bluuebunny/crossref_metadata_2025 huggingface dataset:
The NS3 protein of rice hoja blanca virus suppresses RNA silencing in mammalian cells
Authors: Schnettler Esther , Hemmes Hans , Goldbach Rob , Prins Marcel
Published: December 2007

The NS3 protein of the tenuivirus rice hoja blanca virus (RHBV) has previously been shown to represent the viral RNA interference (RNAi) suppressor and is active in both plant and insect cells by binding short interfering RNAs (siRNAs) in vitro. Using a firefly luciferase-based silencing assay it is described here that NS3 is also active in mammalian cells. This activity is independent of the inducer molecule used. Using either synthetic siRNAs or a short hairpin RNA construct, NS3 was able to significantly suppress the RNAi-mediated silencing of luciferase expression in both monkey (Vero) and human (HEK293) cells. These results support the proposed mode of action of NS3 to act by sequestering siRNAs, the key molecules of the RNAi pathway conserved in all eukaryotes. The possible applications of this protein in modulating RNAi and investigating the proposed antiviral RNAi response in mammalian cell systems are discussed.
Intranasal immunization of mice with a formalin-inactivated bovine respiratory syncytial virus vaccine co-formulated with CpG oligodeoxynucleotides and polyphosphazenes results in enhanced protection
Authors: Mapletoft John W. , Oumouna Mustapha , Kovacs-Nolan Jennifer , Latimer Laura , Mutwiri George , Babiuk Lorne A. , van Drunen Littel-van den Hurk Sylvia
Published: December 2007

As respiratory syncytial virus (RSV) targets the mucosal surfaces of the respiratory tract, induction of both systemic and mucosal immunity will be critical for optimal protection. In this study, the ability of an intranasally delivered, formalin-inactivated bovine RSV (FI-BRSV) vaccine co-formulated with CpG oligodeoxynucleotides (ODN) and polyphosphazenes (PP) to induce systemic and mucosal immunity, as well as protection from BRSV challenge, was evaluated. Intranasal immunization of mice with FI-BRSV formulated with CpG ODN and PP resulted in both humoral and cell-mediated immunity, characterized by enhanced production of BRSV-specific serum IgG, as well as increased gamma interferon and decreased interleukin-5 production byin vitro-restimulated splenocytes. These mice also developed mucosal immune responses, as was evident from increased production of BRSV-specific IgG and IgA in lung-fragment cultures. Indeed, the increases in serum and mucosal IgG, and in particular mucosal IgA and virus-neutralizing antibodies, were the most critical differences observed between FI-BRSV formulated with both CpG ODN and PP in comparison to formulations with CpG ODN, non-CpG ODN or PP individually. Finally, FI-BRSV/CpG/PP was the only formulation that resulted in a significant reduction in viral replication upon BRSV challenge. Co-formulation of CpG ODN and PP is a promising new vaccine platform technology that may have applications in mucosal immunization in humans.
Mechanisms underlying glycosylation-mediated loss of ecotropic receptor function in murine MDTF cells and implications for receptor evolution
Authors: Yoshii Hiroaki , Kamiyama Haruka , Amanuma Hiroshi , Oishi Kazunori , Yamamoto Naoki , Kubo Yoshinao
Published: December 2007

A Mus dunni tail fibroblast (MDTF) cell line is highly resistant to infection by ecotropic Moloney murine leukemia virus (Mo-MLV). The cationic amino acid transporter type 1 (CAT1) paralogues of murine NIH 3T3 and MDTF cells (mCAT1 and dCAT1, respectively) contain two conserved N-linked glycosylation sites in the third extracellular loop (ECL3, the putative Mo-MLV binding site). Glycosylation of dCAT1 inhibits Mo-MLV infection, but that of mCAT1 does not. Compared with mCAT1, dCAT1 possesses an Ile-to-Val substitution at position 214 and a Gly insertion at position 236 in the ECL3. To determine the residues responsible for the loss of dCAT1 receptor function, mutants of mCAT1 were constructed. The mCAT1/insG receptor (with a Gly residue inserted at mCAT1 position 236) had greatly reduced Mo-MLV receptor function compared with mCAT1. Treatment of mCAT1/insG-expressing cells with tunicamycin, an N-linked glycosylation inhibitor, increased the transduction titre. In addition, the reduced susceptibility to Mo-MLV observed with mCAT1/insG-expressing cells correlated with impaired binding of Mo-MLV. These results show that a single amino acid insertion confers mCAT1 receptor properties on dCAT1 and provide an important insight into the co-evolution of virus–host interactions.
A
Salmonella enterica
Serovar Typhimurium Succinate Dehydrogenase/Fumarate Reductase Double Mutant Is Avirulent and Immunogenic in BALB/c Mice
Authors: Mercado-Lubo Regino , Gauger Eric J. , Leatham Mary P. , Conway Tyrrell , Cohen Paul S.
Published: December 2007

