bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment and Maintenance of the Innate Antiviral Response to West Nile Virus Involves both RIG-I and MDA5 Signaling through IPS-1
Authors: Fredericksen Brenda L. , Keller Brian C. , Fornek Jamie , Katze Michael G. , Gale Michael
Published: November 2007

RIG-I and MDA5, two related pathogen recognition receptors (PRRs), are known to be required for sensing various RNA viruses. Here we investigated the roles that RIG-I and MDA5 play in eliciting the antiviral response to West Nile virus (WNV). Functional genomics analysis of WNV-infected fibroblasts from wild-type mice and RIG-I null mice revealed that the normal antiviral response to this virus occurs in two distinct waves. The initial response to WNV resulted in the expression of interferon (IFN) regulatory factor 3 target genes and IFN-stimulated genes, including several subtypes of alpha IFN. Subsequently, a second phase of IFN-dependent antiviral gene expression occurred very late in infection. In cells lacking RIG-I, both the initial and the secondary responses to WNV were delayed, indicating that RIG-I plays a critical role in initiating innate immunity against WNV. However, another PRR(s) was able to trigger a response to WNV in the absence of RIG-I. Disruption of both MDA5 and RIG-I pathways abrogated activation of the antiviral response to WNV, suggesting that MDA5 is involved in the host's defense against WNV infection. In addition, ablation of the function of IPS-1, an essential RIG-I and MDA5 adaptor molecule, completely disabled the innate antiviral response to WNV. Our data indicate that RIG-I and MDA5 are responsible for triggering downstream gene expression in response to WNV infection by signaling through IPS-1. We propose a model in which RIG-I and MDA5 operate cooperatively to establish an antiviral state and mediate an IFN amplification loop that supports immune effector gene expression during WNV infection.
Broad Antiretroviral Activity and Resistance Profile of the Novel Human Immunodeficiency Virus Integrase Inhibitor Elvitegravir (JTK-303/GS-9137)
Authors: Shimura Kazuya , Kodama Eiichi , Sakagami Yasuko , Matsuzaki Yuji , Watanabe Wataru , Yamataka Kazunobu , Watanabe Yasuo , Ohata Yoshitsugu , Doi Satoki , Sato Motohide , Kano Mitsuki , Ikeda Satoru , Matsuoka Masao
Published: November 2007

Integrase (IN), an essential enzyme of human immunodeficiency virus (HIV), is an attractive antiretroviral drug target. The antiviral activity and resistance profile in vitro of a novel IN inhibitor, elvitegravir (EVG) (also known as JTK-303/GS-9137), currently being developed for the treatment of HIV-1 infection are described. EVG blocked the integration of HIV-1 cDNA through the inhibition of DNA strand transfer. EVG inhibited the replication of HIV-1, including various subtypes and multiple-drug-resistant clinical isolates, and HIV-2 strains with a 50% effective concentration in the subnanomolar to nanomolar range. EVG-resistant variants were selected in two independent inductions, and a total of 8 amino acid substitutions in the catalytic core domain of IN were observed. Among the observed IN mutations, T66I and E92Q substitutions mainly contributed to EVG resistance. These two primary resistance mutations are located in the active site, and other secondary mutations identified are proximal to these primary mutations. The EVG-selected IN mutations, some of which represent novel IN inhibitor resistance mutations, conferred reduced susceptibility to other IN inhibitors, suggesting that a common mechanism is involved in resistance and potential cross-resistance. The replication capacity of EVG-resistant variants was significantly reduced relative to both wild-type virus and other IN inhibitor-resistant variants selected by L-870,810. EVG and L-870,810 both inhibited the replication of murine leukemia virus and simian immunodeficiency virus, suggesting that IN inhibitors bind to a conformationally conserved region of various retroviral IN enzymes and are an ideal drug for a range of retroviral infections.
Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein
Authors: Sullivan Brian M. , Coscoy Laurent
Published: November 2007

We have performed a screen aimed at identifying human herpesvirus 6 (HHV-6)-encoded proteins that modulate immune recognition. Here we show that the U24 protein encoded by HHV-6 variant A downregulates cell surface expression of the T-cell receptor (TCR)/CD3 complex, a complex essential to T-cell activation and the generation of an immune adaptive response. In the presence of U24, the TCR/CD3 complex is endocytosed but is not recycled back to the plasma membrane. Instead, it accumulates in early and late endosomes. Interestingly, whereas CD3 downregulation from the cell surface is normally associated with T-cell activation, U24 downregulates CD3 independently of T-cell activation. Moreover, we found that U24-expressing T cells are resistant to activation by antigen-presenting cells. HHV-6 has evolved a unique mechanism of inhibition of T-cell activation that may impair the establishment of an adaptive immune response. Furthermore, lymphocyte activation creates an environment favorable to the reactivation and replication of lymphotropic herpesviruses. Thus, by inhibiting T-cell activation, HHV-6 might limit its reactivation and thus minimize immune recognition.
Influence of the Viral Regulatory Region on Tumor Induction by Simian Virus 40 in Hamsters
Authors: Sroller Vojtech , Vilchez Regis A. , Stewart A. Renee , Wong Connie , Butel Janet S.
Published: November 2007

