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At least 415 records · Page 23

Localisation of Neuregulin 1-{beta}3 to different sub-nuclear structures alters gene expression

Neuregulins are growth factors that signal via the ErbB3 and ErbB4 receptors. Here we show using immunohistochemistry that they are often expressed in the nucleus of a range of tumour types including soft tissue and breast. The Neuregulin 1 type I-{beta}3 (NRG1-{beta}3) isoform localises to two sub-nuclear compartments in animal cells, nucleoli and spliceosomes. We used NRG1-{beta}3 tagged with photoactivatable GFP and demonstrated that this re-localised from nucleoli to spliceosomes over 90 min. Tyrosine kinase activity was not required for retaining the NRG1-{beta}3 within the nucleus. Mutation of the lysines 14 and 16 or 15 and 16 together prevented nucleolar uptake while four positively charged residues were identified which were required for spliceosome uptake. Molecular modelling suggests that three of these may form a binding site. We showed using a kinome array that NRG1-{beta}3 and a mutant exclusively localising to spliceosomes increased phosphorylation and/or expression of the HER4 and HER2 receptors. Using a transcriptomic analysis the same two constructs induced expression of several messenger RNAs and we confirmed the increased expression at the protein level of the most highly induced, Heat Shock Protein 70B'. These results suggest that Neuregulin activates receptor signalling in spliceosomes leading to altered gene expression.

60 APPLIED LIFE SCIENCES↗

IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells

COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.

60 APPLIED LIFE SCIENCES↗

CDK7 activated beta-catenin/TCF signaling in hepatocellular carcinoma

Over-activation of beta-catenin/TCF signaling is very common in the progression of hepatocellular carcinoma (HCC). The molecular mechanisms leading to the aberrant activation of beta-catenin/TCF signaling are not fully understood. In this study, it was found that CDK7 was up-regulated in HCC tissues and its expression inversely correlated with the survival of HCC patients. Functional study showed that CDK7 promoted the growth and migration of HCC cells, and knocking down the expression of CDK7 inhibited the growth of HCC cells in both liquid culture and soft agar. Mechanistically, CDK7 interacted with beta-catenin, enhanced the interaction between beta-catenin and TCF4, and activated beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of CDK7 in HCC and suggested that CDK7 might be a promising therapeutic target.

60 APPLIED LIFE SCIENCES↗

Crystal Structures of Covalent Complexes of [beta]-Lactam Antibiotics with Escherichia coli Penicillin-Binding Protein 5: Toward an Understanding of Antibiotic Specificity

Penicillin-binding proteins (PBPs) are the molecular targets for the widely used {beta}-lactam class of antibiotics, but how these compounds act at the molecular level is not fully understood. We have determined crystal structures of Escherichia coli PBP 5 as covalent complexes with imipenem, cloxacillin, and cefoxitin. These antibiotics exhibit very different second-order rates of acylation for the enzyme. In all three structures, there is excellent electron density for the central portion of the {beta}-lactam, but weak or absent density for the R1 or R2 side chains. Areas of contact between the antibiotics and PBP 5 do not correlate with the rates of acylation. The same is true for conformational changes, because although a shift of a loop leading to an electrostatic interaction between Arg248 and the {beta}-lactam carboxylate, which occurs completely with cefoxitin and partially with imipenem and is absent with cloxacillin, is consistent with the different rates of acylation, mutagenesis of Arg248 decreased the level of cefoxitin acylation only 2-fold. Together, these data suggest that structures of postcovalent complexes of PBP 5 are unlikely to be useful vehicles for the design of new covalent inhibitors of PBPs. Finally, superimposition of the imipenem-acylated complex with PBP 5 in complex with a boronic acid peptidomimetic shows that the position corresponding to the hydrolytic water molecule is occluded by the ring nitrogen of the {beta}-lactam. Because the ring nitrogen occupies a similar position in all three complexes, this supports the hypothesis that deacylation is blocked by the continued presence of the leaving group after opening of the {beta}-lactam ring.

36 MATERIALS SCIENCE↗

Crystal Structure of the Central Coiled-Coil Domain from Human Liprin-[beta]2

Liprins are a conserved family of scaffolding proteins important for the proper regulation and development of neuronal synapses. Humans have four liprin-{alpha}s and two liprin-{beta}s which all contain long coiled-coil domains followed by three tandem SAM domains. Complex interactions between the coiled-coil and SAM domains are thought to create liprin scaffolds, but the structural and biochemical properties of these domains remain largely uncharacterized. In this study we find that the human liprin-{beta}2 coiled-coil forms an extended dimer. Several protease-resistant subdomains within the liprin-{beta}1 and liprin-{beta}2 coiled-coils were also identified. A 2.0 {angstrom} crystal structure of the central, protease-resistant core of the liprin-{beta}2 coiled-coil reveals a parallel helix orientation. These studies represent an initial step toward determining the overall architecture of liprin scaffolds and understanding the molecular basis for their synaptic functions.

