bluuebunny/crossref_metadata_2025 huggingface dataset:
Epithelium: the interplay between innate and Th2 immunity
Authors: Bulek Katarzyna , Swaidani Shadi , Aronica Mark , Li Xiaoxia
Published: January 2010

Mucosal epithelium functions not only as a physical barrier, but also as a regulator of innate and adaptive immune responses against foreign substances and microorganisms. In particular, epithelial cells have been directly implicated in Th2 responses, serving as a critical interface between innate immune responses and Th2 immunity. Emerging studies have revealed the cellular and molecular mechanisms by which the epithelium modulates Th2 responses through the production of a group of epithelial‐derived Th2‐driving cytokines, including interleukin (IL)‐25, IL‐33, and thymic stromal lymphopoietin. These epithelial‐derived Th2‐driving cytokines execute a regulatory function of the epithelium on mucosal immunity by promoting Th2 responses and maintaining the balance of host immune homeostasis and defense against various pathogens. Dysregulation of these Th2‐driving cytokines can lead to detrimental Th2‐dependent inflammatory responses, often manifested in various forms of allergic and inflammatory diseases.
Practical intravital two‐photon microscopy for immunological research: faster, brighter, deeper
Authors: Phan Tri Giang , Bullen Andrew
Published: January 2010

With its emphasis on minimally invasive high‐speed imaging of intact tissues at depth, video‐rate two‐photon microscopy has revolutionized cell biology. This is particularly true in immunology, where the orchestration of cell migration, cell–cell interactions and intracellular signalling events in multiple distinct anatomical compartments within secondary lymphoid organs is fundamental for achieving an effective immune response. Until recently, access to this powerful tool has been limited to a handful of laboratories with the necessary skills and resources to either custom‐build or purchase a commercial two‐photon microscope. However, with the entry of more commercial vendors into the market and availability of turnkey solutions, two‐photon microscopy is now becoming more accessible. Here, we discuss the practical aspects of establishing a basic intravital two‐photon microscopy facility specifically for immunological research and how recent advances in ultrafast lasers, non‐linear optics and localized photochemistry can be used to build more sophisticated instruments to support applications such as photoactivation and photobleaching, spectral fingerprinting and automated single‐cell tracking. In addition, we discuss the next generation of fluorescent dyes and reporter mice and some of the microsurgical principles required to expose the relevant biology to interrogation by two‐photon excitation.
The cellular mechanism by which complementary Id+ and anti‐Id antibodies communicate: T cells integrated into idiotypic regulation
Authors: Jacobsen Johanne T , Lunde Elin , Sundvold‐Gjerstad Vibeke , Munthe Ludvig A , Bogen Bjarne
Published: January 2010

The V region antigenic determinants (idiotopes (Ids)) of antibodies (Abs) have been suggested to be involved in regulating the immune system. Certain diseases such as diabetes mellitus have recently been associated with a disequilibrium between Id+ and anti‐Id Abs. However, it is unknown how Abs carrying complementary idiotypes (that is, Id+ and anti‐Id Abs) regulate each other at the level of B and T cells. In this study, we show that B lymphoma cells genetically equipped with anti‐Id BCR V regions receive a signal when exposed to Id+Ig. Moreover, they become × 104 more efficient at presenting exogenous Id+ Ab to CD4+ T cells in vitro. Activated Id‐specific T cells in turn regulated the Id‐specific B lymphoma cells. Similar results were obtained in vivo in a surrogate model in which an Id‐peptide was incorporated genetically into the C‐region of a recombinant Ab that targeted IgD on B cells. The findings suggest that conventional T–B collaboration can explain communication between complementary Id+ and anti‐Id Ab at the cellular level. A model is suggested that integrates present and previous data on B‐cell regulation by Id‐specific T cells.
A new look at the pathogenesis of asthma
Authors: Holgate Stephen T. , Arshad Hasan S. , Roberts Graham C. , Howarth Peter H. , Thurner Philipp , Davies Donna E.
Published: January 2010

Asthma is an inflammatory disorder of the conducting airways that has strong association with allergic sensitization. The disease is characterized by a polarized Th-2 (T-helper-2)-type T-cell response, but in general targeting this component of the disease with selective therapies has been disappointing and most therapy still relies on bronchodilators and corticosteroids rather than treating underlying disease mechanisms. With the disappointing outcomes of targeting individual Th-2 cytokines or manipulating T-cells, the time has come to re-evaluate the direction of research in this disease. A case is made that asthma has its origins in the airways themselves involving defective structural and functional behaviour of the epithelium in relation to environmental insults. Specifically, a defect in barrier function and an impaired innate immune response to viral infection may provide the substrate upon which allergic sensitization takes place. Once sensitized, the repeated allergen exposure will lead to disease persistence. These mechanisms could also be used to explain airway wall remodelling and the susceptibility of the asthmatic lung to exacerbations provoked by respiratory viruses, air pollution episodes and exposure to biologically active allergens. Variable activation of this epithelial–mesenchymal trophic unit could also lead to the emergence of different asthma phenotypes and a more targeted approach to the treatment of these. It also raises the possibility of developing treatments that increase the lung's resistance to the inhaled environment rather than concentrating all efforts on trying to suppress inflammation once it has become established.
Regulation of invasive growth: similar epigenetic mechanisms underpin tumour progression and implantation in human pregnancy
Authors: Perry Jo K. , Lins Roger J. , Lobie Peter E. , Mitchell Murray D.
Published: January 2010