Previously we showed that the tricarboxylic acid (TCA) cycle operates as a full cycle during
Salmonella enterica
serovar Typhimurium SR-11 peroral infection of BALB/c mice (M. Tchawa Yimga et al., Infect. Immun. 74:1130-1140, 2006). The evidence was that a Δ
sucCD
mutant (succinyl coenzyme A [succinyl-CoA] synthetase), which prevents the conversion of succinyl-CoA to succinate, and a Δ
sdhCDA
mutant (succinate dehydrogenase), which blocks the conversion of succinate to fumarate, were both attenuated, whereas an SR-11 Δ
aspA
mutant (aspartase) and an SR-11 Δ
frdABCD
mutant (fumarate reductase), deficient in the ability to run the reductive branch of the TCA cycle, were fully virulent. In the present study, evidence is presented that a serovar Typhimurium SR-11 Δ
frdABCD
Δ
sdhCDA
double mutant is avirulent in BALB/c mice and protective against subsequent infection with the virulent serovar Typhimurium SR-11 wild-type strain via the peroral route and is highly attenuated via the intraperitoneal route. These results suggest that fumarate reductase, which normally runs in the reductive pathway in the opposite direction of succinate dehydrogenase, can replace it during infection by running in the same direction as succinate dehydrogenase in order to run a full TCA cycle in an SR-11 Δ
sdhCDA
mutant. The data also suggest that the conversion of succinate to fumarate plays a key role in serovar Typhimurium virulence. Moreover, the data raise the possibility that
S. enterica
Δ
frdABCD
Δ
sdhCDA
double mutants and Δ
frdABCD
Δ
sdhCDA
double mutants of other intracellular bacterial pathogens with complete TCA cycles may prove to be effective live vaccine strains for animals and humans.
p38 Mitogen-Activated Protein Kinase Mediates Lipopolysaccharide and Tumor Necrosis Factor Alpha Induction of Shiga Toxin 2 Sensitivity in Human Umbilical Vein Endothelial Cells
Authors: Stone Matthew K. , Kolling Glynis L. , Lindner Matthew H. , Obrig Tom G.
Published: December 2007

Escherichia coliO157:H7 Shiga toxin 2 (Stx2), one of the causative agents of hemolytic-uremic syndrome, is toxic to endothelial cells, including primary cultured human umbilical vein endothelial cells (HUVEC). This sensitivity of cells to Stx2 can be increased with either lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). The goal of the present study was to identify the intracellular signaling pathway(s) by which LPS and TNF-α sensitize HUVEC to the cytotoxic effects of Stx2. To identify these pathways, specific pharmacological inhibitors and small interfering RNAs were tested with cell viability endpoints. A time course and dose response experiment for HUVEC exposure to LPS and TNF-α showed that a relatively short exposure to either agonist was sufficient to sensitize the cells to Stx2 and that both agonists stimulated intracellular signaling pathways within a short time. Cell viability assays indicated that the p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 and the general protein synthesis inhibitor cycloheximide inhibited both the LPS and TNF-α sensitization of HUVEC to Stx2, while all other inhibitors tested did not inhibit this sensitization. Additionally, SB202190 reduced the cellular globotriaosylceramide content under LPS- and TNF-α-induced conditions. In conclusion, our results show that LPS and TNF-α induction of Stx2 sensitivity in HUVEC is mediated through a pathway that includes p38 MAPK. These results indicate that inhibition of p38 MAPK in endothelial cells may protect a host from the deleterious effects of Stx2.
Occupational exposure levels to wood dust in Italy, 1996–2006
Authors: Scarselli A , Binazzi A , Ferrante P , Marinaccio A
Published: December 2007

Background:

Wood dust has been classified as carcinogenic to humans and the association with nasal cancer risk has been observed in a large number of epidemiological studies.

Objectives:

The aim of this study is to summarise data about occupational exposure levels to wood dust in Italy and to examine some exposure determinants.

Methods:

Exposure measurements on wood dust were extracted from the SIREP (Italian Information System on Occupational Exposure to Carcinogens) database between 1996–2006. Descriptive statistics were calculated for exposure-related variables using univariate analyses. The prevalence of elevated exposure levels was estimated overall and for some industrial sectors. A multifactorial analysis of variance was performed to determine which factors influenced exposure levels to wood dust.

Results:

The total number of exposure measurements (n) reported is 10 837, which refer to 10 528 workers and 1181 companies. The overall arithmetic mean is 1.44 mg/m3and the geometric mean is 0.97 mg/m3. Industrial sectors at high risk are “manufacture of wood and wood products” (n = 5539) as well as “manufacture of furniture” (n = 4347). About 74% of exposure measurements report a value <2 mg/m3. In the multifactorial analysis, it has been found that job category, industrial sector, company size and geographical location of the company influence the exposure levels.

