bluuebunny/crossref_metadata_2025 huggingface dataset:
Unstimulated diagnostic marrow tap – a minimally invasive and reliable source for mesenchymal stem cells
Authors: Koppula Reddy Purushotham , Polisetti Naresh , Vemuganti Geeta K.
Published: November 2009

BMMNCs (bone marrow mononuclear cells) were isolated by density gradient centrifugation from unstimulated diagnostic marrow tap to propagate and characterize hBMSCs (human bone marrow stromal cells) and to explore their plasticity towards neuronal and other lineages. hBMSCs were characterized by flow cytometry for established markers, serially passaged and differentiated into adipo, osteo, chondro and neuronal lineages. Neural differentiation was analysed by RT‐PCR (reverse transcriptase‐PCR), ICC (immunocytochemistry) and Western blotting. The hBMSCs (n=39) were spindle‐shaped and immunoreactive for mesenchymal markers such as CD71, CD106, CD105, CD90 and Vimentin and negative for haematopoietic markers such as CD11c, CD34 and CD45. These cells showed differentiation into adipocytes, osteocytes and chondrocytes. Upon neuronal differentiation, hBMSCs expressed neuronal markers, i.e. β‐III tubulin, GAP43 (growth‐associated proteins), neurofilament by ICC, RT‐PCR and Western blotting. Our study demonstrates that minimal volumes of unstimulated diagnostic marrow tap forms a minimally invasive and reliable source for isolation of BMMNCs to establish cultures of mesenchymal stem cells and expand them. The plasticity observed in these cells towards mesenchymal (adipogenic, osteogenic and chondrocytic) and non‐mesenchymal lineage (neural) substantiates the nature of mesenchymal stem cells and warrants further studies to evaluate their functional role
Development of hepatic fibrosis occurs normally in AMPK-deficient mice
Authors: Da Silva Morais Alain , Abarca-Quinones Jorge , Guigas Bruno , Viollet Benoit , Stärkel Peter , Horsmans Yves , Leclercq Isabelle A.
Published: November 2009

Inhibition or blockade of HSCs (hepatic stellate cells), the main matrix-producing cells involved in the wound-healing response, represents an attractive strategy for the treatment of liver fibrosis. In vitro studies have shown that activation of AMPK (AMP-activated protein kinase), a key player in the regulation of cellular energy homoeostasis, inhibits proliferation of myofibroblasts derived from HSCs. If AMPK is a true regulator of fibrogenesis then defective AMPK activity would enhance fibrogenesis and hepatic fibrosis. To test this, in the present work, in vitro studies were performed on mouse primary HSCs treated or not with the AMPK activator AICAR (5-amino-4-imidazolecarboxamide ribonucleotide) or isolated from mice lacking the AMPKα1 catalytic subunit (AMPKα1−/−) or their littermates (AMPKα1+/+). Liver fibrosis was induced in vivo in AMPKα1−/− and AMPKα1+/+ mice by repeated injections of CCl4 (carbon tetrachloride). During culture activation of HSCs, AMPK protein and activity significantly increased and regulatory AMPKγ3 mRNA was specifically up-regulated. Stimulation of AMPK activity by AICAR inhibited HSC proliferation, as expected, as well as collagen α1(I) expression. Importantly, AMPKα1 deletion inhibited proliferation of HSCs, but not fibrogenesis, in vivo. Moreover, AMPKα1 deletion was not associated with enhanced CCl4-induced fibrosis in vivo. In conclusion, our present findings demonstrate that HSC transdifferentiation is associated with increased AMPK activity that could relate to the stabilization of AMPK complex by the γ3 subunits. Activation of AMPK in HSCs inhibits in vitro fibrogenesis. By contrast, low AMPK activity does not prevent HSC activation in vitro nor in in vivo fibrosis.
Evaluation and Treatment of Pediatric Gastroesophageal Reflux and Its Effects on Voice
Authors: Theis Shannon M. , Heatley Diane G.
Published: November 2009

Voice disorders in the pediatric population are common, but have been understudied. Inflammation, trauma, neurologic, and congenital anomalies can all result in childhood dysphonia. Laryngopharyngeal reflux, an extra-esophageal variation of gastroesophageal reflux, has been associated with laryngeal symptoms of dysphonia, globus sensation, throat-clearing, and chronic cough in children. This article reviews the current evaluation and treatment techniques of reflux, and the effects of laryngopharyngeal reflux on voice quality in children. A case study illustrating the importance of a multidisciplinary approach in diagnosing and treating this challenging disorder is presented.
An extension theorem for conformal gauge singularities
Authors: Lübbe Christian , Tod Paul
Published: November 2009

We analyze conformal gauge, or isotropic, singularities in cosmological models in general relativity. Using the calculus of tractors, we find conditions in terms of tractor curvature for a local extension of the conformal structure through a cosmological singularity and prove a local extension theorem along a congruence of timelike conformal geodesics.
In-field Mossbauer study of disordered surface spins in core/shell ferrite nanoparticles
Authors: Sousa E. C. , Rechenberg H. R. , Depeyrot J. , Gomes J. A. , Aquino R. , Tourinho F. A. , Dupuis V. , Perzynski R.
Published: November 2009