Malignant and trophoblastic cells share the capacity to migrate and invade surrounding tissues; however, trophoblast invasion during implantation is tightly regulated, whereas that associated with tumour progression is not. It is likely that similar mechanisms underlie the dynamic regulation of cell invasion and migration in both cases, and that these are based on epigenetic processes. This hypothesis is supported by recent results demonstrating that expression of the intercellular adhesion molecule E-cadherin, deregulation of which is associated with increased cell motility and invasive potential in cancer, is under epigenetic control in trophoblast cell lines. Further elucidation of the epigenetic pathways shared by trophoblasts and malignant cells is likely to lead to the identification of common diagnostic approaches for the early identification both of cancer and pathological pregnancies involving aberrant trophoblast invasion.
Photonic band-gap maps for different two dimensionally periodic photonic crystal structures
Authors: Dyogtyev A. V. , Sukhoivanov I. A. , De La Rue R. M.
Published: January 2010

In this paper, the photonic band-gap (PBG) maps of fundamental photonic crystal (PhC) lattices are presented, and discussed. Two fundamental types of lattice: square and hexagonal (triangular, graphite or honeycomb and kagome) with circular, square, and hexagonal hole shapes are considered. Because they show the largest area gap map and because of the relative ease of fabrication of circular holes, it can be asserted that square and triangular lattices of circular holes offer the best choice of two dimensionally periodic photonic crystal (PhC) structure. Graphite and kagome lattices of circular holes in GaAs also show large area gap maps (and the largest gap map is for the second or third higher PBG region). So graphite and kagome lattices are also relevant for exploitation in PhC devices. At the scale required, fabrication process limitations are a significant problem for the realization of hole shapes other than circular.
On the Sn loss from thin films of the material system Cu–Zn–Sn–S in high vacuum
Authors: Weber A. , Mainz R. , Schock H. W.
Published: January 2010

In this paper the Sn loss from thin films of the material system Cu–Zn–Sn–S and the subsystems Cu–Sn–S and Sn–S in high vacuum is investigated. A combination of in situ x-ray diffractometry and x-ray fluorescence (XRF) at a synchrotron light source allowed identifying phases, which tend to decompose and evaporate a Sn-containing compound. On the basis of the XRF results a quantification of the Sn loss from the films during annealing experiments is presented. It can be shown that the evaporation rate from the different phases decreases according to the order SnS→Cu2SnS3→Cu4SnS4→Cu2ZnSnS4. The phase SnS is assigned as the evaporating compound. The influence of an additional inert gas component on the Sn loss and on the formation of Cu2ZnSnS4 thin films is discussed.
The optical gain and radiative current density of GaInNAs/GaAs/AlGaAs separate confinement heterostructure quantum well lasers
Authors: Wu Shudong , Cao Yongge , Tomić Stanko , Ishikawa Fumitaro
Published: January 2010

The optical gain and radiative current density of GaInNAs/GaAs/AlGaAs separate confinement heterostructure quantum well (QW) lasers with an emission wavelength of 1.3 μm have been theoretically investigated. The effect of carrier leakage from the GaInNAs QW to the GaAs waveguide layer is studied, and its influence on the optical gain and radiative current density is identified. The hole filling caused by an injected carrier has a strong impact on the optical gain and radiative current density, while the effect of electron filling is negligible, reflecting the smaller band-gap discontinuity in the valence band than in the conduction band. Hole occupation in the waveguide layer decreases the optical gain, and increases the radiative and threshold current densities of the laser. Our calculated threshold current density (659.6 A/cm2) at T=300 K is in good agreement with the experimental value (650.9 A/cm2) reported in literature [R. Fehse et al., IEEE J. Sel. Top. Quantum Electron. 8, 801 (2002)].
Accurate evaporation rates of pure and doped water clusters in vacuum: A statistico-dynamical approach
Authors: Calvo F. , Douady J. , Spiegelman F.
Published: January 2010

Unimolecular evaporation of selected pure (H2O)n and heterogeneous (H2O)n−1X+ water clusters containing a single hydronium or ammonium impurity is investigated in the framework of phase space theory (PST) in its orbiting transition state version. Using the many-body polarizable Kozack–Jordan potential and its extensions for X+=H3O+ and NH4+, the thermal evaporation of clusters containing 21 and 50 molecules is simulated at several total energies. Numerous molecular dynamics (MD) trajectories at high internal energies provide estimates of the decay rate constant, as well as the kinetic energy and angular momentum released upon dissociation. Additional Monte Carlo simulations are carried out to determine the anharmonic densities of vibrational states, which combined with suitable forms for the rotational densities of states provide expressions for the energy-resolved differential rates. Successful comparison between the MD results and the independent predictions of PST for the distributions of kinetic energy and angular momentum released shows that the latter statistical approach is quantitative. Using MD data as a reference, the absolute evaporation rates are calculated from PST over broad energy and temperature ranges. Based on these results, the presence of an ionic impurity is generally found to decrease the rate, however the effect is much more significant in the 21-molecule clusters. Our calculations also suggest that due to backbendings in the microcanonical densities of states the variations of the evaporation rates may not be strictly increasing with energy or temperature.
Fully inverted single-digit nanometer domains in ferroelectric films
Authors: Tayebi Noureddine , Narui Yoshie , Franklin Nathan , Collier C. Patrick , Giapis Konstantinos P. , Nishi Yoshio , Zhang Yuegang
Published: January 2010