Most of the simian virus 40 (SV40) genome is conserved among isolates, but the noncoding regulatory region and the genomic region encoding the large T-antigen C terminus (T-ag-C) may exhibit considerable variation. We demonstrate here that SV40 isolates differ in their oncogenic potentials in Syrian golden hamsters. Experimental animals were inoculated intraperitoneally with 10
7
PFU of parental or recombinant SV40 viruses and were observed for 12 months to identify genetic determinants of oncogenicity. The viral regulatory region was found to exert a statistically significant influence on tumor incidence, whereas the T-ag-C played a minor role. Viruses with a single enhancer (1E) were more oncogenic than those with a two-enhancer (2E) structure. Rearrangements in the 1E viral regulatory region were detected in 4 of 60 (6.7%) tumors. Viral loads in tumors varied, with a median of 5.4 SV40 genome copies per cell. Infectious SV40 was rescued from 15 of 37 (40%) cell lines established from tumors. Most hamsters with tumors and many without tumors produced antibodies to T antigen. All viruses displayed similar transforming frequencies in vitro, suggesting that differences in oncogenic potential in vivo were due to host responses to viral infection. This study shows that SV40 strains differ in their biological properties, suggests that SV40 replicates to some level in hamsters, and indicates that the outcome of an SV40 infection may depend on the viral strain present.
Effects of Partial Deletions within the Human Immunodeficiency Virus Type 1 V3 Loop on Coreceptor Tropism and Sensitivity to Entry Inhibitors
Authors: Nolan Katrina M. , Jordan Andrea P. O. , Hoxie James A.
Published: November 2007

The human immunodeficiency virus type 1 (HIV-1) V3 loop is critical for coreceptor binding and principally determines tropism for the CCR5 and CXCR4 coreceptors. The recent crystallographic resolution of V3 shows that its base is closely associated with the conserved coreceptor binding site on the gp120 core, whereas more distal regions protrude toward the cell surface, likely mediating interactions with coreceptor extracellular loops. However, these V3-coreceptor interactions and the structural basis for CCR5 or CXCR4 specificity are poorly understood. Using the dual-tropic virus HIV-1
R3A
, which uses both CCR5 and CXCR4, we sought to identify subdomains within V3 that selectively mediate R5 or X4 tropism. An extensive panel of V3 mutants was evaluated for effects on tropism and sensitivity to coreceptor antagonists. Mutations on either side of the V3 base (residues 3 to 8 and 26 to 33) ablated R5 tropism and made the resulting X4-tropic Envs more sensitive to the CXCR4 inhibitor AMD3100. When mutations were introduced within the V3 stem, only a deletion of residues 9 to 12 on the N-terminal side ablated X4 tropism. Remarkably, this R5-tropic Δ9-12 mutant was completely resistant to several small-molecule inhibitors of CCR5. Envs with mutations in the V3 crown (residues 13 to 20) remained dual tropic. Similar observations were made for a second dual-tropic isolate, HIV-1
89.6
. These findings suggest that V3 subdomains can be identified that differentially affect R5 and X4 tropism and modulate sensitivity to CCR5 and CXCR4 inhibitors. These studies provide a novel approach for probing V3-coreceptor interactions and mechanisms by which these interactions can be inhibited.
Phylogenetic Evidence for Rapid Rates of Molecular Evolution in the Single-Stranded DNA Begomovirus
Tomato Yellow Leaf Curl Virus
Authors: Duffy Siobain , Holmes Edward C.
Published: November 2007

Geminiviruses are devastating viruses of plants that possess single-stranded DNA (ssDNA) DNA genomes. Despite the importance of this class of phytopathogen, there have been no estimates of the rate of nucleotide substitution in the geminiviruses. We report here the evolutionary rate of the tomato yellow leaf curl disease-causing viruses, an intensively studied group of monopartite begomoviruses. Sequences from GenBank, isolated from diseased plants between 1988 and 2006, were analyzed using Bayesian coalescent methods. The mean genomic substitution rate was estimated to be 2.88 × 10
−4
nucleotide substitutions per site per year (subs/site/year), although this rate could be confounded by frequent recombination within
Tomato yellow leaf curl virus
genomes. A recombinant-free data set comprising the coat protein (V1) gene in isolation yielded a similar mean rate (4.63 × 10
−4
subs/site/year), validating the order of magnitude of genomic substitution rate for protein-coding regions. The intergenic region, which is known to be more variable, was found to evolve even more rapidly, with a mean substitution rate of ∼1.56 × 10
−3
subs/site/year. Notably, these substitution rates, the first reported for a plant DNA virus, are in line with those estimated previously for mammalian ssDNA viruses and RNA viruses. Our results therefore suggest that the high evolutionary rate of the geminiviruses is not primarily due to frequent recombination and may explain their ability to emerge in novel hosts.
A Host Factor Involved in Hypovirus Symptom Expression in the Chestnut Blight Fungus,
Cryphonectria parasitica
Authors: Faruk M. Iqbal , Eusebio-Cope Ana , Suzuki Nobuhiro
Published: November 2007