Magnetization and Mossbauer spectroscopy measurements are performed at low temperature under high field, on nanoparticles with a nickel ferrite core and a maghemite shell. These nanoparticles present finite size and surface effects, together with exchange anisotropy. High field magnetization brings the evidences of a monodomain ordered core and surface spins freezing in disorder at low temperature. Mossbauer spectra at 4.2 K present an extra contribution from the disordered surface which is field dependent. Field and size dependences of this latter show a progressive spin alignment along the ferrite core which is size dependent. The weak surface pinning condition of the nanoparticles confirms that the spin disorder is localized in the external shell. The underfield decrease in the mean canting angle in the superficial shell is then directly related to the unidirectional exchange anisotropy through the interface between the ordered core and the disordered shell. The obtained anisotropy field HEa scales as the inverse of the nanoparticle diameter, validating its interfacial origin. The associated anisotropy constant KEa equals 2.5×10−4 J/m2.
Evaluation of the charge density in the contact region of organic thin film transistors
Authors: Bullejos P. Lara , Tejada J. A. Jiménez , Gómez-Campos F. M. , Deen M. J. , Marinov O.
Published: November 2009

This paper presents a procedure to evaluate the charge density in the low conductivity regions between the metal and the accumulated intrinsic channel of an organic thin film transistor (OTFT). This charge links different physical mechanisms in the contacts of OTFTs. The charge density is evaluated in transistors with different metal-organic barriers to study its dependence with the voltage, temperature and the materials forming the contact.
Interference in the radiation of two pointlike charges
Authors: Yaremko Yurij
Published: November 2009

Energy-momentum and angular momentum carried by electromagnetic field of two pointlike charged particles arbitrarily moving in flat space-time are presented. Apart from usual contributions to the Noether quantities produced separately by particles 1 and 2, the conservation laws contain also joint contribution due to the fields of both particles. The mixed part of Maxwell energy-momentum density is decomposed into bound and radiative components which are separately conserved off the world lines of particles. The former describes the deformation of electromagnetic clouds of “bare” charges due to mutual interaction while the latter defines the radiation which escapes to infinity. The bound terms contribute to particles’ individual 4-momenta while the radiative ones exert the radiation reaction. Analysis of energy-momentum and angular momentum balance equations results the Lorentz–Dirac equation as an equation of motion for a pointed charge under the influence of its own electromagnetic field as well as field produced by another charge.
Improvement of windowed type environmental-cell transmission electron microscope for in situ observation of gas-solid interactions
Authors: Kawasaki Tadahiro , Ueda Kouta , Ichihashi Mikio , Tanji Takayoshi
Published: November 2009

We have developed an improved, windowed type environmental-cell (E-cell) transmission electron microscope (TEM) for in situ observation of gas-solid interactions, such as catalytic reactions at atmospheric pressure. Our E-cell TEM includes a compact E-cell specimen holder with mechanical stability, resulting in smoother introduction of the desired gases compared with previous E-cell TEMs. In addition, the gas control unit was simplified by omitting the pressure control function of the TEM pre-evacuation chamber. This simplification was due to the successful development of remarkably tough thin carbon films as the window material. These films, with a thickness of <10 nm, were found to withstand pressure differences >2 atm. Appropriate arrangement of the specimen position inside the E-cell provided quantitatively analyzable TEM images, with no disturbances caused by the windowed films. As an application, we used this E-cell TEM to observe the dynamic shape change in a catalytic gold nanoparticle supported on TiO2 during the oxidation of CO gas.
Solid-liquid equilibria and triple points of n-6 Lennard-Jones fluids
Authors: Ahmed Alauddin , Sadus Richard J.
Published: November 2009

Molecular dynamics simulations are reported for the solid-liquid coexistence properties of n-6 Lennard-Jones fluids, where n=12, 11, 10, 9, 8, and 7. The complete phase behavior for these systems has been obtained by combining these data with vapor-liquid simulations. The influence of n on the solid-liquid coexistence region is compared using relative density difference and miscibility gap calculations. Analytical expressions for the coexistence pressure, liquid, and solid densities as a function of temperature have been determined, which accurately reproduce the molecular simulation data. The triple point temperature, pressure, and liquid and solid densities are estimated. The triple point temperature and pressure scale with respect to 1/n, resulting in simple linear relationships that can be used to determine the pressure and temperature for the limiting ∞-6 Lennard-Jones potential. The simulation data are used to obtain parameters for the Raveché, Mountain, and Streett and Lindemann melting rules, which indicate that they are obeyed by the n-6 Lennard Jones potentials. In contrast, it is demonstrated that the Hansen–Verlet freezing rule is not valid for n-6 Lennard-Jones potentials.
Impact of a surface laser treatment on the dielectric strength of α-alumina
Authors: Decup Michael , Malec David , Bley Vincent
Published: November 2009

The impact of laser treatments on the dielectric strength of α-alumina is investigated. In order to induce low surface modifications to strong damages, different laser processing parameters (fluence, assisting gas and its pressure, and laser wavelength) are applied. The experimental results clearly show that the dielectric strength is not really affected by the laser induced surface modifications. Surface cracks are consequently not considered to be involved in the breakdown mechanism. If any relationship exists between mechanical and dielectric strengths of α-alumina, the assumption considering that the prebreakdown event is the propagation of a mechanical crack from the surface has to be reconsidered.
A soft-core Gay–Berne model for the simulation of liquid crystals by Hamiltonian replica exchange
Authors: Berardi Roberto , Zannoni Claudio , Lintuvuori Juho S. , Wilson Mark R.
Published: November 2009