Achieving stable single-digit nanometer inverted domains in ferroelectric thin films is a fundamental issue that has remained a bottleneck for the development of ultrahigh density (>1 Tbit/in.2) probe-based memory devices using ferroelectric media. Here, we demonstrate that such domains remain stable only if they are fully inverted through the entire ferroelectric film thickness, which is dependent on a critical ratio of electrode size to the film thickness. This understanding enables the formation of stable domains as small as 4 nm in diameter, corresponding to 10 unit cells in size. Such domain size corresponds to 40 Tbit/in.2 data storage densities.
Rotational excitation of CN(X Σ2+) by He: Theory and comparison with experiments
Authors: Lique François , Spielfiedel Annie , Feautrier Nicole , Schneider Ioan F. , Kłos Jacek , Alexander Millard H.
Published: January 2010

Rotational excitation of the CN(X Σ2+) molecule with He is investigated. We present a new two-dimensional potential energy surface (PES) for the He–CN system, calculated at an internuclear CN distance frozen at its experimental equilibrium distance. This PES was obtained using an open-shell, coupled-cluster method including all single and double excitations, as well as the perturbative contributions of connected triple excitations [RCCSD(T)]. Bond functions were placed at mid-distance between the center of mass of the CN molecule and He atom for a better description of the van der Waals interaction. State-to-state collisional excitation cross sections of the fine-structure levels of CN by He are calculated for energies up to 2500 cm−1, which yield after thermal averaging, rate coefficients up to 350 K. The exact spin splitting of the energy levels is taken into account. The propensity rules between fine-structure levels are studied, and it is shown that the rate constants for Δj=ΔN transitions are much larger than those for Δj≠ΔN transitions, as expected from theoretical considerations. Our calculated rate coefficients are compared to experimental results at 295 K of Fei et al. [J. Chem. Phys. 100, 1190 (1994)]. The excellent agreement confirms the accuracy of the PESs and of the scattering calculations.
Guided ion beam and theoretical studies of the reaction of Ag+ with CS2: Gas-phase thermochemistry of AgS+ and AgCS+ and insight into spin-forbidden reactions
Authors: Armentrout P. B. , Kretzschmar Ilona
Published: January 2010

The gas-phase reactivity of the atomic transition metal cation, Ag+, with CS2 is investigated using guided-ion beam mass spectrometry. Endothermic reactions forming AgS+ and AgCS+ are observed but are quite inefficient. This observation is largely attributed to the stability of the closed shell Ag+(S1,4d10) ground state, but is also influenced by the fact that the reactions producing ground state AgS+ and AgCS+ products are both spin forbidden. Analysis of the kinetic energy dependence of the cross sections for formation of these two products yields the 0 K bond energies of D0(Ag+S)=1.40±0.12 eV and D0(Ag+CS)=1.98±0.14 eV. Quantum chemical calculations are used to investigate the electronic structure of the two product ions as well as the potential energy surfaces for reaction. The primary mechanism involves oxidative addition of a CS bond to the metal cation followed by simple AgS or AgCS bond cleavage. Crossing points between the singlet and triplet surfaces are located near the transition states for bond activation. Comparison with analogous work on other late second-row transition metal cations indicates that the location of the crossing points bears directly on the efficiency of these spin-forbidden processes.
The interaction between electrolyte and surfaces decorated with charged groups: A molecular dynamics simulation study
Authors: Calero Carles , Faraudo Jordi
Published: January 2010

In this paper, we perform molecular dynamics simulations of an interface containing charged functional groups of different valences in contact with 2:1 ionic solution. We take into account both the finite sizes of the ions in solution and the functional groups but we neglect the structural details of the solvent (primitive model). We show that the distribution of ions and the electrostatic properties of the system depend strongly on the valence of the interfacial charged groups. In the case of surfaces containing well-separated charged interfacial groups, we observe counterion binding at these groups induced by electrostatic interactions. A detailed analysis of the potential of mean force between interfacial charged groups and ions reveals significant features not anticipated by present theories of electrolytes near interfaces. Overall, our results show that, in primitive models of the ion-interface interaction, not only the ionic size and valence are important but the size and valence of the interfacial charged groups also have a significant impact.
Understanding conductivity anomalies in CuI-based delafossite transparent conducting oxides: Theoretical insights
Authors: Scanlon David O. , Godinho Kate G. , Morgan Benjamin J. , Watson Graeme W.
Published: January 2010