The prototype hypovirus CHV1-EP713 causes virulence attenuation and severe suppression of asexual sporulation and pigmentation in its host, the chestnut blight fungus,
Cryphonectria parasitica
. We identified a factor associated with symptom induction in
C. parasitica
using a transformation of
C. parasitica
strain EP155 with a full-length cDNA clone from a mild mutant virus strain, Cys(72). This was accomplished by using mutagenesis of the transformant fungal strain TCys(72)-1 by random integration of plasmid pHygR, conferring hygromycin resistance. The mutant, nam
A
(after nami-gata, meaning wave shaped), showed an irregular fungal morphology with reduced conidiation and pigmentation while retaining similar levels of virulence and virus accumulation relative to TCys(72)-1- or Cys(72)-infected strain EP155. However, the colony morphology of virus-cured nam
A
(VC-nam
A
) was indistinguishable from those of EP155 and virus-cured TCys(72)-1 [VC-TCys(72)-1]. The phenotypic difference between VC-nam
A
and VC-TCys(72)-1 was found only when these strains infected with the wild type or certain mutant CHV1-EP713 strains but not when infected with
Mycoreovirus 1
. Sequence analysis of inverse-PCR-amplified genomic DNA fragments and cDNA identified the insertion site of the mutagenic plasmid in exon 8 of the
nam-1
gene. NAM-1, comprising 1,257 amino acids, shows sequence similarities to counterparts from other filamentous fungi and possesses the CorA domain that is conserved in a class of Mg
2+
transporters from prokaryotes and eukaryotes. Complementation assays using the wild-type and mutant alleles and targeted disruption of
nam-1
showed that
nam-1
with an extension of the pHygR-derived sequence contributed to the altered phenotype in the nam
A
mutant. The molecular mechanism underlying virus-specific fungal symptom modulation in VC-nam
A
is discussed.
Intermolecular Interactions between Retroviral Gag Proteins in the Nucleus
Authors: Kenney Scott P. , Lochmann Timothy L. , Schmid Cullen L. , Parent Leslie J.
Published: November 2007

The retroviral Gag polyprotein directs virus particle assembly, resulting in the release of virions from the plasma membranes of infected cells. The earliest steps in assembly, those immediately following Gag synthesis, are very poorly understood. For Rous sarcoma virus (RSV), Gag proteins are synthesized in the cytoplasm and then undergo transient nuclear trafficking before returning to the cytoplasm for transport to the plasma membrane. Thus, RSV provides a useful model to study the initial steps in assembly because the early and later stages are spatially separated by the nuclear envelope. We previously described mutants of RSV Gag that are defective in nuclear export, thereby isolating these “trapped” Gag proteins at an early assembly step. Using the nuclear export mutants, we asked whether Gag protein-protein interactions occur within the nucleus. Complementation experiments revealed that the wild-type Gag protein could partially rescue export-defective Gag mutants into virus-like particles (VLPs). Additionally, the export mutants had a
trans
-dominant negative effect on wild-type Gag, interfering with its release into VLPs. Confocal imaging of wild-type and mutant Gag proteins bearing different fluorescent tags suggested that complementation between Gag proteins occurred in the nucleus. Additional evidence for nuclear Gag-Gag interactions was obtained using fluorescence resonance energy transfer, and we found that the formation of intranuclear Gag complexes was dependent on the NC domain. Bimolecular fluorescence complementation allowed the direct visualization of intranuclear Gag-Gag dimers. Together, these experimental results strongly suggest that RSV Gag proteins are capable of interacting within the nucleus.
A METHOD TO STUDY THE HAWKING RADIATION OF THE KERR BLACK HOLE
Authors: CHEN DEYOU , YANG SHUZHENG
Published: November 2007

Using the Hamilton–Jacobi method, we discuss the Hawking radiation of the Kerr black hole. The result shows when the self-gravitational interaction as well as the conservation of energy and angular momentum are taken into account, the radiation spectrum deviates from the purely thermal one and the tunneling probability is related to the change of Bekenstein–Hawking entropy, which is in accordance with Parikh and Wilczek's result and gives a method to study the Hawking radiation of the black hole.
THE NEUTRON AS AN ALTERNATIVE EXPLANATION FOR THE TRANS GZK COSMIC RAYS
Authors: DE UNÁNUE ADOLFO , SAHU SARIRA , SUDARSKY DANIEL
Published: November 2007

We consider the possibility that the Ultra High Energy Cosmic Rays arriving to Earth might be neutrons instead of protons. We stress that in such case the argument for the GZK cutoff is weaker and that it is conceivable that neutrons would not be affected by it. This scenario would require the neutron to start with an energy larger than the observed one, in order to be able to travel the distances involved, within its proper lifetime. It must then lose most of the extra energy through interaction with the galactic dark matter or some other matter in the intergalactic medium.
ASPECTS OF INTEGRABILITY IN $\mathcal{N} = 4$ SYM
Authors: AGARWAL ABHISHEK
Published: November 2007

Various recently developed connections between supersymmetric Yang–Mills theories in four dimensions and two-dimensional integrable systems serve as crucial ingredients in improving our understanding of the AdS/CFT correspondence. In this review, we highlight some connections between superconformal four-dimensional Yang–Mills theory and various integrable systems. In particular, we focus on the role of Yangian symmetries in studying the gauge theory dual of closed string excitations. We also briefly review how the gauge theory connects to Calogero models and open quantum spin chains through the study of the gauge theory duals of D3 branes and open strings ending on them. This invited review is based on a seminar given at the Institute of Advanced Study, Princeton.
A PROPOSAL FOR A NONPERTURBATIVE REGULARIZATION OF $\mathcal{N} = 2 SUSY 4D GAUGE THEORY
Authors: YDRI BADIS
Published: November 2007