The Gay–Berne (GB) potential has proved highly successful in the simulation of liquid crystal phases, although it is fairly demanding in terms of resources for simulations of large (e.g., N>105) systems, as increasingly required in applications. Here, we introduce a soft-core GB model, which exhibits both liquid crystal phase behavior and rapid equilibration. We show that the Hamiltonian replica exchange method, coupled with the newly introduced soft-core GB model, can effectively speed up the equilibration of a GB liquid crystal phase by frequent exchange of configurations between replicas, while still recovering the mesogenic properties of the standard GB potential.
Spontaneous buildup of surface potential with a thin film of a zwitterionic molecule giving noncentrosymmetric crystal structure
Authors: Tsutsumi Jun’ya , Yoshida Hiroyuki , Murdey Richard , Sato Naoki
Published: November 2009

Surface potentials were examined using the Kelvin method for thin films of zwitterionic molecules, pyridinium 1,3-dihydro-1,3-dioxo-2H-inden-2-ylide (PI or IPB) and two nitrogen-substituted derivatives. Spontaneous buildup of the surface potential on the film (5.5 V at a film thickness of 300 nm) was only observed for the compound with unidirectional orientation of the molecular dipole moments in the single crystal. The relationship between the alignment of the molecular dipole moments in the film and the measured surface potentials was investigated using grazing incidence x-ray diffraction, pole-figure measurements, atomic force microscopy, and Kelvin probe force microscopy.
Anomaly of critical stress in stress-induced transformation of NiCoMnIn metamagnetic shape memory alloy
Authors: Xu Xiao , Ito Wataru , Umetsu Rie Y. , Kainuma Ryosuke , Ishida Kiyohito
Published: November 2009

Stress-induced martensitic transformation below room temperature for a Ni45Co5Mn36.1In13.9 single-crystal, in which no martensitic transformation occurs during cooling down to 4.2 K under zero stress, was investigated by using compression test. The equilibrium stress estimated from the critical stresses in stress-induced forward and reverse transformations decreased with decreasing temperature, while it became almost constant at temperatures below about 140 K. This anomaly can be explained by the abnormal temperature dependence of the transformation entropy change, which has also been detected by magnetization measurement.
Pressure enhancement of the isostructural cubic decomposition in Ti1−xAlxN
Authors: Alling B. , Odén M. , Hultman L. , Abrikosov I. A.
Published: November 2009

The influence of pressure on the phase stabilities of Ti1−xAlxN solid solutions has been studied using first principles calculations. We find that the application of hydrostatic pressure enhances the tendency for isostructural decomposition, including spinodal decomposition. The effect originates in the gradual pressure stabilization of cubic AlN with respect to the wurtzite structure and an increased isostructural cubic mixing enthalpy with increased pressure. The influence is sufficiently strong in the composition-temperature interval corresponding to a shoulder of the spinodal line that it could impact the stability of the material at pressures achievable in the tool-work piece contact during cutting operations.
Internal frequency conversion extreme ultraviolet interferometer using mutual coherence properties of two high-order-harmonic sources
Authors: Dobosz S. , Stabile H. , Tortora A. , Monot P. , Réau F. , Bougeard M. , Merdji H. , Carré B. , Martin Ph. , Joyeux D. , Phalippou D. , Delmotte F. , Gautier J. , Mercier R.
Published: November 2009

We report on an innovative two-dimensional imaging extreme ultraviolet (XUV) interferometer operating at 32 nm based on the mutual coherence of two laser high order harmonics (HOH) sources, separately generated in gas. We give the first evidence that the two mutually coherent HOH sources can be produced in two independent spatially separated gas jets, allowing for probing centimeter-sized objects. A magnification factor of 10 leads to a micron resolution associated with a subpicosecond temporal resolution. Single shot interferograms with a fringe visibility better than 30% are routinely produced. As a test of the XUV interferometer, we measure a maximum electronic density of 3×1020 cm−3 1.1 ns after the creation of a plasma on aluminum target.
Photodissociation cross sections of ClOOCl at 248.4 and 266 nm
Authors: Lien Chien-Yu , Lin Wei-Yen , Chen Hsueh-Ying , Huang Wen-Tsung , Jin Bing , Chen I-Cheng , Lin Jim J.
Published: November 2009

This study utilized a mass-resolved detection of ClOOCl to determine its photodissociation cross section, which is the product of the absorption cross section and dissociation quantum yield. An effusive molecular beam of ClOOCl was generated and its photodissociation probability was determined through measuring the decrease in the ClOOCl beam intensity upon laser irradiation. By comparing with a reference molecule, the absolute cross sections of ClOOCl were obtained without knowing its absolute concentration. The determined cross section of ClOOCl at 248.4 nm is (8.85±0.42)×10−18 cm2 at 200 K, significantly larger than previously reported values. The temperature dependence of the cross section was investigated at 248.4 nm in the range of 160–260 K; only a very small and negative temperature effect was observed. Because 248.4 nm is very close to the peak of the UV absorption band of ClOOCl, this work provides a new calibration point for normalizing relative absorption spectra of ClOOCl. In this work, the photodissociation cross section at 266 nm and 200 K was also reported to be (4.13±0.21)×10−18 cm2.
Enhancement of magnetoelectric effect in multiferroic fibrous nanocomposites via size-dependent material properties
Authors: Pan E. , Wang X. , Wang R.
Published: November 2009