Conclusions:

This study confirms the previous findings about occupational exposure to wood dust (mainly in wood industry and among woodworking machine operators) and suggests further investigations on other risk sectors (building and repairing of ships and boats). The potential of the occupational exposure database as a source of data for exposure assessment and surveillance is also confirmed.
AUTOSTEREOSCOPIC STAIRCASE FRACTAL STRUCTURES WITH CSL-PARALLAX
Authors: BULAEV BORIS P.
Published: December 2007

We offer a new approach to the fabrication of remarkable autostereoscopic double-layer computer generated images or autostereoscopic staircase fractal structures (ASFSs) based on staircase fractals and moiré methods. Besides, we have found that the unwanted moiré fringes or moiré noises in the ASFSs will markedly decrease if high frequency fractal noises are employed. These ASFSs were observed to be similar in some sense to Denishuk or reflection holograms. Analyzing the geometry and parallax of the circle of skew lines (CSL-parallax) at the presentation of stereo depth information in ASFSs, we hope to provide design guidelines for autostereoscopic digital printing and so on and so forth. A far more important example is a computer synthesis of three-dimensional graphic symbols, a standard laser printer and this CSL-parallax being employed.
Terrain measurement using automated digital photogrammetry
Authors: Chandler J. H.
Published: December 2007

Introduction

Photogrammetry has traditionally provided a means of generating three-dimensional spatial data to represent terrain surfaces, which complements traditional ground-based surveying methods. Although techniques such as airborne laser scanning (Lohr 1998) and synthetic aperture radar (Hogg
et al.
1993; Vencatasawamy
et al.
1998) have developed, photogrammetry remains the primary method of generating topographic maps (Wolf 1983; Capes 1998). One important advantage of photogrammetry is the flexibility of scale that allows application to imagery acquired from ground, air and space. Indeed, a new generation of high (i.e. 1 m) resolution satellite sensors (Capes 1998) is likely to further increase the potential applications of photogrammetry. Despite many advantages, there have been several problems with the application of photogrammetry using traditional methods. Most significantly, there was the requirement to use an expensive and complex photogrammetric stereoplotter. This ensured that the measurement process was slow and generally required the skills of an experienced operator, particularly if results of the highest accuracy were to be obtained.

Rapid developments in computing hardware and software have allowed the science of photogrammetry to develop rapidly during the last ten years (Gruen 1994; Atkinson 1996; Greve 1996). These developments have radically eased many of the problems and limitations associated with traditional analogue instrumentation. Use of a purely numerical or analytical solution provides flexibility, which assists in two important ways. Satellite imagery, oblique aerial photography and ground-based imagery can be used, in addition to the more traditional vertical aerial perspective. Similarly, imagery acquired using
Surface and groundwater resources survey in Jordan
Authors: Allison R. J.
Published: December 2007

Purpose of survey

Water is one of the most valuable physical resources in the arid zone. Much effort is made by engineers to maximize availability and minimize wastage. In the Hashemite Kingdom of Jordan water scarcity has been exacerbated in recent years by rapidly rising demand. In the early 1990s total national water consumption in Jordan approached 730 x 10
6
m
3
. It is estimated that demand will rise to 1200 x 10
6
m
3
by the year 2000. In the northeast Badia of Jordan there are two major sources of water (Al-Homoud
et al.
1995). Due to the topographic effect of the Jebel Druz, precipitation totals exceed 500 mm a
-1
in the north, declining to <50 mm a
-1
in the south. During winter months, runoff can be considerable but no reasonable data exist on parameters such as wadi discharge, infiltration rates and drainage basin contributing areas under storms of a given magnitude. Groundwater is found in three aquifers. Numerous government-operated and private wells have recently been drilled to exploit groundwater. There is little information on the recharge:extraction balance, changing spatial patterns of water availability and temporal changes in water quality, despite trends which hint at a depleting resource.
Preliminary landslide hazard assessment in remote areas
Authors: Charman J. H.
Published: December 2007

Rationale

In remote areas decisions on the need for remedial and maintenance works on linear projects such as roads and canals may involve the evaluation of risk based on
the identification and distribution of definable hazards
. A terrain model provides the basis for a classification scheme to enable this to be done cost effectively. In addition it facilitates the identification of problem areas that may require more detailed subsequent design investigation. In the absence of more detailed investigation it provides the basis for a conceptual construction approach.

The site

This example relates to hill irrigation schemes in the Himalaya of Nepal and Bhutan and involved the upgrading of existing village canals irrigating between 50 and 200 hectares of agricultural land for rice production. Each canal ran across steep slopes and was experiencing difficulties with slope instability. In the feasibility stage a limited number of projects had to be selected from a large initial listing.

Area model

The Himalaya form part of an active fold mountain belt characterized by moderate to high rates of uplift, regular seismic events and extreme relief. They are also subject to a tropical monsoon climate, at least at lower elevations, which causes significant weathering and erosion.

Mountain-building activity is not uniform but comprises episodes of uplift interposed between quieter periods. In active times rivers rapidly downcut and form steep incised valleys. In quieter periods weathering and slope evolution and more mature rivers result in a less severe landscape. The model in Figure 1 uses this concept to classify the landscape.
Building the geological model: case study of a rock tunnel in SW England
Authors: Fookes P. G. , Shilston D. T.
Published: December 2007

Objectives

A ‘geological model’ is a representation of the geology of a particular location. ‘
The form of the model can vary widely and include written descriptions, two-dimensional sections or plans, block diagrams, or be slanted towards some particular aspect such as groundwater or geomorphological processes, rock structures and so on
’ (Fookes 1997, p. 294). Formal creation of a geological model is one of the fundamental processes by which geologists, geomorphologists and other Earth scientists assemble an understanding of the ground conditions at a site. It is a powerful and cost-effective vehicle for conveying this understanding, often in simplified form, to other disciplines such as civil and structural engineers and planners.