59 BASIC BIOLOGICAL SCIENCES↗

Electronic Perturbations of Iron Dipyrrinato Complexes via Ligand [beta]-Halogenation and meso-Fluoroarylation

Systematic electronic variations were introduced into the monoanionic dipyrrinato ligand scaffold via halogenation of the pyrrolic {beta}-positions and/or via the use of fluorinated aryl substituents in the ligand bridgehead position in order to synthesize proligands of the type 1,9-dimesityl-{beta}-R{sub 4}-5-Ar-dipyrrin [R = H, Cl, Br, I; Ar = mesityl, 3,5-(F{sub 3}C){sub 2}C{sub 6}H{sub 3}, C{sub 6}F{sub 5} in ligand 5-position; {beta} = 2,3,7,8 ligand substitution; abbreviated ({sup {beta},Ar}L)H]. The electronic perturbations were probed using standard electronic absorption and electrochemical techniques on the different ligand variations and their divalent iron complexes. The free-ligand variations cause modest shifts in the electronic absorption maxima ({lambda}{sub max}: 464-499 nm) and more pronounced shifts in the electrochemical redox potentials for one-electron proligand reductions (E{sub 1/2}: -1.25 to -1.99 V) and oxidations (E{sub 1/2}: +0.52 to +1.14 V vs [Cp{sub 2}Fe]{sup +/0}). Installation of iron into the dipyrrinato scaffolds was effected via deprotonation of the proligands followed by treatment with FeCl{sub 2} and excess pyridine in tetrahydrofuran to afford complexes of the type ({sup {beta},Ar}L)FeCl(py) (py = pyridine). The electrochemical and spectroscopic behavior of these complexes varies significantly across the series: the redox potential of the fully reversible Fe{sup III/II} couple spans more than 400 mV (E{sub 1/2}: -0.34 to +0.50 V vs [Cp{sub 2}Fe]{sup +/0}); {lambda}{sub max} spans more than 40 nm (506-548 nm); and the {sup 57}Fe Moessbauer quadrupole splitting (|{Delta}E{sub Q}|) spans nearly 2.0 mm/s while the isomer shift ({delta}) remains essentially constant (0.86-0.89 mm/s) across the series. These effects demonstrate how peripheral variation of the dipyrrinato ligand scaffold can allow systematic variation of the chemical and physical properties of iron dipyrrinato complexes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Kinetic analysis of the phenyl-shift reaction in $\beta$-O-4 lignin model compounds: A computational study.

The phenyl-shift reaction in $\beta$-phenethyl phenyl ether ($\beta - \rm PhCH_2CH_2OPh$, $\beta$-PPE) is an integral step in the pyrolysis of PPE, which is a model compound for the $\beta$-O-4 linkage in lignin. We investigated the influence of natural occurring substituents (hydroxy, methoxy) on the reaction rate by calculating relative rate constant using density functional theory in combination with transition state theory, including anharmonic correction for low-frequency modes. The phenyl-shift reaction proceeds through an intermediate and the overall rate constants were computed invoking the steady-state approximation (its validity was confirmed). Substituents on the phenethyl group have only little influence on the rate constants. If a methoxy substituent is located in para position of the phenyl ring adjacent to the ether oxygen, the energies of the intermediate and second transition state are lowered, but the overall rate constant is not significantly altered. This is a consequence of the dominating first transition from pre-complex to intermediate in the overall rate constant. {\it O}- and di-{\it o}-methoxy substituents accelerate the phenyl-migration rate compared to $\beta$-PPE.

09 BIOMASS FUELS↗

The role of carbon-carbon phenyl migration in the pyrolysis mechanism of beta-O-4 lignin model compounds: phenethyl phenyl ether and alpha-hydroxy phenethyl phenyl ether

We investigate phenyl shift and subsequent beta-scission reactions for PhCHXCHOPh [X = H, OH], which are part of the pyrolysis mechanism of phenethyl phenyl ether (PPE) and alpha-hydroxy PPE. PPE and its derivatives are model compounds for the most common linkage in lignin, the beta-O-4 linkage. We use density functional theory to locate transition states and equilibrium structures, and kinetic Monte Carlo in combination with transition state theory for kinetic simulations. Oxygen-carbon and carbon-carbon phenyl shift reactions proceed through cyclic intermediates with similar barriers. But, while subsequent beta-scission of the oxygen-carbon shift products proceeds with virtually no barrier, the activation energy for beta-scission of the carbon-carbon shift products exceeds 15 kcal/mol. We found that about 15 % of beta-radical conversion can be attributed to carbon-carbon shift for PPE and alpha-hydroxy PPE at 618 K. Whereas the oxygen-carbon shift reaction has been established as an integral part of the pyrolysis mechanism of PPE and its derivatives, participation of the carbon-carbon shift reaction has not been shown previously.