We investigate the effective material properties of a multiferroic fibrous nanocomposite with size effects along its interface. The closed-form expression of the effective moduli of the nanocomposite shows that its response with interface effects depends on the size of the embedded fibers in the composite, a phenomenon different from the result based on the classical theory. We further demonstrate that the magnetoelectric effect can be substantially enhanced via proper design of the interface, providing an alternative avenue for controlling and, in particularly, increasing the magnetoelectric effect.
Thermal-induced refractive-index planar waveguide laser
Authors: Kang Hongxiang , Zhang Haitao , Wang Dongsheng
Published: November 2009

The feasibility of a thermal-induced refractive-index planar waveguide laser was demonstrated. The condition for the guided modes to be confined in the gain region was calculated. A thermal-induced refractive-index planar waveguide laser was made simply by pumping a thin center layer of a slab crystal and its modes can be controlled by the thermal input unit area and the pumped region width. An output power of 23.1 W with an optical to optical conversion efficiency of 46% was obtained. A thermal-induced refractive-index planar waveguide laser is very promising for efficient and bright laser sources due to its simple waveguide structure.
Giant tunneling magnetoresistance up to 330% at room temperature in sputter deposited Co2FeAl/MgO/CoFe magnetic tunnel junctions
Authors: Wang Wenhong , Sukegawa Hiroaki , Shan Rong , Mitani Seiji , Inomata Koichiro
Published: November 2009

Magnetoresistance ratio up to 330% at room temperature (700% at 10 K) has been obtained in a spin-valve-type magnetic tunnel junction (MTJ) consisting of a full-Heusler alloy Co2FeAl electrode and a MgO tunnel barrier fabricated on a single crystal MgO (001) substrate by sputtering method. The output voltage of the MTJ at one-half of the zero-bias value was found to be as high as 425 mV, which is the largest reported to date in MTJs using Heusler alloy electrodes. The present finding suggests that Co2FeAl may be one of the most promising candidates for future spintronics devices applications.
A simple atmospheric pressure room-temperature air plasma needle device for biomedical applications
Authors: Lu X. , Xiong Z. , Zhao F. , Xian Y. , Xiong Q. , Gong W. , Zou C. , Jiang Z. , Pan Y.
Published: November 2009

Rather than using noble gas, room air is used as the working gas for an atmospheric pressure room-temperature plasma. The plasma is driven by submicrosecond pulsed directed current voltages. Several current spikes appear periodically for each voltage pulse. The first current spike has a peak value of more than 1.5 A with a pulse width of about 10 ns. Emission spectra show that besides excited OH, O, N2(C–B), and N2+(B–X) emission, excited NO, N2(B–A), H, and even N emission are also observed in the plasma, which indicates that the plasma may be more reactive than that generated by other plasma jet devices. Utilizing the room-temperature plasma, preliminary inactivation experiments show that Enterococcus faecalis can be killed with a treatment time of only several seconds.
Low-density band-gap states in pentacene thin films probed with ultrahigh-sensitivity ultraviolet photoelectron spectroscopy
Authors: Sueyoshi Tomoki , Fukagawa Hirohiko , Ono Masaki , Kera Satoshi , Ueno Nobuo
Published: November 2009

We detected a very low density of electronic states in the band gap of a nondoped pentacene thin film by using ultraviolet photoelectron spectroscopy with ultrahigh sensitivity and ultralow background. The gap states, which may originate from the highest occupied molecular orbital (HOMO) state in imperfect molecular packing regions, are distributed exponentially up to the Fermi level and control the Fermi level relative to the HOMO band.
Nonequilibrium Fock space for the electron transport problem
Authors: Kosov D. S.
Published: November 2009

Based on the formalism of thermofield dynamics we propose a concept of nonequilibrium Fock space and nonequilibrium quasiparticles for quantum many-body system in nonequilibrium steady state. We develop a general theory as well as demonstrate the utility of the approach on the example of electron transport through the interacting region. The proposed approach is compatible with advanced quantum chemical methods of electronic structure calculations such as coupled cluster theory and configuration interaction.
Nanoscale phase competition accompanies colossal magnetoresistance
Authors: Day Charles
Published: November 2009

Doped manganites manifest competing phases of different electronic and magnetic order. Thanks to a new technique, the phases’ nanoscale battleground can now be mapped.
The Science Case for PILOT I: Summary and Overview
Authors: Lawrence J. S. , Ashley M. C. B. , Bailey J. , Barrado y Navascues D. , Bedding T. R. , Bland-Hawthorn J. , Bond I. , Boulanger F. , Bouwens R. , Bruntt H. , Bunker A. , Burgarella D. , Burton M. G. , Busso M. , Coward D. , Cioni M.-R. , Durand G. , Eiroa C. , Epchtein N. , Gehrels N. , Gillingham P. , Glazebrook K. , Haynes R. , Kiss L. , Lagage P. O. , Le Bertre T. , Mackay C. , Maillard J. P. , McGrath A. , Minier V. , Mora A. , Olsen K. , Persi P. , Pimbblet K. , Quimby R. , Saunders W. , Schmidt B. , Stello D. , Storey J. W. V. , Tinney C. , Tremblin P. , Wheeler J. C. , Yock P.
Published: November 2009