Geological models are not always easy or straight-forward to create. This is particularly so at the desk study and field reconnaissance phases of site investigation. However, it is during these early phases that a model (or models) can be particularly useful by helping to set out what is known, what is conjectured, and where significant gaps in knowledge may lie. Geological field-work provides important information for the model, yet much of the geological interpretation of such fieldwork is necessarily subjective. The case study described here illustrates how the vagaries of geological exposure and ground investigation programmes can be evaluated to give an understanding of the completeness and reliability of such data. This evaluation of data is called here the ‘determinability’ of the geology.
Development of a ground model for the UK Channel Tunnel portal
Authors: Griffiths J. S.
Published: December 2007

Purpose of survey

Engineering geomorphological mapping is primarily concerned with identifying and mapping the features on the ground surface. However, detailed mapping linked to limited subsurface data can provide the first approximation of a ground model in some situations. In this example mapping was carried out at the location of the proposal Channel Tunnel portal at Castle Hill near Folkestone, England, prior to any detailed ground investigations with the aim of establishing the nature
and extent of the landslide complex that existed at the
site. Full details of the study can be found in Griffiths
et al.
1995.

The site

The Channel Tunnel terminal and portal on the UK side is located immediately below the Etchinghill escarpment, a scarp slope developed in the Lower Chalk of the North Downs to the west of Folkestone. Whilst the tunnel itself was positioned within the lower permeability zone of the Chalk Marl, the works for the terminal and portal required excavations in the Lower Chalk, the underlying Gault Clay and through the solifluction cover of Coombe Rock.

The 1: 10 560 scale BGS map identified six landslide complexes within the terminal and portal works area (Aarons
et al.
1977), although there was no information available on the form, depth and current stability of these features. The design for the main tunnel portal, however, required it to enter the hillside through the centre of one of the landslides at Castle Hill.

Techniques used

Field mapping of the geomorphology was undertaken at a scale of 1: 500 using standard procedures for geomorphological survey work (Brunsden
et al.
1975).
Sediment budget analysis for coastal management, west Dorset
Authors: Lee E. M. , Brunsden D.
Published: December 2007

Background

The identification and characterization of geomorphological units or systems is particularly important in the coastal zone. Indeed, the consequences of failure to appreciate the physical environment can be more acute on the coast, as rapid, major changes are a reality for land use planning and development. On the coast, it is often more useful to map the landscape in terms of sediment ‘cells’ (i.e. process units) rather than terrain units (i.e. landform units) as an understanding of the supply and transport of sediment (e.g. sand and shingle) is fundamental to dealing with many shoreline problems. Sediment is circulated in what often can be regarded, for practical purposes, as almost closed cells that are separated by boundaries across which little beach material is transferred. Each cell can be characterized in terms of the inputs, outputs, stores and sinks of sediment.

For example, to understand the development of a beach it is useful to consider it as a store of shingle or sand supplied from source areas on the adjacent coastline or offshore (Fig. 1). Beach building material might be supplied from the seabed, moved onshore by wave energy, or from rivers and eroding cliffs. This material is then redistributed along the shoreline by waves (‘longshore drift’), unless prevented by barriers such as headlands or breakwaters. Although longshore drift might be prevented by these barriers, some of the material can still be ‘lost’ to the system around the seaward end of the barriers or offshore, particularly during large storms.

Sediment inputs
Hazard assessment in Eastern Taiwan
Authors: Petley D. N.
Published: December 2007

Introduction

The topography of Taiwan is dominated by the Central Mountain Range, which has steep, densely vegetated slopes, deeply incised valleys and fractured, unstable rock masses. Although most of the population is located on the low-lying coastal plains, there is a need in this rapidly developing island to construct transportation links through the mountains. Unfortunately, the steep topography makes development difficult and there have been many instances in which poor terrain evaluation has led to inappropriate engineering solutions.

This paper outlines how landslide hazard assessment is being used as part of the planning process for the development of infrastructure along one such road through the mountains.

The physical setting of Taiwan

Taiwan is located on the eastern margin of the Eurasian continental plate (Fig. 1). The island, which is approximately 385 km in length and 143 km in width, has formed as a result of the ongoing collision of the Philippine Sea (oceanic) and Eurasian (continental) plates. Damaging, shallow seismic activity is frequent. The most seismically active region is in the central portion of the east coast of the island. However, the recent ‘Chi-Chi’ earthquake of 21 September 1999 occurred in the centre of Taiwan and caused the loss of over 2100 lives and induced damage island-wide.

Terrain evaluation in Taroko National Park

Taroko National Park is located on the eastern margin of Taiwan 121°40′ E and 24°0′ N (Fig. 1). It is centred upon the drainage basin of the Li-Wu River, with terrain that varies from lowland plains
Ground models for the design and construction of a high-speed rail link
Authors: Phipps P. J.
Published: December 2007

Purpose of survey

Engineering geomorphological, geological and geotechnical information, pertinent to a long linear engineering project, was required to provide support to a Parliamentary Bill and assist the future design and construction of the Channel Tunnel Rail Link. A wide variety of reports, maps and borehole logs had been collated for locations in the vicinity of the route alignment. These were to be supplemented with Phase I ground investigations for limited locations along the route during the winter of 1993/94. Phase I information was to be incorporated with the desk study information to provide an initial classification of the route geomorphology and ground conditions, and provide a sensible basis from which to design subsequent Phase II ground investigations.