Beste, Ariana↗

An autoinhibitory helix in the C-terminal region of phospholipase C-[beta] mediates G[alpaha subscript q] activation

The enzyme phospholipase C-{beta} (PLC{beta}) is a crucial regulator of intracellular calcium levels whose activity is controlled by heptahelical receptors that couple to members of the G{sub q} family of heterotrimeric G proteins. We have determined atomic structures of two invertebrate homologs of PLC{beta} (PLC21) from cephalopod retina and identified a helix from the C-terminal regulatory region that interacts with a conserved surface of the catalytic core of the enzyme. Mutations designed to disrupt the analogous interaction in human PLC{beta}3 considerably increase basal activity and diminish stimulation by G{alpha}{sub q}. G{alpha}{sub q} binding requires displacement of the autoinhibitory helix from the catalytic core, thus providing an allosteric mechanism for activation of PLC{beta}.

59 BASIC BIOLOGICAL SCIENCES↗

Gyrokinetic study of the role of {beta} on electron particle transport in tokamaks

Electromagnetic effects on the radial transport of electrons in the core of tokamak plasmas are studied by means of linear and nonlinear gyrokinetic simulations with the code GYRO[J. Candy and R. E. Waltz, J. Comput. Phys. 186, 545 (2003)] and by an analytical derivation. The impact of a finite {beta}, that is, a finite ratio of the plasma pressure to the magnetic pressure, is considered on the fluctuations of the magnetic field through Ampere's law, as well as on the geometrical modification of the vertical drift produced by the Shafranov shift in the magnetic equilibrium, which, for realistic descriptions, has to be included in both electrostatic and electromagnetic modeling. The condition of turbulent particle flux at the null, which allows the determination of stationary logarithmic density gradients when neoclassical transport and particle sources are negligible, is investigated for increasing values of {beta}, in regimes of ion temperature gradient and trapped electron mode turbulence. The loss of adiabaticity of passing electrons produced by fluctuations in the magnetic vector potential produces an outward convection. When the magnetic equilibrium geometry is kept fixed, this induces a strong reduction of the stationary logarithmic density gradient with increasing {beta}. This effect is partly compensated by the geometrical effect on the vertical drift. This compensation effect, however, is significantly weaker in nonlinear simulations as compared to quasilinear calculations. A detailed comparison between quasilinear and nonlinear results reveals that the predicted value of the logarithmic density gradient is highly sensitive on the assumptions on the wave number spectrum applied in the quasilinear model. The qualitative consistency of the theoretical predictions with the experimental results obtained so far on the dependence of density peaking on {beta} is discussed by considering the additional impact, with increasing {beta}, of a particle source delivered by neutral beam injection heating. (Some figures in this article are in color only in the electronic version.)

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Minority-carrier diffusion length, minority-carrier lifetime, and photoresponsivity of {beta}-FeSi{sub 2} layers grown by molecular-beam epitaxy

We have epitaxially grown undoped {beta}-FeSi{sub 2} films on Si(111) substrates via atomic-hydrogen-assisted molecular-beam epitaxy. {beta}-FeSi{sub 2} films grown without atomic hydrogen exhibited p-type conduction with a hole density of over 10{sup 19} cm{sup -3} at room temperature (RT). In contrast, those prepared with atomic hydrogen showed n-type conduction and had a residual electron density that was more than two orders of magnitude lower than the hole density of films grown without atomic hydrogen (of the order of 10{sup 16} cm{sup -3} at RT). The minority-carrier diffusion length was estimated to be approximately 16 {mu}m using an electron-beam-induced current technique; this value is twice as large as that for {beta}-FeSi{sub 2} prepared without atomic hydrogen. This result could be well explained in terms of the minority-carrier lifetimes measured by a microwave photoconductance decay technique. The 1/e decay time using a 904 nm laser pulse was approximately 17 {mu}s, which is much longer than that for {beta}-FeSi{sub 2} prepared without atomic hydrogen (3 {mu}s). The photoresponsivity reached 13 mA/W at 1.31 {mu}m, which is the highest value ever reported for {beta}-FeSi{sub 2} films.