PILOT (the Pathfinder for an International Large Optical Telescope) is a proposed 2.5-m optical/infrared telescope to be located at Dome C on the Antarctic plateau. Conditions at Dome C are known to be exceptional for astronomy. The seeing (above ∼30 m height), coherence time, and isoplanatic angle are all twice as good as at typical mid-latitude sites, while the water-vapour column, and the atmosphere and telescope thermal emission are all an order of magnitude better. These conditions enable a unique scientific capability for PILOT, which is addressed in this series of papers. The current paper presents an overview of the optical and instrumentation suite for PILOT and its expected performance, a summary of the key science goals and observational approach for the facility, a discussion of the synergies between the science goals for PILOT and other telescopes, and a discussion of the future of Antarctic astronomy. Paper II and Paper III present details of the science projects divided, respectively, between the distant Universe (i.e. studies of first light, and the assembly and evolution of structure) and the nearby Universe (i.e. studies of Local Group galaxies, the Milky Way, and the Solar System).
The future of ice sheets and sea ice: Between reversible retreat and unstoppable loss
Authors: Notz Dirk
Published: November 2009

We discuss the existence of cryospheric “tipping points” in the Earth's climate system. Such critical thresholds have been suggested to exist for the disappearance of Arctic sea ice and the retreat of ice sheets: Once these ice masses have shrunk below an anticipated critical extent, the ice–albedo feedback might lead to the irreversible and unstoppable loss of the remaining ice. We here give an overview of our current understanding of such threshold behavior. By using conceptual arguments, we review the recent findings that such a tipping point probably does not exist for the loss of Arctic summer sea ice. Hence, in a cooler climate, sea ice could recover rapidly from the loss it has experienced in recent years. In addition, we discuss why this recent rapid retreat of Arctic summer sea ice might largely be a consequence of a slow shift in ice-thickness distribution, which will lead to strongly increased year-to-year variability of the Arctic summer sea-ice extent. This variability will render seasonal forecasts of the Arctic summer sea-ice extent increasingly difficult. We also discuss why, in contrast to Arctic summer sea ice, a tipping point is more likely to exist for the loss of the Greenland ice sheet and the West Antarctic ice sheet.
Auditory plasticity and speech motor learning
Authors: Nasir Sazzad M. , Ostry David J.
Published: November 2009

Is plasticity in sensory and motor systems linked? Here, in the context of speech motor learning and perception, we test the idea sensory function is modified by motor learning and, in particular, that speech motor learning affects a speaker's auditory map. We assessed speech motor learning by using a robotic device that displaced the jaw and selectively altered somatosensory feedback during speech. We found that with practice speakers progressively corrected for the mechanical perturbation and after motor learning they also showed systematic changes in their perceptual classification of speech sounds. The perceptual shift was tied to motor learning. Individuals that displayed greater amounts of learning also showed greater perceptual change. Perceptual change was not observed in control subjects that produced the same movements, but in the absence of a force field, nor in subjects that experienced the force field but failed to adapt to the mechanical load. The perceptual effects observed here indicate the involvement of the somatosensory system in the neural processing of speech sounds and suggest that speech motor learning results in changes to auditory perceptual function.
Transcriptional regulator Id2 controls survival of hepatic NKT cells
Authors: Monticelli Laurel A. , Yang Yang , Knell Jamie , D'Cruz Louise M. , Cannarile Michael A. , Engel Isaac , Kronenberg Mitchell , Goldrath Ananda W.
Published: November 2009

Natural killer T cells expressing an invariant T-cell receptor (iNKT) regulate activation of both innate and adaptive immunity in many contexts.iNKT cells accumulate in the liver and rapidly produce prodigious amounts of numerous cytokines upon activation, impacting the immune response to viral infection, immunosurveillance for malignant cells, and liver regeneration. However, little is known about the factors controllingiNKT homeostasis, survival and hepatic localization. Here, we report that the absence of the transcriptional regulator Id2 resulted in a severe, intrinsic defect in the accumulation of hepaticiNKT cells. Id2-deficientiNKT cells showed increased cell death in the liver, although migration and functional activity were not impaired in comparison to Id2-expressingiNKT cells. Id2-deficientiNKT cells exhibited diminished expression of CXCR6, a critical determinant ofiNKT cell accumulation in the liver, and of the anti-apoptotic molecules bcl-2 and bcl-XL, compared to Id2-sufficientiNKT cells. Furthermore, survival and accumulation ofiNKT cells lacking Id2 expression was rescued by deficiency in bim, a key pro-apoptotic molecule. Thus, Id2 was necessary to establish a hepaticiNKT cell population, defining a role for Id2 and implicating the Id targets, E protein transcription factors, in the regulation ofiNKT cell homeostasis.
Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms
Authors: Moench Ian , Prentice Howard , Rickaway Zach , Weissbach Herbert
Published: November 2009