In this letter we show that supersymmetry (like geometry) can be approximated using finite-dimensional matrix models and fuzzy manifolds. In particular, we propose a nonperturbative regularization of [Formula: see text] supersymmetric U(n) gauge action in 4D. In some planar large-N limits we recover exact SUSY together with the smooth geometry of [Formula: see text].
CYCLIC UNIVERSE AND INFINITE PAST
Authors: FRAMPTON PAUL H.
Published: November 2007

We address two questions about the past for infinitely cyclic cosmology. The first is whether it can contain an infinite length null geodesic into the past in view of the Borde–Guth–Vilenkin (BGV) "no-go" theorem, The second is whether, given that a small fraction of spawned universes fail to cycle, there is an adequate probability for a successful universe after an infinite time. We give positive answers to both questions and then show that in infinite cyclicity the total number of universes has been infinite for an arbitrarily long time.
ON THE RELATION BETWEEN UNRUH AND SOKOLOV–TERNOV EFFECTS
Authors: AKHMEDOV EMIL T. , SINGLETON DOUGLAS
Published: November 2007

We show that the Sokolov–Ternov effect — the depolarization of particles in storage rings coming from synchrotron radiation due to spin flip transitions — is physically equivalent to the Unruh effect for circular acceleration if one uses a spin-1/2 particle as the Unruh–DeWitt detector. It is shown that for the electron, with gyromagnetic number g ≈ 2, the exponential contribution to the polarization, which usually characterizes the Unruh effect, is "hidden" in the standard Sokolov–Ternov effect making it hard to observe. Thus, our conclusions are different in detail from previous work.
HOLOGRAPHIC FLAVOR IN THEORIES WITH EIGHT SUPERCHARGES
Authors: RODRÍGUEZ-GÓMEZ DIEGO
Published: November 2007

We review the holographic duals of gauge theories with eight supercharges obtained by adding very few flavors to pure supersymmetric Yang–Mills with 16 supercharges. Assuming a brane-probe limit, the gravity duals are engineered in terms of probe branes (the so-called flavor brane) in the background of the color branes. Both types of branes intersect on a given subspace in which the matter is confined. The gauge theory dual is thus the corresponding flavoring of the gauge theory with 16 supercharges. Those theories have in general a nontrivial phase structure; which is also captured in a beautiful way by the gravity dual. Along the lines of the gauge/gravity duality, we review also some of the results on the meson spectrum in the different phases of the theories.
ANALYSIS OF SURFACE PLASMONS EXCITATIONS FROM FABRICATION DEFECTS OF METALLIC NANOFILM WITH NONSYMMETRICAL AND FINITE GRATING-LIKE CORRUGATION
Authors: LIU JUAN , HU BIN , DI SI , WANG SHANG-QI , SUN XIAO-DONG
Published: November 2007

The influence of fabrication errors of metallic nanofilm with the grating-like and nonsymmetrical corrugation on one or two sides on surface plasmons resonance is analyzed by using boundary integral method. The scattering cross-section and the near-field intensity distribution of its corresponding resonant wavelengths for the finite grating-like nanostructure with or without fabrication defects are numerical investigated. The results show that the resonant wavelength is influenced by the fabrication flaws. More detailed directions of the electric flux lines around the metallic grating-like nanostructure and the near-field intensity distribution indicate that the excitation of surface electrons is influenced. This investigation will provide useful information for the fabrication of the metallic grating-like nanostructure and the experimental error analysis of the scientists.
INFRARED OPTICAL RESPONSE FROM Nb ON SiO2 ULTRATHIN FILMS
Authors: VILLAGÓMEZ R.
Published: November 2007

Oscillations in the infrared reflectance from metallic ultrathin films are described as consequence of quantum size effects. In this contribution, we present experimental evidence of such oscillations for Nb ultrathin films deposited on α-type SiO 2 substrates. Also, it is shown how substrates influence the size effects and the amplitude but not the period of oscillations. Because of the strong influence from the chosen substrate due to absorption, IR reflectivity was fitted to the optical response of our metal-substrate and bare-substrate system by using the three-oscillator model and numerical calculations on the basis of the local field calculation for a single metallic quantum well. Although quantum size effects are well studied in semiconductor compounds, there are few studies of this effect in metallic films where the present investigation has its most important contribution. Measurements for p-polarized reflectance (Rp) are made using a tunable p-polarized CO 2 waveguide laser using wavelengths from the p-branch (9.4 to 9.7 μm) and R-branch (10.0 to 10.4 μm). Nb/SiO 2 ultrathin films were assembled by a conventional RF sputtering technique and tailored thicknesses were deposited from 5.5 to 55 Å.
COMPARISON OF HIGH FIELD STEADY STATE AND TRANSIENT ELECTRON TRANSPORT IN WURTZITE GaN, AlN AND InN
Authors: ARABSHAHI H. , BENAM M. R. , SALAHI B. , GHOLIZADEH M.
Published: November 2007