The CuI-based delafossite structure, CuIMIIIO2, can accommodate a wide range of rare earth and transition metal cations on the MIII site. Substitutional doping of divalent ions for these trivalent metals is known to produce higher p-type conductivity than that occurring in the undoped materials. However, an explanation of the conductivity anomalies observed in these p-type materials, as the trivalent metal is varied, is still lacking. In this article, we examine the electronic structure of CuIMIIIO2 (MIII=Al,Cr,Sc,Y) using density functional theory corrected for on-site Coulomb interactions in strongly correlated systems (GGA+U) and discuss the unusual experimental trends. The importance of covalent interactions between the MIII cation and oxygen for improving conductivity in the delafossite structure is highlighted, with the covalency trends found to perfectly match the conductivity trends. We also show that calculating the natural band offsets and the effective masses of the valence band maxima is not an ideal method to classify the conduction properties of these ternary materials.
Metal-insulator transition in epitaxial V1−xWxO2(≤x≤0.33) thin films
Authors: Shibuya Keisuke , Kawasaki Masashi , Tokura Yoshinori
Published: January 2010

We have fabricated epitaxial V1−xWxO2(0≤x≤0.33) thin films on TiO2 (001) substrates. The metal-insulator transition temperature of VO2 is systematically reduced by W doping, and eventually a metallic ground state is realized at 0.08≤x≤0.09. Tiny resistivity upturn around 50 K observed for these films suggests an electronic phase separation between a majority metallic matrix and minority insulating puddles. With further increasing x above 0.095, another insulating phase appears while increasing the metal-insulator transition temperature. The elucidated phase diagram gives basic knowledge for devices based on Mott transition.
Large amplitude dust acoustic solitary waves and double layers in positively charged warm dusty plasma with nonthermal electrons
Authors: Das Animesh , Bandyopadhyay Anup , Das K. P.
Published: January 2010

Large amplitude dust acoustic solitary waves and double layers in a nonthermal plasma consisting of positively charged dust grains, nonthermal electrons, and isothermal ions including the effect of dust temperature have been studied using the Sagdeev potential technique by a computational scheme. The effect of different parameters on the nature of existence of solitary waves and double layers has been investigated to delimit their compositional parameter space. The physics corresponding to the computational result has been pointed out.
Effect of dielectric thin films on reflection properties of metal hole arrays
Authors: Miyamaru Fumiaki , Sasagawa Yuki , Takeda Mitsuo Wada
Published: January 2010

We study the effect of a dielectric film attached to the surface of a metal hole array (MHA) on the reflection spectrum in the terahertz (THz) region. The frequency of the reflection dip, attributed to the excitation of surface waves in the vicinity of the MHA surface, shifts to lower frequencies with increasing dielectric film thickness. This resonant characteristic of MHAs can be applied to highly sensitive THz sensing for samples attached to the MHA surface. We also investigate the dependence of the reflection spectrum on the MHA’s thickness and the side to which the dielectric film is attached.
Pacific decadal oscillation hindcasts relevant to near-term climate prediction
Authors: Mochizuki Takashi , Ishii Masayoshi , Kimoto Masahide , Chikamoto Yoshimitsu , Watanabe Masahiro , Nozawa Toru , Sakamoto Takashi T. , Shiogama Hideo , Awaji Toshiyuki , Sugiura Nozomi , Toyoda Takahiro , Yasunaka Sayaka , Tatebe Hiroaki , Mori Masato
Published: January 2010

Decadal-scale climate variations over the Pacific Ocean and its surroundings are strongly related to the so-called Pacific decadal oscillation (PDO) which is coherent with wintertime climate over North America and Asian monsoon, and have important impacts on marine ecosystems and fisheries. In a near-term climate prediction covering the period up to 2030, we require knowledge of the future state of internal variations in the climate system such as the PDO as well as the global warming signal. We perform sets of ensemble hindcast and forecast experiments using a coupled atmosphere-ocean climate model to examine the predictability of internal variations on decadal timescales, in addition to the response to external forcing due to changes in concentrations of greenhouse gases and aerosols, volcanic activity, and solar cycle variations. Our results highlight that an initialization of the upper-ocean state using historical observations is effective for successful hindcasts of the PDO and has a great impact on future predictions. Ensemble hindcasts for the 20th century demonstrate a predictive skill in the upper-ocean temperature over almost a decade, particularly around the Kuroshio-Oyashio extension (KOE) and subtropical oceanic frontal regions where the PDO signals are observed strongest. A negative tendency of the predicted PDO phase in the coming decade will enhance the rising trend in surface air-temperature (SAT) over east Asia and over the KOE region, and suppress it along the west coasts of North and South America and over the equatorial Pacific. This suppression will contribute to a slowing down of the global-mean SAT rise.
Tracking of Arctic ternsSterna paradisaeareveals longest animal migration
Authors: Egevang Carsten , Stenhouse Iain J. , Phillips Richard A. , Petersen Aevar , Fox James W. , Silk Janet R. D.
Published: January 2010