We have recently shown that sulindac, an anti-inflammatory drug, enhances the killing of cancer cells, but not normal cells, under conditions of oxidative stress, by mechanisms unrelated to its cyclooxygenase (COX) inhibition. To further study the protective effect of sulindac on cells exposed to oxidative stress, we have investigated the effect of sulindac on rat cardiac myocytes subjected to hypoxia/reoxygenation, as well as in a Langendorff model of myocardial ischemia. Low levels of sulindac could protect cardiac myocytes against cell death due to hypoxia/reoxygenation. In the Langendorff model sulindac provided significant protection against cell death, when the drug was fed to the animals before the removal of the heart for the Langendorff procedure. The results indicate that the primary protective effect of sulindac in these experiments does not involve its role as a COX inhibitor. Numerous signaling pathways have been implicated in myocardial protective mechanisms, many of which involve fluctuations in reactive oxygen species (ROS) levels. The results suggest that low levels of sulindac can induce a preconditioning response, triggered by ROS, to protect cardiac tissues against oxidative damage. Blocking of preconditioning pathways by administration of the PKC blocker chelerythrine abrogated the ischemic protection afforded by sulindac. Secondly, after feeding of sulindac, two end-effectors of preconditioning, inducible nitric oxide synthase and heat shock protein 27, were found to be markedly induced in the heart, dependent on PKC. These results suggest that sulindac may have therapeutic potential as a preconditioning agent.
Mammalian Rif1 contributes to replication stress survival and homology-directed repair
Authors: Buonomo Sara B.C. , Wu Yipin , Ferguson David , de Lange Titia
Published: November 2009

Rif1, originally recognized for its role at telomeres in budding yeast, has been implicated in a wide variety of cellular processes in mammals, including pluripotency of stem cells, response to double-strand breaks, and breast cancer development. As the molecular function of Rif1 is not known, we examined the consequences of Rif1 deficiency in mouse cells. Rif1 deficiency leads to failure in embryonic development, and conditional deletion of Rif1 from mouse embryo fibroblasts affects S-phase progression, rendering cells hypersensitive to replication poisons. Rif1 deficiency does not alter the activation of the DNA replication checkpoint but rather affects the execution of repair. RNA interference to human Rif1 decreases the efficiency of homology-directed repair (HDR), and Rif1 deficiency results in aberrant aggregates of the HDR factor Rad51. Consistent with a role in S-phase progression, Rif1 accumulates at stalled replication forks, preferentially around pericentromeric heterochromatin. Collectively, these findings reveal a function for Rif1 in the repair of stalled forks by facilitating HDR.
From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity
Authors: Niault Théodora , Sobczak Izabela , Meissl Katrin , Weitsman Gregory , Piazzolla Daniela , Maurer Gabriele , Kern Florian , Ehrenreiter Karin , Hamerl Matthias , Moarefi Ismail , Leung Thomas , Carugo Oliviero , Ng Tony , Baccarini Manuela
Published: November 2009

The activity of Raf-1 and Rok-α kinases is regulated by intramolecular binding of the regulatory region to the kinase domain. Autoinhibition is relieved upon binding to the small guanosine triphosphatases Ras and Rho. Downstream of Ras, Raf-1 promotes migration and tumorigenesis by antagonizing Rok-α, but the underlying mechanism is unknown. In this study, we show that Rok-α inhibition by Raf-1 relies on an intermolecular interaction between the Rok-α kinase domain and the cysteine-rich Raf-1 regulatory domain (Raf-1reg), which is similar to Rok-α's own autoinhibitory region. Thus, Raf-1 mediates Rok-α inhibition in trans, which is a new concept in kinase regulation. This mechanism is physiologically relevant because Raf-1reg is sufficient to rescue all Rok-α–dependent defects of Raf-1–deficient cells. Downstream of Ras and Rho, the Raf-1–Rok-α interaction represents a novel paradigm of pathway cross talk that contributes to tumorigenesis and cell motility.
The ubiquitin landscape at DNA double-strand breaks
Authors: Messick Troy E. , Greenberg Roger A.
Published: November 2009

The intimate relationship between DNA double-strand break (DSB) repair and cancer susceptibility has sparked profound interest in how transactions on DNA and chromatin surrounding DNA damage influence genome integrity. Recent evidence implicates a substantial commitment of the cellular DNA damage response machinery to the synthesis, recognition, and hydrolysis of ubiquitin chains at DNA damage sites. In this review, we propose that, in order to accommodate parallel processes involved in DSB repair and checkpoint signaling, DSB-associated ubiquitin structures must be nonuniform, using different linkages for distinct functional outputs. We highlight recent advances in the study of nondegradative ubiquitin signaling at DSBs, and discuss how recognition of different ubiquitin structures may influence DNA damage responses.
Transcellular migration of leukocytes is mediated by the endothelial lateral border recycling compartment
Authors: Mamdouh Zahra , Mikhailov Alexei , Muller William A.
Published: November 2009