The site

The Channel Tunnel Rail Link (CTRL) is to be constructed between St Pancras and the Channel Tunnel Railway Terminal at Cheriton, near Folkestone. The CTRL is a high-speed railway, 108 km in length, and its construction will incorporate a variety of engineered structures. The route traverses a wide range of topography, and solid and drift geology, which produce a wide variety of ground conditions to be considered for design and construction purposes.

At a macroscale the CTRL is located in three distinct geomorphological areas: the London Basin, the North Downs and the northern limb of the Weald. A wide variety of solid and drift geologies were evident from available British Geological Survey mapping: these included Lower London Tertiary deposits. Pleistocene Terrace deposits and recent alluvium in
The structural evolution of dilational stepovers in regional transtensional zones
Authors: De Paola N. , Holdsworth R. E. , Collettini C. , Mccaffrey K. J. W. , Barchi M. R.
Published: December 2007

We propose a theoretical model, supported by a field study, to describe the patterns of fault/fracture meshes formed within dilational stepovers developed along faults accommodating regional scale wrench-dominated transtension. The geometry and kinematics of the faulting in the dilational stepovers is related to the angle of divergence (α), and differs from the patterns traditionally predicted in dilation zones associated with boundary faults accommodating strike-slip displacements (where α = 0°). For low values of oblique divergence (α<30°) and low strain, the fault–fracture mesh comprises interlinked tensile fractures and shear-extensional planes, consistent with wrench-dominated transtension. At higher values of strain, a switch occurs from wrench- to extension-dominated transtension, leading to the reactivation and/or disruption of the early-formed structures. These structural processes lead to the development of a geometrically complex and kinematically heterogeneous fault pattern, which may affect and/or perturb the development of a through-going fault linking and facilitating the slip transfer between the two overlapping fault segments. As a result, dilational stepover zones will tend to form long-lived sites of localized extension and subsidence in regional transtensional tectonic settings. Cyclic increases/decreases of structural permeability will be related to slip on the major boundary faults that control the distribution of fluid-flow paths and, consequently, the long- and short-term structural evolution of these sites. Our model also predicts complex and more realistic subsurface fluid migration pathways relevant to our current understanding of hydrothermal ore deposits and hydrocarbon migration and storage.
The 3D fault and vein architecture of strike-slip releasing- and restraining bends: evidence from volcanic-centre-related mineral deposits
Authors: Berger B. R.
Published: December 2007

High-temperature, volcanic-centre-related hydrothermal systems involve large fluid-flow volumes and are observed to have high discharge rates in the order of 100–400 kg/s. The flows and discharge occur predominantly on networks of critically stressed fractures. The coupling of hydrothermal fluid flow with deformation produces the volumes of veins found in epithermal mineral deposits. Owing to this coupling, veins provide information on the fault–fracture architecture in existence at the time of mineralization. They therefore provide information on the nature of deformation within fault zones, and the relations between different fault sets. The Virginia City and Goldfield mining districts, Nevada, were localized in zones of strike-slip transtension in an Early to Mid-Miocene volcanic belt along the western margin of North America. The Camp Douglas mining area occurs within the same belt, but is localized in a zone of strike-slip transpression. The vein systems in these districts record the spatial evolution of strike-slip extensional and contractional stepovers, as well as geometry of faulting in and adjacent to points along strike-slip faults where displacement has been interrupted and transferred into releasing and restraining stepovers.
Extensional deformation and development of deep basins associated with the sinistral transcurrent fault zone of the Scotia–Antarctic plate boundary
Authors: Bohoyo F. , Galindo-Zaldívar J. , Jabaloy A. , Maldonado A. , Rodríguez-Fernández J. , Schreider A. , Suriñach E.
Published: December 2007

The Scotia–Antarctic plate boundary extends along the southern branch of the Scotia Arc, between triple junctions with the former Phoenix plate to the west (57°W) and with the Sandwich plate to the east (30°W). The main mechanism responsible for the present arc configuration is the development of the Scotia and Sandwich plates from 30–35 Ma, related to breakup of the continental connection between South America and the Antarctic Peninsula. The Scotia–Antarctic plate boundary is a very complex tectonic zone, because both oceanic and continental elements are involved. Present-day sinistral transcurrent motion probably began 8 Ma ago. The main active structures that we observed in the area include releasing and restraining bends, with related deep extensional and compressional basins, and probable pull-apart basins. The western sector of the plate boundary crosses fragmented continental crust: the Western South Scotia Ridge, with widespread development of pull-apart basins and releasing bends deeper than 5000 m, filled by asymmetrical sedimentary wedges. The northern border of the South Orkney microcontinent, in the central sector, has oceanic and continental crust in contact along a large thrust zone. Finally, the eastern sector of the South Scotia Ridge is located within Discovery Bank, a piece of continental crust from a former arc. On its southern border, strike-slip and normal faults produce a 5500-m-deep trough that may be interpreted as a pull-apart basin. In the eastern and western South Scotia Ridge, despite extreme continental-crustal thinning, the basins show no development of oceanic crust. This geometry is conditioned by the distinctive rheological behaviour of the crust involved, with the bulk concentration of deformation within the rheologically weaker continental blocks.
Acute responses of muscle protein metabolism to reduced blood flow reflect metabolic priorities for homeostasis
Authors: Zhang Xiao-jun , Irtun Oivind , Chinkes David L. , Wolfe Robert R.
Published: December 2007