The study of long-distance migration provides insights into the habits and performance of organisms at the limit of their physical abilities. The Arctic ternSterna paradisaeais the epitome of such behavior; despite its small size (<125 g), banding recoveries and at-sea surveys suggest that its annual migration from boreal and high Arctic breeding grounds to the Southern Ocean may be the longest seasonal movement of any animal. Our tracking of 11 Arctic terns fitted with miniature (1.4-g) geolocators revealed that these birds do indeed travel huge distances (more than 80,000 km annually for some individuals). As well as confirming the location of the main wintering region, we also identified a previously unknown oceanic stopover area in the North Atlantic used by birds from at least two breeding populations (from Greenland and Iceland). Although birds from the same colony took one of two alternative southbound migration routes following the African or South American coast, all returned on a broadly similar, sigmoidal trajectory, crossing from east to west in the Atlantic in the region of the equatorial Intertropical Convergence Zone. Arctic terns clearly target regions of high marine productivity both as stopover and wintering areas, and exploit prevailing global wind systems to reduce flight costs on long-distance commutes.
UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination
Authors: An Jee Young , Kim Eun-A. , Jiang Yonghua , Zakrzewska Adriana , Kim Dong Eun , Lee Min Jae , Mook-Jung Inhee , Zhang Yi , Kwon Yong Tae
Published: January 2010

Ubiquitination of histones provides an important mechanism regulating chromatin remodeling and gene expression. Recent studies have revealed ubiquitin ligases involved in histone ubiquitination, yet the responsible enzymes and the function of histone ubiquitination in spermatogenesis remain unclear. We have previously shown that mice lacking the ubiquitin ligase UBR2, one of the recognition E3 components of the N-end rule proteolytic pathway, are infertile associated with meiotic arrest at prophase I. We here show that UBR2 localizes to meiotic chromatin regions, including unsynapsed axial elements linked to chromatin inactivation, and mediates transcriptional silencing via the ubiquitination of histone H2A. UBR2 interacts with the ubiquitin conjugating enzyme HR6B and its substrate H2A and promotes the HR6B–H2A interaction and the HR6B-to-H2A transfer of ubiquitin. UBR2 and ubiquitinated H2A (uH2A) spatiotemporally mark meiotic chromatin regions subject to transcriptional silencing, and UBR2-deficient spermatocytes fail to induce the ubiquitination of H2A during meiosis. UBR2-deficient spermatocytes are profoundly impaired in chromosome-wide transcriptional silencing of genes linked to unsynapsed axes of the X and Y chromosomes. Our findings suggest that insufficiency in UBR2-dependent histone ubiquitination triggers a pachytene checkpoint system, providing a new insight into chromatin remodeling and gene expression regulation.
Lipid-like materials for low-dose, in vivo gene silencing
Authors: Love Kevin T. , Mahon Kerry P. , Levins Christopher G. , Whitehead Kathryn A. , Querbes William , Dorkin J. Robert , Qin June , Cantley William , Qin Liu Liang , Racie Timothy , Frank-Kamenetsky Maria , Yip Ka Ning , Alvarez Rene , Sah Dinah W. Y. , de Fougerolles Antonin , Fitzgerald Kevin , Koteliansky Victor , Akinc Akin , Langer Robert , Anderson Daniel G.
Published: January 2010

Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.
Homeotic effects, somitogenesis and the evolution of vertebral numbers in recent and fossil amniotes
Authors: Müller Johannes , Scheyer Torsten M. , Head Jason J. , Barrett Paul M. , Werneburg Ingmar , Ericson Per G. P. , Pol Diego , Sánchez-Villagra Marcelo R.
Published: January 2010

The development of distinct regions in the amniote vertebral column results from somite formation andHoxgene expression, with the adult morphology displaying remarkable variation among lineages. Mammalian regionalization is reportedly very conservative or even constrained, but there has been no study investigating vertebral count variation across Amniota as a whole, undermining attempts to understand the phylogenetic, ecological, and developmental factors affecting vertebral column variation. Here, we show that the mammalian (synapsid) and reptilian lineages show early in their evolutionary histories clear divergences in axial developmental plasticity, in terms of both regionalization and meristic change, with basal synapsids sharing the conserved axial configuration of crown mammals, and basal reptiles demonstrating the plasticity of extant taxa. We conducted a comprehensive survey of presacral vertebral counts across 436 recent and extinct amniote taxa. Vertebral counts were mapped onto a generalized amniote phylogeny as well as individual ingroup trees, and ancestral states were reconstructed by using squared-change parsimony. We also calculated the relationship between presacral and cervical numbers to infer the relative influence of homeotic effects and meristic changes and found no correlation between somitogenesis andHox-mediated regionalization. Although conservatism in presacral numbers characterized early synapsid lineages, in some cases reptiles and synapsids exhibit the same developmental innovations in response to similar selective pressures. Conversely, increases in body mass are not coupled with meristic or homeotic changes, but mostly occur in concert with postembryonic somatic growth. Our study highlights the importance of fossils in large-scale investigations of evolutionary developmental processes.
Thioredoxin suppresses microscopic hopping of T7 DNA polymerase on duplex DNA
Authors: Etson Candice M. , Hamdan Samir M. , Richardson Charles C. , van Oijen Antoine M.
Published: January 2010