Leukocyte migration across endothelial cell borders (paracellular) and through endothelial cells (transcellular) appear to be distinct processes. During paracellular migration, membrane from a parajunctional reticulum of interconnected vesicles, the endothelial lateral border recycling compartment (LBRC), moves to surround the leukocyte in a kinesin-mediated, microtubule-dependent manner. We show that transcellular migration likewise requires targeted trafficking of LBRC membrane. We show that in addition to platelet/endothelial cell adhesion molecule (PECAM; CD31), CD99 and junctional adhesion molecule A (JAM-A), but apparently not vascular endothelial cell–specific cadherin (cadherin 5, CD144), are components of the LBRC. During transcellular migration, LBRC membrane invests the transmigrating leukocyte. Intracellular adhesion molecule 1 (ICAM-1) on the apical endothelial surface is enriched around adherent leukocytes. Depolymerization of microtubules has no effect on ICAM-1 enrichment but blocks targeted trafficking of LBRC membrane and transcellular migration by >90%. Similar to their effects on paracellular transmigration, antibodies against PECAM or CD99, but not JAM-A, block transcellular migration. We conclude that similar molecular mechanisms promote both para- and transcellular migration.
The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia
Authors: Irani Roxanna A. , Zhang Yujin , Blackwell Sean C. , Zhou Cissy Chenyi , Ramin Susan M. , Kellems Rodney E. , Xia Yang
Published: November 2009

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT1 receptor agonistic autoantibodies (AT1-AAs) that contribute to the disease features. However, the exact role of AT1-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT1 receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT1-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT1-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT1-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT1-AA–induced placental damage. Our findings highlight AT1-AAs as important therapeutic targets.
D-modules on the affine flag variety and representations of affine Kac-Moody algebras
Authors: Frenkel Edward , Gaitsgory Dennis
Published: November 2009

The present paper studies the connection between the category of modules over the affine Kac-Moody Lie algebra at the critical level, and the category of D-modules on the affine flag scheme

G
(
(
t
)
)

/

I

G((t))/I

, where

I
I

is the Iwahori subgroup. We prove a localization-type result, which establishes an equivalence between certain subcategories on both sides. We also establish an equivalence between a certain subcategory of Kac-Moody modules, and the category of quasi-coherent sheaves on the scheme of Miura opers for the Langlands dual group, thereby proving a conjecture of the authors in 2006.
Antioxidant and Hepatoprotective Effects of Silibinin in a Rat Model of Nonalcoholic Steatohepatitis
Authors: Haddad Yara , Vallerand Diane , Brault Antoine , Haddad Pierre S.
Published: November 2009

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease related to the metabolic syndrome, obesity and diabetes. The rising prevalence of NASH and the lack of efficient treatments have led to the exploration of different therapeutic approaches. Milk thistle (Silibum marianum) is a medicinal plant used for its hepatoprotective properties in chronic liver disease since the 4th century BC. We explored the therapeutic effect of silibinin, the plant′s most biologically active extract, in an experimental rat NASH model. A control group was fed a standard liquid diet for 12 weeks. The other groups were fed a high‐fat liquid diet for 12 weeks without (NASH) or with simultaneous daily supplement with silibinin–phosphatidylcholine complex (Silibinin 200 mg kg−1) for the last 5 weeks. NASH rats developed all key hallmarks of the pathology. Treatment with silibinin improved liver steatosis and inflammation and decreased NASH‐induced lipid peroxidation, plasma insulin and TNF‐α. Silibinin also decreased
release and returned the relative liver weight as well as GSH back to normal. Our results suggest that milk thistle′s extract, silibinin, possesses antioxidant, hypoinsulinemic and hepatoprotective properties that act against NASH‐induced liver damage. This medicinal herb thus shows promising therapeutic potential for the treatment of NASH.
Reporting Experiments in Homeopathic Basic Research—Description of the Checklist Development
Authors: Stock-Schröer B. , Albrecht H. , Betti L. , Dobos G. , Endler C. , Linde K. , Lüdtke R. , Musial F. , van Wijk R. , Witt C. , Baumgartner S.
Published: November 2009

The objective of this study was to develop a criteria catalogue serving as a guideline for authors to improve quality of reporting experiments in basic research in homeopathy. A Delphi Process was initiated including three rounds of adjusting and phrasing plus two consensus conferences. European researchers who published experimental work within the last 5 years were involved. A checklist for authors provide a catalogue with 23 criteria. The “Introduction” should focus on underlying hypotheses, the homeopathic principle investigated and state if experiments are exploratory or confirmatory. “Materials and methods” should comprise information on object of investigation, experimental setup, parameters, intervention and statistical methods. A more detailed description on the homeopathic substances, for example, manufacture, dilution method, starting point of dilution is required. A further result of the Delphi process is to raise scientists′ awareness of reporting blinding, allocation, replication, quality control and system performance controls. The part “Results” should provide the exact number of treated units per setting which were included in each analysis and state missing samples and drop outs. Results presented in tables and figures are as important as appropriate measures of effect size, uncertainty and probability. “Discussion” in a report should depict more than a general interpretation of results in the context of current evidence but also limitations and an appraisal of aptitude for the chosen experimental model. Authors of homeopathic basic research publications are encouraged to apply our checklist when preparing their manuscripts. Feedback is encouraged on applicability, strength and limitations of the list to enable future revisions.
Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations
Authors: Gérard Claude , Gonze Didier , Goldbeter Albert
Published: November 2009