36 MATERIALS SCIENCE↗

Whistler anisotropy instability at low electron {beta}: Particle-in-cell simulations

The whistler anisotropy instability is studied in a magnetized, homogeneous, collisionless plasma model. The electrons (denoted by subscript e) are represented initially with a single bi-Maxwellian velocity distribution with a temperature anisotropy T{sub perpendiculare}/T{sub ||e}>1, where perpendicular and || denote directions perpendicular and parallel to the background magnetic field B{sub o}, respectively. Kinetic linear dispersion theory predicts that, if the ratio of the electron plasma frequency {omega}{sub e} to the electron cyclotron frequency {Omega}{sub e} is greater than unity and {beta}{sub ||e}{>=}0.025, the maximum growth rate of this instability is at parallel propagation, where the fluctuating fields are strictly electromagnetic. At smaller values of {beta}{sub ||e}, however, the maximum growth rate shifts to propagation oblique to B{sub o} and the fluctuating electric fields become predominantly electrostatic. Linear theory and two-dimensional particle-in-cell simulations are used to examine the consequences of this transition. Three simulations are carried out, with initial {beta}{sub ||e}=0.10, 0.03, and 0.01. The fluctuating fields of the {beta}{sub ||e}=0.10 run are predominantly electromagnetic, with nonlinear consequences similar to those of simulations already described in the literature. In contrast, the growth of fluctuations at oblique propagation in the low electron {beta} runs leads to a significant {delta}E{sub ||}, which heats the electrons leading to the formation of a substantial suprathermal component in the electron parallel velocity distribution.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Beta dependence of electron heating in decaying whistler turbulence: Particle-in-cell simulations

Two-dimensional particle-in-cell simulations have been carried out to study electron beta dependence of decaying whistler turbulence and electron heating in a homogeneous, collisionless magnetized plasma. Initially, applied whistler fluctuations at relatively long wavelengths cascade their energy into shorter wavelengths. This cascade leads to whistler turbulence with anisotropic wavenumber spectra which are broader in directions perpendicular to the background magnetic field than in the parallel direction. Comparing the development of whistler turbulence at different electron beta values, it is found that both the wavenumber spectrum anisotropy and electron heating anisotropy decrease with increasing electron beta. This indicates that higher electron beta reduces the perpendicular energy cascade of whistler turbulence. Fluctuation energy dissipation by electron Landau damping responsible for the electron parallel heating becomes weaker at higher electron beta, which leads to more isotropic heating. It suggests that electron kinetic processes are important in determining the properties of whistler turbulence. This kinetic property is applied to discuss the generation of suprathermal strahl electron distributions in the solar wind.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Classical integrability for beta-ensembles and general Fokker-Planck equations

Beta-ensembles of random matrices are naturally considered as quantum integrable systems, in particular, due to their relation with conformal field theory, and more recently appeared connection with quantized Painlevé Hamiltonians. Here, we demonstrate that, at least for even integer beta, these systems are classically integrable, e.g., there are Lax pairs associated with them, which we explicitly construct. To come to the result, we show that a solution of every Fokker-Planck equation in one space (and one time) dimensions can be considered as a component of an eigenvector of a Lax pair. The explicit finding of the Lax pair depends on finding a solution of a governing system–a closed system of two nonlinear partial differential equations (PDEs) of hydrodynamic type. This result suggests that there must be a solution for all values of beta. We find the solution of this system for even integer beta in the particular case of quantum Painlevé II related to the soft edge of the spectrum for beta-ensembles. The solution is given in terms of Calogero system of β/2 particles in an additional time-dependent potential. Thus, we find another situation where quantum integrability is reduced to classical integrability.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

LIKELY MEMBERS OF THE {beta} PICTORIS AND AB DORADUS MOVING GROUPS IN THE NORTH

We present first results from follow-up of targets in the northern hemisphere {beta} Pictoris and AB Doradus moving group candidate list of Schlieder et al. We obtained high-resolution, near-infrared spectra of 27 candidate members to measure their radial velocities and confirm consistent group kinematics. We identify 15 candidates with consistent predicted and measured radial velocities, perform analyses of their six-dimensional (UVWXYZ) Galactic kinematics, and compare to known group member distributions. Based on these analyses, we propose that seven {beta} Pic and eight AB Dor candidates are likely new group members. Four of the likely new {beta} Pic stars are binaries, one a double-lined spectroscopic system. Three of the proposed AB Dor stars are binaries. Counting all binary components, we propose 22 likely members of these young, moving groups. The majority of the proposed members are M2 to M5 dwarfs, the earliest being of type K2. We also present preliminary parameters for the two new spectroscopic binaries identified in the data, the proposed {beta} Pic member and a rejected {beta} Pic candidate. Our candidate selection and follow-up has thus far identified more than 40 low-mass, likely members of these two moving groups. These stars provide a new sample of nearby, young targets for studies of local star formation, disks and exoplanets via direct imaging, and astrophysics in the low-mass regime.