An ensemble Monte Carlo simulation is used to compare bulk electron transport in wurtzite phase GaN , AlN and InN materials. Electronic states within the conduction band valleys at the Γ1, U, M, Γ3 and K are represented by non-parabolic ellipsoidal valleys centered on important symmetry points of the Brillouin zone. For all materials, it is found that electron velocity overshoot only occurs when the electric field is increased to a value above a certain critical field, unique to each material. This critical field is strongly dependent on the material parameters. Transient velocity overshoot has also been simulated, with the sudden application of fields up to ~5 × 107 Vm -1, appropriate to the gate-drain fields expected within an operational field effect transistor. The electron drift velocity relaxes to the saturation value of ~1.4 × 105 ms -1 within 4 ps, for all crystal structures. The steady state and transient velocity overshoot characteristics are in fair agreement with other recent calculations.
SYNTHESIS, CHARACTERIZATION, AND SELF-CONTROLLED ORTHORHOMBIC TO TETRAGONAL POLYMORPHIC TRANSFORMATION IN BaTiO3 NANOPARTICLES
Authors: RAM S. , JANA A. , KUNDU T. K.
Published: November 2007

The phase formation and thermal-induced phase transformation are studied in BaTiO 3 nanoparticles. 2 h of heating a polymer precursor at 550°C in air formed a single phase BaTiO 3 of 15 nm average crystallite size D. The X-ray diffraction peaks are analyzed assuming a P nma orthorhombic (o) crystal structure of lattice parameters a = 0.6435 nm , b = 0.5306 nm , and c = 0.8854 nm . The lattice volume V = 0.3023 nm 3, with z = 4 formula units, yields a density ρ = 5.124 g/cm 3. This is a new polymorph in comparison to well-known P m3m tetragonal (t) structure, V = 0.0644 nm 3 or ρ = 6.016 g/cm 3 (z = 1). An o ↦ t transformation appears on heating at temperature as high as 650°C in air. A proposed model explains the transformation above a certain D value in terms of the Gibbs free energy. Unless heating above 750°C, the two phases coexist in a composite structure (D≤27 nm ), with as much residual o-phase trace as ~28 vol%. As a function of temperature both the phases decrease in the V values up to 0.2975 and 0.0643 nm3 at 750°C respectively (0.0650 nm3 at 650°C). This is an important parameter for designing useful ferroelectric and other properties in a hybrid composite structure.
INTER-WIRE TRANSFER OF COLD DRESSED ATOMS
Authors: KOUZAEV GUENNADI A. , SAND KARL J.
Published: November 2007

In this paper, the quantum "synaptic" effect is studied that arises between two cold atom streams guided by cylindrical crossed wires carrying static (DC) and radio-frequency (RF) currents. The potential barrier between the two orthogonal atom streams is controlled electronically and atoms can be transferred from one wire to another under certain critical values of the wires' RF and DC currents and the biasing field. The results are interesting in the study of quantum interferometry and quantum registering of cold atoms.
PHONON DISPERSION IN CHIRAL SINGLE-WALL CARBON NANOTUBES
Authors: MU WEIHUA , VAMIVAKAS ANTHONY NICKOLAS , FANG YAN , WANG BOLIN
Published: November 2007

The method to obtain phonon dispersion of achiral single-wall carbon nanotubes (SWNTs) from 6×6 matrix proposed by Mahan and Jeon7 has been extended to chiral SWNTs. The number of calculated phonon modes of a chiral SWNT (10, 1) is much larger than that of a zigzag one (10, 0) because the number of atoms in the translational unit cell of chiral SWNT is larger than that of an achiral one even though they have relative similar radius. The possible application of our approach to other models with more phonon potential terms beyond Mahan and Jeon's model is discussed.
Recent advances in modelling nitrate transport in the Chalk unsaturated zone
Authors: Mathias S.A. , Butler A.P. , Ireson A.M. , Jackson B.M. , McIntyre N. , Wheater H.S.
Published: November 2007

The Chalk unsaturated zone is crucial in controlling the delivery of nitrate to Chalk streams and groundwater abstraction wells. In this paper, results from a dual-permeability numerical model of the Chalk unsaturated zone are used to illustrate the relative roles of matrix and fracture flow. A major challenge arises in representing the Chalk unsaturated zone within catchment-scale models for nutrient management. These have generally been based on simple conceptual reservoirs or compartments to represent soils and groundwater. A more appropriate conceptualization has recently been developed and applied to the Lambourn catchment within a catchment-scale nutrient model (INCA-Chalk). Preliminary results from this work are discussed, which clearly illustrate the decadal time scales that need to be considered in the context of nutrient management and the Water Framework Directive.
Integrated assessment of nitrate concentrations for the designation of groundwater Nitrate Vulnerable Zones in England and Wales
Authors: Johnson D. , Fletcher S.W. , Bray K.
Published: November 2007

This project had two main aims: (1) to identify surface water and groundwater that is exceeding, or is likely to exceed, 50 mg l
−1
nitrate with agricultural input as a significant source; (2) to identify the parcels of land that drain to these waters. The work brings together and develops the nitrates review methods for surface water and groundwater, and is focused on providing the underpinning evidence for both the Nitrates Directive 2006 review and the requirements of the Water Framework Directive (WFD). The work was conducted within the Environment Agency of England and Wales in three phases: national-scale risk assessment and source attribution; local expert elicitation, source attribution and delineation of Nitrate Vulnerable Zones (NVZs) boundaries; national-scale quality assurance of the outputs. This paper gives an overview of all three phases of the project but focuses on the second phase, comprising the groundwater section of the work. This has been one of the most rewarding parts of the project, as it is the phase that brings a national-scale risk assessment down to a local scale and transfers ownership of risk assessment to the local hydrogeological experts within the Environment Agency. It is also a critical phase in helping to ensure that the measures are targeted as accurately as possible.
Screening for long-term trends in groundwater nitrate monitoring data
Authors: Stuart M.E. , Chilton P.J. , Kinniburgh D.G. , Cooper D.M.
Published: November 2007