Circadian rhythms, which occur spontaneously with a period of about 24 h in a variety of organisms, allow their adaptation to the periodic variations of the environment. These rhythms are generated by a genetic regulatory network involving a negative feedback loop on transcription. Mathematical models based on the negative autoregulation of gene expression by the protein product of a clock gene account for the occurrence of self-sustained circadian oscillations. These models differ by their degree of complexity and, hence, by the number of variables considered. Some of these models can be considered as minimal because they contain a reduced number of biochemical processes and variables capable of producing sustained oscillations. In three of these minimal models, the period of the oscillations significantly changes with the rate of degradation of the clock protein. However, depending on the model considered, the period increases, decreases or passes through a maximum as a function of the protein degradation rate. We clarify the bases for these markedly different results by bringing to light the roles of (i) protein phosphorylation, which is required for protein degradation, and (ii) the velocity and degree of saturation of mRNA and protein degradation. Changes in the parameter values of the more complex of the minimal models can produce the period profiles observed in the other two models. The analysis allows us to reconcile the contradictory predictions for the dependence of the period on the clock protein degradation rate in three minimal models used to describe circadian rhythms.
Endogenous circannual rhythm in luteinizing hormone secretion: insight from signal analysis coupled with mathematical modelling
Authors: Vidal Alexandre , Médigue Claire , Malpaux Benoît , Clément Frédérique
Published: November 2009

In sheep, as in many vertebrates, the seasonal pattern of reproduction is timed by the annual photoperiodic cycle, characterized by seasonal changes in the day length. The photoperiodic information is translated into a circadian profile of melatonin secretion. After multiple neuronal relays (within the hypothalamus), melatonin affects gonadotrophin-releasing hormone (GnRH) secretion, which in turn controls ovarian cyclicity. The pattern of GnRH secretion is mirrored by that of luteinizing hormone (LH) secretion, whose plasmatic level can be easily measured. We addressed the question of whether there exists an endogenous circannual rhythm in a tropical sheep (Blackbelly) population that exhibits clear seasonal ovarian activity when ewes are subject to temperate latitudes. We based our analysis on LH time series collected in the course of 3 years from ewes subject to a constant photoperiodic regime. Owing to intra- and interanimal variability and unequal sampling times, the existence of an endogenous rhythm is not straightforward. We have used time–frequency signal processing methods, and especially the smooth pseudo-Wigner–Ville distribution, to extract possible hidden rhythms from the data. To further investigate the low-frequency (LF) and high-frequency (HF) components of the signals, we have designed a simple mathematical model of the LH plasmatic level accounting for the effect of experimental sampling times. The model enables us to (i) confirm the existence of an endogenous circannual rhythm as detected by the LF signal component, (ii) investigate the action mechanism of the photoperiod on the pulsatile pattern of LH secretion (control of the interpulse interval), and (iii) conclude that the HF component is mainly due to the experimental sampling protocol.
Mathematical modelling of atherosclerosis as an inflammatory disease
Authors: El Khatib N. , Génieys S. , Kazmierczak B. , Volpert V.
Published: November 2009

Atherosclerosis is an inflammatory disease. The atherosclerosis process starts when low-density lipoproteins (LDLs) enter the intima of the blood vessel, where they are oxidized (ox-LDLs). The anti-inflammatory response triggers the recruitment of monocytes. Once in the intima, the monocytes are transformed into macrophages and foam cells, leading to the production of inflammatory cytokines and further recruitment of monocytes. This auto-amplified process leads to the formation of an atherosclerotic plaque and, possibly, to its rupture. In this paper we develop two mathematical models based on reaction–diffusion equations in order to explain the inflammatory process. The first model is one-dimensional: it does not consider the intima’s thickness and shows that low ox-LDL concentrations in the intima do not lead to a chronic inflammatory reaction. Intermediate ox-LDL concentrations correspond to a bistable system, which can lead to a travelling wave that can be initiated by certain conditions, such as infection or injury. High ox-LDL concentrations correspond to a monostable system, and even a small perturbation of the non-inflammatory case leads to travelling-wave propagation, which corresponds to a chronic inflammatory response. The second model we suggest is two-dimensional: it represents a reaction–diffusion system in a strip with nonlinear boundary conditions to describe the recruitment of monocytes as a function of the cytokines’ concentration. We prove the existence of travelling waves and confirm our previous results, which show that atherosclerosis develops as a reaction–diffusion wave. The results of the two models are confirmed by numerical simulations. The latter show that the two-dimensional model converges to the one-dimensional one if the thickness of the intima tends to zero.
Propagation of bursting oscillations
Authors: Ambrosio Benjamin , Françoise Jean-Pierre
Published: November 2009

We investigate a system of partial differential equations of reaction–diffusion type which displays propagation of bursting oscillations. This system represents the time evolution of an assembly of cells constituted by a small nucleus of bursting cells near the origin immersed in the middle of excitable cells. We show that this system displays a global attractor in an appropriated functional space. Numerical simulations show the existence in this attractor of recurrent solutions which are waves propagating from the central source. The propagation seems possible if the excitability of the neighbouring cells is above some threshold.