The present experiment was designed to measure the synthetic and breakdown rates of muscle protein in the hindlimb of rabbits with or without clamping the femoral artery. l-[ ring-13C6]phenylalanine was infused as a tracer for measurement of muscle protein kinetics by means of an arteriovenous model, tracer incorporation, and tracee release methods. The ultrasonic flowmeter, dye dilution, and microsphere methods were used to determine the flow rates in the femoral artery, in the leg, and in muscle capillary, respectively. The femoral artery flow accounted for 65% of leg flow. A 50% reduction in the femoral artery flow reduced leg flow by 28% and nutritive flow by 26%, which did not change protein synthetic or breakdown rate in leg muscle. Full clamp of the femoral artery reduced leg flow by 42% and nutritive flow by 59%, which decreased ( P < 0.05) both the fractional synthetic rate from 0.19 ± 0.05 to 0.14 ± 0.03%/day and fractional breakdown rate from 0.28 ± 0.07 to 0.23 ± 0.09%/day of muscle protein. Neither the partial nor full clamp reduced ( P = 0.27–0.39) the intracellular phenylalanine concentration or net protein balance in leg muscle. We conclude that the flow threshold to cause a fall of protein turnover rate in leg muscle was a reduction of 30–40% of the leg flow. The acute responses of muscle protein kinetics to the reductions in blood flow reflected the metabolic priorities to maintain muscle homeostasis. These findings cannot be extrapolated to more chronic conditions without experimental validation.
Inhibition of RAS-Mediated Transformation and Tumorigenesis by Targeting the Downstream E3 Ubiquitin Ligase Seven in Absentia Homologue
Authors: Schmidt Rebecca L. , Park Cheol Hong , Ahmed Atique U. , Gundelach Justin H. , Reed Nanette R. , Cheng Shen , Knudsen Bruce E. , Tang Amy H.
Published: December 2007

Constitutively active RAS small GTPases promote the genesis of human cancers. An important goal in cancer biology is to identify means of countervailing activated RAS signaling to reverse malignant transformation. Oncogenic K-RAS mutations are found in virtually all pancreatic adenocarcinomas, making the RAS pathway an ideal target for therapeutic intervention. How to best contravene hyperactivated RAS signaling has remained elusive in human pancreatic cancers. Guided by the Drosophila studies, we reasoned that a downstream mediator of RAS signals might be a suitable anti-RAS target. The E3 ubiquitin ligase seven in absentia (SINA) is an essential downstream component of the Drosophila RAS signal transduction pathway. Thus, we determined the roles of the conserved human homologues of SINA, SIAHs, in mammalian RAS signaling and RAS-mediated tumorigenesis. We report that similar to its Drosophila counterpart, human SIAH is also required for oncogenic RAS signaling in pancreatic cancer. Inhibiting SIAH-dependent proteolysis blocked RAS-mediated focus formation in fibroblasts and abolished the tumor growth of human pancreatic cancer cells in soft agar as well as in athymic nude mice. Given the high level of conservation of RAS and SIAH function, our study provides useful insights into altered proteolysis in the RAS pathway in tumor initiation, progression, and oncogenesis. By targeting SIAH, we have found a novel means to contravene oncogenic RAS signaling and block RAS-mediated transformation/tumorigenesis. Thus, SIAH may offer a novel therapeutic target to halt tumor growth and ameliorate RAS-mediated pancreatic cancer. [Cancer Res 2007;67(24):11798–810]
Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand
Authors: Gregory Meredith S. , Saff Rebecca R. , Marshak-Rothstein Ann , Ksander Bruce R.
Published: December 2007

Fas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein. The two different forms of FasL are reported to have opposite functions—membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage. [Cancer Res 2007;67(24):11951–58]
In vivo Imaging and Quantitation of Adoptively Transferred Human Antigen-Specific T Cells Transduced to Express a Human Norepinephrine Transporter Gene
Authors: Doubrovin Mikhail M. , Doubrovina Ekaterina S. , Zanzonico Pat , Sadelain Michel , Larson Steven M. , O'Reilly Richard J.
Published: December 2007