Alarge body of UK groundwater nitrate data has been analysed by linear regression to define past trends and estimate future concentrations. Robust regression was used. The datasets showed too many irregularities to justify more traditional time-series approaches such as ARIMA-type methods. Tests were included for lack of linearity, outliers, seasonality and a break in the trend (by piecewise linear regression). Of the series analysed, 21% showed a significant improvement in the overall fit when a break was included. Half of these indicated an increase in trend with time. Significant seasonality was found in about one-third of the series, with the largest nitrate concentrations usually found during winter months. Inclusion of nearby water-level data as an additional explanatory variable successfully accounted for much of this seasonality. Based on 309 datasets from 191 distinct sites, nitrate concentrations were found to be rising at an average of 0.34 mg NO
3
 l
−1
 a
−1
. In 2000, 34% of the sites analysed exceeded the 50 mg l
−1
EU drinking water standard. If present trends continue, 41% could exceed the standard by 2015. We explored an alternative to the previously proposed Water Framework Directive aggregation approach for estimating trends in whole groundwater bodies (the ‘Grath’ approach: spatially average then find the trend). We first determined the trends for single boreholes and then spatially averaged these. This approach preserves information about the spatial distribution of trends within the water body and is less sensitive to ‘missing data’.
Proximity to a critical point: evidence from, and implications for, hydrocarbon reservoirs
Authors: Heffer K. J.
Published: November 2007

Current models of lithospheric deformation that involve the concept of proximity to a critical point in its statistical mechanical sense are reviewed in the context of implications for fluid flow in hydrocarbon reservoirs. The data from hydrocarbon fields that support the applicability of this concept are listed. In particular, spatial and temporal correlations of fluctuations in oilfield production and injection rates are assessed. The long-range spatial characteristics of these correlations provide strong support for the reservoirs being close to a point of criticality, at least during their development lifetimes. The implications for reservoir simulation modelling, data acquisition and future research to further elucidate this area are outlined.
Damage and localization: two key concepts in rock deformation studies
Authors: Guéguen Y. , Bésuelle P.
Published: November 2007

In upper crustal conditions (the brittle field), rocks subjected to a load can experience a deterioration of physical and mechanical properties. This paper treats two conceptual approaches to model the deterioration that results from a crack distribution, whether the distribution is more or less diffuse or is strongly localized. The first part deals with possible ways to characterize diffuse microcracking (
damage
) to establish how the elastic response reflects the microcracking. This is of direct geophysical interest, as elastic wave velocities carry quantitative information on crack content. The second part summarizes two kinds of theory to predict the failure by crack propagation or strain localization, using either fracture mechanics or bifurcation theory. This is of direct geomechanical interest, as what is looked for is an interpretation of localized structures. The third part presents the complementarities between both concepts, damage and localization, to predict failure in rocks.
The mechanics of fault distribution and localization in high-porosity sands, Provence, France
Authors: Wibberley C. A. J. , Petit J.-P. , Rives T.
Published: November 2007

Excellent quarry exposures have been studied to examine the controls on the growth of fault networks in Cretaceous high-porosity sands. An inverse correlation is found at any one locality between the frequency of faults of an earlier tectonic event and the frequency of later faults. The early faults are cataclastic deformation bands with displacements typically up to 300 mm, and have thicknesses approaching their displacements. Later faults are also deformation bands except where present within a high-frequency array of earlier faults, where they are typically clustered high-displacement ultracataclasite zones that are narrower (smaller width/displacement ratios) than for the deformation band faults. A mechanical model using critical state soil mechanics explains the observed distributions and fault zone characteristics in terms of strength changes in the deforming sand unit and the stress path by which the material is subjected to ‘clastic’–plastic yielding. Localized faulting by constant-volume cataclastic flow at the critical state line will result in deviatoric stress reduction as Coulomb plasticity softening occurs within the fault zone. Elastic unloading of the walls will suppress the continued formation of deformation bands. The point at which the stress state reaches the critical state line, governed by the stress state and position of the ‘clastic’–plastic yield envelope, is therefore crucial in controlling the final distribution of deformation bands and larger faults in the system. Within this framework, the field and microstructural data suggest that earlier deformation became distributed by hardening processes such as compaction and grain-size reduction, resulting in a higher bulk yield strength. In a later tectonic event, the unit behaves in a stronger manner and deformation quickly localizes by fault zone softening processes into fewer fault zones that individually grow larger.
Strain localization in geomaterials
Authors: Desrues J. , Bésuelle P. , Lewis H.
Published: November 2007