The DNA polymerases involved in DNA replication achieve high processivity of nucleotide incorporation by forming a complex with processivity factors. A model system for replicative DNA polymerases, the bacteriophage T7 DNA polymerase (gp5), encoded by gene 5, forms a tight, 1∶1 complex with
Escherichia coli
thioredoxin. By a mechanism that is not fully understood, thioredoxin acts as a processivity factor and converts gp5 from a distributive polymerase into a highly processive one. We use a single-molecule imaging approach to visualize the interaction of fluorescently labeled T7 DNA polymerase with double-stranded DNA. We have observed T7 gp5, both with and without thioredoxin, binding nonspecifically to double-stranded DNA and diffusing along the duplex. The gp5/thioredoxin complex remains tightly bound to the DNA while diffusing, whereas gp5 without thioredoxin undergoes frequent dissociation from and rebinding to the DNA. These observations suggest that thioredoxin increases the processivity of T7 DNA polymerase by suppressing microscopic hopping on and off the DNA and keeping the complex tightly bound to the duplex.
The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics
Authors: Auerbach Tamar , Mermershtain Inbal , Davidovich Chen , Bashan Anat , Belousoff Matthew , Wekselman Itai , Zimmerman Ella , Xiong Liqun , Klepacki Dorota , Arakawa Kenji , Kinashi Haruyasu , Mankin Alexander S. , Yonath Ada
Published: January 2010

Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced byStreptomyces rocheibinds at the peptidyl transferase center of the eubacterial large ribosomal subunit. Biochemical and functional studies verified this finding and showed interference with peptide bond formation. Chemical probing indicated that the macrolide lankamycin, a second antibiotic produced by the same species, binds at a neighboring site, at the ribosome exit tunnel. These two antibiotics can bind to the ribosome simultaneously and display synergy in inhibiting bacterial growth. The binding site of lankacidin and lankamycin partially overlap with the binding site of another pair of synergistic antibiotics, the streptogramins. Thus, at least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome. These results underscore the importance of the corresponding ribosomal sites for development of clinically relevant synergistic antibiotics and demonstrate the utility of structural analysis for providing new directions for drug discovery.
Text and Hypertext
Authors: Defays Jean-Marc
Published: January 2010

Abstract: In this article, we begin by specifying a definition of “text” that will fit our present purpose; then, we will attempt to contribute, in the light of the demands involved in its treatment and the difficulties involved in learning it, to an explanation of its complexity, particularly its double construction, which is both linear and reticulated. In order to do that, we will recall the conditions of its progression along the linear axis, where the reader establishes semantic, syntactic, thematic, logical and argumentative connections between words and propositions that follow each other; and the conditions of its organic composition, which allows the reader to incorporate the words, phrases and paragraphs so constituted into a global structure (sequences, parts of the text, its general structure) as a function of textual models he or she may have experienced. But we insist upon the fact that, in order for these two types of organisation – linear sequence and hierarchical inclusion – to constitute a text, it is necessary for them to be inscribed in an enunciative context and a communicative project that give the text its origin, its finality, and its function. In view of the development of the use of New Information and Communication Technologies, we will ask ourselves to what extent these new supports, in terms of their nature as well as their modes of functionality, require or lead toward new linguistic and cognitive strategies for treatment of text, especially in learners, children and/or non-native speakers, and how these learners can perceive and construct the local and global coherence (semantic, logical, argumentative…) of a document presented in a hypertextual form.
Viral adaptation to immune selection pressure by HLA class I–restricted CTL responses targeting epitopes in HIV frameshift sequences
Authors: Berger Christoph T. , Carlson Jonathan M. , Brumme Chanson J. , Hartman Kari L. , Brumme Zabrina L. , Henry Leah M. , Rosato Pamela C. , Piechocka-Trocha Alicja , Brockman Mark A. , Harrigan P. Richard , Heckerman David , Kaufmann Daniel E. , Brander Christian
Published: January 2010

CD8+ cytotoxic T lymphocyte (CTL)–mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03–restricted +2 frame–encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level.
Experimental and computational study on the phase stability of Al-containing cubic transition metal nitrides
Authors: Rovere Florian , Music Denis , Ershov Sergey , Baben Moritz to , Fuss Hans-Gerd , Mayrhofer Paul H , Schneider Jochen M
Published: January 2010

The phase stability of Al-containing cubic transition metal (TM) nitrides, where Al substitutes for TM (i.e. TM1−x
Al
x
N), is studied as a function of the TM valence electron concentration (VEC). X-ray diffraction and thermal analyses data of magnetron sputtered Ti1−x
Al
x
N, V1−x
Al
x
N and Cr1−x
Al
x
N films indicate increasing phase stability of cubic TM1−x
Al
x
N at larger Al contents and higher temperatures with increasing TM VEC. These experimental findings can be understood based on first principle investigations of ternary cubic TM1−x
Al
x
N with TM = Sc, Ti, V, Cr, Y, Zr and Nb where the TM VEC and the lattice strain are systematically varied.