79 ASTRONOMY AND ASTROPHYSICS↗

He II Ly{beta} GUNN-PETERSON ABSORPTION: NEW HST OBSERVATIONS AND THEORETICAL EXPECTATIONS

Observations of He II Ly{alpha} Gunn-Peterson troughs have proved to be a valuable probe of the epoch of helium reionization at z {approx} 3. Since this optical depth can become unmeasurably large even for modest He II fractions, various alternate techniques have been proposed to push to higher redshift, and among the more promising is looking at higher-order Lyman-series troughs. We here report four new observations of the He II Ly{beta} trough, including new data on the only sightline with a prior Ly{beta} observation. However, the effective optical depth ratio {tau}{sub eff,{beta}}/{tau}{sub eff,{alpha}} is not simply predicted by f{sub {beta}}{lambda}{sub {beta}}/f{sub {alpha}}{lambda}{sub {alpha}} = 0.16, and we analyze cosmological simulations to find that the correct ratio for helium at z {approx} 3 is {approx_equal}0.35. In one case we infer {tau}{sub eff,{alpha}} > 8.8, strong evidence that helium was not fully reionized at z = 3.2-3.5, in agreement with previous measurements suggesting a later completion of reionization.

79 ASTRONOMY AND ASTROPHYSICS↗

ON THE MISALIGNMENT OF THE DIRECTLY IMAGED PLANET {beta} PICTORIS b WITH THE SYSTEM'S WARPED INNER DISK

The vertical warp in the debris disk {beta} Pictoris-an inclined inner disk extending into a flat outer disk-has long been interpreted as the signpost of a planet on an inclined orbit. Direct images spanning 2004-2010 have revealed {beta} Pictoris b, a planet with a mass and orbital distance consistent with this picture. However, it was recently reported that the orbit of planet b is aligned with the flat outer disk, not the inclined inner disk, and thus lacks the inclination to warp the disk. We explore three scenarios for reconciling the apparent misalignment of the directly imaged planet {beta} Pictoris b with the warped inner disk of {beta} Pictoris: observational uncertainty, an additional planet, and damping of planet b's inclination. We find that, at the extremes of the uncertainties, the orbit of {beta} Pictoris b has the inclination necessary to produce the observed warp. We also find that if planet b were aligned with the flat outer disk, it would prevent another planet from creating a warp with the observed properties; therefore planet b itself must be responsible for the warp. Finally, planet b's inclination could have been damped by dynamical friction and still produce the observed disk morphology, but the feasibility of damping depends on disk properties and the presence of other planets. More precise observations of the orbit of planet b and the position angle of the outer disk will allow us to distinguish between the first and third scenarios.

79 ASTRONOMY AND ASTROPHYSICS↗

Logarithmic correction in the deformed AdS{sub 5} model to produce the heavy quark potential and QCD beta function

We study the holographic QCD model, which contains a quadratic term -{sigma}z{sup 2} and a logarithmic term -c{sub 0}log[(z{sub IR}-z)/z{sub IR}] with an explicit infrared cutoff z{sub IR} in the deformed AdS{sub 5} warp factor. We investigate the heavy-quark potential for three cases, i.e., with only a quadratic correction, with both quadratic and logarithmic corrections, and with only a logarithmic correction. We solve the dilaton field and dilation potential from the Einstein equation and investigate the corresponding beta function in the Guersoy-Kiritsis-Nitti framework. Our studies show that in the case with only a quadratic correction, a negative {sigma} or the Andreev-Zakharov model is favored to fit the heavy-quark potential and to produce the QCD beta function at 2-loop level; however, the dilaton potential is unbounded in the infrared regime. One interesting observation for the case of positive {sigma} is that the corresponding beta function exists in an infrared fixed point. In the case with only a logarithmic correction, the heavy-quark Cornell potential can be fitted very well, the corresponding beta function agrees with the QCD beta function at 2-loop level reasonably well, and the dilaton potential is bounded from below in the infrared. At the end, we propose a more compact model which has only a logarithmic correction in the deformed warp factor and has less free parameters.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