won; Park, Hyung-Rae; Kim, Hyun-Nam; Jung, Yeon-Kwan; Choi, Je-Yong; Chae, Soo-Wan; Kim, Hyung-Ryong; Chae, Han-Jung

    2008-01-01

    Tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone are compounds that have been isolated from the root of Salvia miltiorrhiza (SM), which is also known as "Danshen." The SM extract has been used successfully in China for treating postmenopausal syndrome. Furthermore, it was previously reported that SM had inhibitory effect on osteoporosis in ovariectomized rats. Another study reported that the four components, tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone, prevented osteoclast function in an in vitro system. However, there are no reports of a correlation between SM and its components on osteoporosis and osteoclast function. This study was undertaken to examine the effect of SM on osteoclastogenesis and osteoblast differentiation, which are two important markers of the bone physiology. Through a rapid, sensitive and specific isocratic liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantitative determination of four diterpenoids, tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone in SM, the authors tried to correlate the amount of tanshinone compounds in SM into the antiosteoclast activity. The SM fraction (methanol and ethanol isolated) with a low concentration of tanshinone IIA (1 mug/mL) had no effect on the alkaline phosphotase activity (osteoblast differentiation), but completely inhibited osteoclastogenesis. Although the tanshinone compound itself showed similar effects, the concentrations of commercially available tanshinone (diterpenoids, tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone) needed for antiosteoclast activity was almost 1000 times more than that of tanshinone in SM fraction. This suggests that there are other unknown compounds in the SM extract that have a synergistic effect with tanshinone. These results also suggest that tanshinone can be a good marker compound to explain the antiosteoporotic function of SM.

  7. A method to find N = 1 AdS4 vacua in type IIB

    NASA Astrophysics Data System (ADS)

    Solard, Gautier

    2017-01-01

    In this paper, we are looking for N = 1, AdS4 sourceless vacua in type IIB. While several examples exist in type IIA, there exists only one example of such vacua in type IIB. Thanks to the framework of generalized geometry we were able to devise a semi-algorithmical method to look for sourceless vacua. We present this method, which can easily be generalized to more complex cases, and give two new vacua in type IIB.

  8. 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

    NASA Technical Reports Server (NTRS)

    Hammond, Ernest C., Jr.; Peters, Kevein; Boone, Kevin

    1995-01-01

    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 we 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. We 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. The attenuation of beta particles due

  9. Comparative Adjuvant Effects of Type II Heat-Labile Enterotoxins in Combination with Two Different Candidate Ricin Toxin Vaccine Antigens.

    PubMed

    Vance, David J; Greene, Christopher J; Rong, Yinghui; Mandell, Lorrie M; Connell, Terry D; Mantis, Nicholas J

    2015-12-01

    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-IIb(T13I), and LT-IIc, have never been compared side by side. We therefore conducted immunization studies in which LT-IIa, LT-IIb, LT-IIb(T13I), 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.

  10. LMOf2365_0442 Encoding for a Fructose Specific PTS Permease IIA May Be Required for Virulence in L. monocytogenes Strain F2365.

    PubMed

    Liu, Yanhong; Yoo, Brian B; Hwang, Cheng-An; Suo, Yujuan; Sheen, Shiowshuh; Khosravi, Parvaneh; Huang, Lihan

    2017-01-01

    Listeria monocytogenes is a foodborne pathogen that causes listeriosis, which is a major public health concern due to the high fatality rate. LMOf2365_0442, 0443, and 0444 encode for fructose-specific EIIABC components of phosphotransferase transport system (PTS) permease that is responsible for sugar transport. In previous studies, in-frame deletion mutants of a putative fructose-specific PTS permease (LMOf2365_0442, 0443, and 0444) were constructed and analyzed. However, the virulence potential of these deletion mutants has not been studied. In this study, two in vitro methods were used to analyze the virulence potential of these L. monocytogenes deletion mutants. First, invasion assays were used to measure the invasion efficiencies to host cells using the human HT-29 cell line. Second, plaque forming assays were used to measure cell-to-cell spread in host cells. Our results showed that the deletion mutant ΔLMOf2365_0442 had reduced invasion and cell-to-cell spread efficiencies in human cell line compared to the parental strain LMOf2365, indicating that LMOf2365_0442 encoding for a fructose specific PTS permease IIA may be required for virulence in L. monocytogenes strain F2365. In addition, the gene expression levels of 15 virulence and stress-related genes were analyzed in the stationary phase cells of the deletion mutants using RT-PCR assays. Virulence-related gene expression levels were elevated in the deletion mutants ΔLMOf2365_0442-0444 compared to the wild type parental strain LMOf2365, indicating the down-regulation of virulence genes by this PTS permease in L. monocytogenes. Finally, stress-related gene clpC expression levels were also increased in all of the deletion mutants, suggesting the involvement of this PTS permease in stress response. Furthermore, these deletion mutants displayed the same pressure tolerance and the same capacity for biofilm formation compared to the wild-type parental strain LMOf2365. In summary, our findings suggest that the

  11. Clinical, imaging, and immunohistochemical characteristics of focal cortical dysplasia Type II extratemporal epilepsies in children: analyses of an institutional case series.