The main purpose of this paper is a broad review of developments in observation and interpretation of localization in geomaterials in the laboratory, with an emphasis on low mean stress situations. Laboratory investigation of strain localization in granular soils and rocks has been pursued extensively and very accurate strain field evolution measurement techniques have been developed, including false relief stereophotogrammetry (FRS) and computed tomography (CT). These permit full characterization of strain localization, from onset to complete shear band formation. This paper reviews studies of sand, clay, sandstone, stiff marl and concrete, and observations of incipient and developed localization in initially ‘homogeneous’ laboratory tests are presented. Development of localization and peak strength, critical stress and strain, shear band orientation and thickness, and complex localization patterns are discussed. Deformation during triaxial compression of sand is shown to develop complex strain localization patterns. Consequently, the critical void ratio concept in granular materials is reconsidered. Void ratio evolution, global and local, monitored by CT, shows a limiting void ratio being rapidly attained in the strain localization zones. In cohesive materials (clays, rocks and concrete), crack development is also commonly observed. Displacement discontinuity measurement techniques are presented and the results for different cohesive geomaterials are discussed.
Hormone-induced assembly and activation of V-ATPase in blowfly salivary glands is mediated by protein kinase A
Authors: Rein Julia , Voss Martin , Blenau Wolfgang , Walz Bernd , Baumann Otto
Published: November 2007

The vacuolar H+-ATPase (V-ATPase) in the apical membrane of blowfly ( Calliphora vicina) salivary gland cells energizes the secretion of a KCl-rich saliva in response to the neurohormone serotonin (5-HT). We have shown previously that exposure to 5-HT induces a cAMP-mediated reversible assembly of V0 and V1 subcomplexes to V-ATPase holoenzymes and increases V-ATPase-driven proton transport. Here, we analyze whether the effect of cAMP on V-ATPase is mediated by protein kinase A (PKA) or exchange protein directly activated by cAMP (Epac), the cAMP target proteins that are present within the salivary glands. Immunofluorescence microscopy shows that PKA activators, but not Epac activators, induce the translocation of V1 components from the cytoplasm to the apical membrane, indicative of an assembly of V-ATPase holoenzymes. Measurements of transepithelial voltage changes and microfluorometric pH measurements at the luminal surface of cells in isolated glands demonstrate further that PKA-activating cAMP analogs increase cation transport to the gland lumen and induce a V-ATPase-dependent luminal acidification, whereas activators of Epac do not. Inhibitors of PKA block the 5-HT-induced V1 translocation to the apical membrane and the increase in proton transport. We conclude that cAMP exerts its effects on V-ATPase via PKA.
Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin
Authors: White James , Guerin Theresa , Swanson Hollie , Post Steven , Zhu Haining , Gong Ming , Liu Jun , Everson William V. , Li Xiang-An , Graf Gregory A. , Ballard Hubert O. , Ross Stuart A. , Smart Eric J.
Published: November 2007

In the current study, we examined whether diabetes affected the ability of HDL to stimulate nitric oxide (NO) production. Using HDL isolated from both diabetic humans and diabetic mouse models, we found that female HDL no longer induced NO synthesis, despite containing equivalent amounts of estrogen as nondiabetic controls. Furthermore, HDL isolated from diabetic females and males prevented acetylcholine-induced stimulation of NO generation. Analyses of both the human and mouse diabetic HDL particles showed that the HDLs contained increased levels of myristic acid. To determine whether myristic acid associated with HDL particles was responsible for the decrease in NO generation, myristic acid was added to HDL isolated from nondiabetic humans and mice. Myristic acid-associated HDL inhibited the generation of NO in a dose-dependent manner. Importantly, diabetic HDL did not alter the levels of endothelial NO synthase or acetylcholine receptors associated with the cells. Surprisingly, diabetic HDL inhibited ionomycin-induced stimulation of NO production without affecting ionomycin-induced increases in intracellular calcium. Further analysis indicated that diabetic HDL prevented calmodulin from interacting with endothelial NO synthase (eNOS) but did not affect the activation of calmodulin kinase or calcium-independent mechanisms for stimulating eNOS. These studies are the first to show that a specific fatty acid associated with HDL inhibits the stimulation of NO generation. These findings have important implications regarding cardiovascular disease in diabetic patients.
MCP-1 targeting inhibits muscularis macrophage recruitment and intestinal smooth muscle dysfunction in colonic inflammation
Authors: Hori Masatoshi , Nobe Hiromi , Horiguchi Kazuhide , Ozaki Hiroshi
Published: November 2007

Upregulation of muscularis macrophage numbers and activities plays an important role in the intestinal dysmotility associated with intestinal inflammation. The present study aimed to clarify changes in population dynamics of intestinal muscularis macrophages during colonic inflammation and to test possible inhibitory actions of agents targeting monocyte chemoattractant protein-1 (MCP-1) on muscularis macrophage dynamics and motility disorder in the colonic inflammation elicited by 2,4,6-trinitrobenzene sulfonic acid. In the inflamed muscle layer, ED1 antibody-positive monocytes and monocyte-derived macrophages were increased, followed by increasing resident macrophages positively staining for ED2 antibody. Initiation of the ED1-positive macrophage dynamic is associated with MCP-1 mRNA expression. MCP-1 was expressed in both ED1- and ED2-positive macrophages after inflammation. Electromicroscopic analysis revealed that the cell-division phase of muscularis macrophages was seen only in the early stages of inflammation. In addition, ED1 and ED2 double-positive macrophages can be detected during inflammation. Treatment with dominant negative MCP-1 or neutralizing MCP-1 antibodies markedly inhibited numbers of both ED1- and ED2-positive macrophages. Inflammation-mediated dysmotility was partially recovered by treatment with neutralizing MCP-1 antibodies. These results suggest that the inflamed muscle layer is initially infiltrated by monocytes, which then differentiate and develop into muscularis-resident macrophages. These macrophages express MCP-1 for further recruitment of monocytes. MCP-1 may be one potential therapeutic target for inhibiting intestinal motility disorders in gut inflammation.
Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531
Authors: Li Chen-Hong , Zhang Qi , Teng Bunyen , Mustafa S. Jamal , Huang Jian-Ying , Yu Han-Gang
Published: November 2007

