bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTWe 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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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.
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

Abstract
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

Abstract

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

Abstract
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

Abstract
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.
MUC1 Is a Counter-Receptor for Myelin-Associated Glycoprotein (Siglec-4a) and Their Interaction Contributes to Adhesion in Pancreatic Cancer Perineural Invasion
Authors: Swanson Benjamin J. , McDermott Kimberly M. , Singh Pankaj K. , Eggers John P. , Crocker Paul R. , Hollingsworth Michael A. 
Published: November 2007

Abstract
Perineural invasion in pancreatic adenocarcinoma, a common pathologic phenomenon whereby cancer cells invade and intimately contact the endoneurium of pancreatic nerves, is thought to contribute to both pain and local disease recurrence. MUC1, a type I transmembrane mucin that can affect the adhesive properties of cells, contains a large extracellular tandem repeat domain, which is heavily glycosylated in normal epithelia, but is overexpressed and differentially glycosylated in pancreatic cancer. This altered glycosylation includes the shortened core I O-glycans for monosialyl and disialyl T antigens. Myelin-associated glycoprotein (MAG), a membrane-bound protein expressed on oligodendrocytes and Schwann cells, binds myelin to neurons. MAG's preferred ligands are derivatives of the monosialyl and disialyl T antigen. We investigated whether MUC1 is a counter-receptor for MAG and if their interaction contributed to pancreatic perineural invasion. Results showed that MAG binds pancreatic cells expressing MUC1, that this binding is sialidase-sensitive, and that MAG physically associates with MUC1. Heterotypic adhesion assays between pancreatic cancer cells and Schwann cells revealed that increased expression of MUC1 or MAG enhanced adhesion. Conversely, specific inhibition of MAG or sialyl-T MUC1 partially blocked adhesion. Immunohistochemical analysis of pancreatic perineural invasion showed the expression of both MUC1 and MAG. These results support the hypothesis that the adhesive interactions between MUC1 and MAG are of biological significance in pancreatic cancer perineural invasion. [Cancer Res 2007;67(21):10222–9]
RbAp48 Regulates Cytoskeletal Organization and Morphology by Increasing K-Ras Activity and Signaling through Mitogen-Activated Protein Kinase
Authors: Scuto Anna , Zhang Hongling , Zhao Haiyan , Rivera Maria , Yeatman Timothy J. , Jove Richard , Torres-Roca Javier F. 
Published: November 2007

Abstract
RbAp48 is a WD-40 protein that plays an important role in chromatin metabolism and regulates Ras signaling. Here, we report that RbAp48 is involved in the regulation of cytoskeletal organization, a novel function. First, we show that transfection of RbAp48 into Hs-578T breast cancer cells (Hs-RbAp48-hi) leads to cell size reduction, a rounded cell shape, decreased cellular protrusions, and a higher nuclear/cytoplasmic ratio. Furthermore, we observed cytoskeletal F-actin organization disruption with loss of actin stress fibers and formation of membranous F-actin rings in Hs-RbAp48-hi cells. These morphologic changes were partially reversed by RbAp48 knockdown. Interestingly, mitogen-activated protein kinase (MAPK) was activated in Hs-RbAp48-hi cells, and this activity was also partly reversed by RbAp48 down-regulation. Furthermore, pharmacologic inhibition of MAPK led to the reappearance of organized actin fibers and focal contacts, suggesting MAPK as the effector pathway. Moreover, we show an increase in total Ras activity in Hs-RbAp48-hi cells with K-Ras-GTP becoming the dominant isoform. This reverted to baseline activity levels on RbAp48 small interfering RNA transfection, thus suggesting a direct role for RbAp48 in Ras regulation. Finally, we tested the model in transformed 3T3-K-Ras-G12V fibroblasts. As expected, RbAp48 knockdown in 3T3-K-Ras-hi fibroblasts resulted in reappearance of an organized cytoskeleton and shutdown of K-Ras activity. In conclusion, our data support a model whereby RbAp48 regulates cellular morphology and cytoskeletal organization by increasing K-Ras activity and signaling through MAPK. [Cancer Res 2007;67(20):10317–24]
AS1411 Alters the Localization of a Complex Containing Protein Arginine Methyltransferase 5 and Nucleolin
Authors: Teng Yun , Girvan Allicia C. , Casson Lavona K. , Pierce William M. , Qian Mingwei , Thomas Shelia D. , Bates Paula J. 
Published: November 2007

Abstract
AS1411 is a quadruplex-forming oligonucleotide aptamer that targets nucleolin. It is currently in clinical trials as a treatment for various cancers. We have proposed that AS1411 inhibits cancer cell proliferation by affecting the activities of certain nucleolin-containing complexes. Here, we report that protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the formation of symmetrical dimethylarginine (sDMA), is a nucleolin-associated protein whose localization and activity are altered by AS1411. Levels of PRMT5 were found to be decreased in the nucleus of AS1411-treated DU145 human prostate cancer cells, but increased in the cytoplasm. These changes were dependent on nucleolin and were not observed in cells pretreated with nucleolin-specific small interfering RNA. Treatment with AS1411 altered levels of PRMT5 activity (assessed by sDMA levels) in accord with changes in its localization. In addition, our data indicate that nucleolin itself is a substrate for PRMT5 and that distribution of sDMA-modified nucleolin is altered by AS1411. Because histone arginine methylation by PRMT5 causes transcriptional repression, we also examined expression of selected PRMT5 target genes in AS1411-treated cells. For some genes, including cyclin E2 and tumor suppressor ST7, a significant up-regulation was noted, which corresponded with decreased PRMT5 association with the gene promoter. We conclude that nucleolin is a novel binding partner and substrate for PRMT5, and that AS1411 causes relocalization of the nucleolin-PRMT5 complex from the nucleus to the cytoplasm. Consequently, the nuclear activity of PRMT5 is decreased, leading to derepression of some PRMT5 target genes, which may contribute to the biological effects of AS1411.