Sequential imaging of genetically marked effector cells after adoptive transfer in vivo has greatly enhanced analyses of their biodistribution, growth, and activity both in animal models and in clinical trials of cellular immunotherapy. However, the immunogenicity of cells expressing xenogeneic reporter constructs limits their survival and clinical utility. To address this limitation, we have evaluated a human norepinephrine transporter (hNET) permitting imaging of transduced cells in vivo with a previously approved clinical grade radiolabeled probe, metaiodobenzylguanidine (MIBG). The hNET gene cDNA was cloned from the SK-N-SH cell line and inserted into a bicistronic retroviral vector also encoding green fluorescent protein. Following transfection, human EBV-specific T lymphocytes seemed fully functional in vitro and also selectively accumulated [123I]MIBG. In nonobese diabetic/severe combined immunodeficient mice bearing human EBV lymphoma xenografts, as few as 104 transduced T cells injected into the tumors could be imaged by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after i.v. infusion of [123I]MIBG or [124I]MIBG, respectively. When hNET+ EBV-specific T cells were infused i.v., their migration and specific accumulation in EBV+ tumors expressing their restricting HLA allele could be imaged by SPECT or PET over 28 days. Image intensity was closely correlated with the number of T cells accumulated in targeted tumors. The use of two reporter probes (MIBG and 2′-deoxy-2′-fluoro-β-d-arabinofuranosyl-5-iodouracil) permitted independent contemporaneous tracking of two distinct EBV-specific T-cell subpopulations expressing different reporter genes (hNET-CD4+ T cells and HSV-TK-CD8+ T cells) in the same animal using three-dimensional nuclear modalities (SPECT and PET). The hNET-based system described may thus have significant potential as a nonimmunogenic reporter for extended repeated quantitative in vivo imaging of transduced cells in man. [Cancer Res 2007;67(24):11959–69]
Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα
Authors: Lee Hong Jin , Ji Yan , Paul Shiby , Maehr Hubert , Uskokovic Milan , Suh Nanjoo
Published: December 2007

Bone morphogenetic proteins (BMP) are members of the transforming growth factor-β superfamily, and they play an important role for embryonic development, for bone and cartilage formation, and during carcinogenesis. We have previously shown that the novel Gemini vitamin D3 analogue, Ro-438-3582 [Ro3582; 1α,25-dihydroxy-20S,21(3-hydroxy-3-methylbutyl)-23-yne-26,27-hexafluorocholecalciferol], inhibited cell proliferation and activated the BMP/Smad signaling pathway in MCF10AT1 breast epithelial cells. In this report, we investigated the upstream signaling pathways responsible for the activation of BMP/Smad signaling by Ro3582. Among seven different serine/threonine kinase inhibitors that we tested, protein kinase C (PKC) inhibitors blocked the effects of Ro3582 on the phosphorylation of Smad1/5, mRNA synthesis for BMP-2 and BMP-6, and cell growth in MCF10AT1 cells. Overexpression of PKCα, but not PKCε, PKCδ or PKCζ isoforms, increased Ro3582-induced phosphorylation of Smad1/5, suggesting that PKCα mediates the activation of Smad signaling and inhibition of cell proliferation. Interestingly, the activation of Smad signaling by Ro3582 was shown in Ha-ras–transfected MCF10AT1 cells, but not in the parent cell line (MCF10A without Ras). Inhibiting Ras activity blocked the translocation of PKCα to the plasma membrane and the phosphorylation of Smad1/5 induced by Ro3582, indicating that Ras is necessary for the activation of PKCα and Smad signaling. In conclusion, Ro3582 inhibits cell proliferation and activates BMP/Smad signaling via a Ras and PKCα pathway in breast epithelial cells. [Cancer Res 2007;67(24):11840–7]
mTORC2 Activity Is Elevated in Gliomas and Promotes Growth and Cell Motility via Overexpression of Rictor
Authors: Masri Janine , Bernath Andrew , Martin Jheralyn , Jo Oak D. , Vartanian Raffi , Funk Alexander , Gera Joseph
Published: December 2007

mTORC2 is a multimeric kinase composed of the mammalian target of rapamycin kinase (mTOR), mLST8, mSin1, and rictor. The complex is insensitive to acute rapamycin exposure and has shown functions in controlling cell growth and actin cytoskeletal assembly. mTORC2 has recently been shown to phosphorylate and activate Akt. Because ∼70% of gliomas harbor high levels of activated Akt, we investigated whether mTORC2 activity was elevated in gliomas. In this study, we found that mTORC2 activity was elevated in glioma cell lines as well as in primary tumor cells as compared with normal brain tissue (P < 0.05). Moreover, we found that rictor protein and mRNA levels were also elevated and correlated with increased mTORC2 activity. Overexpression of rictor in cell lines led to increased mTORC2 assembly and activity. These lines exhibited increased anchorage-independent growth in soft agar, increased S-phase cell cycle distribution, increased motility, and elevated integrin β1 and β3 expression. In contrast, small interfering RNA–mediated knockdown of rictor inhibited these oncogenic activities. Protein kinase Cα (PKCα) activity was shown to be elevated in rictor-overexpressing lines but reduced in rictor-knockdown clones, consistent with the known regulation of actin organization by mTORC2 via PKCα. Xenograft studies using these cell lines also supported a role for increased mTORC2 activity in tumorigenesis and enhanced tumor growth. In summary, these data suggest that mTORC2 is hyperactivated in gliomas and functions in promoting tumor cell proliferation and invasive potential due to increased complex formation as a result of the overexpression of rictor. [Cancer Res 2007;67(24):11712–20]
A Role for Glial Cell–Derived Neurotrophic Factor–Induced Expression by Inflammatory Cytokines and RET/GFRα1 Receptor Up-regulation in Breast Cancer
Authors: Esseghir Selma , Todd S. Katrina , Hunt Toby , Poulsom Richard , Plaza-Menacho Ivan , Reis-Filho Jorge S. , Isacke Clare M.
Published: December 2007