We recently discovered that the constitutively active Src tyrosine kinase can enhance hyperpolarization-activated, cyclic nucleotide-gated (HCN) 4 channel activity by binding to the channel protein. To investigate the mechanism of modulation by Src of HCN channels, we studied the effects of a selective inhibitor of Src tyrosine kinase, 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), on HCN4 and its mutant channels expressed in HEK 293 cells by using a whole cell patch-clamp technique. We found that PP2 can inhibit HCN4 currents by negatively shifting the voltage dependence of channel activation, decreasing the whole cell channel conductance, and slowing activation and deactivation kinetics. Screening putative tyrosine residues subject to phosphorylation yielded two candidates: Tyr531 and Tyr554. Substituting HCN4-Tyr531 with phenylalanine largely abolished the effects of PP2 on HCN4 channels. Replacing HCN4-Tyr554 with phenylalanine did not abolish the effects of PP2 on voltage-dependent activation but did eliminate PP2-induced slowing of channel kinetics. The inhibitory effects of HCN channels associated with reduced Src tyrosine activity is confirmed in HL-1 cardiomyocytes. Finally, we found that PP2 can decrease the heart rate in a mouse model. These results demonstrate that Src tyrosine kinase enhances HCN4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of Src's actions on HCN4 channels is Tyr531.
Overexpression of CLC-3 in HEK293T cells yields novel currents that are pH dependent
Authors: Matsuda James J. , Filali Mohammed S. , Volk Kenneth A. , Collins Malia M. , Moreland Jessica G. , Lamb Fred S.
Published: November 2007

ClC-3 is a member of the ClC family of anion channels/transporters. Recently, the closely related proteins ClC-4 and ClC-5 were shown to be Cl−/H+ antiporters ( 39 , 44 ). The function of ClC-3 has been controversial. We studied anion currents in HEK293T cells expressing wild-type or mutant ClC-3. The basic biophysical properties of ClC-3 currents were very similar to those of ClC-4 and ClC-5, and distinct from those of the swelling-activated anion channel. ClC-3 expression induced currents with time-dependent activation that rectified sharply in the outward direction. The reversal potential of the current shifted by −48.3 ± 2.5 mV per 10-fold (decade) change in extracellular Cl− concentration, which did not conform to the behavior of an anion-selective channel based upon the Nernst equation, which predicts a −58.4 mV/decade shift at 22°C. Manipulation of extracellular pH (6.35–8.2) altered reversal potential by 10.2 ± 3.0 mV/decade, suggesting that ClC-3 currents were coupled to proton movement. Mutation of a specific glutamate residue (E224A) changed voltage dependence in a manner similar to that observed in other ClC Cl−/H+ antiporters. Mutant currents exhibited Nernstian changes in reversal potential in response to altered extracellular Cl− concentration that averaged −60 ± 3.4 mV/decade and were pH independent. Thus ClC-3 overexpression induced a pH-sensitive conductance in HEK293T cells that is biophysically similar to ClC-4 and ClC-5.
Effects of anoxia, aglycemia, and acidosis on cytosolic Mg2+, ATP, and pH in rat sensory neurons
Authors: Henrich Michael , Buckler Keith J.
Published: November 2007

Sensory neurons can detect ischemia and transmit pain from various organs. Whereas the primary stimulus in ischemia is assumed to be acidosis, little is known about how the inevitable metabolic challenge influences neuron function. In this study we have investigated the effects of anoxia, aglycemia, and acidosis upon intracellular Mg2+ concentration [Mg2+]i and intracellular pH (pHi) in isolated sensory neurons. Anoxia, anoxic aglycemia, and acidosis all caused a rise in [Mg2+]i and a fall in pHi. The rise in [Mg2+]i in response to acidosis appears to be due to H+ competing for intracellular Mg2+ binding sites. The effects of anoxia and aglycemia were mimicked by metabolic inhibition and, in a dorsal root ganglia (DRG)-derived cell line, the rise in [Mg2+]i during metabolic blockade was closely correlated with fall in intracellular ATP concentration ([ATP]i). Increase in [Mg2+]i during anoxia and aglycemia were therefore assumed to be due to MgATP hydrolysis. Even brief periods of anoxia (<3 min) resulted in rapid internal acidosis and a rise in [Mg2+]i equivalent to a decline in MgATP levels of 15–20%. With more prolonged anoxia (20 min) MgATP depletion is estimated to be around 40%. With anoxic aglycemia, the [Mg2+]i rise occurs in two phases: the first beginning almost immediately and the second after an 8- to 10-min delay. Within 20 min of anoxic aglycemia [Mg2+]i was comparable to that observed following complete metabolic inhibition (dinitrophenol + 2-deoxyglucose, DNP + 2-DOG) indicating a near total loss of MgATP. The consequences of these events therefore need to be considered in the context of sensory neuron function in ischemia.