    PubMed

    Knerlich-Lukoschus, Friederike; Connolly, Mary B; Hendson, Glenda; Steinbok, Paul; Dunham, Christopher

    2017-02-01

    OBJECTIVE Focal cortical dysplasia (FCD) Type II is divided into 2 subgroups based on the absence (IIA) or presence (IIB) of balloon cells. In particular, extratemporal FCD Type IIA and IIB is not completely understood in terms of clinical, imaging, biological, and neuropathological differences. The aim of the authors was to analyze distinctions between these 2 formal entities and address clinical, MRI, and immunohistochemical features of extratemporal epilepsies in children. METHODS Cases formerly classified as Palmini FCD Type II nontemporal epilepsies were identified through the prospectively maintained epilepsy database at the British Columbia Children's Hospital in Vancouver, Canada. Clinical data, including age of seizure onset, age at surgery, seizure type(s) and frequency, affected brain region(s), intraoperative electrocorticographic findings, and outcome defined by Engel's classification were obtained for each patient. Preoperative and postoperative MRI results were reevaluated. H & E-stained tissue sections were reevaluated by using the 2011 International League Against Epilepsy classification system and additional immunostaining for standard cellular markers (neuronal nuclei, neurofilament, glial fibrillary acidic protein, CD68). Two additional established markers of pathology in epilepsy resection, namely, CD34 and α-B crystallin, were applied. RESULTS Seven nontemporal FCD Type IIA and 7 Type B cases were included. Patients with FCD Type IIA presented with an earlier age of epilepsy onset and slightly better Engel outcome. Radiology distinguished FCD Types IIA and IIB, in that Type IIB presented more frequently with characteristic cortical alterations. Nonphosphorylated neurofilament protein staining confirmed dysplastic cells in dyslaminated areas. The white-gray matter junction was focally blurred in patients with FCD Type IIB. α-B crystallin highlighted glial cells in the white matter and subpial layer with either of the 2 FCD Type II subtypes

  12. Use of Dual-Grating Sensors Formed by Different Types of Fiber Bragg Gratings for Simultaneous Temperature and Strain Measurements

    NASA Astrophysics Data System (ADS)

    Shu, Xuewen; Zhao, Donghui; Zhang, Lin; Bennion, Ian

    2004-04-01

    We report on a systematic investigation of the dependence of both temperature and strain sensitivities on the fiber Bragg grating type, including the well-known Type I, Type IIA, and a new type that we have designated Type IA, using both hydrogen-free and hydrogenated B/Ge codoped fibres. We have identified distinct sensitivity characteristics for each grating type, and we have used them to implement a novel dual-grating, dual-parameter sensor device. Three dual-grating sensing schemes with different combinations of grating type have been constructed and compared, and that of a Type IA-Type IIA combination exhibits the best performance, which is also superior to that of previously reported grating-based structures. The characteristics of the measurement errors in such dual-grating sensor systems is also presented in detail.

  13. The incidence of accessory navicular bone types in Turkish subjects.

    PubMed

    Keles Coskun, Nigar; Arican, Ramazan Yavuz; Utuk, Arzu; Ozcanli, Haluk; Sindel, Timur

    2009-11-01

    Accessory ossicles are the skeletal variations of the ankle and foot that can cause painful syndromes. The accessory navicular bone is one of the most common accessory ossicle of the foot (4-21%) and is also known as os tibiale, os tibiale externum and os naviculare secundarium. This bone can be adjacent to the posteromedial tuberosity of the navicular bone or can be separated and may cause various diseases in the foot and mimic fractures of foot bones. The aim of this study was to document a detailed investigation of incidence and types of accessory navicular bones of Turkish subjects according to sex in both extremities. The accessory navicular bone was detected (11%) via the posterior-anterior radiographs of 650 subjects in the radiological examination. The incidences of accessory navicular bones were identified as 6.1-4.9% in female and male participants. Accessory navicular bones were classified into three groups as Type I, Type II and Type III and the incidences of these bones were determined as 3.3, 3.1, 4.6%, respectively. Each group was also divided into subgroups. The incidences of the subgroups are as Type Ia 0.6%, Type Ib 1.5%, Type Ic 1.2%, Type IIA/a 0.8%, Type IIA/b 0.4%, Type IIA/c 0%, Type IIB/a 1.1%, IIB/b 0.3%, IIB/c 0.5%, Type IIIa 1.5%, Type IIIb 1.4%, Type IIIc 1.7%. Finally, the types of accessory navicular bones were discussed and the imaging modalities for diagnosis were presented.