However, our experimental data indicate that, in addition to the decomposition energetics (cubic TM1−x
Al
x
N → cubic TMN + hexagonal AlN), future stability models have to include nitrogen release as one of the mechanisms that critically determine the overall phase stability of TM1−x
Al
x
N.
The necessity for response indicators in fisheries management
Authors: Piet G. J. , van Overzee H. M. J. , Pastoors M. A.
Published: January 2010

Piet, G. J., van Overzee, H. M. J., and Pastoors, M. A. 2010. The necessity for response indicators in fisheries management. – ICES Journal of Marine Science, 67: 559–566. Results are used from traditional fisheries management to explore two potential response indicators: (i) the extent to which scientific advice is incorporated in decision-making, and (ii) the compliance of industry and the relevant authorities to these decisions. Based on the most comprehensive set of data on the management process of 125 stocks for which ICES provided advice over the period 1987–2006, we explored these response indicators and found that for just 8% of the stocks, the official total allowable catch (TAC) equalled the scientific advice, and that in recent years the official TAC overshot scientific advice by >50%. Compliance levels appear to be reflected in the percentage of stocks for which landings exceeded the official TAC, decreasing from ∼8 to 2%. However, because the TAC appears not to be limiting, compliance may not be the most appropriate indicator. Without transparent decision-making that takes scientific advice into account, or the compliance of industry as reflected by the type of response indicators explored, the effectiveness of new developments in fisheries management, such as the application of an ecosystem approach, will be compromised, as has been the case with conventional fisheries management measures.
Toll‐like receptor 9 expression in breast and ovarian cancer is associated with poorly differentiated tumors
Authors: Berger Regina , Fiegl Heidi , Goebel Georg , Obexer Petra , Ausserlechner Michael , Doppler Wolfgang , Hauser‐Kronberger Cornelia , Reitsamer Roland , Egle Daniel , Reimer Daniel , Müller‐Holzner Elisabeth , Jones Allison , Widschwendter Martin
Published: January 2010

Toll‐like receptor 9 (TLR9) activates the innate immune response when exposed to non‐methylated CpG‐DNA. TLR9 was recently shown to be expressed by cancer cells which have been previously characterized by global hypomethylation. We set out to examine the expression and molecular activity of TLR9 in breast and ovarian cancer cells. Firstly, we confirmed higher levels of hypomethylated DNA in the serum of patients with metastatic breast cancer (n = 18) versus age‐matched tumor‐free women (n = 18). In breast cancer cell lines and tissues, TLR9 mRNA expression was associated with estrogen‐receptor (ER) status (n = 124, P = 0.005). Expression also correlated with increasing tumor grade in both breast (P = 0.03) and ovarian cancer specimens (n = 138, P = 0.04). Immunohistochemical analysis of formalin‐fixed paraffin‐embedded (FFPE) breast cancer tissues revealed higher TLR9 protein expression in hormone‐receptor (HR)‐negative specimens (n = 116, P < 0.001). Using an in vitro scratch assay, we observed that cell lines transfected to overexpress TLR9 demonstrated increased cellular migration when stimulated with CpG‐DNA. When assessing the molecular activity of TLR9 in breast cancer, we found a strong positive correlation of nuclear factor‐kappa B (NF‐κB) activity with TLR9 mRNA expression (correlation coefficient r = 0.7, P < 0.001). Finally, immunofluorescence analysis of BT‐20 and Hs578T breast cancer cell lines showed partial colocalizations of CpG‐DNA with TLR9, which diminished when the cells were exposed to methylated CpG‐DNA (mCpG‐DNA) or control GpC‐DNA. In summary we demonstrate that TLR9 expression is associated with poor differentiation in breast and ovarian cancer specimens, and that TLR9 overexpression and stimulation with hypomethylated DNA augments the migratory capacity of cancer cell lines.

(Cancer Sci 2010; 101: 1059–1066)
Up‐regulation of pro‐inflammatory genes as adaptation to hypoxia in MCF‐7 cells and in human mammary invasive carcinoma microenvironment
Authors: Tafani Marco , Russo Andrea , Di Vito Maura , Sale Patrizio , Pellegrini Laura , Schito Luana , Gentileschi Stefano , Bracaglia Roberto , Marandino Ferdinando , Garaci Enrico , Russo Matteo A
Published: January 2010

The role of tumor cells in synthesizing pro‐inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF‐7 human mammary adenocarcinoma cell line induced activation of hypoxia‐inducible factor 1α (HIF‐1α) and nuclear factor‐kappa B (NF‐κB). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up‐regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute‐phase protein pentraxin‐3 (PTX3). Hypoxia also stimulated chemokine (C‐X‐C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal‐derived factor‐1α (SDF‐1α) increased invasion and migration of hypoxic MCF‐7 cells. Inhibition of HIF‐1α by chetomin and NF‐κB by parthenolide reduced mRNA and protein expression of the studied molecules and prevented invasion of hypoxic MCF‐7 cells. Moreover, solid invasive mammary tumor microenvironment was analyzed after laser‐capture microdissection (LCMD) comparing tumor versus host normal tissue. Nuclear translocation of HIF‐1α and NF‐κB and up‐regulation of IR, CXCR4, estrogen receptor α (ERα), and epithelial growth factor receptor (EGFR) was observed in tumor but not in host normal tissue in the absence of a local inflammatory leukocyte infiltrate. We conclude that under hypoxic conditions MCF‐7 cells acquire a pro‐inflammatory phenotype, and that solid human mammary carcinoma evidenced a similar activation of HIF‐1α, NF‐κB, and IR genes in malignant tumor cells as compared to the normal host tissues. We suggest a role for IR activation in the malignant progression of transformed cells.