By screening a tissue microarray of invasive breast tumors, we have shown that the receptor tyrosine kinase RET (REarranged during Transfection) and its coreceptor GFRα1 (GDNF receptor family α-1) are overexpressed in a subset of estrogen receptor–positive tumors. Germ line–activating oncogenic mutations in RET allow this receptor to signal independently of GFRα1 and its ligand glial cell–derived neurotrophic factor (GDNF) to promote a spectrum of endocrine neoplasias. However, it is not known whether tumor progression can also be driven by receptor overexpression and whether expression of GDNF, as has been suggested for other neurotrophic factors, is regulated in response to the inflammatory microenvironment surrounding many epithelial cancers. Here, we show that GDNF stimulation of RET+/GFRα1+ MCF7 breast cancer cells in vitro enhanced cell proliferation and survival, and promoted cell scattering. Moreover, in tumor xenografts, GDNF expression was found to be up-regulated on the infiltrating endogenous fibroblasts and to a lesser extent by the tumor cells themselves. Finally, the inflammatory cytokines tumor necrosis factor-α and interleukin-1β, which are involved in tumor promotion and development, were found to act synergistically to up-regulate GDNF expression in both fibroblasts and tumor cells. These data indicate that GDNF can act as an important component of the inflammatory response in breast cancers and that its effects are mediated by both paracrine and autocrine stimulation of tumor cells via signaling through the RET and GFRα1 receptors. [Cancer Res 2007;67(24):11732–41]
Implication of AMP-Activated Protein Kinase and Akt-Regulated Survivin in Lung Cancer Chemopreventive Activities of Deguelin
Authors: Jin Quanri , Feng Lei , Behrens Carmen , Bekele B. Nebiyou , Wistuba Ignacio I. , Hong Waun-Ki , Lee Ho-Young
Published: December 2007

Survivin plays important roles in maintaining cell proliferation and survival and promoting tumorigenesis. The present study was conducted to determine the stage of lung carcinogenesis at which survivin expression is induced and to investigate how survivin affects the chemopreventive action of deguelin. In in vitro studies, we observed higher levels of survivin expression in a subset of premalignant and malignant human bronchial epithelial (HBE) and non–small-cell lung cancer (NSCLC) cell lines than in normal HBE cells, and in in vivo studies, a higher level of survivin expression in specimen of human lung dysplasia than in normal lung specimens. Treatment with deguelin inhibited de novo synthesis of survivin protein and induced apoptosis, resulting in suppression of transformation phenotypes, in the premalignant and malignant HBE and NSCLC cell lines. Deguelin inhibited survivin expression in tuberous sclerosis complex 2 (TSC2) wild-type mouse embryonic fibroblasts (MEF) but not in TSC2-knockout MEFs in which mammalian target of rapamycin (mTOR) is constitutively active. Deguelin induced activation of AMP-activated protein kinase (AMPK) and inactivation of Akt. Overexpression of constitutively active Akt abolished deguelin-induced modulation of AMPK activity and survivin expression. Conversely, inactivation of AMPK by compound C or AMPKα1/2 small interfering RNA restored Akt and mTOR activities and survivin expression in deguelin-treated HBE cells. These results suggest that survivin expression is induced as an early event in lung carcinogenesis, and deguelin acts as a chemopreventive agent by inducing a reciprocal regulation between AMPK and Akt, resulting in the inhibition of mTOR-mediated survivin. [Cancer Res 2007;67(23):11630–9]
CDC25B Involvement in the Centrosome Duplication Cycle and in Microtubule Nucleation
Authors: Boutros Rose , Lobjois Valérie , Ducommun Bernard
Published: December 2007

Centrosome amplification is frequently reported in human cancers, although the molecular mechanisms that are responsible for this remain unclear. There is significant evidence to support a role for cyclin-dependent kinase (CDK)–cyclin complexes in centrosome duplication. The activities of CDK-cyclin complexes are, in turn, regulated by the CDC25 family of phosphatases in a strict spatiotemporal manner, and we have recently reported that CDC25B localizes to the centrosomes from early S phase. In the present study, we have investigated the role of centrosomally localized CDC25B in centrosome duplication. We first observed that overexpression of CDC25B under an inducible promoter in S phase results in centrosome overduplication. We found that forced expression of wild-type but not phosphatase-inactive CDC25B at the centrosomes results in centrosome amplification, aberrant microtubule organization, and abnormal accumulation of γ-tubulin. In contrast, inhibition of CDC25B phosphatase activity inhibits the assembly of interphase microtubules and the centrosomal localization of γ-tubulin. We propose that CDC25B is part of the pathway that controls the localization of γ-tubulin to the centrosomes, thereby regulating centrosome duplication during S phase and the nucleation of microtubules. We speculate that abnormal expression of CDC25B in numerous human tumors might therefore have a critical role in centrosome amplification and genomic instability. [Cancer Res 2007;67(24):11557–64]