  14. Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn's disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration.

    PubMed

    Wang, Qiong; Jiang, Chao; Zheng, Xiao; Zhu, Xuanxuan; Yan, Shihai; Wang, Haidan; Fu, Rui; Fan, Hongwei; Chen, Yugen

    2017-01-01

    1. Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn's disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug. 2. Although the systemic TSA exposures were low (AUC0-t approximately 330 ng*h/ml) in both the normal and colitis models after oral administration TSA 20 mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies. 3. Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2 h after TSA administration. 4. Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.

  15. 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.

  16. Foundations of chemical microscopy. 1. Solid-state characterization of 5-nitrobarbituric acid (dilituric acid) and its complexes with group IA and group IIA cations.

    PubMed

    Brittain, H G

    1997-05-01

    5-Nitrobarbituric acid (dilituric acid) has been used as a chemical microscopic reagent for the qualitative identification of alkali metal (Group IA) and alkaline earth (Group IIA) cations. This methodology was based on the characterization of observed crystal morphologies, since a unique crystal habit could be associated with each adduct product. To understand the scientific foundations which permitted chemical microscopy to function as a useful analytical technique, the products formed between dilituric acid and the Group IA and IIA cations were characterized using polarizing optical microscopy, powder X-ray diffraction, thermal analysis and solid-state nuclear magnetic resonance. It was found that the origins of the different crystal morphologies associated with each of the adduct arose from the ability of the systems to form various hydrate species, which could also contain structural variations due to cation/diliturate packing patterns.

  17. The calibration of photographic and spectroscopic films: Reciprocity failure and thermal responses of IIaO film at liquid nitrogen temperatures

    NASA Astrophysics Data System (ADS)

    Hammond, E. C., Jr.; Peters, K. A.; Gunther, S. O.; Cunningham, L. M.; Wright, D. D.

    1985-04-01

    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.

  18. ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study.

    PubMed

    Pavone, V; Ricardi, U; Luminari, S; Gobbi, P; Federico, M; Baldini, L; Iannitto, E; Ucci, G; Marcheselli, L; Orsucci, L; Angelucci, E; Liberati, M; Gavarotti, P; Levis, A

    2008-04-01

    In 1997, the Intergruppo Italiano Linfomi started a randomized trial to evaluate, in unfavorable stage IA and IIA Hodgkin's lymphoma (HL) patients, the efficacy and toxicity of the low toxic epirubicin, vinblastine and etoposide (EVE) regimen followed by involved field radiotherapy in comparison to the gold standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimen followed by the same radiotherapy program. Patients should be younger than 65 years with unfavorable stage IA and IIA HL (i.e. stage IA or IIA with bulky disease and/or subdiaphragmatic disease, erythrocyte sedimentation rate higher than 40, extranodal (E) involvement, hilar involvement and more than three involved lymph node areas). Ninety-two patients were allocated to the ABVD arm and 89 to the EVE arm. Complete remission (CR) rates at the end of treatment program [chemotherapy (CT) + RT] were 93% and 92% for ABVD and EVE arms, respectively (P = NS). The 5-year relapse-free survival (RFS) rate was 95% for ABVD and 78% for EVE (P < 0.05). As a consequence of the different relapse rate, the 5-year failure-free survival (FFS) rate was significantly better for ABVD (90%) than for EVE (73%) arm (P < 0.05). No differences in terms of overall survival (OS) were observed for the two study arms. In unfavorable stage IA and IIA HL patients, no differences were observed between ABVD and EVE arms in terms of CR rate and OS. EVE CT, however, was significantly worse than ABVD in terms of RFS and FFS and cannot be recommended as initial treatment for HL.

  19. 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, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Approved testing devices (I-A, I-B, I-C, II-A... Ventilation § 57.22227 Approved testing devices (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). (a... be used in Subcategory I-C mines. (c)(1) If electrically......

  20. 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... Ventilation § 57.22227 Approved testing devices (I-A, I-B, I-C, II-A, II-B, III, IV, V-A, and V-B mines). (a... be used in Subcategory I-C mines. (c)(1) If electrically......