(Cancer Sci 2010; 101: 1014–1023)
Pigpen, a nuclear coiled body component protein, is involved in angiogenesis
Authors: Yoshida Tomoko , Sato Yasufumi , Morita Ikuo , Abe Mayumi
Published: January 2010

We previously reported that puromycin‐insensitive leucyl‐specific aminopeptidase (PILSAP) is required for vascular endothelial growth factor (VEGF)‐ and basic fibroblast growth factor (bFGF)‐induced angiogenesis and for endothelial differentiation from embryonic stem (ES) cells via the aminopeptidase activity of PILSAP. In this study, we searched for molecules that function during angiogenesis with PILSAP. We performed proteome analysis of nuclear extracts from embryoid bodies (EBs) made from ES cells transfected with mutant PILSAP lacking aminopeptidase activity and mock EBs. We identified pigpen, a 67‐kDa nuclear coiled body component protein. Immunoprecipitation and western blotting demonstrated the binding of PILSAP and pigpen in endothelial cells (ECs), and this interaction was enhanced by VEGF and bFGF. Pigpen was reported to be expressed in actively growing ECs such as those in embryos and tumors. However, whether Pigpen is involved in angiogenesis is not known. Therefore, we examined the effect of pigpen on angiogenesis by silencing pigpen with siRNA (siPigpen). Compared with scrambled RNA (scrPigpen), transfection of siPigpen into mouse ECs inhibited proliferation, migration, and network formation. These results were confirmed with other two siRNAs. Moreover, siPigpen suppressed bFGF‐induced angiogenesis in a Matrigel plug assay, and injection of siPigpen into Lewis lung carcinoma cell tumors implanted subcutaneously into 5‐week‐old C57/BL male mice prevented tumor growth and tumor angiogenesis. These data indicate that Pigpen is involved in angiogenesis and that pigpen may be a target for blocking tumor angiogenesis.

(Cancer Sci 2010; 101: 1170–1176)
The arms race between tomato and Fusarium oxysporum
Authors: TAKKEN FRANK , REP MARTIJN
Published: January 2010

The interaction between tomato and Fusarium oxysporum f. sp. lycopersici has become a model system for the study of the molecular basis of disease resistance and susceptibility. Gene‐for‐gene interactions in this system have provided the basis for the development of tomato cultivars resistant to Fusarium wilt disease. Over the last 6 years, new insights into the molecular basis of these gene‐for‐gene interactions have been obtained. Highlights are the identification of three avirulence genes in F. oxysporum f. sp. lycopersici and the development of a molecular switch model for I‐2, a nucleotide‐binding and leucine‐rich repeat‐type resistance protein which mediates the recognition of the Avr2 protein. We summarize these findings here and present possible scenarios for the ongoing molecular arms race between tomato and F. oxysporum f. sp. lycopersici in both nature and agriculture.
Changes in quality of life and sexual health are associated with low‐dose peginterferon therapy and disease progression in patients with chronic hepatitis C
Authors: SNOW K. K. , BONKOVSKY H. L. , FONTANA R. J. , KIM H.‐Y. , STERLING R. K. , DI BISCEGLIE A. M. , MORGAN T. R. , DIENSTAG J. L. , GHANY M. G. ,   The HALT‐C Trial Group
Published: January 2010

Aliment Pharmacol Ther 31, 719–734

Background  Primary analysis of the Hepatitis C Antiviral Long‐Term Treatment against Cirrhosis (HALT‐C) Trial showed long‐term peginterferon therapy did not reduce complications in patients with chronic hepatitis C and advanced fibrosis or cirrhosis.

Aim  To assess the effects of long‐term peginterferon therapy and disease progression on health‐related quality of life (HRQOL), symptoms and sexual health in HALT‐C patients.

Methods  A total of 517 HALT‐C patients received peginterferon alfa‐2a (90 μg/week); 532 received no additional treatment for 3.5 years. Patients were followed up for outcomes of death, hepatocellular carcinoma and hepatic decompensation. Sexual health, SF‐36 scores and symptoms were serially assessed by repeated‐measures analyses of covariance.

Results  Patients with cirrhosis (n = 427) reported lower general well‐being and more fatigue (P < 0.001) than patients with fibrosis (n = 622). Physical scores declined significantly over time, independent of treatment, and patients with cirrhosis reported lower scores. Vitality scores were lower in those with cirrhosis, and treated patients experienced a greater decline over time than untreated patients; HRQOL rebounded after treatment ended. Patients with a clinical outcome had significantly greater declines in all SF‐36 and symptom scores. Among men, Sexual Health scores were significantly worse in treated patients and in those with a clinical outcome.

Conclusion  Clinical progression of chronic hepatitis C and maintenance peginterferon therapy led to worsening of symptoms, HRQOL and, in men, sexual health in a large patient cohort followed up over 4 years (NCT00006164).